PEDIATRIC

SELF-ASSESSMENT PROGRAM

P e d S A P 2 0 1 6 B O OK 1

IMMUNOLOGY
Series Editors
Marcia L. Buck, Pharm.D., FCCP, FPPAG
Kalen B. Manasco, Pharm.D., BCPS, AE-C

AMERICAN COLLEGE OF CLINICAL PHARMACY

 IMPORTANT INFORMATION ON THE RELEASE OF
PedSAP 2016 BOOK 1 IMMUNOLOGY
TESTING
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and contraindications. This is especially important for new, infrequently used, and highly toxic drugs.
Director of Professional Development: Nancy M. Perrin, M.A., CAE
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Library of Congress Control Number: 2016933056

ISBN-13: 978-1-939862-32-7 (PedSAP 2016 BOOK 1, Immunology)

Copyright 2016 by the American College of Clinical Pharmacy. All rights reserved. This book is protected by copyright. No part
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American College of Clinical Pharmacy, 2016:page range.

PedSAP is a registered trademark of the American College of Clinical Pharmacy.

Pediatric
Self-Assessment
Program
TABLE OF CONTENTS
Immunology...................................................................................... 1 Clinical and Practice Updates.....................................67

Routine Childhood Immunization Series Interactive Case: Immunology in Solid Organ

Transplantation
By Stacie J. Lampkin, Pharm.D., BCPPS, BCACP, AE-C; and Amy
Wojciechowski, Pharm.D., BCPS By Barrett Crowther, Pharm.D., FAST, BCPS; and Leslie Stach, Pharm.D.,
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 BCPS
Vaccination Schedules Interactive Case . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
and Adherence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Patient Education on Vaccine Concerns . . . . . . . . . . . . . . . . . . . 10
Interpretation of Vaccine Schedules and Administration Translating Evidence into Practice: Human
Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Papillomavirus Vaccination
Considerations Pertaining to All Vaccinations . . . . . . . . . . . . . . 12
Individual Vaccine Information . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 By Nathan Painter, Pharm.D., CDE; and Stephanie Mayne, MHS
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Translating Evidence into Practice . . . . . . . . . . . . . . . . . . . . . . . . 79
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Vaccine Development and Future Targets Translating Evidence into Practice:

By April Yarbrough, Pharm.D., BCPS; and Scott James, M.D.
Vancomycin-Associated Nephrotoxicity
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 By Jennifer Le, Pharm.D., MAS, BCPS-AQ ID, FCCP, FASHP; and Kristen
Importance of Vaccine Development . . . . . . . . . . . . . . . . . . . . . . 33
Nichols, Pharm.D., BCPS-AQ ID, BCPPS
Novel Vaccines in Development . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Translating Evidence into Practice . . . . . . . . . . . . . . . . . . . . . . . . 83
Maternal Vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Advances in Established Vaccines . . . . . . . . . . . . . . . . . . . . . . . . 41
Advances in Vaccine Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Passive Immunization
By Ann M. Philbrick, Pharm.D., BCPS, BCACP
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Palivizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Immunoglobulins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Hyperimmune Globulins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Pharmacist Role . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

PedSAP 2016 Book 1 Immunology iii Table of Contents

A MESSAGE FROM THE EDITORS
Welcome to the Pediatric Self-Assessment Program (PedSAP),
a new recertification component for the Board Certified Pedi-
atric Pharmacy Specialist (BCPPS). ACCP has a long tradition
of offering the best products for continuing pharmacy educa-
tion and pharmacotherapy specialist certification. PedSAP
continues that tradition by providing the latest in evidence-
based information for the practitioner or clinician working
with this special population.
In designing this series, the primary goal was to provide
updates that would improve clinical pharmacy practice and
patient outcomes. The process began with a careful review
of the content outline developed by the Board of Pharmacy
Specialties for the Pediatric Pharmacy Specialty Certification
Examination. The 20162018 PedSAP chapters will therefore
cover the domains of patient management; practice manage-
ment; information management and education; and public
health and patient advocacy. Specific content for individual
releases in this series was organized on the basis of the sys-
tems and patient-care problems that might be expected of the
BCPPS. Finally, calls went out to recruit faculty panel chairs,
authors, and reviewers committed to this new specialty and to
the board certification process.
The presentation of information, and its incorporation into
practice, was also given careful consideration. In a departure
from ACCPs other self-assessment programs, PedSAP mod-
ules come in two formats: (1) the traditional review chapters;
and (2) Clinical and Practice Update modules that incorpo-
rate new learning formats such as recorded webinars and
HTML pages. These new learning formats are hoped to speed
the dissemination of new clinical information and satisfy the
learning preferences of a wider audience.
Some things have not changed: inside this PedSAP book
you will find user-friendly formatting as well as graphic ele-
ments such as patient-care scenarios (demonstrating the
application of concepts), treatment algorithms, descriptions
of pivotal studies that may change practice, and summative
practice points. All releases in this series are available elec-
tronically, enhancing the portability of this product. Prominent
in each chapter are hyperlinks to reference sources, assess-
ment tools, guidelines and resources, data compilers such as
PubMed, and even informational videos. Our hope is that this
depth of information, ease of access, and emphasis on clinical
application will have an immediate and positive impact on the
care of pediatric patients.
We very much appreciate the efforts of all the faculty panel
chairs, authors, and reviewers who lent their time, energy, and
expertise to this new series.
Marcia L. Buck and Kalen B. Manasco, series editors
Immunology
Immunology Panel

Series Editors: Reviewers

Marcia L. Buck, Pharm.D., FCCP, FPPAG Lindsay C. Trout, Pharm.D., BCPPS
Clinical Coordinator Clinical Pharmacy Specialist
University of Virginia Childrens Hospital Pediatric Critical Care and General Pediatrics
Associate Professor Penn State Milton S. Hershey Medical Center (PSHMC)
Department of Pediatrics Hershey, Pennsylvania
University of Virginia School of Medicine
Clarissa F. Havel, Pharm.D., BCPS
Clinical Professor
Clinical Pharmacist
Virginia Commonwealth University School of Pharmacy
RPh-On-the-Go
Department of Pharmacy Services
Skokie, Illinois
University of Virginia Health System
Charlottesville, Virginia Bernard R. Lee, Pharm.D., BCPS, BCPPS
Kalen B. Manasco, Pharm.D., BCPS Clinical Pharmacist-General Pediatrics
Clinical Associate Professor Department of Pharmacy
Department of Clinical and Administrative Pharmacy Johns Hopkins Medicine-All Childrens Hospital
University of Georgia College of Pharmacy St. Petersburg, Florida
Augusta, Georgia Hazar Alnifaidy, Pharm.D., BCPS
Clinical Pharmacist
Faculty Panel Chair:
Department of Pharmacy
Jennifer Le, Pharm.D., MAS, BCPS, AQ-ID, FCCP, FCSHP Sidra Medical and Research Center
Professor of Clinical Pharmacy Doha, Qatar, Middle East
University of California, San Diego
Skaggs School of Pharmacy and Pharmaceutical Sciences
La Jolla, California VACCINE DEVELOPMENT AND
Faculty-in-Residence FUTURE TARGETS
Long Beach Memorial and Miller Childrens Hospital
Long Beach, California Authors
April H. Yarbrough, Pharm.D., BCPS
ROUTINE CHILDHOOD IMMUNIZATIONS Pediatric Infectious Disease Pharmacist
Pharmacokinetic Specialist
Authors Department of Pharmacy
Stacie J. Lampkin, Pharm.D., BCACP, BCPPS, AE-C Childrens of Alabama
Birmingham, Alabama
Clinical Assistant Professor
Pharmacy Practice Scott James, M.D.
DYouville College School of Pharmacy Assistant Professor
Buffalo, New York Department of Pediatrics, Division of Infectious Diseases
Amy Lynn Wojciechowski, Pharm.D., BCPS, AQ-ID University of Alabama at Birmingham
Birmingham, Alabama
Clinical Assistant Professor
Department of Pharmacy Practice
Reviewers
DYouville College School of Pharmacy
Buffalo, New York Jessica Cottreau, Pharm.D., BCPS
Infectious Diseases Clinical Pharmacist Associate Professor
Department of Pharmacy Rosalind Franklin University of Medicine and Science
Niagara Falls Memorial Medical Center Chicago, Illinois
Niagara Falls, New York
Ashli Rasmussen, Pharm.D., BCPS
Clinical Research Pharmacist
Celerion, Inc.
Phoenix, Arizona
PASSIVE IMMUNIZATION
Author
Ann M. Philbrick, Pharm.D., BCPS, BCACP
Associate Professor
Pharmaceutical Care & Health Systems
University of Minnesota College of Pharmacy
Family Medicine & Community Health
University of Minnesota Medical School
Minneapolis, Minnesota
Reviewers
Jenna Halilovic Maker, Pharm.D., BCPS
Associate Professor
Department of Pharmacy Practice
University of the Pacific Thomas J Long
School of Pharmacy & Health Sciences
Stockton, California
Clinical Pharmacist
Pediatric and Young Adult Infectious Diseases
University of California Davis Medical Center
Sacramento, California
Ewha Bridget Kim, Pharm.D., BCPS, BCOP
Clinical Pharmacist, Ambulatory Oncology
Department of Pharmacy
Massachusetts General Hospital
Boston, Massachusetts
Elias B. Chahine, Pharm.D., BCPS-AQ ID
Associate Professor of Pharmacy Practice
Pharmacy Practice
Palm Beach Atlantic University, Lloyd
L. Gregory School of Pharmacy
West Palm Beach, Florida
Clinical Pharmacy Specialist
Pharmacy Services
Wellington Regional Medical Center
Wellington, Florida
The American College of Clinical Pharmacy and the authors
thank the following individuals for their careful review
of the Immunology I chapters:
Marisel Segarra-Newnham, Pharm.D., MPH, FCCP, BCPS
Clinical Pharmacy Specialist, Infectious Diseases/HIV
Antimicrobial Stewardship Program Pharmacy Director
Veterans Affairs Medical Center
West Palm Beach, Florida
Clinical Assistant Professor of Pharmacy Practice
University of Florida College of Pharmacy
Gainesville, Florida
Ralph H. Raasch, Pharm.D., BCPS
Associate Professor of Pharmacy (retired)
Division of Practice Advancement and Clinical Education
Eshelman School of Pharmacy
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Consultancies: Stacie J. Lampkin (American Lung Association, Inside Patient Care); Jenana Maker (Actavis Pharma, Inc.)

Stock Ownership:

Royalties:

Grants: Elias B. Chahine (Cubist); Scott James (NIH/NIAID)

Honoraria: Elias B. Chahine (Merck and Co, The Medicines Company, Cubist); Stacie J. Lampkin (Western New York Society of
Health-System Pharmacists)

Other:

Nothing to disclose: Hazar Alnifaidy; Jessica Cottreau; Clarissa F. Havel; Bridget Kim; Bernard R. Lee; Ann M. Philbrick; Ashli
Rasmussen; Lindsay C. Trout; Amy Lynn Wojciechowski; April H. Yarbrough

ROLE OF BPS: The Board of Pharmacy Specialties (BPS) is an autonomous division of the American Pharmacists Association
(APhA). BPS is totally separate and distinct from ACCP. The Board, through its specialty councils, is responsible for specialty
examination content, administration, scoring, and all other aspects of its certification programs. PedSAP has been approved by
BPS for use in BCPPS recertification. Information about the BPS recertification process is available online.

Other questions regarding recertification should be directed to:

Board of Pharmacy Specialties

2215 Constitution Avenue NW
Washington, DC 20037
(202) 429-7591
CONTINUING PHARMACY EDUCATION
AND RECERTIFICATION INSTRUCTIONS
 ontinuing Pharmacy Education Credit: The American College of Clinical Pharmacy is accredited by the Accreditation
C
Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education (CPE).

PedSAP: Target Audience: The target audience for PedSAP 2016 Book 1 (Immunology) is pediatric pharmacotherapy spe-
cialists and advanced-level clinical pharmacists caring for pediatric patients with several immunologic and antimicrobial
considerations.

Available CPE credits: Purchasers who successfully complete all posttests for PedSAP 2016 Book 1 (Immunology) can earn
9.0 contact hours of continuing pharmacy education credit. The universal activity numbers are as follows: Immunology
0217-0000-16-019-H01-P, 5.0 contact hours; and Clinical and Practice Updates 0217-0000-16-020-H01-P, 4.0 contact hours.
You may complete one or all available modules for credit. Tests may not be submitted more than once.

BCPPS test deadline: 11:59 p.m. (Central) on May 16, 2016.

ACPE test deadline: 11:59 p.m. (Central) on January 14, 2019.

Posttest access: Go to www.accp.com and sign in with your e-mail address and password. Technical support is available from
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Recertification Dashboard is a free online tool that can track recertification credits as they are earned through ACCP and schedule
new opportunities for credits from upcoming ACCP professional development programs.

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Routine Childhood Immunization Series
By Stacie J. Lampkin, Pharm.D., BCPPS, BCACP, AE-C; and
Amy Wojciechowski, Pharm.D., BCPS, AQ-ID

Reviewed by Lindsay C. Trout, Pharm.D., BCPPS; Clarissa F. Havel, Pharm.D., BCPS; Bernard R. Lee, Pharm.D., BCPS, BCPPS; and Hazar
Alnifaidy, Pharm.D., BCPS

LEARNING OBJECTIVES

1. Distinguish the considerations for administering live versus inactivated vaccines.

2. Assess the role of a pharmacist in promoting the vaccination of pediatric patients to reduce the global burden of vaccine-
preventable infections.
3. Evaluate the current evidence to educate patients and caregivers about vaccination considerations, including safety,
efficacy, and common misconceptions.
4. Justify the role of combination vaccines for the pediatric population.
5. Given a pediatric case, develop a vaccine administration plan using current vaccination recommendations.
6. Distinguish the similarities and differences in childhood vaccine availability, administration, efficacy in disease preven-
tion, adverse effects, contraindications, and warnings.

ABBREVIATIONS IN THIS CHAPTER
ACIP Advisory Committee on
Immunization Practices
DTaP Diphtheria, tetanus, and pertussis
(vaccine)
HepA Hepatitis A (vaccine)
HepB Hepatitis B (vaccine)
Hib Haemophilus influenzae type B
HPV Human papillomavirus (2-valent,
4-valent, 9-valent vaccine)
IIV Inactivated influenza vaccine
(3-trivalent, 4-quadrivalent)
IPV Inactivated poliovirus vaccine
LAIV Live attenuated influenza vaccine
MenACWY Meningococcal quadrivalent
(vaccine)
MMR Measles, mumps, and rubella
vaccine
MMRV Measles, mumps, rubella, and vari-
cella (vaccine)
PCV Pneumococcal conjugate vaccine
(7-valent, 13-valent)
PPSV23 Pneumococcal polysaccharide
vaccine
RIV3 Recombinant influenza vaccine
trivalent
RV Rotavirus vaccine
INTRODUCTION
Vaccines advance health care by dramatically reducing the morbidity
and mortality associated with infectious diseases. Vaccines provide
protection from infectious agents by promoting an immune response
within the body. The first published attempt to induce immunity by
inoculation with an infectious agent was by made Edward Jenner in
1798. He found that by introducing small amounts of fluid from cow-
pox lesions into susceptible people, immunity was developed that
could prevent the deadly disease smallpox. Since then, the global
burden of many infectious diseases has been dramatically reduced
through the development of other effective vaccines. Smallpox has
been eradicated globally, and significant reductions in many other
various diseases have occurred, including polio, diphtheria, mea-
sles, mumps, rubella, pertussis, tetanus, and Haemophilus influenzae
type B (Hib) (CDC 2011a). Routine immunizations in children are cru-
cial to reduce the risk of an epidemic and prevent the significant
morbidity and mortality from vaccine-preventable disease (VPD).
How Vaccines Work
Immunization is the process of generating humoral immunity or pro-
viding protection from disease. The immunity conferred can be either
active or passive. Active immunization involves provoking the immune
system to mount a sustained immune response; passive immuniza-
tion involves introducing exogenous antibodies to provide temporary,
transient protection. Vaccines are an example of active immunization,
stimulating the immune system to produce antibodies, cell-mediated

PedSAP 2016 Book 1 Immunology 7 Routine Childhood Immunization Series


Td Tetanus and diphtheria (vaccine)
Tdap Tetanus, diphtheria, and acellular
pertussis (vaccine)
VAERS Vaccine Adverse Event Reporting System
VPD Vaccine-preventable disease
Table of other common abbreviations.
immunity, or both. When a suspension or fraction of microor-
ganism (the antigen) is administered into the body, it activates
antigen-presenting cells; these, in turn, secrete proinflamma-
tory cytokines and chemokines, which recruit other leukocytes
in response to the inoculation. T and B lymphocytes are then
replicated, differentiated, and stored in large pools of mem-
ory cells, which can be quickly stimulated to provide immune
BASELINE KNOWLEDGE STATEMENTS
Readers of this chapter are presumed to be familiar
with the following:
Concepts on taking a patient history in preparation
for assessing appropriateness of vaccines
General knowledge on interpreting the routine
vaccination schedule for healthy children
Availability, interchangeability and FDA approved
indications and ages for vaccines available in the
United States.
Techniques and how to administer vaccines in
pediatric patients
Familiarity with the pathophysiology of vaccine-
preventable diseases
Benefits and risks of assessing data from the
Vaccine Adverse Event Reporting System
ADDITIONAL READINGS
The following free resources have additional back-
ground information on this topic:
CDC. Vaccines & Immunization Topics
Epidemiology and Prevention of Vaccine-Preventable
Diseases. The Pink Book: Course Textbook, 13th
Edition (2015)
Advisory Committee for Immunization Practices.
Vaccine Recommendations.
Infectious Disease Society of America. 2013
Clinical Practice Guideline for Vaccination of the
Immunocompromised Host
American Pharmacist Association. Immunization
Resources
Table of common pediatric laboratory reference values.
PedSAP 2016 Book 1 Immunology
protection in subsequent exposures to the same or a biologi-
cally similar antigen.
Live vs. Inactivated vs. Toxoid Vaccines
Most vaccines contain a live attenuated organism or killed
microorganisms, or a modified bacterial toxin. Live attenuated
vaccines consist of a viable microorganism that undergoes
limited replication in an individual after administration. The
attenuation process decreases the microorganisms viru-
lence while retaining immunogenicity. Because live vaccines
more closely mimic natural infection, they often confer life-
long immunity. A potential drawback, however, is that a true
infection can occasionally develop and lead to morbidity and
mortality in immunocompromised hosts. In contrast, inacti-
vated vaccines cannot infect the host because they contain
no viable organisms. They tend to be less immunogenic than
live vaccines and often must be given in multiple doses to pro-
duce lasting immune response. Inactivated vaccines consist
of antigens from the organism that can be recognized by the
immune system to stimulate an antibody response. Booster
doses can further stimulate B cells and antibody response,
producing long-lasting immunity.
Inactivated vaccines differ in composition in the resulting
immune response. In contrast to protein-containing vaccines,
pure polysaccharide vaccines do not generate a T-lymphocyte
immune response; they stimulate B lymphocytes directly
to produce a solely humoral immune response. In infants
and children younger than 2 years, polysaccharide vac-
cines have poor immunogenicity and are not recommended.
Linking or conjugating the polysaccharide to a protein carrier
converts it to a T lymphocytedependent antigen. Protein-
conjugated polysaccharide vaccines can produce a better
immune response in infants and young children because of
T-lymphocyte involvement (Offit 2002).
Toxoid vaccine contain bacterial toxins that have been
inactivated by either chemical or heat treatment. The immu-
nogenicity remains after the inactivation process and
stimulates an immune response to the toxin that causes the
disease, rather than to the bacteria itself. Examples of toxoid
vaccines include tetanus and diphtheria.
Pharmacist Role
Pharmacists should play a role in immunization advocacy
by administering vaccines, if permitted; assessing vaccine
status for referral; and providing education to families and
children. All 50 states, the District of Columbia, and Puerto
Rico permit pharmacists to vaccinate in some capacity, with
state-specific variances in degrees of scope, type, and auton-
omy. However, seven states/territories (Connecticut, Florida,
Massachusetts, New York, Vermont, West Virginia, and Puerto
Rico) still do not allow pharmacists to immunize children. In
addition, 12 states limit the types of vaccinations a pharma-
cist can administer to children (APhA 2015). Efforts to expand
the pharmacists role as a health care provider should include
8 Routine Childhood Immunization Series
a focus on authorization to administer all types of vaccines to
Box 1-1. Available Vaccination Products
all ages of children.
Pharmacists practicing in states where pediatric immu- Individual Vaccines
DTaP (Daptacel, Infanrix)
nizations are not allowed can still provide assessment and
Tdap (Adacel, Boostrix)
referral of children for vaccination. With respect to providing DT (generic)
education to families, pharmacists should be able to dis- Td (Decavac, Tenivac)
cuss information about vaccine efficacy and safety, school TT (generic)
requirements, risks associated with not vaccinating children, HPV2 (Cervarix)
and common misconceptions surrounding vaccines. HPV4 (Gardasil)
HPV9 (Gardasil 9)
MenACWY-CRM (Menveo)
VACCINATION SCHEDULES MecACWY-D (Menactra)
AND ADHERENCE Meningococcal polysaccharide (Menomune)
Meningococcal group B (Bexsero, Trumenba)
Publication of Childhood Immunization PCV13 (Prevnar)
Schedules PPSV23 (Pneumovax)
MMR (M-M-R II)
The CDC annually publishes routine and catch-up vaccine
V (Varivax)
schedules for children ages 018 years; these schedules are IIV3 or IIV4 (Afluria, Agriflu, Fluarix, Flucelvax,
based on recommendations from the Advisory Committee FluLaval, Fluvirin, Fluzone)
on Immunization Practices (ACIP) and approval from the IIV4 (Fluarix, FluLaval, Fluzone)
American Academy of Pediatrics, the American Academy of LAIV4 (FluMist)
Family Physicians, and the American College of Obstetricians HepA (Havrix, Vaqta)
HepB (Engerix-B, Recombivax HB)
and Gynecologists (CDC 2016). Box 1-1 lists available vac-
Hib (PedvaxHIB, ActHIB, and Hiberix)
cines and brand names. IPV (IPOL)
Rotavirus (RotaTeq and Rotarix)
Pediatric Vaccination Coverage Combination Vaccines
Failure to routinely vaccinate children increases the risk of DTaP-IPV/Hib (Pentacel)
an epidemic from VPDs. In 1974, when almost 80% of children DTaP-IPV/HepB (Pediarix)
in Japan were vaccinated for pertussis, there were 393 cases DTaP-IPV (Kinrix, Quadracel)
Hib and meningococcal (MenHibrix)
of pertussis reported and no deaths. By 1976, following rumors
Hib and HepB (Comvax)
that the vaccine was unsafe and not needed, only 10% of HepA and HepB (Twinrix)
infants were vaccinated. In 1979, Japan had a pertussis MMRV (ProQuad)
epidemic, with more than 13,000 cases of pertussis and 41
deaths. In 1981, the number of pertussis cases decreased Information from: Hamborsky J, Kroger A, Wolfe C, eds.
Epidemiology and Prevention of Vaccine-Preventable Diseases
again after the government reinitiated pertussis vaccination (Appendix B-3 and B-4). The Pink Book, 13th ed. Washington,
(Gangarosa 1998). DC: Public Health Foundation, 2015.
Vaccination rates in U.S. children are monitored and
reported in the Morbidity and Mortality Weekly Report. For
children aged 1935 months, coverage was stable from 2013
to 2014. Less than 1% of children received no vaccinations; Among adolescents (ages 1317 years), recommended
however, other children did not receive the recommended vaccination coverage increased in 20132014. In teenagers,
number of injections for each vaccination. Receiving two or the 2014 reported rates were 87.6% for tetanus, diphtheria,
more doses of hepatitis A vaccine (HepA) had the worst per- and acellular pertussis vaccine (Tdap) and 79.3% for first
centage rate at 57.5%, and receiving three or more doses of meningococcal quadrivalent vaccine (MenACWY). Ranges
inactivated poliovirus vaccine (IPV) had the best percentage varied by state; for example, the rate for the first MenACWY
rate at 93.3%. Healthy People 2020 coverage targets were was 46% in Mississippi and 95.2% in Pennsylvania. Moreover,
reached for four vaccination series (i.e., three or more doses of the overall rate for second dose of MenACWY for 17-year-olds
IPV; one or more dose of measles, mumps, and rubella vaccine was only 28.5%. For the human papillomavirus (HPV) vaccine,
[MMR]; three or more doses of hepatitis B vaccine [HepB]; and only 39.75% of girls and 21.6% of boys completed the three-
one or more dose of varicella vaccine). However seven targets dose HPV vaccine series (Reagan-Steiner 2015).
did not (i.e., four or more doses of diphtheria, tetanus, and per- Children enrolled in kindergarten in 20132014 had vacci-
tussis vaccine [DTaP]; the full series of Hib vaccine; HepB birth nation coverage rates of 94.7% for two doses of MMR, 95.0%
dose; four or more doses of pneumococcal conjugate vaccine for the varying local requirements for DTaP, and 93.3% for
[PCV]; two or more doses of HepA; the full series of rotavirus two doses of varicella vaccine among states with a two-
vaccine [RV]; and the combined vaccine series) (Hill 2015). dose requirement. The median total exemption rate was

PedSAP 2016 Book 1 Immunology 9 Routine Childhood Immunization Series

1.8%, with a range of less than 0.1% for Mississippi to 7.1%
in Oregon. Eleven states had an exemption rate of 4% or
greater (Seither 2014).
Among children ages 1935 months, coverage rates for
many vaccines were lower for those living below the fed-
eral poverty level than for those at or above the poverty level
(Hill 2015). Across all age ranges, vaccination coverage rates
varied across states and by vaccine, but there was no con-
sistency across any region (Hill 2015; Reagan-Steiner 2015;
Seither 2014).
Reasons for under-vaccination and refusal range from vac-
cination access to negative patient perceptions; therefore,
improving adherence and decreasing exemption requires a
multifaceted approach. When data are available, initiatives to
improve adherence should be tailored toward local or county
vaccination or exemption rate concerns. The CDC Community
Guide lists the recommended methods to increase appro-
priate vaccination. The programs fall under three themes:
(1) enhancing access to vaccination services, (2) increasing
community demand for vaccinations, and (3) ensuring pro-
vider or system-based interventions.
Public Policy and Risks
Individual states require vaccinations for entry into school
and even day care facilities. Each state passes its own reg-
ulations, and there is great variance in what qualifies as an
exemption. All states allow for medical exemptions, many
allow for religious exemptions, and some even permit exemp-
tions because of philosophical beliefs. States also vary in
required documentation and enforcement of regulations.
During an epidemic, many states forego exemptions and
exclude students without the required vaccinations from
school (CDC 2015b).
In July 2016, California State Bill 277, one of the strictest
school vaccine laws, will go into effect. Allowing only med-
ically necessary exemptions, the bill requires parents who
choose not to vaccinate for other reasons to homeschool
their children because they will not be allowed to attend
school with other students.
Currently, the CDCs Public Health Law Program is com-
piling summaries of school exemption information by each
state. However, pharmacists should know the pertinent local
law so that they can educate parents about the potential
impact of vaccination refusal.
Beyond access to school, the risks and consequences of
vaccine refusal may affect the health of children and those
around them. Pharmacists should educate parents to inform
medical staff of their childs vaccination status when they
call 911, ride in an ambulance, visit a hospital ED, or visit a
physicians office. This information will greatly affect the dif-
ferential diagnoses because the child could have a VPD. If the
child has a VPD, additional precautions (e.g., isolation) must
be taken to protect others who have immunocompromise or
who may not be vaccinated. In an outbreak, parents must be
PedSAP 2016 Book 1 Immunology
able to recognize the signs and symptoms of the VPD and be
cognizant that some diseases can be spread by those who
are asymptomatic (CDC 2015b).
PATIENT EDUCATION ON VACCINE
CONCERNS
Among the many reasons why parents refuse to have their
children vaccinated are unfounded misconceptions. To effec-
tively communicate with families refusing to vaccinate, it is
important to understand their concerns. Common miscon-
ceptions surround four themes: (1) fear that vaccines or their
additives are harmful, (2) fear that the vaccine will cause the
infection, (3) belief that too many vaccines will overwhelm
the childs immune system, and (4) belief that getting the
natural VPD is healthier (CDC 2015b; Healy 2011).
Because vaccines have reduced the incidence and mor-
tality of disease, firsthand experience of the devastating
consequences of VPD is rare today. A lack of familiarity with
these consequences had increased the misconception that
getting the natural disease is healthier than receiving the
vaccine (Healy 2011).
Misconceptions of Autism Linkage
The most common misconception about vaccines is that
MMR or its additive, thimerosal, can cause autism (AAP 2016;
CDC 2015b). The concern with the MMR vaccine and autism
began in 1998 with Andrew Wakefields study published in
Lancet. His article claimed that the MMR vaccine caused
inflammatory bowel disease, which allowed harmful proteins
to damage the brain. In 2010, Lancet retracted his article for
ethical misconduct, and 10 of the 13 authors retracted the
findings (AAP 2016; IAC 2013).
Other concerns regarding autism may be caused by the
timing of MMR administration; the vaccine is given at age
1215 months, and the first symptoms of autism usually
develop at 15 months (Roberts 2002). However, to date, more
than 20 articles have found no association between the MMR
vaccine and autism (healthychildren.org 2015; IAC 2013).
Thimerosal, a preservative that contains mercury, was
never used in MMR (CDC 2015b). In the 1990s, it was found
in other vaccines but was removed in 1999 as a precaution-
ary safety measure; however, it can still be found in multidose
flu vaccines today. To date, studies have found no relation-
ship between early exposure to thimerosal and autism (CDC
2015b; healthychildren.org 2015).
Other Vaccine Substances
Further vaccine safety concerns surround adjuvants, preser-
vatives, or trace substances such as formaldehyde from the
manufacturing process (CDC 2015b). The adjuvant aluminum
continues to raise safety concerns because of its potential
for negative health consequences. Vaccines in the United
States that contain aluminum are HepA, HepB, DTaP, Tdap,
10 Routine Childhood Immunization Series
Hib, HPV, and PCV13 (CDC 2015b). The amount of aluminum
in each ranges from 0.125 mg to 0.625 mg, which is about 1%
of the estimated average daily aluminum intake (3050 mg)
from foods, drinking water, and medicines (CDC 2015b).
Because aluminum has been in vaccines for 70 years and is
only associated with minor injection-site reactions, there is no
current recommendation to remove aluminum adjuvants
from vaccines. However, further research is evaluating the
toxicology and pharmacokinetics of aluminum adjuvants in
infants and children (Eickhoff 2002).
Vaccines as a Disease Cause
Some families may believe that their child will contract the
disease from the vaccine (Healy 2011). As discussed earlier,
inactivated vaccines cannot cause the illness, and live
vaccines only rarely cause disease in healthy children.
Occasionally, live vaccines can cause a mild form of the dis-
ease that is not harmful (CDC 2015b). For example, less than
5% of children will develop a localized or generalized varicella-
like rash 526 days after vaccination. Usually, the rash has
two to five lesions (IAC 2016). An exception is the patient with
immunocompromise, who may develop a more severe form
of illness (Kroger 2011). Another exception was the live oral
polio vaccine, which was known to rarely cause severe illness
even in healthy children. However, the oral polio vaccine is no
longer used in the United States (CDC 2015b).
Overwhelming the Immune System
In a national survey, 25% of parents reported believing that too
many immunizations can weaken a childs immune system
(Gellin 2000). This concern leads to the belief that giving the
recommended number of vaccines at pertinent clinic visits
is unsafe because too many vaccines are given too soon
(Oft 2009). Children currently receive 1426 injections by the
time they are 2 years old.
Advocates argue that the high antigen exposure from vac-
cines will weaken the immune system. In reality, children are
exposed to around 130 antigens in currently recommended
vaccines, compared with the 200 antigens that were in the
only vaccine, smallpox, administered in the 1900s (Offit 2002).
It has been estimated that, based on the number of circulat-
ing B cells in the body, their capacity to respond to antigens,
and the number of antigenic epitopes contained in each vac-
cine, infants have the capacity to respond to 10,000 vaccines
at any given time. Thus, giving 11 vaccines concurrently to
an infant would use only about 0.1% of the immune system
capacity (Offit 2002). The CDC maintains that the immune
system will not be overwhelmed by multiple vaccinations,
and the recommended immunization schedule provides the
best protection from infection (CDC 2015b).
Parents may also believe the infants immune system is
too immature. This belief is not medically justified, because
neonates can generate both humoral and cellular immune
responses from the time of birth, regardless of gestational age.
PedSAP 2016 Book 1 Immunology
The only major deficiency in the immune system of children
younger than 2 years is a decreased B-cell response rela-
tive to older children and adults. T celldependent immunity,
however, is robust even before birth. Pure polysaccharide
vaccines invoke immune response solely by B-cell stimu-
lation and are thus less effective in children younger than
2 years. To ensure that polysaccharide vaccines are effective
in this age group, they are conjugated to a protein so that the
child can respond through T celldependent mechanisms
(Offit 2002).
Alternative Schedules
Concerned parents may request an alternative vaccine
schedule. Currently, The Vaccine Book: Making the Right
Decision for Your Child by Dr. William Sears offers alterna-
tive vaccine schedules for concerned parents (Offit 2009).
These alternative schedules are not recommended; they lack
evidence of efficacy and do not decrease adverse events
(Fisher 2009; Offit 2009). In fact, there are risks of following
an alternative schedule that spreads out vaccine adminis-
tration. Children may be unprotected when they are most
vulnerable to a VPD. Moreover, there would be a decrease in
the benefits of herd immunity and an increase in the number
of physician visits for an immunization (Fisher 2009).
Patient Education Resources
Parents and families may have additional concerns about
vaccinations. Patient-friendly information specific to each
vaccine and vaccines in general can be found on the CDC
website. These materials include vaccine basics and bene-
fits, frequently asked questions, and true stories of families
negatively affected by VPD. Other patient resources are found
in Box 1-2.
INTERPRETATION OF VACCINE
SCHEDULES AND ADMINISTRATION
CONSIDERATIONS
In addition to patient education materials and the vaccine
schedules, the CDC website provides great resources to aid
providers in assessing vaccination status and staying up
to date with evolving research and recommendations. It is
essential to review the website regularly because the most
up-to-date recommendations may change in between annual
publication of the standard schedules. For example, in March
2015, the recommendation for HPV vaccination changed to
Box 1-2. Patient-Friendly Immunization
Education Resources
Parents Guide to Childhood Immunizations
American Academy of Pediatrics
Vaccine Education Center at the Childrens Hospital of
Philadelphia
11 Routine Childhood Immunization Series
include the addition of HPV9; this recommendation was not
incorporated into the official schedule until the 2016 publica-
tion. In addition, when each new vaccine schedule appears, it
should be reviewed for updates.
Interpreting the schedule for routine vaccine administra-
tion in healthy children is straightforward. The footnotes
associated with the schedule provide additional details such
as minimal and maximal administration age and intervals
between vaccinations. Of note, the minimal administrations
interval between live vaccines not given simultaneously
is always 28 days. Administering a vaccine before the min-
imum age or recommended interval will likely result in a
suboptimal immune response (Kroger 2011). Factors that
lead to a suboptimal immune response if a child is too young
include immaturity of the immune system and interference
from maternal antibodies (IAC 2016; Chung Wai Ng 2014). If
a multi-series dose of a vaccine is given too early, protec-
tion to that dose may be reduced because of interference in
antibody response between the two doses (CDC 2015a; IAC
2016). However, vaccines administered 4 days or less before
the minimal interval or age are still considered valid, though
the mandate at the local or state level to count the vaccine
as valid may be different. If a dose is administered before the
minimal interval, the repeat dose should be spaced appro-
priately after the invalid vaccine. If a vaccine is given before
the minimal age, the dose should be repeated when the child
reaches the age limit (Kroger 2011).
Assessing the Need for Vaccines
Assessing vaccine status and appropriateness becomes more
challenging in patients who require catch-up vaccines or who
have additional considerations (e.g., immunocompromise).
The Pink Book Appendix A-15, Summary of Recommendations
for Child/Teen Immunization, is an essential resource for
assessing the need for vaccination in more complex situa-
tions or patients (Hamborsky 2015). However, for full details
of all considerations for a specific vaccine, the Morbidity and
Mortality Weekly Report with ACIP recommendations should
be consulted.
Administering Multiple Vaccines
When patients require several vaccines to catch up, a com-
mon question is, Which vaccines are most important to give
at that visit? The American Academy of Pediatrics and ACIP
recommend to give all needed vaccines at the visit and not
to delay vaccines. Currently, the number of injections that
can be administered at one time is without limit. If possible,
intramuscular vaccines should be spaced by at least 1 inch
to potentially reduce the risk of overlapping local reactions
(IAC 2016).
In addition, simultaneous administration of most vaccines
has not been shown to increase the incidence of adverse
effects or decrease the efficacy of vaccines (Kroger 2011).
An exception to this is in children with functional or anatomic
PedSAP 2016 Book 1 Immunology
asplenia; these patients should not have PCV13 and Menactra-
brand meningococcal conjugate vaccine administered at the
same visit. Rather, these vaccines should be separated by at
least 4 weeks because Menactra is thought to interfere with
the antibody response to PCV13 (CDC 2015a).
Although not recommended or necessary, there may
realistically be situations in which a parent or provider
is uncomfortable administering the quantity of vaccines
required at one visit. At this time, a clinical decision will need
to be made in order to determine which vaccines are most
important. Factors to consider may include, but are not lim-
ited to, current outbreaks in the area, prevalence of disease
for the recommended vaccines, and common age for severe
negative effects if the child contracts the VPD.
Combination Vaccines
Administering vaccines with combination products can help
reduce the number of injections at a visit. Currently, in the
United States, the only four vaccines that are not available
in any combination form for pediatric patients are influenza,
PCV13, pneumococcal polysaccharide vaccine (PPSV23),
and HepA. Although it is ideal to use combination products
in most situations, there are special considerations with cer-
tain products, such as ProQuad and febrile seizure risk (as
discussed later). Another consideration for combination vac-
cines is the potential for confusion about the components
and which vaccines should be administered for subsequent
doses (Kroger 2011).
CONSIDERATIONS PERTAINING TO
ALL VACCINATIONS
Contraindications and Precautions
To prevent the risk of an adverse outcome, contraindications
and precautions should be assessed before administering
a vaccine. For specific contraindications and precautions
to each vaccine, see Pink Book Appendix A-15, Summary of
Recommendations for Child/Teen Immunization (Hamborsky
2015). Across all vaccines, the only truly universal contrain-
dication is history of severe anaphylaxis to a component in
the vaccine, and the only universal precaution is moderate or
severe acute illness with or without fever (CDC 2015a; Kroger
2011). There is no concise definition of moderate or severe
acute illness; rather, it is based on subjectivity of the sever-
ity of symptoms and the cause of illness. Of note, the use of
antibiotics or antivirals does not automatically indicate mod-
erate or severe illness. Mainly, this precaution is meant to
prevent confusion between diagnosing the underlying illness
and confounding it with a vaccination adverse effect (Kroger
2011). Therefore, it will be up to the provider to determine the
appropriateness of withholding vaccines because of illness.
However, many misconceptions cause health care profes-
sionals to withhold vaccines unnecessarily (Box 1-3). A full
list of common perceived contraindications/precautions by
12 Routine Childhood Immunization Series
 Patient Care Scenario
A 12-month-old boy with no significant medical history HepB 0 months, 2 months
comes to your clinic for a well visit in October. He started
RV 2 months, 4 months
his routine vaccinations appropriately but fell out of care
DTaP 2 months, 4 months
because of a lack of health insurance and has received no
vaccines since he was 4 months old. His vaccine history Hib (ActHIB) 2 months, 4 months
is as follows: PCV13 2 months, 4 months
IPV 2 months, 4 months

What vaccinations are best to administer to this patient

ANSWER
First, look at figure 1 of the Recommended Immunization
Schedule for Persons Aged 0 Through 18 Years to evalu-
ate which vaccines he is behind schedule on, as well as
which ones would normally be due at 12 months of age.
Then, consult the catch-up schedule in figure 2 of the
today?
Recommended Immunization Schedule for Persons Aged
0 Through 18 Years to determine how to approach the vac-
cines he has fallen behind on.
The following table describes an evaluation for each
vaccine:

Vaccine Vaccine Indicated? Notes

HepB Yes Administer third dose on schedule now
RV No Contraindicated in those > 8 mo
DTaP Yes Catch up for third dose now; in 6 mo, give fourth dose
Tdap No Not indicated for those < 7 yr
Hib Yes Catch up for third dose now; no longer will need fourth dose
PCV13 Yes Catch up for third dose now; no longer will need fourth dose
PPSV23 No Not indicated for those < 2 yr
IPV Yes Administer third dose on schedule now
IIV Yes Administer first dose now; in 4 wk, give second dose
LAIV No Contraindicated in those < 2 yr
MMR Yes Administer first dose on schedule now
Varicella Yes Administer first dose on schedule now
HepA Yes Administer first dose on schedule now
HPV No Not indicated for those < 9 yr
Meningococcal No Only indicated in patients < 11 yr if high risk

This patient currently needs HepB, DTaP, Hib, PCV13,
IPV, IIV, MMR, varicella, and HepA. Although it may seem
like nine vaccines is a large number to administer in a sin-
gle visit, ACIP and the AAP recommend giving all needed
vaccines at the visit and not to delay vaccines. It is safe
to give multiple vaccines at the same visit, whereas defer-
ring some until a later date may expose the child to an
unnecessary risk of delayed immunity. The number of
injections required may be reduced by offering com-
bination vaccines. Several different combinations of
formulations can provide the necessary vaccines in as
few as six injections. One example is ProQuad (MMRV)
plus IIV plus PCV13 plus Pentacel (DTaP/Hib/IPV) plus
HepA plus HepB. Twinrix (HepA/HepB) is not approved in
pediatric patients and should be given as a separate HepA
and HepB vaccine in this population. If administering
ProQuad, it is recommended to counsel the family on the
small increased risk of febrile seizures compared with
administering the vaccine as MMR and varicella as two
separate injections. If several intramuscular injections
are given into the same muscle, they should be adminis-
tered at least 1 inch apart. Because DTaP and PCV13 are
the most likely to cause local injection-site reactions, it
may be prudent to give the injections containing these
vaccines in separate limbs, if possible.
1. Immunization Action Coalition. Ask The Experts:
Topics [homepage on the Internet].
2. Robinson CL. Advisory Committee on Immunization
Practices recommended immunization schedules
for persons aged 0 through 18 years United States,
2016. MMWR 2016; 65:86-7.

vaccine can be found in Table 7 of the Morbidity and Mortality the risk of adverse reactions or overburden the immune sys-
Weekly Report General Recommendations on Immunization. tem. However, the rates of antibody response and vaccine
Special considerations do exist. Some parents may worry adverse reactions in children with mild illness are similar to
that vaccinating a child with mild acute illnesses will increase those in healthy children (Offit 2002). Regardless, it would

PedSAP 2016 Book 1 Immunology 13 Routine Childhood Immunization Series

 Box 1-3. Conditions Generally Not
Considered Contraindications to
Vaccination
Minor acute illness such as diarrhea and minor upper
respiratory tract illnesses (including otitis media) with
or without low-grade fever
Mild to moderate local reactions and/or low-grade or
moderate fever after a prior dose of the vaccine
Current antimicrobial therapy
Recent exposure to infectious disease
Convalescent phase of illness
Pregnant or immunosuppressed person in the household
Preterm birth
Breastfeeding
Allergies to products presumed to be in vaccine, but are
not in vaccine
Information from: Kroger AT, Sumaya CV, Pickering LK, et al.
Centers for Disease Control and Prevention. General rec-
ommendations on immunization: recommendations of the
Advisory Committee on Immunization Practices (ACIP).
MMWR 2011;60:1-61; Hamborsky J, Kroger A, Wolfe C, eds.
Epidemiology and Prevention of Vaccine-Preventable Diseases.
The Pink Book, 13th ed. Washington, DC: Public Health
Foundation, 2015.
be important in this situation to appropriately educate and
empower parents to decide whether they still want to with-
hold vaccines until after illness has improved. Prematurity
is generally not a contraindication to vaccinations; however,
one exception is RV, which should be deferred until discharge
for any child who has been in the hospital since birth (Kroger
2011). Waiting to administer RV until a premature infant is
clinically stable and no longer in the hospital will outweigh
the theoretical risk of an adverse reaction as the result of a
lower level of rotavirus maternal antibody in very preterm
infants (Cortese 2009).
All children should receive all routine vaccines, including
MMR, varicella, and RV, even if there are household or close
contacts with immunocompromise. The only exception to this
is the smallpox vaccine, which should not be administered
if household members have immunocompromise; however,
smallpox vaccination is no longer routinely recommended in
the United States since the eradication of the naturally occur-
ring disease (Kroger 2011). Inactivated influenza vaccine
(IIV) is recommended over live attenuated influenza vaccine
(LAIV) for individuals in close contact with a severely immu-
nocompromised person. Because of theoretical transmission
of the virus, if LAIV is received, contact should be avoided for
7 days after administration (Grohskopf 2015). Viruses from
the MMR vaccine are not transmitted to contacts, and it is
rare for varicella to be transmitted (Kroger 2011). To reduce
the transmission of rotavirus that is shed during the first
weeks after vaccine administration, everyone should wash
hands after changing the childs diaper (Cortese 2009).
PedSAP 2016 Book 1 Immunology
Box 1-4. Specific Immunodeficiencies
Primary
Severe antibody deficiencies (e.g., X-linked, agamma-
globulinemia and common variable immunodeficiency)
Less severe antibody deficiencies (e.g., selective IgA
deficiency and IgG subclass deficiency)
Complete T-lymphocyte defects (e.g., severe combined
immunodeficiency [SCID] disease, complete DiGeorge
syndrome)
Partial T-lymphocyte defects (e.g., most patients with
DiGeorge syndrome, Wiskott-Aldrich syndrome, ataxia
telangiectasia)
Persistent complement, properdin, or factor B defi-
ciency chronic granulomatous disease, leukocyte
adhesion defect, and myeloperoxidase deficiency
Secondary
HIV/AIDS
Malignant neoplasm (leukemia, lymphoma, or general-
ized malignancy)
Transplantation
Immunosuppressive or radiation therapy
Asplenia
Chronic renal disease
IgA = immunoglobulin A; IgG = immunoglobulin G.
Information from: Hamborsky J, Kroger A, Wolfe C, eds.
Appendix A-26; Epidemiology and Prevention of Vaccine-
Preventable Diseases. The Pink Book, 13th ed. Washington, DC:
Public Health Foundation, 2015.
Immunosuppression
Another controversy in vaccine administration is determining
the safety and efficacy of administering vaccines in chil-
dren with altered immunocompetence. Immunodeficiencies
are classified into primary and secondary (Box 1-4).
Immunodeficiencies make patients more susceptible to
infection, so additional vaccines are often warranted; how-
ever, they also increase the risk of complications with live
vaccines, so some immunizations may be contraindicated.
Even after classification, it is difficult to assess the degree
to which a drug or disease causes immunosuppression and
whether a vaccine is indicated or should be withheld until
later (Kroger 2011). The Pink book appendix Vaccination of
Persons with Primary and Secondary Immune Deficiencies
summarizes vaccine efficacy, contraindications, and rec-
ommendations by type of immunodeficiency. For example,
asplenia makes patients particularly susceptible to infection
with encapsulated bacteria, so recommended vaccines are
targeted toward these organisms.
Timing of vaccination is important to ensure adequate
immunity as well. For planned splenectomies, vaccination
at least 14 days before surgery is optimal. For emergency
splenectomies when preoperative vaccination is not pos-
sible, waiting until at least 14 days after surgery produces
the best immune response (Shatz 1998). In some situations,
14 Routine Childhood Immunization Series
consultation with an infectious disease or immunology spe-
cialist is indicated (Kroger 2011).
From a safety standpoint, risk and benefit must be consid-
ered when deciding to administer a vaccine. All inactivated
vaccines can safely be administered to children with immu-
nosuppression, who are already at an increased risk of the
disease and its complications. Live vaccines may increase
the risk of severe complications because of uninhibited rep-
lication (Kroger 2011). However, depending on the type of
immunodeficiency and degree of immunosuppression, certain
live vaccines may be recommended. This includes varicella in
patients with HIV infection who are not severely immunocom-
promised (defined as a CD4+ T-lymphocyte count greater than
200 cells/mm3 for adolescents and a percentage greater than
15 for infants and children (CDC 2015a; Rubin 2014).
Another consideration with altered immunocompetence
is vaccine effectiveness. This also depends on the degree
of immunosuppression and the type of immunodeficiency.
Because they are safe to give, inactivated vaccines are rec-
ommended to be given as scheduled, even though there may
be a suboptimal immune response. However, patients receiv-
ing chemotherapy or radiation will likely have a suboptimal
immune response, and inactivated vaccines should be with-
held, if possible. If vaccines are administered, both live and
inactivated vaccines may potentially require readministra-
tion after immune function has improved to ensure adequate
immunity, though no specific criteria for revaccination have
been established (Kroger 2011)
Drugs Affecting Immune Status
Corticosteroids and certain drugs can cause some level of
immunosuppression, although to what degree is not clearly
established. Because of safety concerns, the consensus is
that live vaccines should be delayed if a patient is receiv-
ing high-dose steroids (defined as either 2 mg/kg or more or
20 mg/day or more of prednisone or equivalent) for 14 days or
more. Live vaccines can safely be administered 1 month after
discontinuing high-dose therapy. Patients receiving chronic
maintenance physiologic replacement corticosteroids should
not have vaccines deferred. However, doses higher than
physiologic maintenance may reduce the immune response
(Kroger 2011).
In general, children who are going to receive chemother-
apy, other immunosuppressive drugs, or radiation should
optimally have all types of vaccines administered at least
14 days before starting therapy. When vaccines are admin-
istered less than 14 days before or during therapy, they
should be readministered at least 3 months after therapy is
discontinued, if immunosuppression has resolved. This rec-
ommendation stems from a possible suboptimal response
to vaccines and potential safety concerns for live vaccines
during this time. One exception is IIV; it should be adminis-
tered even during immunosuppression and does not need to
be repeated (Kroger 2011).
PedSAP 2016 Book 1 Immunology
Table 1-1. Intervals Between Administration of MMR
or Varicella and Immune Globulin Preparations
Interval
(months) Products
3 RBCs, adenine-saline added blood
transfusion
Hepatitis A IG
Hepatitis B IG
Tetanus IG
4 Rabies IG
5 Varicella IG
6 Blood transfusion with packed RBCs
Blood transfusion with whole blood
Botulinum immune globulin intravenous
(human)
CMV (cytomegalovirus) IG
Measles IG
7 Blood transfusion with plasma/platelet
products
8 IGIV dose 400 mg/kg/dose IV
10 IGIV dose 1000 mg/kg/dose IV
IG = immunoglobulin; IGIV = intravenous immunoglobulin;
IV = intravenously.
Information from: Hamborsky J, Kroger A, Wolfe C, eds.
Appendix A-24. In Epidemiology and Prevention of Vaccine-
Preventable Diseases. The Pink Book, 13th ed. Washington,
DC: Public Health Foundation, 2015.
Administration of antibody-containing products are
thought to interfere with live vaccine replication of the MMR
and varicella vaccines (CDC 2015a). Therefore, it is recom-
mended to give the vaccines at least 2 weeks before the
antibody product. However, the intervals for administration
vary by product (Table 1-1).
Because of the many exceptions and considerations to
these recommendations, the guidelines from the Infectious
Diseases Society of America and CDC should also be con-
sulted when administering vaccines in children with altered
immunocompetence. For example, children may retain
immune memory and not require repeat vaccination if they are
receiving chemotherapy or radiation for certain malignancies.
Inactivated vaccines may also be recommended in patients
receiving low-dose intermittent or maintenance therapy of
immunosuppressive agents. Moreover, if the benefit of vacci-
nation outweighs the risk, a live vaccine might be indicated in
the patient with immunocompromise (Kroger 2011).
General Adverse Effects
Common vaccine-specific adverse effects are discussed
in the following. Some adverse effects encompass most
15 Routine Childhood Immunization Series
vaccines: these include pain, injection-site reactions, fever
or flu-like illness, syncope, and anaphylaxis. Clinically sig-
nificant adverse effects after vaccine administration should
be reported to the Vaccine Adverse Event Reporting System
(VAERS), a national surveillance reporting system (CDC 2015a).
The pain associated with childhood vaccines can lead to
long-term negative effects, such as conditioned fear of nee-
dles and avoidance of associated procedures. Even though
the perception of pain varies from patient to patient, there
are methods to reduce the pain associated with vaccination.
These measures include breastfeeding, giving sweetened
solutions for infants younger than 12 months, injecting the
most painful vaccine last, using tactile stimulation in chil-
dren 4 years and older, using distraction, and applying topical
anesthetics (CDC 2015a).
Injection-site reactions usually present as soreness, red-
ness, itching, or swelling at the injection site. If a reaction
occurs, the symptoms usually resolve within a few days but
may last up to a week. Treatment consists of cold compresses
and, depending on the severity of the reaction, analgesics or
antipyretics (Rosenblatt 2015; Schmitt 2015). Injection-site
reactions can occur with any vaccine and are not associated
with specific vaccine components. If a skin reaction (e.g.,
rash) varies from the typical presentation of an injection-site
reaction, the patient should be referred for a follow-up. Many
vaccines can cause rare skin reactions that are specific to the
vaccine or its components (Rosenblatt 2015).
Fever or flu-like illness is also a common adverse effect.
Usually, the fever begins within 24 hours of vaccine admin-
istration and resolves in 12 days. For live vaccines such
as MMR and varicella, fever may be delayed for 14 weeks
(Schmitt 2015). A fever from vaccines should be approached
similarly to any other fever. Children who develop fever from
vaccinations have no higher risk of febrile seizures. The
only exception is the slight increase risk of febrile seizures
within 512 days after the first dose of the MMR vaccine or
the measles, mumps, rubella, and varicella vaccine (MMRV)
(CDC 2015b). When MMR and varicella are administered
separately to children 1247 months of age, about 4 of
10,000 children will have a febrile seizure compared with 8
of every 10,000 children who receive MMRV. It is therefore
recommended to discuss this risk with all families before
administering MMRV so that they can decide whether the
combination MMRV vaccine or separate injections of MMR
and varicella are most appropriate, especially if there is a
personal or family history of febrile seizures or epilepsy
(CDC 2015b).
For all of the previously mentioned vaccines, prophylactic
acetaminophen or ibuprofen are not recommended because
of insufficient evidence that they reduce discomfort, fever
associated with vaccines, or risk of febrile seizures (Kroger
2011; Sullivan 2011). In addition, pretreatment with antipy-
retics may decrease immune response to the vaccines (Das
2014). Although more studies are needed to determine the
PedSAP 2016 Book 1 Immunology
true risk, antipyretics should be reserved for postvaccination
treatment of an adverse event (Das 2014).
Syncope after vaccinations is common, especially in those
1118 years of age. A VAERS report found that 62% of reported
fainting episodes occurred in this age range (CDC 2015b). It is
recommended to observe patients while they sit or lie down
for 15 minutes after vaccinating. In addition, giving patients
a beverage or snack may reduce the chance of fainting (CDC
2015b; Kroger 2011).
Anaphylaxis occurs in about 1 of 1.5 million doses of vac-
cines administered to children and adolescents. If an allergic
reaction occurs, the person administering the vaccine should
be prepared to care for the patient and have an emergency
plan in place. It is also recommended that all individuals
administering vaccines be certified in cardiopulmonary resus-
citation (CDC 2015a).
INDIVIDUAL VACCINE INFORMATION
Diphtheria, Tetanus, and Pertussis
Overview of Infection Disease
Diphtheria is caused by the bacterium Corynebacterium diph-
theriae, a gram-positive bacillus, and manifests as an upper
respiratory tract infection. C. diphtheriae produces a toxin
that is responsible for producing the clinical features and
complications of the disease. The infection affects mucous
membranes, primarily in the tonsils, pharynx, larynx, and
nasal mucosa, and can lead to formation of the diseases hall-
mark, a pseudomembrane. As the pseudomembrane grows
in size, it can extend into the airway space and cause respira-
tory obstruction and subsequently death from asphyxiation.
Additional complications of the toxin include myocarditis,
neuropathy, paralysis, and pneumonia. Without treatment,
about 50% of patients with diphtheria will die; even with
proper treatment, the mortality rate remains about 10%.
Vaccination is extremely effective in preventing diphthe-
ria. Because of high vaccination rates, fewer than five U.S.
cases were reported in the past decade. However, diphtheria
remains a significant threat in other areas of the world such
as India and Nepal (CDC 2015a; WHO 2015).
Tetanus is disease caused by Clostridium tetani; this
gram-positive anaerobic bacterium produces a neurotoxin
that causes muscles to contract. C. tetani enters the body
through a wound or cut in the skin and travels through-
out the body to manifest its effects on various sites of the
CNS. The resulting unopposed muscular contraction can
lead to spasms, seizures, and autonomic nervous system
dysfunction. The associated death rate, even with appropri-
ate treatment, is 10%20%. Vaccination has made tetanus
uncommon in the United States, with an average of around
30 cases per year, primarily in those who are unvaccinated or
not up to date with booster shots (CDC 2015a).
Pertussis (whooping cough) is a respiratory disease
caused by Bordetella pertussis, a gram-negative aerobic
16 Routine Childhood Immunization Series
bacterium. Pertussis is known for its paroxysmal coughing
spells, which lead to the characteristic high-pitched whoop
sound on inspiration. Pertussis was a common childhood ill-
ness and a major cause of child mortality. From 1922 to 1940,
the incidence averaged 150 reported cases per 100,000; this
was significantly reduced after introduction of the vaccine
in the 1940s, and the incidence was 0.5 cases per 100,000
in 1976 (Faulkner 2015). However, pertussis incidence in the
United States has increased during the past 3 decades. The
annual number of cases in 2012 was 48,000, up from a low of
1300 in 1981. This can be attributed to more vaccine refus-
als as well as to the switch to acellular vaccine from whole
cell vaccine, which was more immunogenic. In response, the
ACIP has expanded its recommendations regarding pertussis
vaccination several times since 2010 to combat the growing
threat of disease (CDC 2015a).
Recommended Administration Schedule
The DTaP vaccine is given as a five-dose series to children
younger than 7 years. Minimal intervals after the first two
doses are 4 weeks, with a 6-month interval before each of the
last two doses. The Tdap vaccine is recommended for adoles-
cents as a single dose. For children and adolescents 7 years
and older who have not completed the primary DTaP series, a
three-dose series should be given: one dose of Tdap, followed
at least 4 weeks later with a dose of tetanus and diphtheria
vaccine (Td) and a second dose of Td at least 6 months after
the first. For pediatric patients, the formulations including
pertussis should always be used unless there is a contraindi-
cation (Robinson 2016).
In 2011, ACIP expanded its pertussis vaccine recommen-
dations to include all individuals 11 years and older who have
not received a dose of Tdap, emphasizing the need for this
vaccine in adults who will be in contact with infants younger
than 12 months. The intent is to protect infants, who are most
at risk of pertussis complications, by preventing carrier trans-
mission before they develop adequate immunity from their
primary vaccination series (CDC 2011b). In addition, since
2012, Tdap has been recommended for pregnant women dur-
ing each pregnancy (regardless of the timing of previous
vaccinations), preferably between 27 and 36 weeks gesta-
tion to maximize antibody transfer through the placenta for
protection of the infant after birth (CDC 2013b).
Vaccine-Specific Considerations
Arthus reactions have been described for patients receiv-
ing vaccines that contain tetanus or diphtheria toxoid. This
immune-mediated type III hypersensitivity reaction causes
a localized vasculitis at the injection site, leading to severe
pain, swelling, induration, and hemorrhage within 412 hours
after the injection. Arthus reactions are generally self-limiting
and resolve without treatment in 12 days; however, symp-
tomatic management with analgesics or anti-inflammatory
drugs can be considered (Butler 1976). A history of Arthus
PedSAP 2016 Book 1 Immunology
reaction after previous vaccination is not a contraindication
to further receipt of the Td or Tdap vaccines; however, it is
generally recommended to wait at least 10 years between
boosters because the severity of the reaction is correlated
with the frequency of toxoid exposure.
Human Papillomavirus
Overview of Infection Disease
Human papillomavirus is a DNA virus that can cause infec-
tion in the skin or mucous membranes; spread primarily
through contact with infected skin, mucous membranes, or
body fluids, it is the most common sexually transmitted infec-
tion, affecting most sexually active individuals. An estimated
79 million people in the United States are infected with HPV,
with 14 million new infections annually, half of which are in
individuals 1524 years of age (Satterwhite 2013). There
are more than 150 serotypes of HPV, many of which cause
subclinical infection and go unnoticed. Of primary clinical
concern, however, are the infections that can lead to cancer
or warts. Human papillomavirus is strongly associated with
cancers of the cervix, penis, anus, and oropharynx, with sero-
types 16 and 18 being the most common culprits, followed
by serotypes 31, 33, 45, 52, and 58. Anogenital warts are also
caused by HPV, with more than 90% associated with sero-
types 6 and 11 (Markowitz 2014).
Recommended Administration Schedule
As recommended by ACIP, boys and girls should have routine
HPV vaccination with a three-dose series beginning at age 11
or 12, with a minimal starting age of 9 years. Female patients
926 years of age should be vaccinated with HPV vaccine,
with no preference given by ACIP between HPV2, HPV4, and
HPV9. Male patients 921 years of age, as well as up to age 26
for high-risk patients (i.e., men who have sex with men, those
with immunocompromise), should be vaccinated with HPV4
or HPV9. If the formulation of previous doses is unknown, or
unavailable, any of the available HPV vaccine formulations
may be used to complete the series for female patients; HPV4
or HPV9 is preferred for male patients.
Approved in 2014, HPV9 is a new formulation with
expanded serotypes that offers protection against an addi-
tional 10%15% of HPV-associated cancers (Petrosky 2015).
However, ACIP has made no recommendations about revac-
cinating (or restarting the vaccine series) for those who
previously received HPV vaccine doses and who desire the
additional serotype coverage offered by HPV9. Clinical and
pharmacoeconomic evidence is currently insufficient to sup-
port revaccination of those who have already completed the
vaccine series; however, some data suggest that revacci-
nation with HPV9 after completing a series of HPV4 is safe
(Petrosky 2015).
Several studies showing the noninferiority of two-dose or
even one-dose regimens compared with the full three-dose
HPV vaccine series have prompted some organizations to
17 Routine Childhood Immunization Series
alter their recommendations (Kriemer 2015; Dobson 2013).
For example, WHO now recommends only a two-dose sched-
ule for adolescents who initiate the vaccine series before
14 years of age (WHO 2014). However, ACIP has not altered its
recommendations and continues to support completion of a
three-dose series.
Vaccine-Specific Considerations
Adherence to recommended vaccination schedules for HPV
vaccine has lagged behind that of many other vaccines, with
completion of the recommended three-dose series in only
around one-half of adolescent girls by age 17 and less than
one-fourth of boys by age 17 (Reagan-Steiner 2015). Reasons
for the low vaccine uptake include lack of knowledge about
the risks of HPV-associated cancer, general concerns about
vaccine efficacy and safety, high cost of the vaccine, and
unfounded concerns about the vaccines promoting sexual
promiscuity (Fernndez 2014). Several studies have shown
that HPV vaccination does not increase sexual activity
among teens and is not associated with an increase in over-
all sexually transmitted infection rates (Jena 2015; Liddon
2012). Pharmacists can significantly affect the prevention of
HPV and related cancers by educating patients and screen-
ing for vaccination status. In addition, because most states
now allow pharmacists to administer the HPV vaccine, immu-
nization can be performed at the time of assessment in the
pharmacy to reduce the risk of lack of patient follow-through
on recommendations.
Meningococcus
Overview of Infection Disease
Meningococcal disease is caused by the bacterium Neisseria
meningitidis, an aerobic gram-negative diplococcus that can
cause severe infections including meningitis and bactere-
mia. N. meningitidis strains are classified according to the
antigenic structure of their polysaccharide capsule, with
serotypes A, B, C, W135, X, and Y causing the most clinically
important infections. Disease is spread by transmission of
the bacteria from droplets and close contact with an infected
or colonized individual. Patients most at risk of the invasive
disease are those without a functional spleen, with comple-
ment deficiency, or living in crowded housing situations.
The disease generally has a rapid onset of fever, headache,
and stiff neck, and patients may also have nausea, vomiting,
photophobia, and confusion. Overall rates of meningococcal
disease are highest in children younger than 1 year, with a
second peak in adolescence associated with close contact
with classmates in school and dormitories on college cam-
puses. Most clinical disease in the United States is caused
by serogroup B (about 60%), followed by serogroups C and
Y (CDC 2015a). Periodic outbreaks have gained public atten-
tion in recent years, including several on college campuses
(Soeters 2015) and in urban populations of men who have sex
with men (MDH 2015; CDC 2013a).
PedSAP 2016 Book 1 Immunology
Recommended Administration Schedule
Vaccination with a quadrivalent meningococcal vaccine
(MenACWY) is routinely recommended for adolescents as
well as younger children who are at high risk of disease,
including patients with functional or anatomical asplenia,
with complement deficiency, or living in an area of high menin-
gococcal disease prevalence or in outbreak settings (Cohn
2013). The prevalence of meningococcal disease caused by
serogroup B has prompted the development and recent U.S.
approval of new recombinant vaccines. Additional adminis-
tration of a vaccine covering serogroup B is recommended
in patients at high risk of disease because of the conditions
listed earlier or in the setting of an outbreak (Folaranmi 2015).
The serogroup B meningococcal vaccine was incorporated
into the 2016 vaccination schedule for high-risk groups and
nonhigh-risk groups that may receive the vaccine based on
individual clinical decision making.
Vaccine-Specific Considerations
One particularly dangerous drug-related risk factor for menin-
gococcal disease is the monoclonal antibody eculizumab.
Eculizumab is used in the treatment of paroxysmal nocturnal
hemoglobinuria and atypical hemolytic uremic syndrome; it
works by interfering with complement-mediated hemolysis.
The complement deficiency induced by eculizumab has been
associated with cases of severe and deadly meningitis from
N. meningitidis and has prompted the FDA to require a boxed
warning and a Risk Evaluation and Mitigation Strategies
(REMS) program for this drug. According to the package
insert, a main component of the REMS program is adminis-
tration of the quadrivalent meningococcal vaccine at least
14 days before initiating eculizumab. Although the prescribing
information and REMS program do not specifically mention
vaccination with the newer serogroup B meningococcal vac-
cine, it would be prudent to consider adding this vaccine in
patients undergoing eculizumab therapy who are at risk of
all serotypes of meningococcal infection. In addition, eculi-
zumab increases the risk of infection with other encapsulated
bacteria, including H. influenzae and Streptococcus pneumo-
niae, so the need for vaccines against those agents should
also be assessed.
Pneumococcus
Overview of Infection Disease
S. pneumoniae is a gram-positive aerobic bacterium that
causes many types of illnesses, with the most severe mor-
bidity and mortality associated with pneumonia, bacteremia,
and meningitis. In the United States, an estimated 900,000
people acquire pneumococcal pneumonia each year, with
almost 50% of these patients requiring hospitalization and
a mortality rate of 5%7%. An additional 3700 deaths annu-
ally are attributable to bacteremia or meningitis caused by
S. pneumoniae. Since the introduction of the pneumococcal
vaccines, rates of infection and death from S. pneumoniae
18 Routine Childhood Immunization Series
have decreased substantially, both among the specific sero-
types covered by the vaccine and overall. For example, before
PCV7, the incidence of PCV7-type invasive pneumococcal
disease was 80 cases per 100,000 in children younger than
5 years; this decreased to less than 1 case per 100,000 by
2007 (CDC.gov 2015a).
Recommended Administration Schedule
Vaccination with a four-dose series of PCV13 is univer-
sally recommended for all children beginning at 2 months
of age. The PPSV is recommended for children 2 years and
older with high-risk conditions (e.g., sickle cell disease, ana-
tomic or functional asplenia, chronic cardiac, pulmonary or
renal disease, diabetes, CSF leaks, HIV infection, immuno-
suppression, diseases associated with immunosuppressive
and/or radiation therapy, solid organ transplantation, those
who have or will have a cochlear implant). In addition, chil-
dren 618 years of age at high risk of pneumococcal disease
should receive doses of both PCV13 (unless they have com-
pleted the PCV13 series) and PPSV23, separated by at least
8 weeks.
In older children with high-risk conditions, extra attention
should be paid to the primary PCV series because these chil-
dren may or may not have received PCV13, given that until
2010, the routine vaccination consisted of PCV7. See Pink
Book Appendix A-15, Summary of Recommendations for
Child/Teen Immunization, for details of recommended timing
of vaccine administration.
Vaccine-Specific Considerations
In addition to the invasive infections that pneumococcal
vaccine was designed to prevent, including meningitis and
bacteremia, PCV has a benefit in reducing otitis media caused
by S. pneumoniae (Fortanier 2014). From a public health
standpoint, this is an important benefit, given the frequency
of otitis media in young children. However, data cannot be
extrapolated to a patient-specific level because many organ-
isms can cause otitis media.
Measles, Mumps, and Rubella
Overview of Infection
Measles virus, a species in the genus Morbillivirus, caused
disease in almost all children in the pre-vaccine era. Measles,
also known as rubeola, spreads by the respiratory route and
manifests systemically as the virus spreads throughout
the body. Typical early clinical features include a prodrome
phase, which begins with a fever followed by the three Cs
(i.e., cough, coryza, and conjunctivitis). Koplik spots, which
are punctate bluish white spots on mucous membranes, are
considered pathognomonic for measles. The generalized
rash that occurs with measles typically begins at the hair-
line of the face and upper neck and then continues downward
and outward across the body until it reaches the hands and
feet. The rash usually resolves after several days in the same
PedSAP 2016 Book 1 Immunology
order in which it appears, beginning at the head and ending
in the extremities. Measles is generally self-limiting but can
occasionally be severe, leading to complications including
pneumonia, encephalopathy, and even death in a small pro-
portion of patients.
The burden of measles has decreased significantly in the
United States since the vaccine was introduced in 1963, with
the incidence decreasing by more than 95% from its peak.
However, several recent outbreaks have brought about a
resurgence of measles; in 2014 there were 668 cases across
27 states. Most of the outbreaks were associated with virus
that was imported from an endemic area of the world, or by
people who traveled to one of those areas. Because measles
is highly contagious, a single source can quickly spread dis-
ease throughout a community, particularly through patients
who are unvaccinated or under-vaccinated (CDC 2015a).
The outbreak that garnered the most attention was in
Orange County, California, because it was associated with
exposure to the virus at a Disney theme park. A total of 125
confirmed measles cases were associated with this out-
break (Zipprich 2015).
Mumps is a virus in the Paramyxoviridae family that is
spread by the respiratory route. The virus replicates in the
nasopharynx and surrounding lymph nodes, then spreads
throughout the body in the bloodstream. After an initial pro-
drome, consisting of nonspecific symptoms of fever, malaise,
myalgia, anorexia, and headache, mumps most commonly
manifests as parotitis. The inflammation can affect several
salivary glands and can be unilateral or bilateral. Orchitis
can also occur in up to 50% of postpubescent males infected
with mumps, which can lead to further complications includ-
ing testicular atrophy. Other serious complications, though
rare, can also occur, including meningitis, deafness, myocar-
ditis, and death (CDC 2015a). After the introduction of routine
vaccination the incidence of mumps declined sharply to less
than 1% of previous rates. However, outbreaks have occurred
in the past few years, primarily attributed to communities
with low vaccination rates or to close contact in crowded set-
tings. Public interest in mumps spiked during a 2014 outbreak
that occurred among players and staff in the National Hockey
League (Ruderfer 2015).
Rubella virus, also known as German measles, is a viral
illness spread by the respiratory route. It manifests pri-
marily as a mild illness with a primary feature of rash that
begins on the face and spreads down through the trunk and
to the feet and hands, similar to measles. Systemic symp-
toms of rubella are generally mild and can include low-grade
fever, malaise, lymphadenopathy, upper respiratory symp-
toms, and arthralgias. The biggest concern with rubella, and
the primary motivation for vaccination against the virus, is
congenital rubella syndrome (CRS). Rubella infection early
during a womans pregnancy can cause severe problems
with the fetus and may lead to fetal death, spontaneous abor-
tion, or preterm delivery. If the child survives the infection
19 Routine Childhood Immunization Series
and is born alive, CRS can affect all organ systems, with
severity and location depending on the stage of gestation
when the infection occurred. The most common complica-
tion of CRS is permanent deafness, which can often be the
sole manifestation of the disease in an infant. Other compli-
cations of CRS include eye defects, cardiac defects, bone
alterations, liver damage, spleen damage, and mental retar-
dation (CDC 2015a).
Recommended Administration Schedule
The MMR vaccine is universally recommended for all chil-
dren as a two-dose series beginning at 12 months of age, or
for any child who has not yet completed the primary immuni-
zation series. In addition, the MMR vaccine may be given to
children as young as 6 months if they will be traveling outside
the United States. These children should still subsequently
receive the full two-dose series according to the immuniza-
tion schedule (McLean 2013).
Vaccine-Specific Considerations
Because MMR is a live-attenuated virus vaccine, all the con-
siderations pertaining to immunosuppression and blood
products for live vaccines apply. Of note, the vaccine con-
tains gelatin and neomycin, so patients who are allergic
to these components should not be vaccinated with MMR
(CDC 2015b).
Public concerns about the MMR vaccine causing autism
have been shown to be unfounded and based on fraudulent
work, as discussed previously (Retraction 2010).
Varicella
Overview of Infection Disease
Varicella (chickenpox) is caused by the varicella zoster virus.
This herpesvirus causes a pruritic rash that appears first on
the head and trunk and then spreads to the rest of the body.
It progresses from macules to papules to vesicles before
finally crusting over and healing. It is highly infectious and
easily spreads person-to-person through aerosolized virus
particles. Among household members and close contacts,
an estimated 90% of susceptible individuals will contract the
virus after exposure to an infected person.
Initial infection is generally mild, and symptoms resolve
without specific treatment, although occasionally, bacterial
superinfection can cause severe complications. After initial
varicella zoster virus infection, the virus remains dormant
in the dorsal root ganglia of the nervous system and can
be reactivated later in life to cause herpes zoster (shingles)
during periods of stress or decreased immunity. Before the
varicella vaccine was introduced in 1995, around 150,000
200,000 cases of varicella disease occurred annually, leading
to 100150 deaths each year. Significant declines of more
than 80%90% in both incidence and mortality from varicella
have occurred since widespread vaccination was initiated in
the United States in the 1990s (CDC 2015a).
PedSAP 2016 Book 1 Immunology
Recommended Administration Schedule
The recommended immunization regimen for varicella virus
is a two-dose series that is initiated at 12 months of age.
Varivax should not be confused with Zostavax. Zostavax is
the zoster vaccine used in adults for shingles prevention and
is about 14 times more potent.
Vaccine-Specific Considerations
Because varicella vaccine is a live-attenuated virus, all the
considerations pertaining to immunosuppression and blood
products for live vaccines apply. Of note, the vaccine con-
tains gelatin and neomycin, so patients who are allergic to
these components should not be vaccinated with varicella,
MMRV, or shingles (CDC 2015b). Occasionally, a child will
develop a mild, localized rash resembling chickenpox after
varicella vaccination. When this occurs, concern for trans-
mission exists because the virus, though attenuated, is
actively replicating in vivo. In general, if the rash is limited
to maculopapular lesions, there is no risk of transmission.
If the lesions become open vesicles, it is theoretically pos-
sible to transmit disease until they all crust over, although it
is still quite rare. However, if vesicles develop after varicella
vaccination, a noncontagious vaccine-induced rash cannot
be differentiated from a true varicella infection. Therefore,
if a rash develops 721 days after vaccine administration,
contact should be avoided with susceptible individuals or
immunocompromised patients who are at risk of severe com-
plications of disease until the rash resolves (IAC 2016).
Some antiviral agents may interfere with the efficacy
of the varicella vaccine because, as a live vaccine, it
requires active replication to stimulate the immune system;
this can be impaired in the presence of antiviral medica-
tions active against varicella zoster virus (e.g., acyclovir,
ganciclovir). See Pink Book Appendix A-15, Summary of
Recommendations for Child/Teen Immunization, for more
specific recommendations on timing of antivirals around the
vaccine (Hamborsky 2015).
Influenza
Overview of Infection Disease
Influenza is a respiratory illness spread by respiratory drop-
lets after an infected person coughs or sneezes. Generally a
seasonal disease that peaks in the winter months, the exact
timing and the length of influenza season vary with location
and climate. Influenza is characterized by an abrupt onset
of severe systemic and respiratory symptoms including, but
not limited to, fever, chills, myalgia, headache, malaise, non-
productive cough, sore throat, and rhinitis. Uncomplicated
influenza generally resolves within 7 days; however, chil-
dren with comorbid conditions may have more severe or
prolonged disease or secondary bacterial infections. These
complications and secondary infections can lead to signifi-
cant morbidity and mortality, particularly from post-influenza
pneumonia or respiratory failure. In addition, febrile seizures
20 Routine Childhood Immunization Series
have been reported in up to 20% of children hospitalized with
influenza (CDC 2015a).
The influenza vaccine varies in efficacy each year because
of the variability in influenza strains circulating. Efficacy is
generally in the 50%60% range; however, in some recent
years, it has been as low as 23% (CDC 2015a). Although this
is much lower than what we have come to expect from many
other types of vaccines, influenza vaccination can still play
an important role in reducing the burden of influenza morbid-
ity and mortality. A recent Cochrane review found a number
needed to vaccinate of 3971 to prevent one case of influ-
enza or influenza-like illness, whereas adverse effects were
similar to placebo (Demicheli 2014). In addition, prevention
of influenza can reduce complications of the disease, includ-
ing pneumonia and associated hospitalizations (Grijalva
2015). However, still less than one-half of eligible patients
in the United States receive the influenza vaccine each year,
which further limits the vaccines potential to reduce influ-
enza illness and related complications. Pharmacists can
help improve vaccination rates by educating patients and
administering vaccinations throughout the influenza season
(CDC 2015a).
Recommended Administration Schedule
Annual vaccination against influenza at the beginning of
each influenza season is universally recommended for all
patients 6 months and older. The vaccine should be adminis-
tered before the onset of influenza activity in the community.
Vaccination should continue to be offered as long as influ-
enza viruses are circulating. No preference is given for
quadrivalent or trivalent vaccine, and the 20152016 guide-
lines removed the previous preference for LAIV over IIV in
healthy children 28 years of age. The guidance now suggests
that any product that is available and for which the patient is
eligible should be administered. The rationale for this recom-
mendation is to decrease the chance of missed opportunity
for vaccination because of waiting for the availability of a pre-
ferred product. In addition, evidence is conflicting regarding
the previously reported superiority of LAIV that had led ACIP
to give it a preferential recommendation in younger children
(Grohskopf 2015). A recently published study reports that
rates of influenza during the 20132014 season were actually
higher amongst children who received the LAIV compared to
those that received IIV (Chung 2016).
Children 6 months to 8 years of age require a second dose
of influenza vaccine at least 4 weeks after the first dose in
the first season they are vaccinated to optimize response.
Response rate after a single dose improves with age and
varies by influenza serotype, but it improves with a second
dose for all serotypes in children younger than 9 years (Neuzil
2006). If a child in this age group previously received only a
single dose in an influenza season, it is still recommended
that the child be given two doses in the current season to
ensure optimal response. The only exception to this would be
PedSAP 2016 Book 1 Immunology
if the initial vaccine the child received contained exactly the
same influenza strains as the current season; then, a single
dose would be adequate. However, it is often difficult to deter-
mine this with certainty, so it is recommended to err on the
side of caution and give the two-dose series to optimize effi-
cacy (Grohskopf 2015).
Vaccine-Specific Considerations
Influenza vaccines have traditionally been grown in chicken
eggs; there is therefore a potential risk to patients with severe
egg allergy. However, several studies have shown that even
patients with documented egg allergies have an extremely
low chance of a severe allergic reaction, and even mild aller-
gic reactions to the influenza vaccine are uncommon (Des
Roches 2012). Current ACIP recommendations state that
children with a history of egg allergy that includes only hives
(but not anaphylaxis or angioedema) can be given IIV3 or IIV4
as long as they are monitored for at least 30 minutes after
vaccination by an appropriate health care provider. In addi-
tion, patients who can tolerate eating lightly cooked eggs are
unlikely to have a true allergy and can be administered IIV
using the same general precautions. The LAIV formulation
has not been extensively studied in egg allergy and should
be avoided until further information is available. Alternatively,
there is a completely egg-free recombinant vaccine for-
mulation, recombinant influenza vaccine trivalent (RIV3),
which can be administered to patients with any severity of
egg allergy. However, RIV3 is currently not approved for use
in pediatric patients, so any use in children younger than
18 years would be off-label (Grohskopf 2015). Several clinical
trials assessing safety and immunogenicity in children have
been completed, although the full results are not yet available
at the time of writing this chapter (NIH 2015a, 2015b).
A prevalent misconception about the influenza vaccine,
and a common reason given for declining to be vaccinated, is
the concern that the vaccine can cause influenza illness. The
inactivated injectable vaccine is a completely nonviable form
of the virus that cannot replicate, so it cannot cause illness.
However, the vaccine can cause adverse effects includ-
ing low-grade fever, headaches, and muscle aches, which
patients may falsely attribute to the influenza virus. Some
patients may coincidentally contract influenza after vacci-
nation, but not from the vaccine itself. It takes 1014 days
to develop an adequate antibody response to the vaccine to
provide protection, so if patients are exposed to the virus dur-
ing this time, they may develop disease despite receiving the
vaccine. Other non-influenza viruses can also present with
similar symptoms, which could be mistaken by patients to be
influenza disease.
Although LAIV is an attenuated form that theoretically
could cause illness, it is a weakened form of the virus and has
been adapted to replicate only in the colder temperatures of
the nasal passages, so it cannot cause infection in the lungs.
Because of the small theoretical risk of causing disease,
21 Routine Childhood Immunization Series
however, LAIV is contraindicated in immunocompromised
individuals, as are other live virus vaccines (CDC 2015a).
Hepatitis A
Overview of Infection Disease
Hepatitis A is an RNA virus in the Picornaviridae family that
is transmitted by the fecal-oral route and causes an inflam-
matory disease of the liver. Unlike some other hepatitis
viruses, hepatitis A virus is generally self-limiting and does
not progress to a chronic long-term infection. Symptoms
of the disease include nausea, anorexia, fever, malaise, and
abdominal pain. Patients may also present with jaundice,
scleral icterus, and elevated transaminases. Primary sources
of infection are close contact with an infected household
member or sex partner. In addition, outbreaks can occur in
the food industry when a food handler has the infection and
spreads the virus through raw or undercooked foods.
Vaccination has significantly reduced the burden of hep-
atitis A disease, with an annual incidence of 25,00035,000
cases before universal vaccination, decreasing to less than
2000 cases annually in recent years (CDC 2015a).
Recommended Administration Schedule
The HepA vaccine is universally recommended for all children
beginning at 12 months of age, followed by a second dose at
least 6 months later. Older children who have not yet been
vaccinated should follow the catch-up schedule to receive
adequate protection against the virus (CDC 2015a).
Vaccine-Specific Considerations
The HepA vaccine is preferred for postexposure prophylaxis
in healthy patients 140 years of age who have been exposed
to the virus in the previous 2 weeks. Immunocompromised
patients, those with preexisting liver disease, or those who
have contraindications to the vaccine must still use immune
globulin rather than vaccination for postexposure prophy-
laxis because of decreased response to the vaccine. Children
who have previously received immune globulin should
still receive the routine HepA vaccine as recommended
(CDC 2015a).
Hepatitis B
Overview of Infection Disease
Hepatitis B virus causes an inflammatory disease of the liver.
It is a double-stranded DNA virus in the Hepadnaviridae fam-
ily that is transmitted by blood or body fluids, most often
through sexual contact or sharing needles with infected
individuals. Some people clear hepatitis B virus after initial
infection, but some will develop a long-term, chronic infec-
tion. The frequency of developing a chronic infection declines
with age and occurs in about 90% of infants infected with
hepatitis B virus compared with 2%6% of adults. Chronic
hepatitis B can cause significant morbidity, including cirrho-
sis or hepatocellular carcinoma. The incidence of hepatitis B
PedSAP 2016 Book 1 Immunology
has declined since the vaccine was introduced. At its peak in
the 1980s, the annual number of reported cases in the United
States was greater than 25,000, compared with around 3000
cases in recent years. True incidence is estimated to be
10-fold higher than these reported numbers because many
people asymptomatically have the infection chronically
(CDC 2015a).
Recommended Administration Schedule
Vaccination with HepB is universally recommended for all
children as a three-dose series beginning at birth. Of note,
this is the only vaccine that is routinely recommended in neo-
nates. All doses administered before 6 weeks of age should
be the monovalent HepB rather than combination products
with any other vaccines. For catch-up vaccination in children
who did not receive the initial vaccination series, the adult
formulation with a higher amount of HepB antigen than the
pediatric vaccine may be used in children 11 years or older
(CDC 2015a).
Vaccine-Specific Considerations
For infants born to hepatitis B virus antigen-positive moth-
ers, hepatitis B immune globulin should also be administered
within 12 hours of birth plus the original required vaccine. In
these patients, postvaccination testing should be performed
12 months after the completion of at least three doses of
HepB to ensure immunity (CDC 2015a).
The HepB vaccine can also be used for postexposure pro-
phylaxis in children who have potentially been exposed to the
virus and lack documented immunity. The vaccine can be
given with or without immune globulin, depending on the hep-
atitis B status of the source and the vaccination status of the
patient (Mast 2006).
H. influenzae Type B
Overview of Infection Disease
H. influenzae is a gram-negative coccobacillus that com-
monly colonizes the respiratory tract and can cause invasive
infections including pneumonia, bacteremia, meningitis,
and epiglottitis, as well as relatively superficial infections
including otitis media and cellulitis. There are six strains of
H. influenzae with a polysaccharide capsule (types af), as
well as nonencapsulated (non-typeable) strains. Historically,
Hib has been associated with the most invasive infections
and the greatest morbidity and mortality. Invasive Hib is
associated with a mortality rate of 3%6%, and Hib menin-
gitis can cause long-term sequelae, including hearing loss
and neurologic deficits in up to 20% of survivors. Before the
introduction of the Hib vaccine, the annual incidence of Hib
disease was around 20,000 cases. The vaccine has dramat-
ically decreased the incidence by more than 99% since its
introduction in the late 1980s. Most H. influenzae infections in
the United States are now from non-typeable strains that are
not covered by the vaccine (CDC 2015a).
22 Routine Childhood Immunization Series
Recommended Administration Schedule
The Hib vaccine is universally recommended for all chil-
dren beginning at age 2 months, with catch-up vaccination
routinely recommended for unimmunized children up to
age 5 years. The number of total doses and schedule varies
depending on the specific vaccine formulation used. ActHIB,
MenHibrix, and Pentacel require a three-dose primary series
followed by a booster dose of any Hib-containing vaccine.
PedvaxHIB and COMVAX require a two-dose series followed
by a booster dose of any Hib-containing vaccine. The dif-
ferent number of doses required is because of the varying
levels of immunogenicity to the vaccines with different car-
rier proteins in their formulation (Kelly 2004). Select high-risk
children older than 5 years should also be given the Hib vac-
cine if they are not already immune, including patients with
asplenia or HIV (Briere 2014).
Vaccine-Specific Considerations
Although is it generally recommended to complete a vac-
cination series with the same vaccine formulation, if the
same formulation is not available for subsequent doses,
any other Hib-containing vaccine may be administered
and still be considered valid. An exception is the Hiberix
vaccine, which is only indicated for use as a booster dose
in children 12 months to 4 years of age who have already
received at least one prior dose of Hib-containing vaccine
(CDC 2015a).
Polio
Overview of Infection Disease
Polio is a potentially fatal infection that has historically
caused significant morbidity and mortality throughout the
world. Polio is an RNA enterovirus in the Picornaviridae fam-
ily that is spread by the fecal-oral route. Most infections
are asymptomatic or subclinical; however, in around 5% of
infections, manifestations such as fever, pharyngitis, gas-
troenteritis, and flu-like symptoms occur. In addition, in a
smaller percentage of patients (0.5%), polio can invade the
CNS, resulting in irreversible paralysis by damage to dorsal
root ganglia and motor and autonomic neurons of the spinal
cord and gray matter of the brain. The neuronal damage can
manifest as flaccid paralysis of the extremities, respiratory
failure, and neurogenic bladder (CDC 2015a).
Before the introduction of polio vaccine, the virus was
responsible for more than 15,000 cases of paralysis annu-
ally in the United States. Because of diligent vaccination
efforts, endogenous polio was eradicated from the United
States in 1979. Vaccination continues to be recommended
because of the existence of polio disease in other parts of
the world that can potentially be brought into the country
through travelers. The overall incidence of polio disease has
declined by more than 99% since the launch of global polio
eradication efforts in 1988 (CDC 2015a). Several hundred
cases still occur annually throughout the world, primarily
PedSAP 2016 Book 1 Immunology
concentrated in Pakistan and Afghanistan, with sporadic
cases still occurring in other parts of the Middle East and
Africa (Global Polio 2015).
Recommended Administration Schedule
The IPV is universally recommended as a four-dose series
beginning at age 2 months and as a catch-up vaccine for any-
one younger than 18 years who has not completed the series
(CDC 2015b). The IPV is the only polio vaccine product that
has been available in the United States since 2000. However,
the oral polio vaccine is used in areas of the world where
endemic polio is still circulating (CDC 2015a).
Vaccine-Specific Considerations
Of note, although IPV protects the recipient from developing
polio disease, if a child immunized with IPV travels to an area
of the world where polio is endemic and is exposed, the virus
may still be able to actively replicate in the intestinal tract
and be passed on to others. General precautions, including
good hand hygiene, should be taken on return from travel to
polio-endemic areas (CDC 2015a).
Rotavirus
Overview of Infection Disease
Rotavirus commonly causes intestinal disease in pediatric
patients, particularly infants and young children. Infection
with rotavirus manifests as severe watery diarrhea, often
with vomiting, fever, and abdominal pain. Complications
from rotavirus are primarily because of dehydration from
excessive diarrhea and vomiting. Rotavirus is spread by the
fecal-oral route and is most prevalent during the winter and
spring months (CDC 2015a).
Recommended Administration Schedule
The RV is universally recommended for all children beginning
at 2 months of age. If using RotaTeq, three doses are neces-
sary, whereas Rotarix requires only two doses. No preference
for one formulation or the other is given by ACIP, and both
are effective at preventing disease. It is acceptable to use a
different formulation on subsequent administrations, but if a
RotaTeq product is used for any of the doses, a total of three
doses of RV should be given. Of note, the RV series should not
be initiated after age 15 weeks. The maximal age for the final
dose of the series is 8 months, after which no further doses
should be given even if the series has not been completed
(Cortese 2009).
Vaccine-Specific Considerations
The RV is generally well tolerated, with GI upset being most
prevalent adverse effect. A rare but serious complication of
RV is intussusception. This complication occurred more com-
monly with a previous formulation of RV, RotaShield, which
was removed from the market in 1999. Current vaccines pose
a much lower risk (CDC 1999).
23 Routine Childhood Immunization Series
CONCLUSION
Infections with VPDs remain a significant cause of morbid-
ity and mortality in the United States and throughout the
world. Improvement in vaccine coverage will continue to
reduce the burden of, and in some cases eliminate, VPDs.
Pharmacists impact on routine pediatric immunizations
will continue to evolve as authorization to vaccinate chil-
dren expands across state laws and regulations. With this
increasing role comes the added responsibility of assessing
the appropriateness of vaccines according to recommended
CDC schedules and determining risks and benefits among all
vaccines regardless of patient complexity. In states that do
not permit them to vaccinate children, pharmacists should
still assess and refer all patients for appropriate vaccines.
Sustaining proper adherence to vaccine schedules is a con-
tinuous public health problem; pharmacists should educate
families about the importance of vaccination and be able to
address concerns and dispel misconceptions that may lead
to vaccine refusal.
Practice Points
Infectious diseases have been a source of great mor-
bidity and mortality throughout history. The introduction
of vaccines to prevent infections has proven to be one of
the greatest medical achievements to date. Pharmacists
should be familiar with the scientific, social, and politi-
cal issues related to vaccines and public health:
Vaccines induce protection from disease by provoking an
immune response by administration of microorganisms, or
fractions of microorganisms, into the body.
Vaccines can be classified in various ways, including live
versus inactivated versus toxoid and polysaccharide versus
protein conjugated. Each type differs in its consider-
ations regarding the mechanism of provoking an immune
response, number of doses required, duration of immunity,
and patient eligibility criteria.
Pharmacists play several important roles related to pedi-
atric immunization, including administering vaccines, as-
sessing vaccine eligibility, and providing patient education,
provider guidance, and legislative advocacy.
Recommended pediatric immunization schedules are pub-
lished annually by the CDC according to the best available
evidence regarding the efficacy and safety of available
vaccines.
Adherence to these recommended schedules is the best
way to reduce the burden of VPDs.
Pharmacists play a critical role in educating the public
about vaccinations and clarifying myths and misconcep-
tions that patients may have.
Pharmacists should be able to interpret immunization
schedules and recommend appropriate vaccines according
to patient-specific factors.
In addition to general considerations that pertain to all vac-
cines, each individual vaccine has specific considerations
related to efficacy, safety, formulation, immunization
timing, and technique.
PedSAP 2016 Book 1 Immunology
REFERENCES
American Academy of Pediatrics (AAP). Immunization.
[homepage on the Internet]. 2016.
American Pharmacists Association (APhA). Guidelines for
Pharmacy-Based Immunization Advocacy.
American Pharmacists Association (APhA); NASPA
Foundation. 2015. Pharmacist-Administered Vaccines:
Based upon APhA/NASPA Survey of State IZ Laws/Rules.
Briere EC, Rubin L, Moro PL, et al. CDC. Prevention and
control of Haemophilus influenzae type b disease: recom-
mendation of the Advisory Committee on Immunization
Practices (ACIP) recommendations and reports. MMWR
2014; 63:1-14.
Butler K, Lewis GP. The effect of anti-inflammatory com-
pound on the biochemical changes in the Arthus reaction.
J Pathol 1976; 119:175-82.
CDC. Birth-18 Years and Catch-up Immunization Schedules.
2016.
CDC. Parents Guide to Childhood Immunizations. 2015a.
CDC. Withdrawal of rotavirus vaccine recommendation.
MMWR 1999; 48:1007.
CDC. Recommended adult immunization schedule United
States, 2011. MMWR 2011a; 60:49-57.
CDC. Notes from the field: serogroup C invasive meningo-
coccal disease among men who have sex with men New
York City, 2010-2012. MMWR 2013a; 61:1048.
CDC. Updated recommendations for use of tetanus toxoid,
reduced diphtheria toxoid, and acellular pertussis vac-
cine (Tdap) in pregnant women Advisory Committee
on Immunization Practices (ACIP), 2012. MMWR 2013b;
62:131-5.
CDC. Updated recommendations for use of tetanus toxoid,
reduced diphtheria toxoid, and acellular pertussis vaccine
(Tdap) in pregnant women and persons who have or antic-
ipate having close contact with an infant aged <12 months
Advisory Committee on Immunization Practices (ACIP),
2011. MMWR 2011b; 60:1424-6.
CDC. CDC A-Z index.
CDC. Vaccines & Immunizations. 2016.
Chung JR, Flannery B, Thompson MG, et al. Seasonal effec-
tiveness of live attenuated and inactivated influenza
vaccine. Pediatrics 2016; 137:1-10.
Cohn AC, MacNeil JR, Clark TA, et al. Prevention and con-
trol of meningococcal disease: recommendations of the
Advisory Committee on Immunization Practices (ACIP).
MMWR 2013; 62:1-22.
Cortese MM, Parashar UD. Centers for Disease Control and
Prevention. Prevention of rotavirus gastroenteritis among
infants and children: recommendations of the ACIP.
MMWR 2009; 58:1-25.
24 Routine Childhood Immunization Series
Das RR, Panigrahi I, Naik SS. The effect of prophylactic
antipyretic administration on post-vaccination adverse
reactions and antibody response in children: a systematic
review. PLoS One 2014; 9:e10662.
Des Roches A, Paradis L, Gagnon R, et al. Egg-allergic
patients can be safely vaccinated against influenza.
J Allergy Clinical Immunol 2012; 130:1213-6.
Dobson SR, McNeil S, Dionne M, et al., Immunogenicity of 2
doses of HPV vaccine in younger adolescents vs 3 doses
in young women. JAMA 2013; 309:1793-802.
Eickhoff TC, Myers M. Workshop summary: aluminum in
vaccines. Vaccine 2002; 20:S1-4.
Faulkner A, Skoff T, Martin S, et al. Pertussis. MPH Manual
for the Surveillance of Vaccine-Preventable Diseases.
Atlanta: CDC, 2015:10.1-12.
Fernndez ME, Le YL, Fernndez-Espada N, et al. Knowledge,
attitudes, and beliefs about human papillomavirus (HPV)
vaccination among Puerto Rican mothers and daughters,
2010: a qualitative study. Prev Chronic Dis 2014; 11:1-8.
Fisher MC, Bocchini JA. Adhering to vaccine schedule is
best way to protect children from disease. AAP News
2009; 30:1-2.
Folaranmi T, Rubin L, Martin SW, et al. Use of Serogroup B
Meningococcal Vaccines in Persons Aged 10 Years at
Increased Risk for Serogroup B Meningococcal Disease:
Recommendations of the Advisory Committee on
Immunization Practices, 2015. MMWR 2015; 64:608-12.
Fortanier AC, Venekamp RP, Boonacker CWB, et al.
Pneumococcal conjugate vaccines for preventing otitis
media. Cochrane Database Syst Rev 2014; 4:CD001480.
Gangarosa EJ, Galazka AM, Wolfe CR, et al. Impact of
anti-vaccine movements on pertussis control: the untold
story. Lancet 1998; 351:356-61.
Gellin BG, Maiback EW, Marcuse EK. Do parents understand
immunizations? A national telephone survey. Pediatrics
2000; 106:1097-102.
Global Polio Eradication Initiative. Data and Monitoring:
Polio This Week.
Grijalva CG, Zhu Y, Williams DJ, et al. Association between
hospitalization with community-acquired laboratory-con-
firmed influenza pneumonia and prior receipt of influenza
vaccination. JAMA 2015; 314:1488-97.
Grohskopf LA, Sokolow LZ, Olsen SJ, et al. Prevention and
control of influenza with vaccines: recommendations
of the Advisory Committee on Immunization Practices,
United States, 201516 influenza season. MMWR 2015;
64:818-25.
Guide to Community Preventive Services. Increasing appro-
priate vaccination. 2016.
Hamborsky J, Kroger A, Wolfe C, eds. Epidemiology and
Prevention of Vaccine-Preventable Diseases. The Pink Book,
13th ed. Washington, DC: Public Health Foundation, 2015.
PedSAP 2016 Book 1 Immunology
Healthychildren.org. Vaccine Studies: Examine the Evidence.
Healy CM, Pickering LK. How to communicate with vaccine-
hesitant parents. Pediatrics 2011; 127:S127133.
Hill HA, Elam-Evans LD, Yankey D, et al. National, state, and
selected Local area vaccination coverage among children
aged 1935 months United States, 2014. MMWR 2015;
63:889-96.
Immunization Action Coalition (IAC). MMR Vaccine Does Not
Cause Autism: Examine the evidence! 2013.
Immunization Action Coalition (IAC). Ask the Experts:
Topics. 2016.
Jefferson T, Di Pietrantonj C, Rivetti A, et al. Vaccines for pre-
venting influenza in healthy adults. Cochrane Database
Syst Rev 2014; 3:CD001269.
Jena AB, Goldman DP, Seabury SA. Incidence of sexually
transmitted infections after human papillomavirus
vaccination among adolescent females. JAMA Intern Med
2015;175:617-23.
Kelly DF, Moxon ER, Pollard AJ. Haemophilus influenzae type
b conjugate vaccines. Immunology 2004;113:163-74.
Kriemer AR, Struyf F, Del Rosario-Raymundo MR, et al.
Efficacy of fewer than three doses of an HPV-16/18 AS04-
adjuvanted vaccine: combined analysis of data from the
Costa Rica Vaccine and PATRICIA trials. Lancet Oncol
2015; 16:776-86.
Kroger AT, Sumaya CV, Pickering LK, et al. Centers for
Disease Control and Prevention. General recommenda-
tions on immunization: recommendations of the Advisory
Committee on Immunization Practices (ACIP). MMWR
2011; 60:1-61.
Liddon NC, Leichliter JS, Markowitz LE. Human papilloma-
virus vaccine and sexual behavior among adolescent and
young women. Am Journal Prev Med 2012; 42:44-52.
Markowitz LE, Dunne EF, Saraiya M, et al. Centers for
Disease Control and Prevention. Human papillomavirus
vaccination: recommendations of the Advisory Committee
on Immunization Practices (ACIP). MMWR 2014; 63:1-30.
Mast EE, Margolis HS, Fiore AE, et al. A comprehensive
immunization strategy to eliminate transmission of
hepatitis B virus infection in the United States: recom-
mendations of the Advisory Committee on Immunization
Practices (ACIP) part 1: immunization of infants, children,
and adolescents. MMWR 2006; 55:30-3.
McLean HQ, Fiebelkorn AP, Temte JL, Centers for Disease
Control and Prevention, et al. Prevention of measles,
rubella, congenital rubella syndrome, and mumps, 2013
summary: recommendations of the ACIP. MMWR 2013;
62:1-34.
Minnesota Department of Health (MDH). Meningococcal
Meningitis: 2015
Neuzil KM, Jackson LA, Nelson J, et al. Immunogenicity and
reactogenicity of 1 versus 2 doses of trivalent inactivated
25 Routine Childhood Immunization Series
 influenza vaccine in vaccine-nave 5-8 year old children.
J Infect Dis 2006; 194:1302-9.
Ng M, How C. Childhood immunisation. Singapore Med J
2014; 55:12-7.
NIH. Immunogenicity and safety of FluBlok trivalent recom-
binant hemagglutinin influenza vaccine in healthy
pediatrics. ClinicalTrials.gov Bethesda, MD: National
Library of Medicine (US), 2000a.
NIH. Safety, reactogenicity and immunogenicity of Flublok
quadrivalent (recombinant influenza vaccine, seasonal
formulation). (NCT01959945). ClinicalTrials.gov, Bethesda,
MD: National Library of Medicine (US), 2000b.
Offit PA, Moser CA. The problem with Dr Bobs alternative
vaccine schedule. Pediatrics 2009; 123:e164-9.
Shatz DV, Schinsky MF, Pais LB, et al. Immune responses of
splenectomized trauma patients to the 23-valent pneumo-
coccal polysaccharide vaccine at 1 versus 7 versus
14 days after splenectomy. J Trauma 1998; 44:760-5.
Soeters HM, McNamara LA, Whaley M, et al. Serogroup B
meningococcal disease outbreak and carriage evaluation
at a college Rhode Island, 2015. MMWR 2015; 64:606-7.
Sullivan JE, Farrar HC. Section on Clinical Pharmacology and
Therapeutics; Committee on Drugs. Fever and Antipyretic
Use in Children. Pediatrics 2011; 127:580-7.
World Health Organization. Diphtheria Reported Cases. 2015.
World Health Organization. Human papillomavirus vaccines:
WHO position paper, October 2014. Wkly Epidemiol Rec
2014; 43:465-92.

Offit PA, Quarles J, Gerber MA, et al. Addressing parents Zipprich J, Winter K, Hacker J, et al. Measles outbreak
concerns: do multiple vaccines overwhelm or weaken the California, December 2014-February 2015. MMWR 2015;
infants immune system? Pediatrics 2002;109:124-9. 64:153-4.
Petrosky E, Bocchini JA, Hariri S, et al. Use of 9-valent
human papillomavirus (HPV) vaccine: updated HPV vac-
cination recommendations of the Advisory Committee on
Immunization Practices. MMWR 2015; 64:300-4.

Reagan-Steiner S, Yankey D, Jeyarajah J, et al. National,

regional, state, and selected local area vaccination cover-
age among adolescents aged 1317 years United States,
2014. MMWR 2015; 64:784-92.

Retraction ileal-lymphoid nodular hyperplasia, non-

specific colitis, and pervasive developmental disorder in
children. Lancet 2010; 375:445.

Roberts W, Harford M. Immunization and children at risk for

autism. Paediatr Child Health 2002; 7:623-32.

Robinson CL. Advisory Committee on Immunization

Practices recommended immunization schedules for
persons aged 0 through 18 years United States, 2016.
MMWR 2016; 65:86-7.

Rosenblatt AE, Stein SL. Cutaneous reactions to vaccina-

tions. Clin Dermatol 2015; 33:327-32.

Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical

practice guideline for vaccination of the immunocompro-
mised host. Clin Infect Dis 2014; 58:309-18.

Ruderfer D, Krilov LR. Vaccine-preventable outbreaks: still

with use after all these years. Pediatr Ann 2015; 44:e76-81.

Satterwhite CL, Torrone E, Meites E, et al. Sexually trans-

mitted infections among US women and men: prevalence
and incidence estimates; 2008. Sex Transm Dis 2013;
40:187-93.

Schmitt BD; for Seattle Childrens Hospital Research

Foundation. Should Your Child See a Doctor: Immunization
Reactions. 2015.

Seither R, Masalovich S, Knighton CL, et al. Vaccination cov-

erage among children in kindergarten United States,
2013-14 school year. MMWR 2014; 63:913-20.

PedSAP 2016 Book 1 Immunology 26 Routine Childhood Immunization Series

Self-Assessment Questions
1. A 12-year-old boy with no significant medical history
comes to your clinic for a routine checkup. After review-
ing his medical chart and immunization history, you
recommend that he be given tetanus, diphtheria, and
acellular pertussis vaccine (Tdap), human papillomavi-
rus 9 vaccine (HPV9), and meningococcal quadrivalent
vaccine (MenACWY-D) today. His mother states that he
needs the Tdap and MenACWY-D vaccines but not the
HPV9 vaccine because he is not yet sexually active.
Which one of the following is the best response to give
this patients mother?
A. Recommend vaccination with HPV2 today and
recommend returning for HPV9 when he is sexually
active.
B. Emphasize the importance of giving MenACWY-D
at the same time as the HPV vaccine for optimal
efficacy.
C. Recommend that the HPV9 vaccine be given today
because of the importance of developing immunity
to HPV early.
D. Emphasize that all recommended vaccines should
be given today because that is what the vaccine
schedule recommends.
Questions 2 and 3 pertain to the following case.
M.M. is 10-year-old boy who is up to date on all of his routine
childhood vaccinations, including pneumococcal conju-
gate vaccine 7 (PCV7). He is brought to the ED after being in
a motor vehicle crash. The physician determines that there
is internal organ damage and decides M.M. needs an emer-
gency splenectomy.
2. Which one of the following vaccines and timing of vacci-
nation is best to recommend for M.M.?
A. Meningococcal, pneumococcal, and Haemophilus
influenzae type B (Hib) as soon as possible
B. Meningococcal and pneumococcal as soon as
possible
C. Meningococcal, pneumococcal, and Hib at least
14 days after surgery
D. Meningococcal and pneumococcal at least 14 days
after surgery
3. Which one of the following is best to recommend for
pneumococcal vaccination administration in M.M.?
A. PCV13 only
B. PCV13 first, followed by PPSV23 8 weeks later
C. PPSV13 first, followed by PCV23 12 weeks later
D. PPSV23 only
PedSAP 2016 Book 1 Immunology
4. A 4-year-old girl (weight 15 kg) with asthma presents to
your clinic for a checkup. She is on day 4 of her second
5-day course of prednisolone solution (30 mg/day) for an
asthma exacerbation. The pediatrician plans to admin-
ister the vaccines recommended for 4-year-olds but has
concerns about possible contraindications to live vac-
cines, including the measles, mumps, and rubella (MMR)
and varicella vaccines. Which one of the following is best
to recommend for this patient?
A. Wait 1 month after completion of prednisone, then
administer MMR and V vaccines separately.
B. Wait 1 month after completion of prednisone, then
administer MMRV combination vaccine.
C. Administer MMR and varicella vaccines separately
today.
D. Administer MMRV combination vaccine today.
Questions 5 and 6 pertain to the following case.
J.K. is a 34-year-old woman who is 30 weeks pregnant with
her second child. She has gestational diabetes but no other
significant medical history. Her husband, R.K., and 3-year-old
son, A.L., accompany her to her clinic visit in October. R.K. is
a 37-year-old man with a medical history of hypertension and
hypercholesterolemia. A.L. is up to date with his vaccinations
and has a history of egg allergy, but he can eat scrambled
eggs. J.K. and R.K currently live alone with their son, but R.K.s
mother (G.M.) will be moving in with them to help care for the
child when it is born. G.M is a 74-year-old woman with osteo-
arthritis, hypertension, heart failure, and chronic obstructive
pulmonary disease.
5. The most recent tetanus-containing vaccine received
by each of the family members is as follows: J.K. Tdap
9 years ago and 3 years ago; R.K. tetanus and diphtheria
(Td) 4 years ago; G.M. Td 10 years ago; and A.L. diphthe-
ria, tetanus, and pertussis (DTaP) 2 years ago. Which one
of the following is best to recommend regarding who in
this family should receive Tdap at this time?
A. J.K., R.K., and G.M.
B. J.K. and G.M.
C. R.K. and G.M.
D. G.M. only.
6. Which one of the following is the most appropriate influ-
enza vaccine for A.L. today, assuming all are readily
available in the clinic?
A. Inactivated influenza vaccine trivalent (IIV3)
B. Inactivated influenza vaccine quadrivalent (IIV4)
C. Live attenuated influenza vaccine (LAIV4)
D. Recombinant influenza vaccine trivalent (RIV3)
27 Routine Childhood Immunization Series
7. For which one of the following patients would it be best
to withhold varicella vaccine?
A. A 2-year-old girl with asthma who received the MMR
vaccine 14 days ago
B. A 4-year-old girl currently receiving amoxicillin/
clavulanate for otitis media
C. A 6-year-old boy with chronic kidney disease and a
glomerular filtration rate of 30 mL/minute/1.73 m2
D. A 12-year-old boy with HIV and a CD4+ count of 600
cells/mL (25%)
8. For community pharmacists in states that do not permit
pharmacists to vaccinate pediatric patients, which one
of the following strategies would have the most imme-
diate effect on increasing vaccination coverage among
their patients?
A. Organize a petition to lobby the state legislature to
expand the age group of patients that pharmacists
are allowed to vaccinate.
B. Evaluate each childs profile to evaluate which
vaccines should be administered and communicate
this information to the parent and pediatrician.
C. Place informational brochures about vaccine-
preventable illnesses in every prescription bag that
is dispensed from the pharmacy.
D. Play informational videos in the waiting area of
the pharmacy with guidance on recommended
immunization schedules.
9. An 18-month-old girl is brought to the clinic by her mother
for a routine checkup in late September. You determine
that the child is due for vaccination with hepatitis B vac-
cine (HepB), DTaP, inactivated polio vaccine (IPV), IIV,
and hepatitis A vaccine (HepA). Which one of the follow-
ing is best to administer to this patient today?
A. Pediarix (DTaP-IPV-HepB), IIV, and HepA vaccines
B. Kinrix (DTaP-IPV), IIV, and Twinrix (HepA-HepB)
vaccines
C. Pediarix (DTaP-IPV-HepB) and HepA vaccines;
advise the mother to return after November 1 for IIV
D. DTaP, IPV, HepB, IIV, and HepA vaccines
10. An outbreak of hepatitis A is reported in a local pizza
shop related to a cook who was infected with the virus.
A 7-year-old boy attended a birthday party and ate
lunch at the restaurant 5 days ago. He is brought in by
his mother, who requests postexposure prophylaxis.
The boy has never received the HepA vaccine. Which
one of the following recommendations is best for this
patient?
A. Do not give postexposure prophylaxis.
B. Give immunoglobulin for hepatitis A and HepA
vaccine.
PedSAP 2016 Book 1 Immunology
C. Give immunoglobulin for hepatitis A only.
D. Give HepA vaccine only.
Questions 11 and 12 pertain to the following case.
B.B. is in the clinic for his 4-month-old checkup. The boys
medical history includes prematurity (born at 28 weeks) and
a complex neonatal ICU (NICU) stay. Currently, B.B. is sta-
ble and has diagnoses of bronchopulmonary dysplasia (BPD)
(on budesonide), gastroesophageal reflux disease (on lanso-
prazole), and developmental delay. B.B. received HepB at
birth, but his mother refused 2-month vaccines during the
NICU stay. The mother again refuses vaccines at this visit
because she is concerned that receiving all the vaccines at
once will overwhelm B.B.s immune system and he will end
up in the hospital.
11. Which one of the following approaches would best
ensure B.B. receives all the recommended vaccines?
A. Provide his mother with educational materials and
honor her vaccine refusal.
B. Recommend an alternative vaccine schedule so that
he can receive vaccines over an extended period
rather than all at once.
C. Administer DTaP and PCV13 because he is less likely
to be protected from these diseases through herd
immunity.
D. Educate the mother about her misconceptions and
reinforce that it is safe and effective to give all the
recommended vaccines at this visit.
12. If B.B.s mother agrees to receive all vaccines today and
future vaccines on schedule, which one of the following
would be the best recommendation for when B.B. should
return for catch-up vaccines and which vaccines should
be given?
A. 8 weeks to receive DTaP, IPV, Hib, HepB, rotavirus
vaccine (RV), and Prevnar
B. 4 weeks to receive DTaP, IPV, Hib, RV, and Prevnar
and 8 weeks to receive HepB
C. 4 weeks to receive DTaP, IPV, Hib, HepB, and Prevnar
D. 4 weeks to receive DTaP, IPV, Hib, and Prevnar and
8 weeks to receive HepB
13. An infant girl was born at 24 weeks gestation; she is
now aged 7 weeks and 5 days and is stable in the NICU.
Her current diagnoses include BPD. She receives budes-
onide, chlorothiazide, and potassium chloride. Which
one of the following is best to recommend regarding this
patients vaccines?
A. Hold all vaccines until she is corrected to full term.
B. Hold all vaccines until she is 2 months old.
C. Give DTaP, IPV, Hib, HepB, RV, and Prevnar.
D. Give DTaP, IPV, Hib, HepB, and Prevnar.
28 Routine Childhood Immunization Series
14. A 48-month-old boy with a history of febrile seizures is PCV13 2 months, 4 months, 6 months, 15 months
to receive DTaP-IPV, MMR, and varicella today. Which IPV 2 months, 4 months, 15 months
one of the following is best to recommend for this MMRV 15 months
patient? HepA 15 months, 24 months

A. Give prophylactic acetaminophen, and give MMRV Which one of the following vaccines is best to recom-
combination. mend for this patient to receive today?
B. Give prophylactic acetaminophen, and give MMR
A. DTaP, IPV, MMRV, PPSV23
and varicella as separate vaccinations.
B. DTaP, IPV, MMRV
C. Do not give prophylactic acetaminophen, and give
C. DTaP, IPV, PPSV23
MMRV combination.
D. DTaP, IPV
D. Do not give prophylactic acetaminophen, and give
MMR and varicella as separate vaccinations. 17. You wish to advocate for expansion of pharmacist autho-
rization to administer vaccines in pediatric patients. In
15. A 15-month-old girl received the MMRV vaccine 10 days which one of the following age ranges would pharma-
ago. Two days ago, she developed a rash on her trunk cists be most likely to demonstrate the greatest effect
that consists of five or six vesicular lesions. Her mother on vaccination adherence rates?
calls the clinic and asks if she should be concerned
A. 018 months
about infection and if they should take any precautions.
B. 1935 months
Which one of the following is the best response to this
C. 46 years
inquiry?
D. 1317 years
A. MMRV cannot cause infection, so the rash is likely
18. A 4-year-old girl (DOB August 3, 2011) is about to start
an allergy. Give your daughter diphenhydramine,
kindergarten. Her parents come to the office on Septem-
apply 1% hydrocortisone cream, and the infection
ber 8, 2015, because the school called to say that the
should improve.
girls cant attend until she receives her 4-year-old vac-
B. The rash is likely a low-level infection caused by the
cines. The mother is irate and states that the girl already
weakened measles virus in the vaccine. No cases of
received them. The state law does not count vaccines
disease transmission from a rash like this have been
valid if they are administered any earlier than the recom-
reported, so no extra precautions are needed.
mended minimum age or interval by the CDC schedule. A
C. The rash is likely a low-level infection caused by the
review of the patients record shows the following:
weakened varicella virus in the vaccine. No cases of
disease transmission from a rash like this have been
10/4/11 Pediarix, Comvax, Prevnar, RV
reported, so no extra precautions are needed.
12/8/11 Pediarix, Comvax, Prevnar, RV
D. It is impossible to distinguish a non-contagious 2/6/12 Pediarix, Prevnar, RV
vaccine-induced rash from a true varicella infection. 8/20/12 Prevnar, HepA, MMR, varicella
Keep her isolated from susceptible individuals until 12/5/12 Hib, DTaP
the vesicular lesions crust over. 8/8/13 HepA
8/1/15 Varicella, Kinrix
16. A 4-year-old boy is in your clinic in late July for a rou-
8/28/15 MMR
tine checkup. His medical history is significant for
asthma, which is controlled with montelukast and Which one of the following would best resolve this issue?
as-needed albuterol. He received rabies immune glob-
A. Tell the parents that you will call the school and
ulin and vaccine in early May after being exposed to a
inform them the vaccines she received are still
raccoon at the family cabin in the woods. His mother
efficacious and she can return to school.
asks which vaccines he should receive today to pre-
B. Apologize to the parents and administer the Kinrix
pare him for attending prekindergarten this fall. She
today, and follow school policy for filling out a
states that he has kept on schedule with all of his rou-
temporary medical exemption for MMR.
tine vaccinations to date. His vaccine history shows
C. Apologize to the parents and administer the Kinrix
the following:
today, and follow school policy for filling out a
temporary medical exemption for Varicella.
HepB 0 months, 2 months, 6 months
RV 2 months, 4 months D. Apologize to the parents and administer the
DTaP 2 months, 4 months, 6 months, 15 months Kinrix today, and follow school policy for filling
Hib 2 months, 4 months, 6 months, 15 months out a temporary medical exemption for MMR and
varicella.

PedSAP 2016 Book 1 Immunology 29 Routine Childhood Immunization Series

19. A 13-year-old boy who has no significant medical his-
tory and is not sexually active is in the clinic for an initial
checkup. On questioning, the parents report that the
child is up to date and was vaccinated by the previous
pediatrician, but the office permanently closed, and the
vaccination record is unavailable. The parents do not
want to repeat vaccines and only consent to six vaccines
being given at one time. Which one of the following vac-
cines would be best to administer to this patient today?
A. Give Tdap, HPV, Menactra, HepB, MMR, and varicella.
B. Give Tdap, Menactra, HepB, HepA, IPV, and MMR.
C. Give Tdap, IPV, Menactra, HPV, Twinrix, and MMRV.
D. Give no vaccines and rely on the parents history
that he is up to date.
20. A 12-month-old boy is brought to the pharmacy by his
parents. Eight hours earlier, the boy received his routine
vaccines (Prevnar, HepA, MMR, and varicella). Now, his
parents report that the childs temperature is 101F and
that he is sleeping more than usual. The parents also
state that they think his arms hurt, because he whines
when they touch his arms. Which one of the following is
the best action to take for this patient?
A. Report these adverse effects to VAERS and send the
child to his physician for workup.
B. Report these adverse effects to VAERS and
recommend ibuprofen or acetaminophen.
C. Do not report to VAERS and recommend ibuprofen
or acetaminophen.
D. Do not report to VAERS and send the child to his
physician for further workup.

PedSAP 2016 Book 1 Immunology 30 Routine Childhood Immunization Series

Learner Chapter Evaluation: Routine Childhood Immunizations.
As you take the posttest for this chapter, also evaluate the
materials quality and usefulness, as well as the achievement
of learning objectives. Rate each item using this 5-point scale:
Strongly agree
Agree
Neutral
Disagree
Strongly disagree
1. The content of the chapter met my educational needs.
2. The content of the chapter satisfied my expectations.
3. The author presented the chapter content effectively.
4. The content of the chapter was relevant to my practice
and presented at the appropriate depth and scope.
5. The content of the chapter was objective and balanced.
6. The content of the chapter is free of bias, promotion, or
advertisement of commercial products.
7. The content of the chapter was useful to me.
8. The teaching and learning methods used in the chapter
were effective.
9. The active learning methods used in the chapter were
effective.
10. The learning assessment activities used in the chapter
were effective.
11. The chapter was effective overall.
PedSAP 2016 Book 1 Immunology
Use the 5-point scale to indicate whether this chapter pre-
pared you to accomplish the following learning objectives:
12. Distinguish the considerations for administering live ver-
sus inactivated vaccines.
13. Assess the role of a pharmacist in promoting the vacci-
nation of pediatric patients to reduce the global burden
of vaccine-preventable infections.
14. Evaluate the current evidence to educate patients and
caregivers about vaccination considerations, including
safety, efficacy, and common misconceptions.
15. Justify the role of combination vaccines for the pediatric
population.
16. Given a pediatric case, develop a vaccine administration
plan using current vaccination recommendations.
17. Distinguish the similarities and differences in childhood
vaccine availability, administration, efficacy in disease
prevention, adverse effects, contraindications, and
warnings.
18. Please provide any specific comments related to any
perceptions of bias, promotion, or advertisement of
commercial products.
19. Please expand on any of your above responses, and/or
provide any additional comments regarding this chapter:
31 Routine Childhood Immunization Series
Vaccine Development and
Future Targets
By April Yarbrough, Pharm.D., BCPS; and Scott James, M.D.

Reviewed by Jessica Cottreau, Pharm.D., BCPS; and Ashli Rasmussen, Pharm.D., BCPS

LEARNING OBJECTIVES

1. Design an effective strategy for developing a new vaccine.

2. Develop an appropriate strategy to determine which of the newer vaccines can be considered for frontline health care
employees and/or patients.
3. Evaluate current evidence to determine the appropriateness of maternal vaccinations.
4. Devise a guideline for alternative vaccine administration to pediatric and adult patients.

ABBREVIATIONS IN THIS CHAPTER
CMV Cytomegalovirus
EBOV Ebola virus
GBS Group B streptococcus
HSV Herpes simplex virus
RSV Respiratory syncytial virus
Table of other common abbreviations.
INTRODUCTION
The story of vaccines to prevent infectious diseases in humans pre-
dates Edward Jenners use of material from cowpox pustules to
provide protection against smallpox; evidence suggests that the
Chinese used the first smallpox inoculation as early as 1000 CE
(Common Era). Successful vaccines for diseases such as smallpox
and rabies were developed and used in patients starting in 1796 and
1885, respectively. During the next 150 years, vaccine development
changed not just to target endemic or pandemic infections but also
to provide research focused on innovative technologies and tech-
niques to combat childhood diseases such as polio and measles.
Today, vaccine development is looking to remedy noninfectious ill-
nesses such as allergies and cancer.

IMPORTANCE OF VACCINE
DEVELOPMENT
Almost 300 vaccines are reported to be in current development.
According to the CDC, 10 infectious diseases have been at least 90%
eradicated in the United States as the result of vaccines. These pub-
lic health triumphs show the contributions that vaccines have made
in protecting millions of children and families from vaccine-pre-
ventable illnesses. In 2013, biopharmaceutical research companies
reported 271 vaccines in development for a variety of illness includ-
ing infectious diseases, cancer, neurologic disorders, allergies, and
type 1 diabetes (PhRMA 2013). Vaccine development is a complex
process that includes input from researchers, manufacturers, reg-
ulators, the public health community, and potential purchasers.
Because vaccine development is time- and resource-intensive,

PedSAP 2016 Book 1 Immunology 33 Vaccine Development and Future Targets

establishing and understanding the priorities for develop-
ing and fostering partnerships and collaboration among all
stakeholders is essential to address the challenges of devel-
oping new and improved vaccines (NVAC 2015).
Development of human vaccines remains challenging
because pathogens have highly sophisticated mechanisms
BASELINE KNOWLEDGE STATEMENTS
Readers of this chapter are presumed to be familiar
with the following:
Baseline knowledge of currently available vaccines
and routine schedules
Understanding of the drug development process
as it pertains to preclinical discovery and phase
transitioning
NIH Department of Health and Human Services;
Basic Policies for Protection of Human Research
Subjects, specifically Subpart B Protections for
Pregnant Women, Human Fetuses and Neonates
Involved in Research
The most common congenital/perinatally trans-
mitted infections in pregnancy and the standard of
care for diagnosis and treatment
Risk factors for acquisition of RSV in healthy
neonates/infants
Risks associated with current vaccine therapies
Current vaccine administration techniques
Knowledge of common pediatric infections (CMV,
HSV, influenza, RSV, malaria, TB)
ADDITIONAL READINGS
The following free resources have additional back-
ground information on this topic:
The National Academies Press. Public Health and
Prevention [homepage on the Internet].
CDC. Vaccines and Preventable Diseases [home-
page on the Internet].
Gilbert GL. Infections in pregnant women. Med J
Aust 2002;176:229-36.
U.S. Department of Health and Human Resources.
Protection of Human Research Subjects [home-
page on the Internet].
American Academy of Pediatrics. Chapters:
Immunization in Special Clinical Circumstances;
Cytomegalovirus Infection; Herpes Simplex;
Influenza; Respiratory Syncytial Virus; Malaria;
Group B Streptococcal Infections; Tuberculosis.
Red Book: 2015 Report of the Committee on
Infectious Diseases.
Table of common pediatric laboratory reference values.
PedSAP 2016 Book 1 Immunology
to evade the hosts immune system. A vaccines success is
based on its ability to induce antibodies that block or neutral-
ize an infectious agent or its products. Antibody-mediated
protection is not sufficient in all infectious diseases. The pri-
mary killers of today, for which there are not yet vaccines,
are restrained to some extent not only by antibodies but also
by cell-mediated immunity. These infections include HIV,
respiratory syncytial virus (RSV), and malaria, which are dis-
cussed later. Several candidates are entering clinical trials
for infectious diseases as the result of evidence for protec-
tive efficacy in a human challenge model. The ultimate goal
of a vaccine is to develop long-lived immunologic protection,
in which the first encounter with a pathogen is remem-
bered, leading to enhanced memory responses that either
completely prevent reinfection or greatly reduce the severity
of disease (Kaech 2002).
Controversies in Vaccine Advances
All stages of vaccine research and development carry chal-
lenges. These include shortening the time of discovery of
vaccine candidates, producing and clinically developing vac-
cines, and ensuring that vaccines generate an appropriate
immune response (generation of neutralizing antibodies)
that is of adequate strength to provide effective protection
(Kaufmann 2014). As with all drug, vaccines in development
must go through many years of clinical testing. However,
advances in scientific fields such as genomics and manu-
facturing technologies are becoming increasingly useful in
vaccine development.
Maternal immunization has emerged in the past decade
as a promising public health strategy to prevent and
combat maternal, fetal, and neonatal infections. Several
recommended maternal vaccines are already available;
however, lack of widespread acceptance by all involved
stakeholders (medical providers and mothers) has limited
massive vaccination initiatives like those with childhood
immunizations.
SMART Vaccine Tool
A priority of the 2010 National Vaccine Plan (DHHS 2014a,
2014b) was to develop a catalogue of priority vaccine tar-
gets of domestic and global health importance to aid
decision-makers and stakeholders in prioritizing the develop-
ment of vaccines and targets. With this in mind, the Institute
of Medicine, with support of the National Vaccine Program
Office, developed a new vaccine decision-support tool called
the Strategic Multi-Attribute Ranking Tool for Vaccines,
or SMART tool. The tool, which is moving through several
phases of development (currently at phase 3), ranks vaccines
according to many attributes (Table 2-1). As described by its
developers, the SMART tool is intended to help with decision
support, not to be the decision-maker.
34 Vaccine Development and Future Targets
 Table 2-1. Choices of Attributes in SMART Vaccines 1.1

Health considerations Premature deaths averted per year

Economic considerations
Demographic considerations
Public concerns
Scientific and business
considerations
Programmatic considerations
Intangible values
Policy considerations
User-defined attributes
Incident cases prevented per year
QALYs gained or DALYs averted
Net direct costs (savings) of vaccine use per year
Workforce productivity gained per year
One-time costs
Cost-effectiveness ($/QALY or $/DALY)
Benefits infants and children
Benefits women
Benefits socioeconomically disadvantaged
Benefits military personnel
Benefits other priority population
Availability of alternative public health measures
Potential complications caused by vaccines
Disease raises fear and stigma in the public
Serious pandemic potential
Likelihood of financial profitability for the manufacturer
Demonstrates new production platforms
Existing or adaptable manufacturing techniques
Potential litigation barriers beyond usual
Interests from NGOs and philanthropic organizations
Potential to improve delivery methods
Fits into existing immunization schedules
Reduces challenges relating to cold-chain requirements
Eradication or elimination of the disease
Vaccine raises public health awareness
Interest for national security, preparedness, and response
Advances nations foreign policy goals
Up to seven attributes

DALYs = disability-adjusted life-years; NGOs = nongovernmental organizations; QALYs = quality-adjusted life-years.

Information from: Institute of Medicine and National Research Council. Ranking Vaccines: Applications of a Prioritization Software
Tool: Phase III: Use Case Studies and Data Framework. Washington, DC: National Academies Press, 2015.

NOVEL VACCINES IN DEVELOPMENT
Researchers are using promising new scientific approaches
to build on the successful history of vaccination against
infectious diseases. Recent developments have focused on
minimizing risks in prominent outbreaks (e.g., Ebola virus
[EBOV]) and highlighted the need for accelerated develop-
ment and testing of vaccines for communicable diseases.
Malaria Vaccine
The burden of malaria has declined in many endemic settings
in Africa and elsewhere (WHO 2015b). Some areas consider
the local elimination of malaria achievable with current con-
trol approaches, but this is thought to be effective only where
transmission intensity is low and reintroduction is unlikely.
In more endemic areas, the WHO reports that one child dies
every 30 seconds from malaria. Economic disadvantaged
individuals are most afflicted, resulting in further deterio-
ration of economic status. Currently, a staggering statistic
reported by the WHO is that one-half of the worlds popula-
tion is at risk of malaria infection, with infants and pregnant
women being most vulnerable to severe morbidity and mortal-
ity (Lorenz 2014). In 2008, the WHO reported that the malaria
burden constituted almost 250 million cases of disease and
almost 1 million deaths.
There is currently no available vaccine for malaria. Further
complicating this epidemic, the parasite that causes malaria
has developed advanced drug resistance to the most read-
ily available treatments. During the past decade, several

PedSAP 2016 Book 1 Immunology 35 Vaccine Development and Future Targets

antimalarials have been subsequently removed from the mar-
ket after they were deemed completely ineffective because
of widespread drug resistance. Currently, Cambodia and
Thailand have the highest cases of drug resistance to malaria
(WHO 2015b).
Malaria is usually caused when Plasmodium falciparum is
transmitted by the Anopheles mosquito. The Plasmodium par-
asite has a complex life cycle, forming sporozoites that the
mosquito inoculates into its host. Once sporozoites enter the
host, a replication cycle begins within 214 days. Sporozoites
enter the plasma and red blood cells, undergo morphologic
changes, and release malarial toxin and a variety of antigens,
causing increasing symptoms and later sequelae (Chia 2014).
The life cycle of P. falciparum in humans consists of the pre-
erythrocytic, asexual, and gametocyte stages. Each stage
can be characterized by the expression of stage-specific
proteins that are targets of host immune responses. The var-
ious stages of the life cycle are the current target for vaccine
development (Arama 2014).
The purpose of vaccination strategies is to induce protec-
tive memory immune responses that will provide protection
if the disease-causing agent (sporozoites) are encountered
(Arama 2014). Protective immunity against malaria requires
a timely and coordinated interplay between innate and adap-
tive immunity and further involves dendritic cells, NK cells,
B cells, and CD4+ and CD8+ T cells (Chia 2014). The parasites life
cycle inside the host enables it to evade the normal protective
immune responses. Research on the genome of Plasmodium
shows that the parasite is composed of about 5400 differ-
ent protein-encoding genes, some expressed at only specific
stages in the life cycle. Most current vaccine development
efforts are focused on only four antigens (WHO 2015b).
The ideal malaria vaccine requires three essential fea-
tures: (1) components that will induce an effective immune
response to the different stages of the malaria infection
(sporozoites and reproduction); (2) components that will over-
come the parasites complex antigenic variation and genetic
variation; and (3) induction of more than one type of immune
response in the host, including cell-mediated and humoral
components. Such a multi-compartmental vaccine would
likely increase the probability of a sustainable and effective
host immune response (Beeson 2014; Chia 2014).
Despite decades of effort to develop vaccines against
malaria, no strong candidate has yet emerged. Vaccines for
other types of infection have a high rate of efficacy (90% or
greater) (Lorenz 2014); many experts agree that a potential
malaria vaccine is unlikely to meet these high standards.
Three types of vaccine candidates target different stages
in the life cycle of the parasite: (1) transmission-block-
ing vaccines, helpful in preventing the spread of disease;
(2) preerythrocytic vaccines, aimed at preventing disease
progression in the infected host; and (3) blood-stage vac-
cines, designed at eliciting anti-invasion and anti-disease
responses (Arama 2014).
PedSAP 2016 Book 1 Immunology
The most clinically advanced candidate, RTS,S, specifi-
cally targets the preerythrocytic stage; in initial clinical trials,
it conferred about 50% protection from clinical malaria in
children 517 months of age and about 30% protection in
children 612 weeks of age (Agnandji 2012). However, vac-
cine efficacy was undetectable 3 years after vaccination. In
phase III studies, subjects received four doses of RTS,S. The
overall incidence of malaria was reduced by 39% over 4 years
in children and by 27% over 3 years in infants. This level of
protection, although not optimal and possibly too low to
achieve malaria eradication, has cleared the way for its spon-
sors to apply for prequalification with the WHO, specifically
for immunization in specific sub-Saharan African countries
(Tinto 2015).
Further advances are clearly still needed in malaria vaccine
development. Further development of a newer generation of
malaria vaccines largely depends on a better understanding
of the parasites life cycle and how different adjuvants affect
host responses, as well as discovery of ways to identify and
target potentially new antigens.
HIV Vaccine
More than 2 million AIDS-related deaths occurred globally
in 2008, and more than 33 million people are living with HIV/
AIDS. Despite promising advances in prevention, an estimated
2.7 million new HIV infections occurred that same year, with
the CDC predicting that number to double by 2015 census
statistics. This pandemic poses an ever-growing challenge
to the overall development and progress of global society
more than 30 years after HIV was first recognized (OConnell
2012). Development of a safe, globally effective, and afford-
able HIV vaccine offers the best hope for future control of this
pandemic.
Prophylactic vaccines against HIV-1 prevent the estab-
lishment of infection through the generation of neutralizing
antibodies, or generation of T-cell responses that result in
attenuation of pathogenesis once infection occurs (Douek
2006). The latter approach has been called T-cell vaccination.
Whole inactivated HIV-1 vaccines have not been considered
serious candidates for human immunization, largely because
of concerns that inactivation would be incomplete, thus allow-
ing for the replication of active virus. Together with complex
host responses, developing an effective HIV vaccine faces
other formidable scientific challenges such as high genetic
variability of the virus, lack of immune correlates of protec-
tion, limitations within existing animal models, and logistical
problems associated with the conduct of many clinical trials
(Girard 2006).
More than 35 vaccine candidates have been tested in
phase I/II clinical trials, involving more than 10,000 volun-
teers, and two phase III trials have been completed, involving
more than 7500 volunteers. In total, more than 187 sepa-
rate trials have been conducted since 1987 (OConnell 2012).
Many vaccine concepts and vaccination strategies have been
36 Vaccine Development and Future Targets
tested, including DNA vaccines, subunit vaccines, live-vector
recombinant vaccines, and various prime-boost vaccine
combinations. However, only five vaccine candidates have
been advanced to efficacy testing.
The recombinant glycoprotein (rgp) 120-subunit vaccines
AIDSVAX B/B and AIDSVAX B/E and the Merck Adenovirus
serotype (Ad) viral-vector expressing vaccine failed to show
a reduction in infection rate or lowering of postinfection viral
set point. In 2009, a phase III trial tested a combination of two
vaccine types. The ALVAC-HIV (vCP1452) given with a biva-
lent rgp 120 (AIDSVAX B/E) booster showed only 31% efficacy
in protection compared with placebo from infection among
community-risk participants in Thailand and was deemed
ineffective for overall protection (OConnell 2012). Building
on the results of this study when combining antibody neu-
tralization with vector priming agents, a fifth efficacy trial
was begun in 2009. The HVTN 505 study tested a DNA/
recombinant adenovirus prime-boost combination but was
terminated in 2013 because of lack of efficacy compared with
placebo after 4 years of more than 2500 participants (Rubens
2015; Hammer 2013). Table 2-2 reviews the five most reported
phase II and III HIV clinical vaccine trials by vaccine type and
their results (Brown 2015).
EBOV Vaccine
The largest documented outbreak of Ebola hemorrhagic fever
caused by EBOV started in rural Guinea in 2013. It quickly
spread regionally, predominantly to Sierra Leone and Liberia.
This global health crisis to date accounts for almost 27,200
cases, with a mortality rate of greater than 50% (Marzi 2015).
Ebola is a member of the Filoviridae family of enveloped,
single-stranded, negative-sense RNA viruses. Although sev-
eral promising EBOV vaccines have recently been described,
Table 2-2. Pertinent Phase II and II Human HIV-1 Vaccine Trials
Candidate Phase Volunteers
ALVAC-HIV (vCP1521)/AIDSVAX III 16,403
MN-CM244 rgp120
AIDSVAX B/E III 2500
AIDSVAX B/B III 5400
MRKAd5 HIV-1 gag/pol/nef trivalent IIb 3000
(Step Trial)
DNA (VRC-HIVDNA016-00-VP)/rAd5 IIb 2504
(VRC-HIVADV014-00-VP)
RSA = Republic of South Africa.
Information from: OConnell RJ, Kim JH, Corey L, et al. Human immunodeficiency virus vaccine trials. Cold Spring Harb Perspect Med
2012;2:a007351; and Rubens M, Ramamoorthy V, Saxena A, et al. HIV vaccine: recent advances, current roadblocks, and future
directions. J Immunol Res 2015;2015:560347.
PedSAP 2016 Book 1 Immunology
various limitations (efficacy, safety, recurrent outbreaks) have
hindered each candidates realization into FDA trials (Cooper
2015). Most existing vaccines focus on the EBOV glycopro-
tein as the target immunogen because of its predominant
surface expression, essential role in viral entry, and primary
role in development of neutralizing antibodies.
One of the most promising vaccines for EBOV to date is a
recombinant vesicular stomatitis virus platform (VSV-EBOV),
which consists of a live-attenuated vaccine vector that has
shown an acceptable preclinical safety profile and marked
efficacy in pre- and postexposure vaccination in rodent and
monkey models. In recent phase I clinical trials, VSV-EBOV
was reported to cause arthritis in about 20% of volunteers
who were given the highest available dose. Overall, however,
the vaccine was safe and immunogenic, warranting further
evaluation in phase II and III trials (Marzi 2015). These further
trials failed to achieve long-term immunogenicity.
Currently, the vaccine has been remodeled as rVSV-
ZEBOV and is studied using a strategy deemed ring
vaccination, in which contacts, and contacts of contacts, of
an infected patient are vaccinated. This vaccine consists of
a live-attenuated virus, but it is now a recombinant vesicular
stomatitis virus (rVSV) expressing Zaire Ebola virus (ZEBOV)
glycoproteins. This vaccine was highly successful in prevent-
ing infection in a recent study that enrolled of two groups
determined at random: the immediate group, which received
the vaccine shortly after coming in contact with a patient
with EBOV (4123 patients randomized, 2014 vaccinated);
and the delayed group, which were vaccinated 3 weeks after
contact with patients with EBOV (3528 patients randomized,
1498 vaccinated). Ten days after randomization, none of the
patients in the immediate group developed EBOV, whereas
16 patients from the delayed group developed the disease.
Location Year Result
Published
Thailand 2009 31% efficacy, deemed no
efficacy
Thailand 2006 No efficacy
United States 2005 No efficacy
United States, 2008 No efficacy (HVTN 502/
Peru, RSA Merck 023)
US 2013 Terminated in 2013 because of
lack of efficacy (HVTN 505)
37 Vaccine Development and Future Targets
The 10-day cutoff was used to account for the normal
accepted incubation time of EBOV and to allow the adap-
tive immune responses induced by the vaccine to develop
(Henao-Restrepo 2015). The WHO has called these new data
a landmark in the future of controlling Ebola outbreaks
(Kmietowicz 2015). The WHO has reported that the trial will
continue to collect more conclusive evidence on the vaccines
capacity to protect populations through herd immunity. Given
the vaccines safety, the extended study will likely include
13- to 17-year olds and possibly children 612 years of age
(Kmietowicz 2015).
Staphylococcus aureus Vaccine
S. aureus, the most commonly isolated human bacterial
pathogen, is an important cause of skin and soft tissue
infections, pneumonia, and invasive infections (Daum 2012).
An epidemic of S. aureus cases began in the 1990s, and the
past decade has seen an increase in cases of community-
acquired infections caused by strains with two new genetic
backgrounds (USA400 and USA300). The increase in the
clinical burden of S. aureus disease associated with the
recent epidemic and the occurrence of many infections
among previously healthy individuals has prompted dis-
cussions about whether there is a need for a universal or a
niche-based immunization strategy (Daum 2012). Attempts
to target subsets of the population for immunization
(e.g., neonates, dialysis patients, postoperative cardiac sur-
gery patients) have been unsuccessful to date.
Similar to other vaccine developments, attempts to
develop S. aureus vaccine have used a variety of mecha-
nisms. Taking a cue from the Haemophilus influenzae vaccine,
a polysaccharide-specific vaccine (types 5 and 8) was devel-
oped and studied in 3600 dialysis patients in California. The
vaccine overall was well tolerated. However, at the end of the
trial, it was deemed insignificant in maintaining any long-term
efficacy, with overall infection rates after week 50 (p=0.23)
no different between treated and placebo groups (overall
efficacy no greater than 57% at 40 weeks) (Shinefield 2002).
Current studies focus on protective antigens and protein
immunogenicity. Several host proteins (primarily protein A)
have been identified in mice and monkeys causing a spe-
cific rise in antibody response when present. This protein A is
believed to be protective for S. aureus from antibody attack;
further, it has been theorized to limit the efficacy of current
vaccine trends against S. aureus. Of particular promise is the
potential to select antigens that induce both humoral and
T cellmediated immunity in order to generate immune syn-
ergy against S. aureus infections (Spellberg 2012). In addition,
although neutralizing antibodies are known to be important
against toxic shock syndrome, antitoxoid vaccines have yet
to be fully explored. Table 2-3 summarizes current S. aureus
vaccine research.

Table 2-3. S. aureus Vaccines Receiving Clinical Evaluation as of 2014

Currently enrolling or about to enroll

Manufacturer Vaccine Study Phase Composition of Vaccine

Novartis 4 component I-adult Not disclosed. All proteins
Pfizer 4 component I-adult Conjugated capsular polysaccharides,
5 & 8; clumping factor A, manganese
transporter C
Novodigm Recombinant protein I-adult rA13p-N
GSK 4 component I-adult Not disclosed
Enrollment complete

Merck 1 component II/III efficacy isdBa

Biosynexus Passive monoclonal IIb/III efficacy Anti-lipoteichoic acid antibodyb
antibody
Nabi 2 component III Conjugate 5 & 8, recombinant
exoprotein A

a
Enrollment halted in 2011 by recommendation of the Independent Data Monitoring Committee.
b
No significant decrease in staphylococcal sepsis among very low-birth-weight neonates.
c
Efficacy in reduction of infection at 54 weeks nonsignificant.
Information from: Daum RS, Spellberg B. Progress toward a Staphylococcus aureus vaccine. Clin Infect Dis 2012;54:560-7;
and Fowler VG, Proctor RA. Where does a Staphylococcus aureus vaccine stand? Clin Microbiol Infect 2014;20:66-75.

PedSAP 2016 Book 1 Immunology 38 Vaccine Development and Future Targets

 Given all that we have learned about the organism during
vaccine development, and the wide range of clinical devel-
opment programs available, a vaccine against S. aureus
targeting community-acquired infection looks promising.
Uncovering the true role of host-specific infection biomark-
ers and the ways in which they may help prevent disease
seems to be the most promising area of research for vaccine
development. Researchers are optimistic that a vaccine will
be ready for human efficacy studies within the next decade
(Fowler 2014).
MATERNAL VACCINATION
The concept of maternal immunization has been established
for some time; however, there has been recent renewed
interest and focus in maternal immunization as a means to
protect young infants from vaccine-preventable infections
(Lindsey 2013).
Maternal immunization continues to exemplify an effec-
tive vaccination strategy by protecting the mother, her
developing fetus, and her later-born infant against infec-
tious disease. Maternal immunization yields this trifecta of
protection by enhancing antibody levels against particular
infections. These antibodies are transferred to the fetus by
the placenta or to the infant through breast milk. Studies have
established the benefits of maternal influenza vaccination. In
a randomized controlled trial in Bangladesh, pregnant women
vaccinated against influenza were significantly less likely to
develop febrile respiratory illness and had fewer clinical visits
than pregnant women in the control group who received pneu-
mococcal vaccine only. In addition, infants whose mothers
had been immunized with inactivated influenza vaccine dur-
ing pregnancy had a 63% reduction in laboratory-confirmed
influenza and a 29% reduction in respiratory illness with fever
compared with infants whose mothers had only received
pneumococcal vaccine (Zaman 2008).
Importance of Maternal to Fetal Immunization
The main rationale for maternal vaccination is that humoral
immunity can be passively transferred to the fetus and new-
born. Historically, the fetuss susceptibility to infections was
believed to be because of the immaturity of the fetal immune
system and its tendency to mount tolerogenic responses
to antigens. Neonates are at heightened risk because of a
less intact mucosal barrier and lack of immunologic mem-
ory, as well as the immaturity of the neonatal immune
system, with its inability to develop adult-like protective
immune responses when exposed to certain pathogens
(Faucette 2015). Maternal vaccination generates active,
innate, humoral, and cell-mediated immune protection in the
mother to increase resistance against infections and reduce
the chance of vertical transmission. In addition, maternal
vaccination elicits systemic immunoglobulin (Ig)G antibod-
ies that are transferred to the fetus through the placenta in
humans, as well as mucosal IgG, IgA, and IgM antibodies
PedSAP 2016 Book 1 Immunology
that are secreted into the colostrum and milk and ingested
by the newborn during breastfeeding (Gall 2005).
Complications of Maternal Vaccination
Although many maternal vaccines have been successful, our
overall knowledge of this strategy is lacking in many areas.
All current maternal vaccines were initially designed for
and tested in nonpregnant women, but the diverse immune
changes during pregnancy may cause pregnant women to
respond suboptimally or differently than nonpregnant women
(Faucette 2015). Although the influenza vaccine has been
shown safe and effective in maternal immunization, many
concerns are still raised over vaccines during pregnancy,
including ethical and legal issues and, most importantly, con-
cern for potential short- and long-term deleterious effects of
in utero exposure of vaccines on the fetus and newborn.
Currently, the CDC recommends routine maternal vac-
cination with hepatitis A and B, influenza (annually),
meningococcal (if indicated), and tetanus, diphtheria, and
pertussis (Tdap) (with each pregnancy). Other vaccines are
not routinely recommended because of the significant knowl-
edge gap in their short- and long-term safety in pregnancy.
Until further research is completed regarding the safety of
these non-routine vaccines during pregnancy, the CDC
relies heavily on the risk-benefit ratio of specific diseases
before making recommendations for maternal immunization
with these specific vaccines (Faucette 2015).
Another major concern surrounding maternal vaccination
stems from the long-standing observation that the pres-
ence of maternal antibodies in the infant can interfere with
the infants humoral immune response to vaccines both sys-
temically and at mucosal sites (by breastfeeding), although
cell-mediated immune responses are not affected. The inhib-
itory effect on infant response to vaccination has been highly
variable among different vaccines and even different studies
of the same vaccine (Beigi 2014). Thus, although maternal
immunization is a potential intervention to prevent many
early childhood infections, many are researching strategies
that allow infant immunization to be deferred until infant
immune responses have matured, believing that it is more
cost-effective for the developing world (Healy 2006).
Several vaccine prospects are in the pipeline for additional
maternal immunizations. This review focuses on the most
developed of these, which include RSV, cytomegalovirus
(CMV), group B Streptococcus (GBS), and herpes simplex virus
(HSV).
Respiratory Syncytial Virus
Respiratory syncytial virus is a ubiquitous cause of acute
respiratory illness in early childhood, infecting most children
by the end of their first year of life. Globally, RSV is the most
common cause of acute lower respiratory tract infection and
is a major contributor to morbidity and mortality, leading to
an estimated 3.4 million hospitalizations and at least 66,000
39 Vaccine Development and Future Targets
deaths per year in children younger than 5 years (Nair 2010).
Although mortality occurs predominantly in developing
countries, hospitalization rates remain high in industrialized
countries: about 1% of all children will be hospitalized for RSV
lower respiratory tract infection within 1 year of life. Because
of this significant burden of disease and the lack of an effec-
tive treatment beyond supportive care, developing a vaccine
to prevent RSV-related illness is a high priority.
Although RSV has only one known serotype, many anti-
genically distinct strains circulate in communities, causing
yearly epidemics in the winter and early spring in temperate
climates. After primary infection, host immunity wanes rap-
idly, and subsequent reinfection is common. The fact that
natural immunity affords so little protection also speaks to
the challenges in developing an effective RSV vaccine.
Accordingly, infants can be provided passive immunity
through monthly injections of palivizumab, a recombinant
monoclonal antibody, during the yearly RSV epidemic season.
Palivizumab is given by intramuscular injection at a dose of
15 mg/kg once every 30 days for up to 5 consecutive months
during RSV season. Palivizumab effectively reduces the risk
of severe lower respiratory tract infection caused by RSV in
certain categories of high-risk infants, including premature
infants born before 29 weeks gestational age, those with
chronic lung disease of prematurity, and those with hemo-
dynamically significant congenital heart disease. However,
cost-benefit analyses show that palivizumab prophylaxis
is unsuitable as the long-term mainstay of RSV prevention
efforts (AAP 2015).
In an effort to address the highest burden of RSV dis-
ease, the approach to developing an RSV vaccine has largely
prioritized young infants as the most appropriate target
population, but investigations into vaccine candidates for
women of childbearing age have also been under way. Live-
attenuated vaccines are predominantly being developed for
use in infants, whereas a variety of subunit vaccines are in
preclinical and phase IIII clinical testing in adults (Anderson
2013). Maternal vaccination as a means of providing passive
immunity to vulnerable infants in the first 6 months of life is
increasingly becoming a realistic endeavor, so much so that
the WHO RSV Vaccine Consultation Expert Group has stated
that a licensed RSV vaccine could be commercially available
within 510 years (Modjarrad 2016).
Cytomegalovirus
Cytomegalovirus is the leading cause of congenital infection
worldwide and, although the incidence varies in different pop-
ulations, affects 0.5%2% of all live births (Kenneson 2007).
Infants congenitally infected with CMV are at significant risk
of developing permanent sequelae, including sensorineural
hearing loss and neurodevelopmental delay. Maternal CMV
seroprevalence can be 45%100%, with higher prevalence
and earlier CMV acquisition associated with lower socioeco-
nomic status and non-white race (Cannon 2010).
PedSAP 2016 Book 1 Immunology
In utero transmission of CMV occurs in mothers without
preexisting CMV immunity (primary infection) or in women
with preexisting antibody to CMV either by reactivation of
previous maternal infection or acquisition of a different viral
strain during pregnancy (Boppana 2001). Primary maternal
CMV infection during pregnancy is associated with a greater
risk of in utero transmission than nonprimary infection, but
because of the high prevalence of disease in the overall pop-
ulation, almost two-thirds of infants with congenital CMV
infection are born to mothers who are already seropositive
(Wang 2011).
Strategies exist for preventing mother-to-child trans-
mission and for treatment aimed at reducing the long-term
sequelae of symptomatic congenital CMV infection. These
strategies include antenatal interventions (e.g., CMV hyper-
immunoglobulin, counseling on behavioral risk modification)
and postnatal interventions (e.g., antiviral therapy for symp-
tomatic neonates) (Manicklal 2013). Even as further studies
advance these interventions, prevention of congenital CMV
infection through vaccination remains an attractive goal.
Because of public health impact and a favorable cost analy-
sis, the Institute of Medicine ranked the development of a CMV
vaccine as the highest priority in its 2000 report (IOM 2000).
Investigation into CMV vaccines began more than 4 decades
ago with live-attenuated virus candidates, but these failed to
yield adequate protection. More recent efforts with recom-
binant live-attenuated CMV vaccines with deletion of genes
responsible for immune evasion have shown promise in ani-
mal models (Schleiss 2015). Subunit vaccines are another
class of candidates that have focused on surface glycopro-
tein B (gB). A phase II study of a gB/MF59 adjuvant subunit
vaccine in seronegative women showed vaccine efficacy of
50% for prevention of CMV infection in young mothers (Pass
2009). Given the molecular diversity of CMV infections, it
is unlikely that a single antigenic component will generate
sufficiently broad immunogenicity. As such, several mul-
ticomponent subunit and DNA vaccine candidates aimed
at achieving broad cross-neutralizing humoral and cellular
immune responses are in the early stages of investigation
(Manicklal 2013).
Group B Streptococcus
Group B Streptococcus is the most common cause of neo-
natal sepsis in the United States. Implementation of routine
screening for GBS for pregnant women in the third trimester
of gestation and administration of intrapartum antibiotic pro-
phylaxis have resulted in a dramatic drop in the incidence of
early-onset neonatal sepsis associated with GBS, but rates
are at a plateau at 0.34 cases per 1000 live births (CDC 2010).
However, maternal intrapartum antibiotic prophylaxis has no
effect on late-onset GBS infection in the newborn.
Group B Streptococcus is a normal part of human GI flora
and colonizes in the vagina in up to 50% of women. Infant
acquisition of GBS occurs during delivery by the birth canal.
40 Vaccine Development and Future Targets
The onset of infection shortly after birth does not allow for
infant immunization as a method of prevention. Experimental
vaccines for one the most common serotypes, GBS type III,
have been evaluated in phase III trials of pregnant women.
These vaccines were safe and well tolerated, resulting in a
substantial antibody response in women and significantly
higher antibody levels in infants at the time of birth and in the
first few weeks of life when compared with controls (Munoz
2013). Vaccines to protect mothers and infants against sev-
eral prevalent serotypes have the potential to reduce the
morbidity and mortality caused by GBS in the neonatal period.
Development of a GBS maternal immunization work group
has brought to light many opportunities to advance current
knowledge of GBS infection and disease. The work group has
suggested several areas of research that deserve consider-
ation when evaluating a GBS vaccine and implementing a
maternal immunization program. The immunogenicity and
efficacy of the vaccine should be well established in clinical
trials before implementation. Immunologic correlates of pro-
tection should be determined (T-cell function in pregnancy,
antibody response in GBS-positive mother vs. GBS-negative).
Finally, the group suggests that determining the duration of
serum antibodies and of the protection they confer in mothers
and infants is necessary to assess the need for repeated vac-
cination of mothers in subsequent pregnancies (Black 2013).
There are many unanswered questions related to GBS
vaccine development. Although several vaccine candidates
are in phase I studies, no vaccine has reached beyond
phase II because of the lack of efficacy data. A GBS vaccine
for pregnant women would likely add to the currently avail-
able vaccines that can be given during pregnancy to protect
mothers and infants against serious and potentially lethal dis-
eases. Successful introduction of the vaccine during routine
prenatal care and further education to the public and provider
regarding GBS and importance of vaccination will be critical
components of a GBS maternal immunization program.
Herpes Simplex Virus
Herpes simplex virus infections are common worldwide in
adolescents and adults. The two distinct types of HSV are
type 1 (HSV-1) and type 2 (HSV-2). Primary acquisition of HSV
results in lifelong infection, with periodic episodes of viral
reactivation, which can be clinical or subclinical. Although
less common than primary acquisition, mother-to-child
transmission of HSV can cause substantial morbidity and
mortality in infants. Neonatal acquisition of HSV infection
occurs in about 1 in 3200 live births in the United States and
is most likely to occur during labor and delivery than in utero
or postnatally (Brown 2003).
The antiviral treatment of choice for neonatal HSV infec-
tion is acyclovir, which is given intravenously at a dose of
60 mg/kg/day divided every 8 hours. After completing intrave-
nous therapy, infants should be transitioned to oral acyclovir
for a 6-month suppressive course. Although this therapy has
PedSAP 2016 Book 1 Immunology
improved mortality, it is not entirely effective, and infants can
be left with significant long-term morbidity. Vaccine strat-
egies aimed at preventing or controlling HSV infections in
women, and thereby preventing mother-to-child transmission
of HSV, are an ongoing need.
Despite much effort by researchers, an effective HSV vac-
cine has yet to advance beyond clinical trials. Several factors
make HSV a particularly difficult target for an effective vac-
cine strategy, including a relatively large genome that makes
it difficult to identify optimal protein targets, gene-encoded
immune evasion mechanisms, viral latency, and the fact that
host reinfection is not uncommon even with established
immunity to a primary infection. In addition, because of the
intricate interaction of HSV with innate and adaptive immune
responses, there is incomplete understanding of the most
appropriate correlates of immunity with which to objectively
discern host protective immunity when evaluating vaccine
candidates (Chung 2012).
Many vaccine candidates have gone through preclinical
studies and clinical trials to date. Most strategies have aimed
at preventing or controlling genital herpes, which would
potentially also reduce maternal transmission to newborns.
Subunit vaccines have been the most evaluated platform.
One candidate, an adjuvant recombinant HSV-2 gD vaccine,
progressed to a phase III trial, where it failed to prevent HSV-2
genital disease in seronegative women. However, of interest,
this vaccine was 58% effective at protecting against HSV-1
genital disease compared with a control (hepatitis A) vaccine
(Belshe 2012). The overall failure of this candidate highlights
the concern that the single antigenic component vaccine may
be unable to generate broad and effective immunogenicity.
Although several other vaccine platforms are being evalu-
ated, including live-attenuated viruses, replication-defective
viruses, killed viruses, recombinant vector vaccines, and DNA
vaccines, none is beyond preclinical or phase 1 clinical test-
ing (Chung 2012).
ADVANCES IN ESTABLISHED
VACCINES
Vaccines are overwhelmingly recognized as one of the great-
est medical advances of the past 160 years. Scientists are
discovering not only the evolution of new preventable diseases
but also the need for continuous research and improvement
of established vaccines. The growing number and type of
vaccine targets within established vaccines, as well as the
new vaccine technology allowing for more effective formula-
tions, contribute the growing advances of accepted, routine
vaccines.
Influenza
The influenza virus can cause serious respiratory disease,
leading to hospitalization and sometimes death in some
patients. An annual, seasonal flu vaccine is recommended
for all individuals older than 6 months to reduce the risk of
41 Vaccine Development and Future Targets
contracting seasonal flu and spreading it to others who may
be at high risk of complications. Although the primary strain
of influenza each year cannot be predicted with exact cer-
tainty, the CDC evaluates random samples circulating during
the flu season to evaluate how closely the vaccine matches
the circulating virus. In addition to virus matching, the CDC
conducts various studies throughout the season to evaluate
how well the vaccine actually protects against mild, moderate,
and severe illness from the flu. All of these data are factored
in at the end of each season to prepare for the next season to
estimate which strains should be included in the annual vac-
cine (CDC 2015).
The 20142015 influenza season received much media
attention as the CDC released reports that more than 80% of
influenza A (H3N2) strains were antigenically different from
the available vaccine component. Given this new information,
in March 2015, the FDA Vaccine Advisory Committee reported
that the U.S. influenza vaccine composition for the 20152016
season would include influenza A/California/7/2009(H1N1),
A/Switzerland/9715293/2013 (H3N2, replacing A/Texas/
50/2012 from 2014), and B/Phuket/3073/2013 (Yamagata).
The quadrivalent vaccines will include all of these as well as
B/Brisbane/60/2008 (Victoria) (ACIP 2015).
In June 2015, the CDC advised vaccine developers of influ-
enza outbreaks with the H5N1 strain in Africa, the Middle
East, and Asia. In November 2014, Canadian officials reported
highly pathogenic avian influenza (HPAI) H5N2 detection in
birds. Novel HPAI viruses have been found in wild birds and
poultry in the United States. These viruses now include new
H5N1 reassortant viruses, H5N8, and H5N2. The Q-Pan H5N1
vaccine is cross-reactive with the H5N1 viruses, but not the
poultry H5N2 or H5N8 viruses. Production of the Q-Pan H5N1
vaccine is anticipated in 2016, with availability for vaccination
in mid-2017 (CDC 2015).
Even when the seasonal flu vaccine is not an exact match,
it can still provide protection against different but related
viruses that also cause respiratory illness. Although not
100% effective against illness, the seasonal flu vaccine does
provide protection against potentially serious disease. For
this reason, even when the match is suboptimal, an annual
seasonal flu vaccine is still routinely recommended for all
patients older than 6 months unless contraindications exist.
Tuberculosis
Once considered a disease of the past, tuberculosis (TB) has
reemerged in the past 30 years as a major threat in many parts
of the world. In 2013, the CDC reports suggested that more
than one-third of worlds population was infected with TB, and
an estimated 9 million people became sick with the disease.
The most recent WHO report estimates 1.5 million deaths
in 2014 and an incidence of 9.6 million TB cases. New tools
are urgently needed to control TB at a global level, and the
availability of an effective vaccine could help reduce TB inci-
dence and mortality. The WHO reports a goal of introducing
PedSAP 2016 Book 1 Immunology
worldwide TB vaccination, together with new drug therapies,
by 2025 (WHO 2015a).
Bacillus Calmette-Gurin (BCG) remains the only vaccine
available for TB. It is routinely administered to newborns in
countries with endemic TB because of its efficacy in prevent-
ing the most severe forms of TB in early childhood. However,
there is a true consensus that BCG cannot provide significant
protection against pulmonary TB in adults (Anderson 2005;
Fine 1995). In the past 10 years, a resurgence in TB research
has resulted in the development of many new experimen-
tal vaccines. More than 15 (8 in phase II/III, 7 in phase I) of
these new vaccines have entered or completed clinical trials,
most showing a better protective immune response than BCG
(Evans 2013). Development of an effective TB vaccine focuses
on many designs: (1) activation of T cellbased immunity;
(2) block transmission of Mycobacterium tuberculosis (Mtb)
by inducing immune response that limits tissue damage or
prevents infection by enhancing host antimicrobial response
occurring early in infection; and (3) antibody-mediated
immunity by humoral responses as well as the specific role of
B cells in TB immunity.
The consensus on how to develop anti-infective vaccines
against TB requires better characterization of Mtb surface
constituents, the use of Mtb bacteria that resemble bacilli
released by a patient with active pulmonary TB, and an exper-
imental model with a very low dose of active bacteria being
given to the patient (Delogu 2014). Progress on the next
generation of TB vaccines will require creative testing and
research to answer the many questions involved.
Meningococcus
Development and widespread use of quadrivalent vaccines
(Menactra, Sanofi Pasteur; Menveo, GlaxoSmithKline) against
meningococcal serogroups A, C, Y, and W (based on the poly-
saccharide outer capsule of bacteria) have shown the impact
of these vaccines on preventing life-threatening diseases.
However, a meningococcal serogroup B (MenB) vaccine has
remained a difficult challenge because the outer capsule of
this serogroup is poorly immunogenic and closely resem-
bles polysaccharides in human cells. With introduction of
the quadrivalent vaccine, MenB remains a leading cause of
bacterial meningitis among certain groups, specifically peo-
ple living together in places like college dorms and boarding
schools. In 20132014, two major U.S. universities, Princeton
and University of California Santa Barbara, had outbreaks of
MenB (CDC 2015).
Because of the low incidence of MenB, vaccine efficacy
estimates in clinical studies were based on demonstration of
immune response, as measured by serum bactericidal activity
using human complement (hSBA), against a few MenB strains.
In studies supporting U.S. licensure, immunogenicity was
assessed by the proportion of subjects who achieved a 4-fold
or greater increase in hSBA titer for each the strains tested.
The two new (licensed in 2015) MenB vaccines in the United
42 Vaccine Development and Future Targets
States are Trumenba (Pfizer), a three-dose series; and Bexsero
(Novartis), a two-dose series. In February 2015, the Advisory
Committee on Immunization Practices (ACIP) officially rec-
ommended use of MenB vaccines among certain groups of
individuals 10 years or older at increased risk of MenB.
ADVANCES IN VACCINE DELIVERY
Researchers are conducting preclinical studies using vaccine
delivery methods other than routine intramuscular injections.
Although some vaccines already have an alternative delivery
route (rotavirus-oral), most vaccines require needlesticks,
which for some patients is a major deterrent to getting rou-
tine vaccinations. Administration by needle and syringe also
places vaccination efforts solely in the hands of trained
health care professionals, which may be a constraint to vac-
cine access in many settings. New developments in vaccine
administration techniques, including transdermal, mucosal,
and inhalation delivery, may appeal to those with a needle
phobia or a low threshold for pain and potentially simultane-
ously improve vaccination rates. The CDC, NIH, and FDA lead
major efforts to broaden administration options to boost vac-
cine uptake (HHS 2014).
Inhalation
Aerosolized drug delivery has been highly successful in the
treatment of pulmonary diseases, specifically in the arena of
asthma and cystic fibrosis, where it is considered standard
of care. Medications other than corticosteroids (e.g., opioids,
dihydroergotamines, insulin) have all had successful tri-
als in treating various conditions when given by aerosolized
delivery.
An inhaled measles vaccine is the further along in drug
development than other inhaled vaccine candidates. In 1983,
Dr. Albert Sabin published the first successful use of aero-
solized measles vaccine. Since then, other trials have shown
that vaccine delivery in this manner provided a superior
boosting response compared with vaccination by injection
in school-aged children (Bennett 2002; Dilraj 2000). At the
time of these studies, a major challenge to further develop-
ment of the aerosolized vaccine was the need for new delivery
devices. New, efficient, portable devices able to deliver dry
powder inhalants and liquid aerosols have been developed,
but only in the past 5 years have these devices been incorpo-
rated into clinical trials for testing of vaccine delivery.
Vaccination by inhalation is a promising new method for
immunization. Already used in large populations, it appears
to be a feasible method for mass vaccination. Recent devel-
opments in device innovation have made reliable, portable
aerosol dosing in mass campaigns possible. Improvement in
delivery to infants and in the development of vaccines that
do not require refrigeration (i.e., dry powders) that are stable
at room temperatures could make inhalation the preferred
route of administration for several vaccines in the future
(Laube 2014).
PedSAP 2016 Book 1 Immunology
Figure 2-1. Microneedle patch.
Reprinted from the CDC website.
Transdermal
The CDC, in partnership with industry and academia, demon-
strated that novel microneedle technology can deliver
rotavirus vaccine to animals. A microneedle patch has been
developed and tested to deliver measles and rubella vaccine
(Edens 2013). In addition, NIH-supported researchers are
developing an influenza patch that uses microneedles, which
could be sent by mail for patients to administer to themselves
(Figure 2-1). This low-cost, single-use patch can be applied
easily and quickly and should not require refrigeration. More
than 100 adults recently completed an acceptability and
usability test for researchers, and clinical trials are set to
start in late 2015 (Norman 2014).
In addition to emerging technology of the microneedle,
the FDA recently approved the use of one specific jet injector
device supported by the Biomedical Advanced Research and
Development Authority for administering a specific influ-
enza vaccine. This is the first needle-free delivery system
approved by the FDA for administration of inactive influenza
vaccine. Only one influenza vaccine has been approved to
use with the needleless injector (marketed as PharmaJet
Stratis Needle-Free Injection system): AFLURIA, a trivalent
inactivated influenza vaccine, providing protection against
influenza A (H1N1, H3N2) and influenza B (CDC) (Figure 2-2).
Although data analyses show that vaccination with this new
method provides a level of immune protection similar to the
same vaccine administered by needle, current approval is only
for adults 1864 years of age. Previously, these jet injectors,
invented in the 1960s, were used successfully to mass
vaccinate against smallpox and other endemic diseases.
This technology, although not new, appears to provide
another option for effective and easily tolerable vaccine
delivery.
43 Vaccine Development and Future Targets

Figure 2-2. Needleless injector.
Reprinted from: PharmaJet.
Mucosal
The idea of mucosal immunity became important when
vaccine researchers began to realize that intramuscular
vaccine likely did not provide optimal protection against
Patient Care Scenario
A 17-year-old female adolescent (weight 50 kg) is
admitted to the high-risk obstetrics/gynecology unit for
observation for symptoms of preterm labor and worsening
URI symptoms, making it difficult to breathe at home. She
is 32 weeks gestation, and preliminary prenatal screen-
ing shows the following:
Urine culture with 100,000 colonies GBS, 1+ glucose on
urinalysis, all other studies negative
Blood culture negative
Vaginal swab positive for HSV, type 2 (800,000 copies by
PCR)
Nasal and oral swab RSV and HSV, type 1 positive by PCR
(no quantity given)
ANSWER C
The first step in treating this mother would be ade-
quate treatment of her UTI. During delivery, she will need
to receive ampicillin prophylaxis, and she should be given
ampicillin at this time to decrease GBS bacterial burden
in her urine. She could be a candidate for GBS vaccina-
tion because of positive urine at this time. If appropriate
antibiotics are given to the mother during delivery, vac-
cination may not be warranted. Given her positive HSV
status both in oral and vaginal areas, the infant could
be at high risk of transmission of HSV, and the mother
would be a candidate for HSV vaccination. No CMV test-
ing is performed on neonates until birth, and none has
been done on the mother thus far; hence, she is not a can-
didate for vaccination consideration at this time. This
infant is at low risk of severe RSV infection, even though
the mother is positive, and should not be vaccinated. The
child would not currently meet the criteria for palivizumab
PedSAP 2016 Book 1 Immunology
infection at mucosal sites, where it is believed most patho-
gens initiate infection. The mucosal epithelium, which
covers about 400 m2 of surface in humans, is protected
by specialized antibodies and resident immune cells. To
optimize vaccine/adjuvant combinations for mucosal
immunity, NIH/National Institute of Allergy and Infectious
Diseases is funding two promising approaches at the pre-
clinical stage. A primary goal is to develop several vaccines
that are administered intranasally, sublingually, or orally to
elicit protective cellular and humoral immune responses at
these sites (HHS 2014).
First, an influenza vaccine combined with an innate
immune activating adjuvant was given sublingually to mice,
where it induced high levels of protective antibody responses.
Second, vaccine candidates for both HSV-2 and RSV given
intranasally (and co-delivered with novel oral nanoemulsion
adjuvants) have shown great promise in eliciting a greater
mucosal immune response than intranasal alone. Both of
these novel approaches have led to further investigation of
mucosal immunity and discovery of yet another new vaccine
delivery method (HHS 2014).
Contractions are stopped by standard institutional
protocol, but the pediatric infectious disease team is con-
sulted with respect to positive screening regarding any
prophylactic measure that should be taken for this child.
Assuming the availability of maternal vaccines, which one
of the following treatment options would be best to initi-
ate at this time in the mother?
A. CMV
B. RSV
C. HSV
D. GBS
therapy unless undiagnosed heart or pulmonary condition
develops after birth. Answer C is most correct assuming
the mother received intrapartum antibiotics for her GBS
(standard of care)
1. Belshe RB, Leone PA, Bernstein DI, et al. Efficacy
results of a trial of a herpes simplex vaccine. N Engl J
Med 2012;366:34-43.
2. Faucette AN, Unger BL, Gonik B et al. Maternal vac-
cination: moving the science forward. Hum Reprod
Update 2015;21:119-35.
3. Lindsey B, Kampmann B, Jones C. Maternal immu-
nization as a strategy to decrease susceptibility to
infection in newborn infants. Curr Opin Infect Dis
2013;26:248-53.
44 Vaccine Development and Future Targets

Practice Points
Vaccines are a vital component of routine health and
preventive care. Pharmacists play a vital role in encour-
aging patients to obtain routine vaccinations, such as
influenza and pneumococcal, and are often responsi-
ble for administering vaccines. New data analyses are
available showing that pharmacists should now assist
in educating both patients and prescribers on potential
vaccines that could be of benefit in special populations
and new routes of vaccine delivery that could increase
patient compliance.
Current vaccines in development could further protect
patients against some of the most common and endemic
infections to date, including malaria and EBOV for travel-
ers, HIV, and MRSA.
Maternal vaccinations are anticipated to be beneficial
in decreasing early infant morbidity AND mortality for
common neonatal infections including RSV, HSV, CMV, and
GBS. Each of these infections carries a high risk of devel-
opmental complications when transmitted to neonates/
infants.
Pharmacists should be aware of recent advances in the
meningococcal vaccine, specifically with the addition of
MenB, and which patients meet the criteria for vaccination.
The ever-changing face of the annual influenza vaccine
appears to be having a major change again in the 2016
2017 flu season because we are learning more about what
viruses are causing the most problematic disease.
Needle-less delivery methods for vaccine administration
will hopefully increase patient compliance with vaccina-
tion exponentially because fear of being stuck is the No. 1
excuse patients give for not receiving routine vaccines.
The evolution of vaccine therapy changes at least annually,
if not more often. Pharmacists are encouraged to review
the CDC website to stay up to date on immunization infor-
mation, including information about pipeline vaccines.
CONCLUSION
Vaccines are one of the most profound achievements of bio-
medical science and public health. Spanning more than 200
years of research and development, 10 infectious diseases
have been at least 90% eradicated in the United States because
of vaccines. Using promising new scientific approaches,
researchers are building on the successful history of vacci-
nation against infectious diseases and expanding research
to maternal immunization programs. Further advancement of
already established vaccines is also occurring by the addition
of immune-activating adjuvants. Finally, the advancing tech-
nology of vaccine delivery allows pharmacists to continue their
efforts as advocates for widespread vaccination programs for
all patients, which should expand access and availability.
REFERENCES
Agnandji ST, Lell B, Fernandes JF, et al, for the RTS,S
Clinical Trials Partnership. A phase 3 trial of RTS,S/
AS01 malaria vaccine in African infants. N Engl J Med
2012;367:2284-95.
PedSAP 2016 Book 1 Immunology
American Academy of Pediatrics (AAP). Respiratory
syncytial virus. In: Kimberlin DW, Brady MT, Jackson
MA, et al, eds. Red Book: 2015 Report of the Committee
on Infectious Diseases. Elk Grove Village, IL: AAP,
2015:667-76.
Anderson LJ, Dormitzer PR, Nokes DJ, et al. Strategic
priorities for respiratory syncytial virus (RSV) vaccine
development. Vaccine 2013;31:S209-15.
Anderson P, Doherty TM. The success and failure of BCG
implications for a novel TB vaccine. Nat Rev Microbiol
2005;3:656-62.
Arama C, Troye-Blomberg M. The path of malaria vaccine
development: challenges and perspectives. J Intern Med
2014;275:456-66.
Beeson JG, Fowkes FJI, Reiling L, et al. Correlates of
protection for Plasmodium falciparum malaria vaccine
development: current knowledge and future research. In:
Corradin H, Engers H, eds. Malaria Vaccine Development:
Over 40 Years of Trials and Tribulations 2014:80-104.
Beigi RH, Fortner KB, Munoz FM, et al. Maternal immunization:
opportunities for scientific advancement. Clin Infect Dis
2014;59:S408-14.
Belshe RB, Leone PA, Bernstein DI, et al. Efficacy results
of a trial of a herpes simplex vaccine. N Engl J Med
2012;366:34-43.
Black S, Margari I, Rappuoli R. Preventing newborn infection
with maternal immunization. Sci Transl Med 2013;5:ps11
Boppana SB, Rivera LB, Fowler KB, et al. Intrauterine
transmission of cytomegalovirus to infants of
women with preconceptional immunity. N Engl J Med
2001;344:1366-71.
Brown J, Excler JL, Kim JH. New prospects for a preventive
HIV-1 vaccine. J Virus Erad 2015;1:78-88.
Brown ZA, Wald A, Morrow RA, et al. Effect of serologic
status and cesarean delivery on transmission rates
of herpes simplex virus from mother to infant. JAMA
2003;289:203-9.
Cannon MJ, Schmid DS, Hyde TB. Review of cytomegalo-
virus seroprevalence and demographic characteristics
associated with infection. Rev Med Virol 2010;20:202-13.
Chia WN, Goh YS, Renia L. Novel approaches to identify
protective malaria vaccine candidates. Front Microbiol
2014;5:586.
Chung E, Sen J. The ongoing pursuit of a prophylactic HSV
vaccine. Rev Med Virol 2012;22:285-300.
Cooper CL, Bavari S. A race for an Ebola vaccine: promises
and obstacles. Trends Microbiol 2015;23:65-6.
Daum RS, Spellberg B. Progress toward a Staphylococcus
aureus vaccine. Clin Infect Dis 2012;54:560-7.
Delogu G, Manganelli R, Brennan MJ. Critical research
concepts in tuberculosis vaccine development. Clin
Microbiol Infect 2014:20:S59-65.
45 Vaccine Development and Future Targets
Douek DC, Kwong PD, Nabel GJ, et al. The rational design
of an AIDS vaccine. Cell 2006;124:677-81.
Evans TB, Brennan MJ, Barker L, et al. Preventive vaccines
for tuberculosis. Vaccine 2013;31:B223-6.
Faucette AN, Unger BL, Gonik B, et al. Maternal vaccination:
moving the science forward. Hum Reprod Update 2015;
21:119-35.
Fine PE. Variation in protection by BCG: implications of
and for heterologous immunity. Lancet 1995;346:1339-45.
Folaranmi T, Rubin L, Martin SW, et al. Use of serogroup B
meningococcal vaccines in persons aged >10 years
at increased risk for serogroup B meningococcal dis-
ease: recommendations of the Advisory Committee on
Immunization Practices, 2015. MMWR 2015;64:608-12.
Fowler VG Jr, Proctor RA. Where does a Staphylococcus
aureus vaccine stand? Clin Microbiol Infect 2014;20
(suppl 5):66-75.
Gall SA. Maternal immunization to protect the mother
and neonate. Expert Rev Vaccines 2005;4:813-8.
Gershon AA. Varicella zoster vaccines and their impli-
cations for development of HSV vaccines. Virology
2013;435:29-36.
Girard MP, Osmanov Sk, Kieny MP. A review of vaccine
research and development: the human immunodeficiency
virus (HIV). Vaccine 2006;24:4062-81.
Grohskopf LA, Sololow LZ, Olsen SJ, et al. Prevention and
Control of Influenza with Vaccines: Recommendations
of the Advisory Committee on Immunization Practices,
United States, 2015-2016 Influenza Season. MMWR 2015;
64:818-825.
Gruber MF. Global and national initiatives to facilitate
studies of vaccines in pregnant women. Clin Infect Dis
2014;59:S395-9.
Hammer SM, Sobieszczyk ME, Janes H, et al. HVTN 505
Study Team. Efficacy trial of a DNA/rAd5 HIV-1 preventive
vaccine. N Engl J Med 2013;369:2083-92.
Healy CM, Baker CJ. Prospects for prevention of childhood
infections by maternal immunization. Curr Opin Infect Dis
2006;19:271-6.
Henao-Restrepo AM, Longini IM, Egger M, et al. Efficacy
and effectiveness of an rVSV-vectored vaccine express-
ing Ebola surface glycoprotein: interim results from the
Guinea ring vaccination cluster-randomized trial. Lancet
2015;386:857-66.
Institute of Medicine (IOM). (US) Committee to Study
Priorities for Vaccine Development. Vaccines for the
21st Century: A Tool for Decision Making. Stratton KR,
Durch JS, Lawrence RS, eds. Washington, DC: National
Academies Press (US), 2000.
Kaech SM, Wherry EJ, Ahmed R. Effector and memory T-cell
differentiation: implications for vaccine development. Nat
Rev Immunol 2002;2:251-62.
PedSAP 2016 Book 1 Immunology
Kaufmann SHE, McElrath MJ, Lewis DJM, et al. Challenges
and responses in human vaccine development. Curr Opin
Immunol 2014;28:18-26.
Kenneson A, Cannon MJ. Review and meta-analysis of
the epidemiology of congenital cytomegalovirus (CMV)
infection. Rev Med Virol 2007;17:253-76.
Kmietowicz Z. Ebola vaccine trial results are extremely
promising, says WHO. BMJ 2015;351:h4192.
Laube B. The expanding role of aerosols in systemic drug
delivery, gene therapy and vaccination: an update. Transl
Respir Med 2014;2:3.
Lindsey B, Kampmann B, Jones C. Maternal immunization
as a strategy to decrease susceptibility to infection in
newborn infants. Curr Opin Infect Dis 2013;26:248-53.
Lorenz V, Karanis G, Karanis P. Malaria vaccine development
and how external forces shape it: an overview. Int J Environ
Res Public Health 2014;11:6791-807.
Manicklal S, Emery VC, Lazzarotto T, et al. The silent global
burden of congenital cytomegalovirus. Clin Microbiol Rev
2013;26:86-102.
Marzi A, Robertson SH, Haddock E, et al. VSV-EBOV rapidly
protects macaques against infection with the 2014/15
Ebola virus outbreak strain. Science 2015;349:739-42.
Modjarrad K, Giersing B, Kaslow DC, et al; Group WRVCE.
WHO consultation on respiratory syncytial virus vaccine
development report from a World Health Organization
meeting held on 23-24 March 2015. Vaccine 2016;34:190-7.
Munoz FM, Ferrieri P. Group B Streptococcus vaccination in
pregnancy: moving toward a global maternal immuniza-
tion program. Vaccine 2013;31S:D46-D51.
Nair H, Nokes DJ, Gessner BD, et al. Global burden of
acute lower respiratory infections due to respiratory
syncytial virus in young children: a systematic review and
meta-analysis. Lancet 2010;375:1545-55.
National Vaccine Advisory Committee (NVAC). The National
Vaccine Advisory Committee: reducing patient and
provider barriers to maternal immunizations. Public Health
Rep 2015;130:10-42.
OConnell RJ, Kim JH, Corey L, et al. Human immunodeficiency
virus vaccine trials. Cold Spring Harb Perspect Med
2012;2:a007351.
Pass RF, Zhang C, Evans A, et al. Vaccine prevention of
maternal cytomegalovirus infection. N Engl J Med
2009;360:1191-9.
Pharmaceutical Research and Manufacturers of America
(PhRMA). Medicines in Development. Vaccines: a report
on the prevention and treatment of disease through
vaccines 2013 report.
Rubens M, Ramamoorthy V, Saxena A, et al. HIV vaccine:
recent advances, current roadblocks, and future
directions. J Immunol Res 2015;2015:560347.
Schleiss MR, Bierle CJ, Swanson EC, et al. Vaccination with a
live attenuated cytomegalovirus devoid of a protein kinase R
46 Vaccine Development and Future Targets
 inhibitory gene results in reduced maternal viremia and
improved pregnancy outcome in a guinea pig congenital
infection model. J Virol 2015;89:9727-38.

Shinefield H, Black S, Fattom A, et al. Use of a staphylo-

coccus aureus conjugate vaccine in patients receiving
hemodialysis. N Engl J Med 2002;346:491-6.

Spellberg B, Daum R. Development of a vaccine

against Staphylococcus aureus. Semin Immunopathol
2012;34:335-48.

Tinto H, DAllesandro U, Sorgho H, et al, for the RTS,S Clinical

Trials Partnership. Efficacy and safety of RTS,S/AS01
malaria vaccine with or without booster dose in infants
and children in Africa: final results of a phase 3, individu-
ally randomized, controlled trial. Lancet 2015;386:31-45

U.S. Department of Health and Human Services (DHHS).

National Vaccine Plan Implementation: Protecting the
Nations Health Through Immunization - 2014a.

U.S. Department of Health and Human Services (DHHS). The

Annual Reports of the State of the National Plan 2014b.

Verani JR, McGee L, Schrag SJ, et al. Prevention of perinatal

group B streptococcal disease revised guidelines from
CDC, 2010. MMWR 2010;59(RR10):1-36.

Wang C, Zhang X, Bialek S, et al. Attribution of congenital

cytomegalovirus infection to primary versus non-primary
maternal infection. Clin Infect Dis 2011;52:e11-3.

WHO. Global Tuberculosis Report 2015 October 2015.

2015a

WHO. Status Report on Artemisinin and ACT Resistance.

2015b.

Zaman K, Roy E, Arifeen SE, et al. Effectiveness of maternal

influenza immunization in mothers and infants. N Engl J
Med 2008;359:1555-64.

Zhu XP, Muhammad ZS, Wang JG, et al. HSV-2 vaccine: cur-
rent status and insight into factors for developing an
efficient vaccine. Viruses 2014;6:371-90.

PedSAP 2016 Book 1 Immunology 47 Vaccine Development and Future Targets

Self-Assessment Questions
21. You have been asked by your international travel division
to deliver an update on necessary vaccinations for fami-
lies traveling to various regions of the world for extended
stays. Specifically, your division seeks guidance on an
update for malaria, Ebola virus (EBOV), and tuberculosis
(TB). Which one of the following statements is best to
provide in your update?
A. The TB vaccine has been deemed safe and greater
than 80% effective for people traveling to endemic
countries and should be received.
B. When studied postexposure, the EBOV vaccine was
deemed as effective in preventing infection in all age
groups exposed compared with those who received
vaccine before exposure.
C. The RTS,S vaccine against malaria appears to be the
most highly efficacious of the vaccines developed
for use in children and infants.
D. Ring vaccination was shown to be the most effective
method in preventing EBOV.
22. A 17-year-old male adolescent comes to your pharmacy
to request information on the potential for an HIV vac-
cine. He reports being treated for chlamydia/gonorrhea
in the past 18 months and having received an annual
influenza vaccine. He has heard about local recruit-
ment for HIV vaccine studies and wonders how when the
vaccine will be available. Which one of the following edu-
cation points is best to give this patient?
A. Currently, not enough patients are enrolled in
studies to determine the efficacy or safety of HIV
studies.
B. The safety of HIV vaccines has not been
established, so use caution before considering
enrollment.
C. It is better to avoid high-risk behaviors, use
condoms during sex, and regularly consult your
primary care physician.
D. Vaccine developers are challenged by HIVs ability to
genetically self-alter and replicate its own immunity.
23. You are charged with developing a new protocol for
the employee vaccination program at your hospital.
You would like to include alternative administration
techniques for vaccines, specifically for the influenza
vaccine, in order to increase compliance rates. Which
one of the following is the best education point to pro-
vide to employees?
A. The only approved delivery methods for influenza
vaccine administration are intramuscular
(inactivated influenza vaccine) and inhaled (live
attenuated influenza vaccine [LAIV]).
PedSAP 2016 Book 1 Immunology
B. Microneedle administration by a patch is available
for patients and can be mailed directly to the
employees office.
C. A needleless influenza vaccine requires only a single
injector per administrator and is available to those
1864 years of age.
D. Alternative routes of vaccine delivery have
not proved cost-effective and should not be
considered.
24. Researchers studying a new vaccine for the prevention
of staphylococcal disease enrolled 500 patients. Dis-
ease rates were 78.3% in the placebo group and 48.7%
in the treatment group. Which one of the following best
describes the number needed to treat with the new vac-
cine to prevent infection?
A. 3
B. 7
C. 10
D. 30
25. Which one of the following vaccine features would be
best to consider as part of a vaccination program against
malaria?
A. Ability to overcome the hosts complex antigenic
variation and genetic variation.
B. Development of a single antigenic component that
will induce an effective immune response to the
different stages of the malaria life cycle.
C. Increase in the hosts ability to convert appropriate
antibody response in order to kill the parasite.
D. Ability to induce more than one type of host immune
response, including cell-mediated and humoral
components.
26. Assuming vaccine availability, which one of the following
patients would be the best candidate to receive a mater-
nal vaccine?
A. A mother who is positive for herpes simplex virus
type 1 (HSV-1), 29 weeks gestation, who has had six
recurrences in the past 14 months before pregnancy
and was placed on valacyclovir prophylaxis during
pregnancy.
B. A cytomegalovirus (CMV)-positive mother who is
placed on bed rest at 22 weeks gestation and is at
risk of preterm delivery before week 32.
C. A mother worried about respiratory syncytial
virus (RSV) who is at 26 weeks gestation with
twins who are positive for severe congenital heart
disease (hypoplastic left heart syndrome and
ventricular septal defect) and due to be delivered
at week 30.
48 Vaccine Development and Future Targets
 D. A group B Streptococcus (GBS)-positive mother who
is at 32 weeks gestation and has been hospitalized
twice for magnesium infusions to stop preterm
labor.
27. Which one of the following patient groups showed the
most benefit when treated with EBOV vaccine?
A. Patients older than 12 years administered the
vaccine before exposure.
B. Patients younger than 65 years administered the
EBOV vaccine at any time during exposure.
C. Patients older than 18 years who lived in any EBOV
area administered the vaccine before exposure.
D. Patients of all ages administered the EBOV vaccine
because they showed a decreased risk of acquiring
infection.
28. Your hospital infection control department is looking at
case rates of Staphylococcus aureus bacteremia in oth-
erwise healthy individuals to determine which patients
to target for S. aureus immunization when a vaccine
becomes available. For this strategy, which one of the
following patient groups would be best to target?
A. Patients at high risk of invasive infection from
community-acquired S. aureus
B. Patients with immunocompromise
C. Patients at risk of hospital-acquired staphylococcal
infections
D. All infants younger than 1 year
29. A 24-year-old woman sees her obstetrician early in the
course of her first pregnancy. After hearing an overview
of the routinely recommended maternal vaccinations,
she asks the physician about the benefits of receiving
these vaccinations. Which one of the following is the
best education point to give this patient in regards to
maternal vaccination?
A. The risk of vertical transmission of infection from
mother to fetus is not significantly reduced.
B. Although the mother does receive immunologic
protection from infection as a result of vaccination,
it is not necessary because pregnancy is not
typically considered a high-risk state of health.
C. The newborn infant benefits from passive humoral
immunity that occurs by transplacental passage of
maternal antibodies.
D. Vaccines have been shown to be ineffective in
pregnant women.
30. A 7-year-old patient with severe epidermolysis bullosa
needs routine vaccinations (part of a catch-up sched-
ule). His care team asks you about the availability of
non-injectable vaccine delivery to avoid the pain this
patient has with intramuscular injections. Which one of
the following is best to recommend for this patient?
PedSAP 2016 Book 1 Immunology
A. No alternative vaccine delivery methods are
currently available for this patient.
B. The LAIV may be given intranasally, but all other
vaccines need to be given either subcutaneously or
intramuscularly.
C. The patient should delay the catch-up vaccines until
non-injectable administration is available.
D. All vaccines should be administered by injectable
route regardless of availability because efficacy is
greater with that route of administration.
31. A randomized controlled trial is comparing a new vaccine
for influenza with the existing quadrivalent inactivated
vaccine. The study is designed to detect a minimum 15%
difference in response rates between the groups, if one
exists (p0.05). Which one of the following changes in
the study parameters would best ensure that the study
detects a minimum 10% difference in response?
A. Decrease the sample size
B. Increase the sample size
C. Select a p<0.1 as the cutoff for statistical
significance
D. Change the design to an observational study
32. At birth, a full-term neonate is small for gestational
age, with hepatosplenomegaly, mild hypotonia, and a
few scattered petechiae. Laboratory evaluation reveals
thrombocytopenia and elevated ALT. A test for CMV DNA
PCR performed on a saliva specimen is positive. The
primary care physician asks how mother-to-child trans-
mission may have occurred. Which one of the following
best answers this question?
A. The mother acquired a primary CMV infection during
pregnancy.
B. The mother previously had a CMV infection that was
reactivated during pregnancy.
C. The mother, who had serologic evidence of previous
CMV infection, became infected with a different
CMV strain during pregnancy.
D. Any one of the above may have resulted in mother-
to-child transmission.
33. When seeking to reduce the burden of severe RSV infec-
tion in high-risk infants through passive immunization,
which one of the following infants would be considered
the best candidate for immunoprophylaxis with palivi-
zumab during RSV season?
A. A 7-month-old girl born at full term who is small for
gestational age.
B. A 6-month-old boy born at 30 weeks gestational age
who no longer requires respiratory support.
C. A 3-month-old full-term girl with hemodynamically
insignificant congenital heart disease.
D. A 15-month-old boy born at 31 weeks gestational
age who continues to require supplemental oxygen.
49 Vaccine Development and Future Targets
34. A full-term infant presents on day of life 16 with poor oral
intake and lethargy. Physical examination reveals that
the infant, who becomes inconsolably irritable, has a
full fontanelle. He has no sign of rash. Lumbar puncture
is performed, and an elevated WBC is found in the CSF.
The CSF is also tested by PCR, and HSV DNA is detected.
Which one of the following intravenous acyclovir regi-
mens is best to recommend for this patient?
A. 30 mg/kg/day in three divided doses for 21 days;
if a repeat HSV DNA PCR on CSF is negative,
discontinue all antiviral therapy.
B. 60 mg/kg/day in three divided doses for 21 days;
if a repeat HSV DNA PCR on CSF is negative,
discontinue all antiviral therapy.
C. 60 mg/kg/day in three divided doses for 21 days; if a
repeat HSV DNA PCR on CSF is negative, transition
to oral acyclovir for a 3-month suppressive course.
D. 60 mg/kg/day in three divided doses for 21 days; if a
repeat HSV DNA PCR on CSF is negative, transition
to oral acyclovir for a 6-month suppressive course.
35. A 12-year-old boy presents for annual influenza vacci-
nation. He is healthy, with no significant medical history
and no known allergies. His mother asks that he receive
the best formulation of influenza vaccine. Which one of
the following is best to recommend for this patient?
A. Intranasal quadrivalent live-attenuated influenza
vaccine
B. Intramuscular trivalent inactivated influenza vaccine
C. Intramuscular quadrivalent inactivated influenza
vaccine
D. Any vaccine formulation with FDA label approval for
his age
36. A 28-year-old woman in her 39th week of gestation
presents to the hospital in labor with no rupture of mem-
branes. She has received appropriate prenatal care
throughout the pregnancy and has had no complica-
tions. At 36 weeks gestation, her screen for GBS was
negative. During her previous pregnancy, her GBS screen
was positive at 37 weeks gestation, and she received
intrapartum antibiotic prophylaxis before giving birth to
a healthy full-term boy. Which one of the following is best
to recommend for this patient?
A. Intrapartum antibiotic prophylaxis is not indicated
because her GBS screen during this pregnancy was
negative.
B. She should receive intrapartum antibiotic prophylaxis
because she has a history of being a GBS carrier.
C. The GBS screen should be repeated on admission
to the labor and delivery unit due to her previous
positive status.
D. Cesarean section should be performed to lower the
risk of mother-to-child transmission of GBS.
PedSAP 2016 Book 1 Immunology
37. A 5-year-old boy is known to have had contact with a
person confirmed to have multidrug-resistant (MDR)
pulmonary TB. The boy is healthy and has no signifi-
cant medical history. Born outside the United States, he
received the Bacillus Calmette-Gurin (BCG) vaccine as
an infant. Which one of the following is best to recom-
mend for initial evaluation of this patient for TB infection?
A. Place a tuberculin skin test (TST) and interpret the
result as if he had no history of receiving BCG.
B. Place a TST and interpret the result using a
classification scale adjusted for patients who have
received BCG.
C. Obtain a blood sample for an interferon-gamma
release assay (IGRA).
D. Obtain chest radiography to determine the presence
of active vs. latent disease.
38. A new study compared infection acquisition rates in sub-
jects given a new S. aureus vaccine with rates in subjects
who did not receive the vaccine. Subjects in both groups
were examined at 3, 6, and 12 months for any new infec-
tion caused by S. aureus, as detected by culture. Results
(total n=1100) showed that the mean rate of infection
from the three time points was 51.5% (2.5%) for non-
vaccinated patients and 33.7% (3.5%) for those receiv-
ing the vaccine (p=0.005 using the t-test). Which one of
the following best describes the results of this study?
A. No clinically important difference occurred in mean
incidence of infection in the two groups.
B. Follow-up of 12 months is probably not long enough
to show significance.
C. The absolute risk reduction with the vaccine was
greater than 10%.
D. The number needed to treat to prevent one
staphylococcal infection was 8.
39. When given the opportunity to review alternative methods
of administering vaccines, which route has effectiveness
that is most likely to approach that of standard routes
such as intramuscular or subcutaneous?
A. Inhalation
B. Transdermal jet injector
C. Microneedle
D. Intranasal
40. According to current data, which novel vaccine shows
the most promise to be available for patients by 2020?
A. HSV
B. EBOV
C. HIV
D. CMV
50 Vaccine Development and Future Targets
Learner Chapter Evaluation: Vaccine Development and Future Targets.

As you take the posttest for this chapter, also evaluate the Use the 5-point scale to indicate whether this chapter pre-
materials quality and usefulness, as well as the achievement pared you to accomplish the following learning objectives:
of learning objectives. Rate each item using this 5-point scale:
Strongly agree 31. Design an effective strategy for developing a new
vaccine.
Agree 32. Develop an appropriate strategy to determine which

Neutral of the newer vaccines can be considered for frontline
Disagree health care employees and/or patients.
Strongly disagree 33. Evaluate current evidence to determine the appropriate-
ness of maternal vaccinations.
20. The content of the chapter met my educational needs.
34. Devise a guideline for alternative vaccine administration
21. The content of the chapter satisfied my expectations. to pediatric and adult patients.
22. The author presented the chapter content effectively. 35. Please provide any specific comments related to any
23. The content of the chapter was relevant to my practice perceptions of bias, promotion, or advertisement of com-
and presented at the appropriate depth and scope. mercial products.
24. The content of the chapter was objective and balanced. 36. Please expand on any of your above responses, and/or
provide any additional comments regarding this chapter:
25. The content of the chapter is free of bias, promotion, or
advertisement of commercial products.
26. The content of the chapter was useful to me.
27. The teaching and learning methods used in the chapter
were effective.
28. The active learning methods used in the chapter were
effective.
29. The learning assessment activities used in the chapter
were effective.
30. The chapter was effective overall.

PedSAP 2016 Book 1 Immunology 51 Vaccine Development and Future Targets

Passive Immunization
By Ann M. Philbrick, Pharm.D., BCPS, BCACP

Reviewed by Jenana Halilovic Maker, Pharm.D., BCPS; Ewha Bridget Kim, Pharm.D., BCPS, BCOP; and Elias B. Chahine, Pharm.D.,
BCPS (AQ ID)

LEARNING OBJECTIVES

1. Distinguish the unique features of specific formulations of immunoglobulins.

2. Assess the appropriateness of palivizumab for specific patient populations.
3. Evaluate the warnings, precautions, and contraindications of agents used in passive immunization.
4. Devise a plan for preventing and treating the adverse effects associated with immunoglobulins.
5. Evaluate the appropriateness of hyperimmune globulin therapy for specific patient exposures.

ABBREVIATIONS IN THIS CHAPTER
CDI Clostridium difficile infection
CLD Chronic lung disease
CMVIG Cytomegalovirus immunoglobulin
HBIG Hepatitis B immunoglobulin
IVIG Intravenous immunoglobulin
PEP Postexposure prophylaxis
PIDD Primary immunodeficiency disease
RSV Respiratory syncytial virus
SCIG Subcutaneous immunoglobulin
Table of other common abbreviations.
INTRODUCTION
Active and passive immunity are ways in which the body protects
itself from infection. Active immunity occurs after the body comes
in direct contact with an antigen and subsequently produces
mediators of the immune response, consisting of antibodies and
activated helper and cytotoxic T lymphocytes specific to that anti-
gen (CDC 2015a). Examples of active immunity include infection and
immunization.
Passive immunity occurs when a foreign antibody is introduced
into the body. The most common form of passive immunity occurs
when a mother passes immunoglobulin (Ig)A antibodies to her fetus
in utero or IgG antibodies during breastfeeding. In other instances,
antibody can be administered to the body directly. Examples of this
include administering tetanus antibodies to exposed individuals so
that they can neutralize the toxins; and administering immunoglobu-
lins or monoclonal antibodies (CDC 2015a) to treat specific infections
or diseases. This chapter focuses on the use of palivizumab and
immunoglobulins in pediatric patients.

PALIVIZUMAB
Palivizumab is a humanized, recombinant monoclonal antibody
(IgG1) directed against the respiratory syncytial virus (RSV) F pro-
tein inhibitor. Under normal circumstances, RSV binds to the host cell
by a G protein. The F protein mediates the fusion of RSV into the host
cell, where it replicates and releases new RSV particles. According
to the prescribing information, palivizumab binds to the F protein on
the host cell, thereby inhibiting the fusion of RSV into the host cell.

Clinical Uses
According to the prescribing information, palivizumab is approved for
the prevention of RSV in pediatric patients who are at high risk of the
disease. Respiratory syncytial virus can cause both upper and lower

PedSAP 2016 Book 1 Immunology 53 Passive Immunization

respiratory tract infections, including bronchiolitis and pneu-
monia. Almost all children will have been exposed to RSV
by 2 years of age. Most children who acquire RSV infection
will recover within 2 weeks; however, children with immuno-
suppression or other at-risk diseases such as chronic lung
disease (CLD) and congenital heart disease may develop
severe infections (CDC 2015b).
The IMpact-RSV trial was the first study to show
palivizumabs efficacy against RSV. This randomized, pla-
cebo-controlled, double-blind trial enrolled 1501 infants and
children with a history of prematurity (35 weeks or less) or
bronchopulmonary dysplasia (BPD) during the 19961997
RSV season. When compared with placebo, palivizumab
decreased the hospitalization rate in all subjects (10.6% vs.
4.8%; p<0.001), subjects with a history of prematurity without
BPD (8.1% vs. 1.8%; p<0.001), and subjects with BPD (12.8%
vs. 7.9%; p=0.038) (IMpact-RSV 1998).
The American Academy of Pediatrics has established a
policy guide for using palivizumab in pediatric patients at
increased risk of hospitalization for RSV infection (Box 3-1).
Infants born before 29 weeks gestation, regardless of
comorbidities, should receive palivizumab if they are born dur-
ing RSV season or are younger than 12 months at the start of
the season. This age was selected because data suggest that
children younger than 29 weeks gestation have a 24 times
higher risk of RSV hospitalization (AAP 2014b). There is no
evidence to suggest that this population would benefit from
the medication during their second year of life (AAP 2014a).
Infants born at or after 29 weeks gestation may qualify for
palivizumab, depending on their comorbid conditions. One of
these comorbidities is CLD, which, for this guideline, is defined
as a gestational age less than 32 weeks, with a requirement of
greater than 21% oxygen therapy for at least the first 28 days
of life (AAP 2014a). These patients should receive palivizumab
therapy during their first year of life. Patients who continue to
require treatment with corticosteroids, diuretics, or supple-
mental oxygen during their second year of life in the 6 months
leading up to the RSV season should receive palivizumab dur-
ing the RSV season (AAP 2014a).
BASELINE KNOWLEDGE STATEMENTS
Readers of this chapter are presumed to be familiar
with the following:
Principles of active and passive immunity
ADDITIONAL READINGS
The following free resources have additional back-
ground information on this topic:
CDC. Principles of Vaccination [homepage on the
Internet]. 2015.
PedSAP 2016 Book 1 Immunology
Box 3-1. Recommended Use of
Palivizumab in Pediatric Patients
Preterm infants born < 29 weeks gestation and during
RSV season or < 1 year at the start of RSV season
Preterm infants with chronic lung disease of
prematuritya
Children < 12 months with hemodynamically significant
congenital heart disease
Children with anatomic pulmonary abnormalities or
neuromuscular disorders
Children who are profoundly immunocompromised
during RSV season
Navajo and White Mountain Apache Native American
children
a
Defined as gestational ages < 32 weeks and a requirement of
at least 21% oxygen for at least the first 28 days of life.
RSV = respiratory syncytial virus.
Information from: American Academy of Pediatrics (AAP).
Committee on Infectious Diseases and Bronchiolitis Guidelines
Committee. Updated guidance for palivizumab prophylaxis
among infants and young children at increased risk of hospi-
talization for respiratory syncytial virus infection. Pediatrics
2014a;134:415-20.
Infants with diseases that impair the lungs ability to
clear secretions (e.g., neuromuscular disorders, pulmonary
abnormalities) are considered at high risk of prolonged hos-
pitalization because of RSV and are therefore candidates for
palivizumab therapy during their first year of life. Children with
cystic fibrosis are not considered candidates for palivizumab
therapy unless they have evidence of CLD or nutritional com-
promise (AAP 2014a).
Another disease state that qualifies an infant for palivi-
zumab therapy is hemodynamically significant congenital
heart disease. This includes infants with moderate to severe
pulmonary hypertension or acyanotic heart disease that
requires treatment for congestive heart failure, as well as car-
diac surgery. Palivizumab is recommended only during the
first year of life; however, children who undergo cardiac trans-
plantation before their second year of life may benefit from
a second year of palivizumab. In addition, surgery requiring
cardiopulmonary bypass has been shown to reduce serum
concentrations of palivizumab by 58% (AAP 2014a). Therefore,
those who receive palivizumab prophylaxis and undergo
this procedure should receive a booster dose of 15 mg/kg.
Palivizumab is not recommended in patients with hemody-
namically insignificant congenital heart disease who are not
receiving cardiac therapy; this includes those with secundum
atrial septal defect, small ventricular septal defect, pulmonic
stenosis, uncomplicated aortic stenosis, mild coarctation of
the aorta and patent ductus arteriosus, cardiac lesions cor-
rected by surgery, and mild cardiomyopathy that does require
medical treatment (AAP 2014a).
Data are limited on the hospitalization rates for RSV in
infants who undergo hematopoietic stem cell transplant
54 Passive Immunization
(HSCT) or solid organ transplantation. However, RSV is
associated with severe and fatal disease in patients who
are immunosuppressed because of chemotherapy or other
conditions. The effectiveness of palivizumab in this popu-
lation is unknown. With the potential benefits outweighing
the risks, children younger than 24 months who are severely
immunocompromised are considered good candidates for
palivizumab therapy (AAP 2014a).
Finally, although data are limited regarding the burden of
RSV infection in Native Americans, palivizumab can be con-
sidered for Navajo and White Mountain Apache patients
residing in areas where the incidence of RSV infection is high
(AAP 2014a).
For patients taking palivizumab who are hospitalized for
RSV, continued therapy is not recommended because the
likelihood of disease recurrence is minimal. In addition, no
data analyses support using palivizumab during hospital-as-
sociated outbreaks of RSV. During outbreaks, the optimal way
to reduce the spread of RSV is through infectious disease pre-
cautions, including proper hand hygiene and restricted visitor
access to areas where outbreaks are present (AAP 2014a,
2014b).
Administration
In general, palivizumab is administered monthly for a total
of 5 months, with the first dose in November (just before the
RSV season begins) and the last dose in March. This pro-
vides protection from RSV into April. Respiratory syncytial
virus seasons can vary in Alaska and Florida, so it is rec-
ommended to use regional surveillance data to determine
the onset of the RSV season and the best time to initiate
palivizumab (AAP 2014a). According to the prescribing infor-
mation, palivizumab is to be given intramuscularly in the
anterolateral thigh at a dose of 15 mg/kg and is available
in preservative-free, single-dose vials. If a patient requires
more than 1 mL of palivizumab, it should be administered in
divided doses.
Adverse Effects
According to the palivizumab prescribing information, the
most commonly associated adverse reactions include
fever (27% vs. 12% in placebo) and rash (25% vs. 10% in pla-
cebo). Postmarketing data show an increased rate of severe
thrombocytopenia and injection-site reactions with ther-
apy. In addition, palivizumab has been associated with
hypersensitivity reactions, including anaphylaxis and anaph-
ylactic shock, occurring during initial and subsequent doses.
Anaphylaxis and severe hypersensitivity reactions warrant
discontinuation of palivizumab. According to the palivi-
zumab prescribing information, continuation of therapy after
less severe hypersensitivity reactions is at the clinical judg-
ment of the provider, and there are no contraindications for
the use of palivizumab with other medications or vaccines
(AAP 2014b).
PedSAP 2016 Book 1 Immunology
IMMUNOGLOBULINS
The administration of immunoglobulin is another form of
passive immunity. The administration of exogenous immu-
noglobulin assists in the treatment of many disease states,
including primary and secondary immunodeficiencies.
Immunoglobulins are antibodies naturally present in the body
in several forms, including IgG, IgA, and IgM. Immunoglobulin
G is found in all body fluids, is present in the highest concen-
trations (around 45 times higher than IgA and 7.59.5 times
higher than IgM), and is primarily responsible for the bodys
ability to fight infections caused by pathogens such as bacte-
ria, viruses, and fungi (Chapel 2014; Gonzalez-Quintela 2008).
To a lesser extent, IgM and IgA also play a role in immune
response. Immunoglobulin M is present in the blood and
lymph fluid and is the first antibody made during an infec-
tion. Immunoglobulin A is produced in mucosal membranes
and is often the first line of defense when it comes to foreign
antigens.
Exogenous immunoglobulin is a biological product that
is fractionated from human plasma donations. The com-
mercial formulations of immunoglobulin are pooled from
thousands of donors. These formulations primarily con-
sist of IgG but may contain other subclasses, including IgA.
Pooling IgG from different donors ensures that the product
has a wide range of antibodies to treat an array of diseases
(Laguna 2015). When administered, exogenous immunoglob-
ulin is used either to replace absent immunity or to bolster the
bodys natural immune process.
The 12 immunoglobulin formulations available in the United
States are described in Table 3-1. Most of these are designed
to be administered intravenously (IVIG), but there are also
formulations for subcutaneous immunoglobulin (SCIG) and
intramuscular immunoglobulin injections. Formulations dif-
fer primarily by preparation (liquid or lyophilized powder),
concentration of IgG, type of stabilizer, amount of IgA, and
osmolality/osmolarity. Immunoglobulin formulations are
available as liquid solutions; or as lyophilized powders that
must be reconstituted before administration. Gammagard SD
comes in kits with sterile water as the diluent; Carimune does
not come with its own diluent but can be mixed with sterile
water for injection, 0.9% sodium chloride for injection, or 5%
dextrose.
Stabilizers are added to IVIG formulations to prevent IgG
aggregation and dimer and polymer formation during manu-
facturing and storage; these stabilizers (e.g., sucrose, sorbitol,
glycine, glucose, maltose, proline) are thought to contribute
to adverse effects. All IVIG formulations have been associ-
ated with renal failure, although renal failure has been most
established in formulations using sucrose as a stabilizer
(Dantal 2013). It has been hypothesized that this is because
sucrase, the enzyme responsible for metabolizing sucrose,
is only expressed in the small intestine and therefore, when
administered intravenously, cannot be appropriately metab-
olized. This causes sucrose to accumulate in the kidneys
55 Passive Immunization
 Table 3-1. Immunoglobulin Formulations

Brand Name Form IgA Osmolarity/ Average Wholesale

(Route of Administration) (Stabilizer) (mcg/mL) Osmolality Price ($)

Carimune NF Lyophilized, 3%12% 720 1921074 mOsm/kg 318 (3 g) to 1353.60

(IV) (Sucrose) (12 g)
Flebogamma DIF 5% 5% liquid < 50 240370 mOsm/kg 41.94 (10 mL vial) to
(IV) (Sorbitol) 2013.12 (400 mL vial)
Flebogamma DIF 10% 10% liquid < 100 240370 mOsm/kg 419.40 (50 mL) to
(IV) (Sorbitol) 1677.60 (200 mL)
GamaSTAN S/D 15%18% liquid Not measured Not available 90.52 (2 mL) to 413.56
(IM) (Glycine) (10 mL)
Gammagard liquid 10% liquid < 37 240300 mOsm/kg 391.90 (25 mL) to
(IV) (Glycine) 4702.68 (300 mL)
Gammagard SD Lyophilized < 12.2 636 mOsm/L (5%) 1012.20 (5 g) to
(IV) (Glucose) 1250 mOsm/L (10%) 2024.40 (10 g)
Gammaplex 10% liquid < 10 460500 mOsm/kg 809.70 (100 mL) to
(IV) (Sorbitol, glycine) 3238.80 (400 mL)
Gamunex-C 10% liquid 46 258 mOsm/kg 122.99 (10 mL) to
(IV or SC) (Glycine) 4919.52 (400 mL)
Hizentra 20% liquid 50 380 mOsm/kg 201.60 (5 mL) to
(SC) (Proline) 2016.00 (50 mL)
Octagam 5% liquid < 100 310380 mOsm/kg 154.92 (20 mL) to
(IV) (Maltose) 3873.00 (500 mL)
Privigen 10% liquid 25 320 mOsm/kg 780.00 (50 mL) to
(IV) (Proline) (isotonic) 6240.00 (400 mL)

IM = intramuscular; IV = intravenous; SC = subcutaneous.

Information from: Stein ER, Orange JS, Ballow M, et al. Therapeutic use of immunoglobulins. Adv Pediatr 2010;57:185-218;
and Redbook Online [online database]. Greenwood Village, CO: Truven Health Analytics.

and proximal tubules, leading to hyperosmolality (Rhodes
2014; Dantal 2013). Immunoglobulin-associated renal failure
occurs primarily in patients who have preexisting conditions
that increase the risk of renal failure, including prior failure,
diabetes mellitus, volume depletion, sepsis, proteinemia, and
concomitant use of nephrotoxic agents (Dantal 2013).
Hyperglycemia is another issue to consider when using
saccharide-stabilized IVIG formulations. Formulations using
glucose, in particular, produce a rapid increase in blood
glucose and insulin concentrations in patients without dia-
betes. In patients with diabetes, IVIG formulations with
glucose should be used with caution, with particular atten-
tion to insulin requirements during and after administration.
Formulations containing sucrose, maltose, and sorbitol
have no significant effect on blood glucose concentrations.
Formulations with maltose can cause falsely elevated read-
ings in blood glucose monitors that are not glucose-specific.
This includes systems using GDH-PQQ (glucose dehydroge-
nase pyrroloquinoline quinone) test strips (Ochs 2010).
Immunoglobulin formulations differ in IgA concentra-
tions. All immunoglobulin formulations contain some IgA,
and for most people, the amount is negligible. However,
in patients who are IgA deficient, administering high con-
centrations of IgA can lead to the formation of anti-IgA
antibodies and a potential anaphylactic reaction. Because
the incidence of this reaction is very low, routine screen-
ing for IgA deficiency before administering immunoglobulin
is not recommended. However, an IgA deficiency should
be considered in a patient who develops an anaphylactic
reaction to a product containing high IgA concentrations
(Rhodes 2014). If an IgA deficiency is diagnosed, IVIG prep-
arations with a low IgA concentration should be selected, or
alternatively, immunoglobulin should be administered sub-
cutaneously, if possible.

PedSAP 2016 Book 1 Immunology 56 Passive Immunization

 The final way in which immunoglobulin formulations dif-
Box 3-2. Common PIDDs Requiring
fer is their osmolarity or osmolality. Hyperosmolar solutions
Immunoglobulin Therapy
are usually older formulations, with osmolarities of 280296
mOsm/kg and higher solute concentrations. As such, they are Antibody deficiencies
more likely to cause local infusion-site reactions and venous X-linked or autosomal agammaglobulinemia
thromboembolism (Rhodes 2014; Ochs 2010). Common variable immunodeficiency disorders
IgG subclass deficiency with IgA deficiency
Clinical Uses Selective IgG subclass deficiency
Immunoglobulin has FDA-approved labeling for only a few
Specific antibody deficiency with recurrent infections
indications, with many clinical uses considered off-label.
Transient hypogammaglobulinemia of infancy
Approved indications include treatment of primary immu- Combined immunodeficiencies
nodeficiency diseases (PIDDs), prevention and control of Severe combined immunodeficiencies (SCIDs)
bleeding in idiopathic thrombocytopenic purpura, prevention
Nuclear factor kappa beta essential modulator (NEMO)
deficiency
of coronary artery aneurysm in Kawasaki disease, treatment
X-linked lymphoproliferative syndromes
of chronic inflammatory demyelinating polyneuropathy, and
Hyper-IgE syndromes
prevention of infection in chronic B-cell lymphocytic leuke- Wiskott-Aldrich syndrome
mia (Dantal 2013). This chapter focuses on replacement Ataxia-telangiectasia patients
therapy for primary and acquired immunodeficiencies and Hyper-IgM syndrome
two off-label uses: measles postexposure prophylaxis (PEP)
and Clostridium difficile infections (CDIs). PIDD = primary immunodeficiency disease.
Information from: Peter JG, Chapel H. Immunoglobulin replace-
Replacement Therapy for Primary ment therapy for primary immunodeficiencies. Immunotherapy
2014;6:853-69.
Immunodeficiencies
Primary immunodeficiency diseases are caused by inherited
defects of the immune system. The more than 230 forms
of PIDD (Al-Herz 2014; Chapel 2014) affect up to 1 in 4000
because it contains live viruses. The mechanism by which
people in the United States (Shehata 2010). Although PIDDs
immunoglobulin benefits during measles PEP is not fully
can be diagnosed at any age, they are typically identified
understood, but it may pertain to the ability of immunoglobu-
at around 6 months of age when maternal IgG diminishes
lin to neutralize the measles virus (Young 2014).
(Shehata 2010). Patients with PIDD have increased sus-
A Cochrane review evaluated the effectiveness of immu-
ceptibility to infections, inflammation, and autoimmunity
noglobulin for measles PEP. This analysis contained seven
(Chapel 2014).
studies (total n=1432) in which IVIG or intramuscular immu-
Two main categories of PIDD are cellular defects and anti-
noglobulin was given as the sole therapy for measles PEP.
body deficiencies. Patients with cellular defects usually
Immunoglobulin formulations decreased the risk of mea-
require replacement of their stem cells; therefore, the treat-
sles by 83% when administered within 7 days of exposure to
ment of choice is HSCT. The other group of patients with
the disease. This represented an absolute risk reduction of
PIDD lack specific antibodies (humoral immunodeficiencies);
37 per 1000 patients and a number needed to treat of 27. In
therefore, the treatment of choice for them is replacement
three studies in this meta-analysis, immunoglobulin prepa-
therapy with immunoglobulin. Although there are two main
rations significantly decreased mortality compared with no
categories of PIDDs, some patients may have a combination
treatment (RR 0.24; 95% CI, 0.130.44). In two studies that
of both components. Common PIDDs requiring immunoglob-
compared immunoglobulin with the measles vaccine, the
ulin therapy are listed in Box 3-2.
measles vaccine appeared to be more effective than immuno-
Because PIDD is a chronic disorder, treatment is lifelong.
globulin for PEP; however, this result is inconclusive because
The goal of therapy is to prevent infections and organ damage
of the limited number of studies (Young 2014). The studies
(Chapel 2014). Targeting a specific IgG serum concentration
in this meta-analysis excluded populations that would most
is only useful in select cases. As a result, the immunoglobu-
benefit from this therapy, including pediatric and immuno-
lin dose must be highly individualized to obtain the desired
compromised patients.
clinical effects. Starting doses vary depending on the type of
A small study completed in Turkey compared IVIG with
PIDD but can be 100600 mg/kg every month (Shehata 2010).
the measles vaccine for PEP. In this setting, the mother of
Measles PEP a patient in a pediatric ward exposed 44 children and 101
A promising use for immunoglobulin is measles PEP, particu- adults to measles. The risk of contagion was high because
larly for children who have not completed the full vaccination the pediatric ward was an open setting with two large rooms
series or who have immunocompromise and therefore can- consisting of 25 and 26 beds each. Of the 44 exposed chil-
not receive the measles, mumps, and rubella (MMR) vaccine dren, 25 (56.8%) were able to provide documentation of a full

PedSAP 2016 Book 1 Immunology 57 Passive Immunization

measles vaccine series. The remaining patients received the
measles vaccine (10 patients) or IVIG (9 patients), depending
on their age and concurrent diseases. At the 21-day follow-up,
none of the children had evidence of measles (Tapisiz 2015).
The CDC recommends 400 mg/kg of IVIG as a single dose
for measles PEP. Administration of the measles or varicella-
containing vaccine should be delayed by 8 months (CDC
2015a).
C. difficile Infections
Reductions in the recurrence of CDIs present another
unique opportunity to use immunoglobulin. C. difficile is a
gram-positive, toxin-producing bacterium. Toxins A and B are
responsible for most symptoms associated with CDI and can
be very resistant to normal eradication methods. More than
70% of adults worldwide have low antibody titers to C. diffi-
cile toxins A and B; therefore, immunoglobulin formulations
may also contain limited quantities of these antibodies (Shah
2015; Johnson 1997). Five pediatric patients with recurrent
CDI were included in the first study to evaluate IVIG for the
treatment of CDI and were treated with 0.4 mg/kg of IVIG
every 3 weeks. These patients had complete resolution of
symptoms and eradication of toxin B from their stool (Leung
1991). Additional studies have had mixed outcomes (Shah
2015). Although immunoglobulin may not be a cost-effective
therapy for all CDIs, it can be a viable option for patients who
are refractory to standard treatment.
Other Uses
Immunoglobulin has more than 150 off-label uses; this rep-
resents about 75% of its clinical use (Wong 2015; Rhodes
2014). One of the primary uses of immunoglobulin in pedi-
atric patients, outside PIDD, is Kawasaki disease. Kawasaki
disease is a vasculitis of small- and medium-sized arteries.
Kawasaki disease can initially cause acute problems, includ-
ing fever, rash, and cervical lymphadenopathy, but can then
progress to dilation and possibly aneurysm of the coronary
arteries (Wong 2015). The American Heart Association rec-
ommends a one-time dose of 2 g/kg of IVIG within 510
days of the onset of fever. A meta-analysis showed that IVIG
decreased coronary artery abnormality formation at 30 days
(RR 0.74 [95% CI, 0.610.90]) compared with placebo (Oates-
Whitehead 2003).
Immune thrombocytopenia (ITP) is another disorder
for which immunoglobulin may offer therapeutic benefits.
Immune thrombocytopenia is one of the most common
acquired bleeding disorders in children, usually occurring after
a viral illness. Most ITP cases involve mild mucosal bleeding
and are self-limiting. However, some may progress to serious
intracranial or GI hemorrhage (Wong 2015). In adults, most
cases of ITP are chronic; therefore, corticosteroids are con-
sidered first-line therapy. In children, however, most cases are
acute, and IVIG is the treatment of choice. In this acute pro-
cess, destruction of platelets occurs through autoantibodies
PedSAP 2016 Book 1 Immunology
against platelet antigens. Intravenous immunoglobulin can
neutralize these antibodies (Wong 2015). Additional adverse
effects associated with the use of IVIG in ITP include asep-
tic meningitis and anaphylaxis. Thromboembolism also may
occur, although it is rare in pediatric patients (Wong 2015).
Immunoglobulin plays an important role in Guillain-Barr
syndrome. Guillain-Barr syndrome is an acute, inflamma-
tory demyelinating neuropathy characterized by symptoms
such as flaccid paralysis, weakness, diminished deep ten-
don reflexes, and, in some cases, respiratory failure requiring
ventilator support. Although most patients recover fully,
some continue to have sequelae of the disease. Predictors of
continued symptoms include age younger than 9 years and
rapid progression of symptoms. Immunoglobulin hinders the
humoral and cell-mediated process that leads to destruction
of the axons and, in animal models, promotes remyelination.
Studies in children, although limited, suggest that IVIG can
lead to early motor function recovery (Wong 2015).
Adverse Effects
Adverse effects associated with immunoglobulin formu-
lations include fever, chills, flushing, headache, back pain,
chest pain, bronchospasm, nausea, myalgias, and asep-
tic meningitis. More serious, but rarer adverse reactions
include seizures, pulmonary edema, hemolysis, anaphy-
laxis, renal impairment, and thromboembolism (Chapel
2014). Reactions can vary with formulations and route of
administration. Administering immunoglobulin at a slower
infusion rate may decrease the occurrence of some adverse
reactions. Historically, there has been a concern regarding
transmission of bloodborne pathogens with immunoglobulin
administration, but the current purification and manufac-
turing processes have minimized this risk and no cases of
disease transmission have been reported in the past 20 years
(Chapel 2014). Hypersensitivity reactions, which are rare,
appear as a typical hypersensitivity reaction and warrant dis-
continuing the product.
Interactions with Live Virus Vaccines
Immunoglobulins can interact with the MMR and varicella
vaccines. However, immunoglobulins do not interact with
other live virus vaccines, including the live attenuated influ-
enza virus, rotavirus, herpes zoster, yellow fever, and typhoid
vaccines. The IVIG product can interfere with the bodys abil-
ity to produce an immune response to MMR or varicella. If
possible, MMR- or varicella-containing vaccines should be
administered at least 14 days before IVIG therapy is initiated.
If this is not possible, these vaccines should be delayed until
311 months after IVIG therapy, depending on the indication.
When the MMR or the varicella vaccine has been given and
IVIG cannot be delayed by 2 weeks, the vaccine should be
readministered at the appropriate time, or serologic testing
may be used to determine whether antibodies have formed to
the corresponding virus (CDC 2015a).
58 Passive Immunization
IG Formulations
As mentioned previously, immunoglobulin can be adminis-
tered intravenously, subcutaneously, and intramuscularly.
Immunoglobulin is usually administered intravenously.
This route is ideal because it has a rapid onset of action
and allows for larger-volume administration (Peter 2014).
However, IVIG requires venous access and the potential for
repeated trips to a hospital or infusion center for treatment.
Some patients can successfully self-administer IVIG at home.
Because SCIG does not require venous access, it has
gained popularity. The subcutaneous formulations have
FDA-approved labeling only for PIDD, but they are often used
off-label. Subcutaneous immunoglobulin can be admin-
istered twice weekly to biweekly and may be particularly
suitable for patients who receive smaller volumes of admin-
istration (2030 mL, depending on the formulation) or those
with small or poor veins. Another advantage of SCIG is that
it is associated with decreased adverse reactions, includ-
ing hypersensitivity in those who are IgA deficient. However,
the incidence of local injection-site reactions (e.g., redness,
swelling) may be increased (Rhodes 2014).
In most instances, IVIG and SCIG are considered equally
efficacious therapies. However, there is debate regarding
whether the conversion is a 1:1 ratio. Subcutaneous immu-
noglobulin has a lower AUC than IVIG, so mathematically, to
meet FDA noninferiority standards, a higher dose of SCIG is
necessary. The FDA has approved a dose adjustment coeffi-
cient of 1.53 to convert IVIG to SCIG. In addition, data analyses
show that equivalent or even lower doses of SCIG can elicit
IgG concentrations equal to those of IVIG. The choice of con-
version method depends on health care system preference.
Regardless of the method used, when transitioning a patient
between IVIG and SCIG, the patient should be monitored for
both IgG concentrations and clinical effect (Peter 2014).
The first commercial immunoglobulin formulations were
given intramuscularly. However, this route has fallen out of
favor because of the large volumes required for administra-
tion and the associated pain.
HYPERIMMUNE GLOBULINS
Hyperimmune globulins are similar to immunoglobulin
except that they contain high concentrations of antibodies to
one specific antigen. Rather than providing general protec-
tion and bolstering the overall immune system, hyperimmune
globulins protect against a specific disease and are often
considered after exposure to a particular disease. Several
hyperimmune globulins are available for use in pediatric
patients.
Hepatitis B Immunoglobulin
Hepatitis B is a bloodborne disease; the hepatitis B virus
(HBV) has been well established to cause acute and chronic
hepatitis, cirrhosis, and hepatocellular carcinoma. In chil-
dren, the most common route of transmission is perinatal.
PedSAP 2016 Book 1 Immunology
Infants born to HBV-positive mothers should receive both
hepatitis B immunoglobulin (HBIG) and HBV vaccine within
24 hours (preferably within 12 hours) of birth. The HBV vac-
cine schedule remains unchanged, with the second dose at
2 months of age and the third at 6 months of age. Testing for
HBV transmission should be performed 12 months after the
final dose, but not in children younger than 9 months of age.
Administration of this combination decreases the rate of peri-
natal transmission of HBV infection by 85%95% (CDC 2015a;
Hsu 2011).
For infants whose mothers HBV status is unknown, the full
vaccine series is recommended, with the first dose within 12
hours of life. An exception to this rule is in preterm infants
(37 weeks gestation or less) weighing less than 2000 g, who
should receive the combination of HBV vaccine and HBIG
within 12 hours of life. Preterm infants weighing less than
2000 g may have a decreased response to the HBV vaccine;
therefore, the vaccine series should be restarted once the
patient becomes chronologically 1 month of age. In a preterm
infant weighing less than 2000 g whose mothers HBV status
is negative, HBV vaccination can be delayed until the infant
is chronologically 1 month of age (CDC 2015a). Hepatitis B
immunoglobulin is usually well tolerated, with hypotension
and nausea as the most common adverse effects.
Rabies Immunoglobulin
Rabies is a rare but fatal disease when left untreated. In the
United States, rabies is primarily transmitted by infected bats,
but raccoons, foxes, skunks, and coyotes are also considered
vectors for the disease. Transmission usually involves being
bitten by an infected animal but can also occur by percuta-
neous, permucosal, and airborne routes. Symptoms of rabies
infection are nonspecific at first and include fever, malaise,
headache, irritability, nausea, and vomiting. This is followed
by an acute neurologic phase consisting of hyperexcitability,
hyperactivity, salivation, and a fear of water and air. Patients
typically die within 5 days of symptom onset.
Human rabies immunoglobulin is available for use as PEP
in patients who have been exposed to a rabid or potentially
rabid animal. The decision to use human rabies immunoglob-
ulin for PEP should be individualized, with consideration for
the type of animal exposure, characteristics or behavior of the
animal, and health department data on local rabies activity.
Human rabies immunoglobulin should be used in combi-
nation with the rabies vaccine. The rabies vaccine should be
given intramuscularly in the anterolateral thigh in children, in
a series of four doses given on days 0, 3, 7, and 14 of exposure
to the animal. A fifth dose may be considered if the patient
is immunocompromised. Human rabies immunoglobulin
should be given on the day of exposure, or as soon as pos-
sible, to provide immediate protection against rabies while
the vaccine begins to take effect. It is unnecessary to give
human rabies immunoglobulin beyond day 8 of rabies expo-
sure because by then, the vaccine will be effective. The dose
59 Passive Immunization
of human rabies immunoglobulin is 20 international units/kg;
this should be administered intramuscularly in small volumes
and, if possible, around the wound site and a site distant to
the wound. Human rabies immunoglobulin may interfere with
live-virus vaccines; therefore, the administration of these
vaccines should be separated by at least 3 months. Soreness
at the injection site and elevated body temperature are the
most common reported adverse effects. Sensitization with
repeated doses has been reported, particularly in those who
are immunoglobulin deficient.
Tetanus Immunoglobulin
Tetanus is caused by Clostridium tetani and can cause
sustained muscle contractions. Tetanus is the only vac-
cine-preventable disease that is noncommunicable; it is
acquired through C. tetani spores found in the environment. If
left untreated, tetanus can be fatal, either from muscle paraly-
sis itself or from associated complications such as aspiration
pneumonia, pulmonary embolism, or dysregulation of the
autonomic nervous system (Hayney 2014).
Tetanus immune globulin can be given to provide passive
immunity in those exposed to the disease. Most cases of
exposure to tetanus can be treated with a booster to tetanus
toxoid vaccine. Administration of tetanus immunoglobulin
with tetanus toxoid is indicated in patients with an unclean
or major wound who have received fewer than three doses
or an unknown number of tetanus toxoid immunizations.
Tetanus immunoglobulin, which is administered intramuscu-
larly, should be given at a site separate from tetanus toxoid.
Adverse effects of tetanus immunoglobulin include pain, ten-
derness, and stiffness at the injection site.
Varicella Zoster Immunoglobulin
Varicella zoster virus causes varicella or chickenpox. In
children, the most common manifestation of this disease is
a maculopapular rash resulting in vesicular lesions and even-
tual crusting. Once the body has been infected, the virus
may return in the form of shingles, which is relatively rare in
children. Unfortunately, disseminated disease is a risk with
varicella zoster virus, particularly in immunocompromised
patients. Disseminated disease can cause complications
including aseptic meningitis, transverse myelitis, Guillain-
Barr syndrome, thrombocytopenia, hemorrhagic varicella,
purpura fulminans, glomerulonephritis, myocarditis, arthritis,
orchitis, uveitis, iritis, and hepatitis (CDC 2015a). Like mea-
sles, varicella zoster vaccine is not initiated until 1 year of
age, and the series is not finished until 46 years of age. In
addition, varicella zoster vaccine is a live attenuated vaccine
that cannot be given to individuals with immunocompromise
(CDC 2016).
Postexposure prophylaxis for varicella zoster virus is
indicated in children who are (1) immunocompromised and
exposed to varicella, (2) born to a mother who develops vari-
cella 5 days before or up to 2 days after delivery, or (3) preterm
PedSAP 2016 Book 1 Immunology
infants less than 28 weeks gestation who weigh less than
1000 g and who have been exposed to varicella in the hospi-
tal. Varicella exposure is defined as direct indoor contact with
an infected person for more than 1 hour.
Varicella zoster immunoglobulin is administered intra-
muscularly and should be given within 10 days of exposure.
Dosing is weight based. According to the varicella zoster
immunoglobulin prescribing information, the dose for new-
borns weighing 2 kg or less is 62.5 plaque-forming units;
otherwise, the dose is 125 plaque-forming units per 10-kg
weight, up to 625 units. The varicella zoster immunoglobulin
may only attenuate the disease, meaning the exposed patient
can still be infectious despite the timely administration of
immunoglobulin. In addition, varicella zoster immunoglobu-
lin can increase the incubation period of varicella disease to
up to 28 days. As a result, isolation precautions may be pru-
dent in children with high-risk exposure.
In all instances, if varicella is prevented, routine administra-
tion of varicella zoster virus vaccine is recommended, when
possible. This immunoglobulin has the potential to interact
with all live attenuated virus vaccines; therefore, administra-
tion of these vaccines should be delayed by 3 months. The
most common adverse effects reported with varicella zoster
immunoglobulin are injection-site pain, headache, rash,
fatigue, chills, and nausea. Varicella zoster immunoglobulin
contains 40 mcg/mL of IgA; thus, it is contraindicated in IgA-
deficient individuals who have had a hypersensitivity reaction
to IgA containing immunoglobulin.
Cytomegalovirus Immunoglobulin
Although cytomegalovirus (CMV) is a fairly benign disease
in the general population, it can be life threatening in immu-
nocompromised patients, particularly in those who have
undergone a solid organ transplant or HSCT. The sequelae
of a disseminated CMV infection in solid organ transplant
recipients include late-onset malignancy, acute and chronic
allograph injury, chronic allograph vasculopathy, and death
(Hsu 2011). The highest risk of transmission occurs when a
CMV-negative patient receives an organ from a CMV-positive
donor. This is one of the primary situations in which CMV
immunoglobulin (CMVIG) is warranted.
Cytomegalovirus immunoglobulin, which contains anti-
bodies to CMV, is used in conjunction with other antiviral
therapies (ganciclovir or valganciclovir). Cytomegalovirus
immunoglobulin use is more established in solid organ trans-
plantation than in HSCT, but it can be used in both situations
(Hsu 2011). The dose and schedule of CMVIG depend on the
type of transplantation, but it is usually given every 2 weeks
after transplantation, with the final dose administered
16 weeks after transplantation. Adverse effects of CMVIG
include flushing, chills, muscle cramps, back pain, chest
tightness, fever, nausea, vomiting, hypertension, and tachy-
cardia. Many of these effects are considered infusion related
and may subside if the infusion rate is slowed.
60 Passive Immunization
PHARMACIST ROLE
Pharmacists can play a vital role in the use of passive immu-
nity in many areas, including product selection. All of these
products are expensive, and cost-effectiveness must be con-
sidered when selecting which products a hospital should
stock. For example, it may be tempting to select an IVIG prod-
uct with the lowest wholesale acquisition cost. However,
confounding factors such as pharmacist compounding
time and dose and administration time should be consid-
ered, which influence nursing support time and availability of
patient turnover in an infusion center. By participating in a
hospitals pharmacy and therapeutics committees, pharma-
cists can assist in selecting the most cost-effective product
for their institution.
Another important function of pharmacists is to verify that
patients who have been prescribed palivizumab or a specific
immunoglobulin truly meet the necessary criteria and have
no contraindications for receiving that product. Using these
products only in patients with an indication can result in a
large cost savings to an institution.
Finally, pharmacists can play a role in identifying and man-
aging the adverse effects associated with these products.
For example, they can assist in selecting alternative thera-
pies for patients who develop adverse reactions associated
with stabilizers, osmolarity, or IgA content.
CONCLUSION
In passive immunization, antibodies are provided for short-
term protection against infectious diseases. Although this
occurs naturally through transmission from mother to infant
transplacentally or through breast milk, it may entail providing
exogenous antibodies. Palivizumab, a monoclonal antibody,
is a form of passive immunization and can prevent RSV infec-
tion in those who are at a particularly high risk of acquiring the
disease. Immunoglobulins are also a form of passive immuni-
zation and are used in many diseases, including replacement
therapy for primary and acquired immunodeficiencies,
measles PEP, and CDI. Finally, hyperimmune globulins, or
Practice Points
Passive immunity is the process of providing antigens to a
patient. This can be done maternally or through products
such as monoclonal antibodies, immunoglobulin, and
hyperimmune globulin.
Palivizumab is indicated for preventing RSV in patients
who are at risk of acquiring the infection.
Immunoglobulin has been used in more than 150 disease
states. Because PIDDs rely on the use of immunoglobulin,
they should be prioritized for therapy.
Many hyperimmune globulins exist and can be particularly
helpful in specific at-risk populations.
Pharmacists can play a vital role in passive immunization,
including product selection, patient prioritization, and
management of adverse effects.
PedSAP 2016 Book 1 Immunology
immunoglobulins for specific diseases, also work as passive
immunizations for the prevention or PEP of specific diseases.
In all of these instances, clinical pharmacists can play a vital
role in selecting the product and treating the patient.
REFERENCES
Al-Herz W, Bousfiha A, Casanova JL, et al. Primary immuno-
deficiency disease: an update on the classification from
the International Union of Immunological Societies expert
committee for primary immunodeficiency. Front Immunol
2014;5:1-33.
American Academy of Pediatrics (AAP). Committee
on Infectious Diseases and Bronchiolitis Guidelines
Committee. Updated guidance for palivizumab prophy-
laxis among infants and young children at increased risk
of hospitalization for respiratory syncytial virus infection.
Pediatrics 2014a;134:415-20.
American Academy of Pediatrics (AAP).Committee
on Infectious Diseases and Bronchiolitis Guidelines
Committee. Updated guidance for palivizumab prophy-
laxis among infants and young children at increased risk
of hospitalization for respiratory syncytial virus infection.
Pediatrics 2014b;134:620-38.
Centers For Disease Control. Principles of Vaccination. 2015a.
Centers For Disease Control. RSV Infection and Incidence.
2015b.
Centers For Disease Control. 2016 Combined Recommended
Immunization Schedule for Persons Aged 0 Through 18 ears.
Chapel H, Prevot J, Gaspar HB, et al. Primary immune defi-
ciencies principles of care. Front Immunol 2014;5:1-12.
Dantal J. Intravenous immunoglobulins: in-depth review
of excipients and acute kidney risk injury. Am J Nephrol
2013;38:275-84.
Gonzalez-Quintela A, Alende R, Gude F, et al. Serum levels of
immunoglobulins (IgG, IgA, IgM) in a general adult popu-
lation and their relationships with alcohol consumption,
smoking and common metabolic abnormalities. Clin Exp
Immunol 2008;151:42-50.
Hayney MS. Vaccines, toxoids and other immunobi-
ologics. In: DiPiro JT, Talbert RL, Yee GC, et al, eds.
Pharmacotherapy, A Pathophysiologic Approach, 9th ed.
New York: McGraw-Hill, 2014:2007.
Hsu JL, Safdar N. Polyclonal immunoglobulins and
hyperimmune globulins in prevention and manage-
ment of infectious disease. Infect Dis Clin North Am
2011;25:773-88.
IMpact-RSV Study Group. Palivizumab, a humanized respi-
ratory syncytial virus monoclonal antibody, reduces
hospitalization from respiratory syncytial virus infection in
high-risk individuals. Pediatrics 1998;102:531-7.
Johnson S. Antibody responses to clostridial infection in
humans. Clin Infect Dis 1997;25(suppl 2):S173-7.
Laguna P, Golebiowska-Staroszczyk S, Trazaska M, et al.
Immunoglobulins and their use in children. Adv Clin Exp
Med 2015;24:153-9.
61 Passive Immunization
Leung DY, Kelly CP, Boguniewicz M, et al. Treatment with
intravenously administered gamma globulin of chronic
relapsing colitis induced by Clostridium difficile toxin.
J Pediatr 1991;118:633-7.

Oates-Whitehead RM, Baumer JH, Haines L, et al.

Intravenous immunoglobulin for the treatment of
Kawasaki disease in children. Cochrane Database Syst
Rev 2003;4:CD004000.

Ochs HD, Siegel J, Young HE. Stabilizers used in intrave-

nous immunoglobulin products: a comparative review.
Pharmacy Practice News. August 2010:1-8.

Peter JG, Chapel H. Immunoglobulin replacement ther-

apy for primary immunodeficiencies. Immunotherapy
2014;6:853-69.

Rhodes RT. Immune globulin: each product is unique. IG

Living. 2014:10-2.

Shah PJ, Vakil N, Kabakov A. Role of intravenous immune

globulin in streptococcal toxic shock syndrome and
Clostridium difficile infection. Am J Health Syst Pharm
2015;72:1013-9.

Shehata N, Palda V, Bowen T, et al. The use of immunoglob-

ulin therapy for patients with primary immune deficiency:
an evidence-based practice guideline. Transfus Med Rev
2010;24:S28-50.

Tapisiz A, Polat M, Kara SS, et al. Prevention of mea-

sles spread on a paediatric ward. Epidemiol Infect
2015;143:720-4.

Wong PH, White KM. Impact of immunoglobulin therapy in

pediatric disease: a review of immune mechanisms. Clin
Rev Allergy Immunol 2015 Jul 4. [Epub ahead of print]

Young MK, Nimmo GR, Cripps AW, et al. Post-exposure

passive immunisation for preventing measles. Cochrane
Database Syst Rev 2014;4:CD010056.

PedSAP 2016 Book 1 Immunology 62 Passive Immunization

Self-Assessment Questions
41. Which one of the following patients is the best candidate
to receive palivizumab during the respiratory syncytial
virus (RSV) season?
A. A premature infant (born at 30 weeks 2 days) with
no apparent health problems
B. A premature infant (born at 31 weeks 3 days) who is
5 weeks old and has required 25% oxygen therapy
since birth
C. A 3-month-old infant with a small ventricular septal
defect
D. A newborn infant with a new diagnosis of cystic
fibrosis but no signs of chronic lung disease (CLD)
42. Which one of the following patients is the best candidate
for a dose of palivizumab during his or her second year of
life?
A. A 13-month-old who has continued to need
corticosteroids for CLD since birth
B. A 15-month-old (born at 28 weeks 4 days gestation)
with no chronic medical issues
C. A 14-month-old with aortic stenosis
D. A 16-month-old who had surgery for acyanotic heart
disease at age 6 weeks
43. Which one of the following patients with congenital heart
disease would most warrant administration of a booster
dose of palivizumab?
A. A 5-month-old whose patent ductus arteriosus was
repaired
B. An 11-month-old with severe pulmonary
hypertension
C. A 10-month-old who received a cardiac transplant 2
weeks ago
D. A 9-month-old with cardiomyopathy requiring
chronic medication
44. As a pediatric ICU pharmacist, you see three patients
with a diagnosis of RSV infection simultaneously in
December. The father of a patient in your care worries
that this is an RSV outbreak and asks that palivizumab be
administered to all patients on the unit. Which one of the
following is the best course of action in this situation?
A. Conduct an in-service on infectious disease
precautions.
B. Give all patients a booster dose of palivizumab.
C. Give patients who appear to have RSV symptoms a
dose of palivizumab.
D. Place all patients on isolation precautions.
Questions 45 and 46 pertain to the following case.
C.F. is a 5-year-old girl with Kawasaki disease. Her medical
history also includes polycystic kidney disease with a
PedSAP 2016 Book 1 Immunology
stable estimated glomerular filtration rate at 52 mL/minute
per 1.73 m2. You would like to initiate intravenous immunoglob-
ulin (IVIG) to treat her Kawasaki disease but are concerned
about this agents association with acute renal failure.
45. Which one of the following products is most likely to
cause acute renal failure in C.F.?
A. Carimune NF
B. Octagam
C. Privigen
D. Hizentra
46. C.F. has been admitted to the pediatric ICU with presumed
sepsis. Which one of the following antibiotics would place
C.F. at highest risk of developing acute renal failure?
A. Vancomycin
B. Ertapenem
C. Ceftazidime
D. Ciprofloxacin
47. A 6-month-old boy receives a diagnosis of a common
variable immunodeficiency disorder. The patients older
sister has an IgA deficiency, and his mother is concerned
that the patient may develop an adverse reaction to
immunoglobulin. Which one of the following immuno-
globulin products is best to recommend for this patient?
A. Carimune NF
B. Gammagard SD
C. Octagam
D. Flebogamma DIF
48. Your institution is experiencing a shortage of immuno-
globulin. Which one of the following patients has the
highest priority to receive immunoglobulin?
A. A 3-year-old girl with Clostridium difficile infection
B. A 6-year-old immunocompetent girl exposed to
measles at school
C. A 7-year-old boy with autosomal
agammaglobulinemia
D. A 5-year-old boy with Guillain-Barr syndrome after
the influenza vaccine
49. A 9-month-old girl with a series of upper respiratory
infections was recently given a diagnosis of IgG subclass
deficiency. She will be initiated on Octagam IVIG therapy.
Which one of the following surrogate markers would best
determine the success of this patients immunoglobulin
therapy?
A. Increase in serum IgG concentrations
B. Decreased frequency of upper respiratory infections
C. Decreased adverse reactions associated with IVIG
infusion
D. Decrease in CRP concentrations
63 Passive Immunization
Questions 50 and 51 pertain to the following case.
J.V. is an 8-month-old boy (weight 8 kg) who has been exposed
to measles at his day care. Because his sister has a history
of a small bowel transplant, J.V.s pediatrician wants to pre-
scribe him IVIG for measles postexposure prophylaxis.
50. Your hospital formulary contains Privigen. Which one of
the following is the most appropriate volume to adminis-
ter to J.V.?
A. 3.2 mL
B. 6.4 mL
C. 32 mL
D. 64 mL
51. After receiving IVIG today, when would it be best for J.V.
to receive the measles vaccine?
A. 1 year of age.
B. 16 months of age.
C. 2 years of age.
D. 5 years of age.
52. An 11-year-old boy has received IVIG for X-linked agam-
maglobulinemia (an antibody deficiency primary
immunodeficiency disease) since 6 months of age.
Immediately after his recent transfusion, he has ten-
derness, warmth, and redness along the vein that was
injected. Which one of the following is best explains this
patients new symptoms?
A. The hospital switched its formulary IVIG from
Privigen to Gammaplex.
B. The patient may have developed acute kidney
failure.
C. The patient is having a drug interaction with a
concurrent antibiotic.
D. The patient is having a hypersensitivity reaction.
53. You believe that one of your patients is having infusion
reactions associated with recently initiated IVIG ther-
apy. Which one of the following would best decrease the
occurrence of these adverse effects?
A. Ask the patient to lie down during IVIG infusion.
B. Decrease the infusion rate.
C. Switch to a formulation with less IgA.
D. Transition the patient to intramuscular
immunoglobulin.
54. Which one of the following patients would be the best
candidate to remain on IVIG as opposed to switching to
subcutaneous immunoglobulin?
A. An 8-year-old girl with a documented IgA deficiency
B. A 6-year-old boy who requires a large volume of
immunoglobulin
C. A 4-year-old girl with a high occurrence of systemic
adverse reactions to immunoglobulin
D. A 15-year-old male adolescent who desires more
independence
PedSAP 2016 Book 1 Immunology
55. A male infant (weight 1580 g) is born at 31 weeks 5 days
gestation to a mother whose hepatitis B virus (HBV) sta-
tus is unknown. Which one of the following is the best
course of action regarding administering the hepatitis B
immunoglobulin (HBIG) and HBV vaccines to this infant?
A. Administer the HBIG and HBV vaccines now.
B. Administer the HBIG vaccine now and the HBV
vaccine at 1 month chronological age.
C. Administer the HBIG vaccine now; the HBV vaccine
is not indicated.
D. Administer the HBV vaccine now; the HBIG vaccine
is not indicated.
56. A 14-year-old male adolescent presents to the local
ED after allegedly being bitten by a bat while vacation-
ing with his family at their cabin. Although the patient
is convinced he was bitten, no visible bite marks are
found. The bat is not available for rabies testing. A
phone call to the local health department informs the
ED care team that several bats in the area have been
confirmed as being infected with rabies. Which one of
the following is best to recommend regarding adminis-
tering the rabies vaccine and rabies immunoglobulin in
this patient?
A. Administer rabies immunoglobulin only.
B. Administer a four-dose series of rabies vaccine only.
C. Administer a four-dose series of rabies vaccine and
one dose of rabies immunoglobulin.
D. Administer a five-dose series of rabies vaccine and
one dose of rabies immunoglobulin.
57. In which one of the following scenarios would it be
best to recommend tetanus toxoid alone over tetanus
immunoglobulin? Assume the patient is a 5-year-old girl
who is otherwise healthy with a potential exposure to
tetanus.
A. A history of one diphtheria, tetanus, and pertussis
(DTaP) vaccine
B. A history of two DTaP vaccines
C. A history of three DTaP vaccines
D. An unknown vaccine history regarding DTaP
vaccines
58. Which one of the following patients is the best candidate
to receive the varicella zoster immunoglobulin?
A. A 7-year-old immunocompetent girl who is up-to-
date on all vaccines and is exposed to varicella at
school
B. A 4-year-old immunocompetent boy who was
exposed to varicella 2 weeks prior
C. A preterm infant (weight 954 g) during a hospital
outbreak of varicella
D. A term newborn whose mother develops varicella 1
week after giving birth
64 Passive Immunization
59. To evaluate the efficacy of cytomegalovirus immuno-
globulin (CMVIG) in preventing CMV in hematopoietic
stem cell transplant (HSCT) recipients, researchers com-
pleted a retrospective chart review of the past 2 years.
They identified 214 patients with an HSCT who received
CMV prophylaxis, either with valganciclovir alone or
CMVIG and valganciclovir in combination. The CMV
infection rate in the patients taking valganciclovir alone
was 25.6% compared with 10.2% in the combination ther-
apy group. Which one of the following best describes the
number needed to treat with CMVIG to prevent one CMV
infection?
A. 4.
B. 7.
C. 16.
D. 31.
60. A 5-year-old boy receives a measles, mumps, and rubella
(MMR) vaccine today for entry into kindergarten. At the
same appointment, he is given a diagnosis of a second-
ary immunodeficiency disease. To maximize the efficacy
of the MMR vaccine, which one of the following best
depicts the soonest he can receive IVIG?
A. 2 weeks
B. 1 month
C. 6 weeks
D. 2 months

PedSAP 2016 Book 1 Immunology 65 Passive Immunization

Learner Chapter Evaluation: Passive Immunization.
As you take the posttest for this chapter, also evaluate the
materials quality and usefulness, as well as the achievement
of learning objectives. Rate each item using this 5-point scale:
Strongly agree
Agree
Neutral
Disagree
Strongly disagree
37. The content of the chapter met my educational needs.
38. The content of the chapter satisfied my expectations.
39. The author presented the chapter content effectively.
40. The content of the chapter was relevant to my practice
and presented at the appropriate depth and scope.
41. The content of the chapter was objective and balanced.
42. The content of the chapter is free of bias, promotion, or
advertisement of commercial products.
43. The content of the chapter was useful to me.
44. The teaching and learning methods used in the chapter
were effective.
45. The active learning methods used in the chapter were
effective.
46. The learning assessment activities used in the chapter
were effective.
47. The chapter was effective overall.
PedSAP 2016 Book 1 Immunology
Use the 5-point scale to indicate whether this chapter pre-
pared you to accomplish the following learning objectives:
48. Distinguish the unique features of specific formulations
of immunoglobulins.
49. Assess the appropriateness of palivizumab for specific
patient populations.
50. Evaluate the warnings, precautions, and contraindica-
tions of agents used in passive immunization.
51. Devise a plan for preventing and treating the adverse
effects associated with immunoglobulins.
52. Evaluate the appropriateness of hyperimmune globulin
therapy for specific patient exposures.
53. Please provide any specific comments related to any
perceptions of bias, promotion, or advertisement of
commercial products.
54. Please expand on any of your above responses, and/or
provide any additional comments regarding this chapter:
Questions 5557 apply to the entire learning module.
55. How long did it take you to read the instructional
materials in this module?
56. How long did it take you to read and answer the assess-
ment questions in this module?
57. Please provide any additional comments you may have
regarding this module:
66 Passive Immunization
Clinical and Practice Updates
Clinical and Practice Updates Panel

Series Editors: Reviewers

Marcia L. Buck, Pharm.D., FCCP, FPPAG Shirley M. Tsunoda, Pharm.D.
Clinical Coordinator Associate Professor
University of Virginia Childrens Hospital Skaggs School of Pharmacy and Pharmaceutical Sciences
Associate Professor University of California San Diego
Department of Pediatrics La Jolla, California
University of Virginia School of Medicine Brenda Winger, Pharm.D., BCPS, BCOP
Clinical Professor
Pharmacy Manager
Virginia Commonwealth University School of Pharmacy
Intermountain Healthcare
Department of Pharmacy Services
Salt Lake City, Utah
University of Virginia Health System
Charlottesville, Virginia Monica A. Puebla, Pharm.D., MBA, MHA, BCPS
Healthcare Professional Reviewer
Kalen B. Manasco, Pharm.D., BCPS
Med-ERRS, Inc.
Clinical Associate Professor Houston, Texas
Department of Clinical and Administrative Pharmacy
University of Georgia College of Pharmacy
Augusta, Georgia TRANSLATING EVIDENCE INTO
PRACTICE: HPV VACCINE
Faculty Panel Chair:
Jennifer Le, Pharm.D., MAS, BCPS-AQ ID, FCCP, FCSHP Authors
Professor of Clinical Pharmacy Nathan Painter, Pharm.D., CDE
University of California, San Diego Associate Clinical Professor of Pharmacy
Skaggs School of Pharmacy and Pharmaceutical Sciences Co-Director, Clinical Pharmacy UCSD Family Medicine Clinics
La Jolla, California University of California, San Diego
Faculty-in-Residence Skaggs School of Pharmacy and Pharmaceutical Sciences
Long Beach Memorial and Miller Childrens Hospital La Jolla, California
Long Beach, California
Stephanie Mayne, MHS
Research Coordinator
Department of Pediatrics
INTERACTIVE CASE ON SOLID ORGAN The Childrens Hospital of Philadelphia
TRANSPLANT IMMUNOLOGY Philadelphia, Pennsylvania

Authors Reviewers

Barrett Crowther, Pharm.D., FAST, BCPS Carlton K.K. Lee, Pharm.D., MPH, FASHP, FPPAG
Pediatric Transplant Clinical Pharmacist Clinical Pharmacy Specialist, Pediatrics
Department of Pharmacy Department of Pharmacy
University Health System The Johns Hopkins Hospital
San Antonio, Texas Associate Professor of Pediatrics
School of Medicine
Leslie Stach, Pharm.D., BCPS John Hopkins University
Solid Organ Transplant Clinical Pharmacist Clinical Professor
Department of Pharmacy School of Pharmacy
Ann and Robert H. Lurie Childrens Hospital of Chicago University of Maryland
Chicago, Illinois Baltimore, Maryland
Nicholas M. Fusco, Pharm.D., BCPS Reviewers
Clinical Assistant Professor Susan McKamy Adams, Pharm.D., BCPS
Pharmacy Practice Lead Clinical Pharmacist Specialist, Pediatrics
University at Buffalo School of Pharmacy Inpatient Pharmacy Department
and Pharmaceutical Sciences Miller Childrens and Womens Hospital of Long Beach
Buffalo, New York Long Beach, California
Melissa Ray, Pharm.D., BCPS
TRANSLATING EVIDENCE INTO PRACTICE: Clinical Pharmacist III
VANCOMYCIN NEPHROTOXICITY UnitedHealth Group
Tampa, Florida
Authors Clinical Assistant Professor of Pharmacy Practice
University of Florida College of Pharmacy
Jennifer Le, Pharm.D., MAS, BCPS-AQ ID, FCCP, FCSHP
Gainesville, Florida
Professor of Clinical Pharmacy
University of California, San Diego The American College of Clinical Pharmacy and the authors
Skaggs School of Pharmacy and Pharmaceutical Sciences thank the following individuals for their careful review of the
La Jolla, California Clinical and Practice Updates chapters:
Faculty-in-Residence
Nicola G. Dahl, Pharm.D.
Long Beach Memorial and Miller Childrens Hospital
Medical Writer
Long Beach, California
Kanab, Utah
Kristen R. Nichols, Pharm.D., BCPPS, BCPS-AQ ID
Ralph H. Raasch, Pharm.D., BCPS, FCCP
Assistant Professor
Associate Professor of Pharmacy (retired)
Pharmacy Practice
Division of Practice Advancement and Clinical Education
Butler University College of Pharmacy & Health Sciences
Eshelman School of Pharmacy
Indianapolis, Indiana
The University of North Carolina at Chapel Hill
Co-Director, Pediatric Antimicrobial Stewardship Program
Chapel Hill, North Carolina
Department of Pharmacy
Riley Hospital for Children at Indiana University Health
Indianapolis, Indiana
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Consultancies: Barrett R. Crowther (Walgreens); Jennifer Le (Pfizer, Cempra); Kristen R. Nichols (Indiana State Health Department);
Grants (ASHP); Nathan Painter (American Association of Diabetes Educators); Melissa Ray (Therapeutic Research Center)

Stock Ownership:

Royalties: Carlton K.K. Lee (Elsevier, Inc.)

Grants: Jennifer Le (National Institutes of Health, Pfizer, Astellas and Cubist); Carlton K.K. Lee Grants (Optimer Pharmaceuticals,
Cerexa Pharmaceuticals, Astellas Pharma); Shirley M. Tsunoda (Novartis)

Honoraria:

Other:

Nothing to disclose: Susan M. Adams; Nicholas M. Fusco; Noelle Leung; Stephanie Mayne; Monica A. Puebla; Leslie M. Stach

ROLE OF BPS: The Board of Pharmacy Specialties (BPS) is an autonomous division of the American Pharmacists Association
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examination content, administration, scoring, and all other aspects of its certification programs. PedSAP has been approved by
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2215 Constitution Avenue NW
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(202) 429-7591
CONTINUING PHARMACY EDUCATION
AND RECERTIFICATION INSTRUCTIONS
 ontinuing Pharmacy Education Credit: The American College of Clinical Pharmacy is accredited by the Accreditation
C
Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education (CPE).

PedSAP: Target Audience: The target audience for PedSAP 2016 Book 1 (Immunology) is pediatric pharmacotherapy specialists
and advanced-level clinical pharmacists caring for pediatric patients with several immunologic and antimicrobial considerations.

Available CPE credits: Purchasers who successfully complete all posttests for PedSAP 2016 Book 1 (Immunology) can earn
9.0 contact hours of continuing pharmacy education credit. The universal activity numbers are as follows: Immunology
0217-0000-16-019-H01-P, 5.0 contact hours; and Clinical and Practice Updates 0217-0000-16-020-H01-P, 4.0 contact hours.
You may complete one or all available modules for credit. Tests may not be submitted more than once.

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Interactive Case: Immunology in Solid
Organ Transplantation
By Barrett Crowther, Pharm.D., FAST, BCPS; and Leslie Stach, Pharm.D., BCPS

Reviewed by Shirley M. Tsunoda, Pharm.D.; Brenda Winger, Pharm.D., BCPS, BCOP; and Monica A. Puebla, Pharm.D., MBA, MHA, BCPS

LEARNING OBJECTIVES

1. Evaluate the differences in vaccine considerations as they apply to candidates for and recipients of solid organ transplan-
tation (SOT).
2. Develop a schedule for catch-up vaccinations for patients with a SOT.
3. Design an appropriate strategy for providing vaccinations to parents and siblings of a SOT recipient.
4. Devise a pharmacotherapeutic plan for SOT recipients based on the individual patients endogenous and passively trans-
ferred antibody status.
5. Develop a plan for managing immunoglobulins and preventing adverse effects using different immunoglobulin preparations.

INTERACTIVE CASE
ABBREVIATIONS IN THIS CHAPTER
Click here to begin this PedSAP activity.
AMR Antibody-mediated rejection
CMV Cytomegalovirus
DSA Donor-specific antibody
DTaP Diphtheria, tetanus, and acellular
pertussis vaccine
Hib Haemophilus influenzae type b
IDSA Infectious Diseases Society of
America
IIV Inactivated influenza vaccine
IVIG Intravenous immunoglobulin
LAIV Live, attenuated influenza vaccine
MMR Measles, mumps, and rubella
PCV Pneumococcal conjugate vaccine
(7-valent, 13-valent)
PPSV23 23-valent pneumococcal polysac-
charide vaccine
PRA Panel of reactive antibody
RSV Respiratory syncytial virus
SCIG Subcutaneous immunoglobulin
SOT Solid organ transplantation
VariZIG Varicella zoster immunoglobulin
Table of other common abbreviations.
Editors Note: The authors wish to acknowledge the
contribution of Eric M. Tichy, Pharm.D., BCPS, FCCP,
FAST, who created the outline for this PedSAP feature.
BASELINE KNOWLEDGE STATEMENTS
Readers of this chapter are presumed to be familiar with the
following:
Interpreting basic laboratory tests
Assessing appropriateness of vaccines for healthy children
Understanding the pathophysiology of vaccine-preventable
diseases
Recognizing the mechanism of action and common
adverse reactions with solid organ transplant maintenance
immunosuppressive agents
ADDITIONAL READINGS
The following free resources have additional background
information on this topic:
CDC. Vaccines & Immunization Topics.
Advisory Committee for Immunization Practices. Vaccine
Recommendations.
Infectious Diseases Society of America. 2013 Clinical
Practice Guideline for Vaccination of the
Immunocompromised Host.
American Society of Transplantation. 2013 Infectious
Disease Guidelines, 3rd ed.
Table of common pediatric laboratory reference values.

PedSAP 2016 Book 1 Immunology 73 Interactive Case: Immunology in Solid Organ Transplantation
Self-Assessment Questions
1. The day after Christmas, a 9-month-old, former 35-week
premature boy receives a heart transplant for a complex
congenital heart defect with heart failure. Four weeks
later, he is ready for discharge home. He was hospital-
ized for 3 months while awaiting a transplant and had
several infections, including Staphylococcus aureus bac-
teremia and a parainfluenza respiratory viral infection,
during that period. He is up-to-date with his 6-month
immunizations. The patient will receive the inactivated
influenza vaccine (IIV) before leaving, but his mother
is concerned about respiratory syncytial virus (RSV)
because the patients 4-year-old sister attends day care.
Which one of the following is best to recommend regard-
ing palivizumab administration for this child?
A. Do not administer; standard precautions should be
sufficient because he is not a less than 29-week
premature infant and no longer has congenital heart
disease.
B. Administer; he recently had a heart transplant, and it
is RSV season.
C. Administer; he should have received palivizumab
while hospitalized in November and December as
well as continuing treatment as an outpatient.
D. Do not administer; he should receive the RSV
vaccine.
2. A 14-year-old girl is admitted for a kidney transplant
from a deceased donor. The patient has end-stage renal
disease caused by renal dysplasia and has received
hemodialysis three times a week for the past 2 years
with a baseline SCr of about 5.5 mg/dL. Her last panel of
reactive antibody (PRA) measurement 1 month ago was
class I 25% and class II 46%. She received induction ther-
apy with methylprednisolone and antithymocyte globulin
and cefazolin for surgical antibiotic prophylaxis. Imme-
diately after the transplant and during the first 24 hours
post-transplantation, her SCr measurements were 5.5
mg/dL, 4.3 mg/dL, and 3.5 mg/dL; however, the last two
measurements were 4.6 mg/dL and 6.7 mg/dL. The sur-
geons inform you that they are concerned about atypical
hemolytic uremic syndrome/thrombotic microangio-
pathy or hyperacute rejection. The patient receives
intravenous immunoglobulin (IVIG) 1 g/kg and rituxi-
mab 375 mg/m2, and the team suggests blocking the
membrane attack complex with eculizumab. The patient
receives her dose before you arrive at the hospital in the
morning. As soon as you arrive at the hospital, which one
of the following actions is best to take for this patient?
A. Review her vaccination record for meningococcal
vaccine against serotypes ACWY and B; initiate
penicillin VK orally for prophylaxis of N. meningitidis.
PedSAP 2016 Book 1 Immunology
B. Administer the measles, mumps, and rubella (MMR)
and varicella vaccines regardless of immune status.
C. Initiate levofloxacin prophylaxis for all bacterial
infections because she has received significant
immunosuppression.
D. Review her vaccination record for meningococcal
vaccine ACWY; initiate levofloxacin for prophylaxis
of N. meningitidis.
3. You are seeing a 12-month-old girl for a follow-up biopsy
in November 1.5 months after an orthotopic heart trans-
plant. Because influenza season began early, everyone
in the waiting room is wearing a mask. The patient is at
the office with her mother, 4-year-old sister, and 8-year-
old brother. The patient was given a diagnosis of viral
myocarditis at 7 months of age and, within 3 weeks of
hospital admission, was listed as status 1a for a heart
transplant. For her maintenance immunosuppression,
she receives tacrolimus (goal 1012), mycophenolate
(600 mg/m2 every 12 hours), and prednisolone (0.5 mg/
kg/dose every 12 hours). Before transplantation, she
received her 6-month vaccinations. Which one of the
following plans is best to recommend for catch-up vacci-
nations for this patient?
A. She should receive all of her 12-month vaccinations
including MMR, varicella vaccine, and influenza
vaccine because she has school-aged siblings who
may expose her to these infections.
B. She should only receive inactivated influenza
vaccine (IIV) because it is flu season and she is
greater than 1 month post-transplantation.
C. She should only receive her inactivated vaccines
such as Haemophilus influenzae type B (Hib)
and pneumococcal conjugate vaccine 13-valent
(PCV13) because live vaccines are not indicated
post-transplantation.
D. She should wait until 6 months post-transplantation
and then receive her entire 12-month vaccinations
including MMR and varicella vaccine.
4. A 4-year-old girl, a new patient in your liver transplant
follow-up clinic, received a deceased donor liver trans-
plant 1.5 years ago for biliary atresia with a failed Kasai
procedure. Her immunosuppressive regimen consists
of tacrolimus 1.5 mg twice daily with a goal concentra-
tion of 68 ng/dL and mycophenolate mofetil 200 mg/
m2/dose twice daily. About 3 months ago, she received
a 3-day steroid burst for acute cellular rejection. Her
family recently transferred her from a childrens hospi-
tal in Atlanta, and her vaccine records are en route. The
patients mother states that she is hesitant for her daugh-
ter to receive too many vaccines at once. She also says
74 Interactive Case: Immunology in Solid Organ Transplantation
 that her daughter once got the flu from a shot so never
again received the influenza vaccine. However, because
the girls healthy cousin was just hospitalized with influ-
enza, the mother is now interested in the vaccine. Which
one of the following counseling points is best to provide
this patients mother?
A. The girl should not receive any vaccines because
she recently had an episode of rejection, which
might cause her to have another episode.
B. The girl should receive LAIV (live, attenuated
influenza vaccine) because it is the only influenza
vaccine available in the clinic today.
C. The girl should receive IIV; her mother does not need
to receive her vaccine because her daughter will
have full immunity.
D. The girl should receive IIV and another vaccine in
1 month to complete her first series of influenza
vaccine.
5. A 7-year-old girl presents 3 years after a deceased donor
kidney transplant for end-stage renal disease related to
nephrotic syndrome. She is at the clinic for her yearly visit
and is in good health with no acute issues. Before trans-
plantation, the patient took steroids since diagnosis at
2 years of age. She has done relatively well but has had
some episodes of acute cellular rejection, requiring short
3-day courses of pulse intravenous methylprednisolone
in the past 3 years with brief escalations in maintenance
therapy. She has not received many of her vaccinations
because she was taking steroids before the transplant.
She has received enough maintenance immunosuppres-
sion that her physician has not wanted her to receive
vaccinations. She has not received any vaccinations
since her 1-year-old shots. By looking at her serologies
before transplantation, you conclude that she is pro-
tected against MMR and hepatitis B but is not immune
to varicella. One week ago, the patient was visited by an
out-of-state cousin who now has chickenpox. According
to the CDCs recommendations for using varicella zoster
immunoglobulin (VariZIG), which one of the following
strategies is best to recommend for this patient?
A. Admit her to the hospital for acyclovir intravenously
10 mg/kg/dose every 8 hours for a total of 7 days.
B. Administer acyclovir orally at home together with
a varicella vaccine to try to confer immunity before
infection.
C. Administer VariZIG because she does not have
immunity, as evidenced by her serology, and it is
less than 10 days from exposure.
D. Do not administer VariZIG because the exposure
was more than 96 hours ago. She is many years out
from transplantation and is therefore at less risk of
developing infection from exposure.
PedSAP 2016 Book 1 Immunology
6. A 5-year-old girl has a medical history of a deceased
donor renal transplant about 2 years ago for end-stage
renal disease caused by a small left solitary kidney at
birth. The patient also has a history of vesicoureteral
reflux and hypertension related to transplantation. One
month ago, she received methylprednisolone 10 mg/kg/
day intravenously for 3 days for mild acute cellular rejec-
tion. Two days ago, she presented to the inpatient acute
care unit for a renal biopsy as a workup for recurrent rejec-
tion, given her recent increase in SCr. The final biopsy
today reveals acute cellular rejection without acute anti-
body-mediated rejection (AMR) (negative C4d staining).
The Luminex assay reveals no evidence of donor-specific
antibodies. Her maintenance drugs include amlodipine
2.5 mg by mouth daily; sulfamethoxazole/trimethoprim
400 mg/80 mg by mouth daily; prednisolone 3 mg by
mouth every Monday, Wednesday, Friday, and Saturday;
mycophenolate mofetil 300 mg by mouth twice daily; and
tacrolimus 2 mg by mouth twice daily. According to the
KDIGO guidelines, which one of the following regimens
would best treat this patients acute cellular rejection
episode?
A. Rituximab.
B. Intravenous rabbit antithymocyte globulin.
C. Subcutaneous immunoglobulin (SCIG).
D. Plasmapheresis plus intravenous immunoglobulin
(IVIG).
7. A 12-year-old African-American girl presents in the
kidney transplant clinic. She received a living unrelated
donor kidney transplant 1 year ago because of end-stage
renal disease secondary to focal segmental glomeru-
losclerosis. At transplantation, she received induction
with intravenous basiliximab and has had no rejec-
tion episodes since transplantation. Her drugs include
tacrolimus 3 mg by mouth twice daily, prednisone 5 mg
by mouth daily, pantoprazole 40 mg by mouth daily,
amlodipine 10 mg by mouth daily, atenolol 25 mg by
mouth daily, and isradipine 2.5 mg by mouth every 6 hours
as needed for blood pressure greater than 140/90 mm
Hg. The patient has a new 2-month-old brother who is
healthy. According to their mother, the patients brother
is due for the following vaccines: inactivated poliovirus
vaccine (IPV), PCV13, Hib, rotavirus, and diphtheria, tet-
anus, and acellular pertussis (DTaP). The mother asks
you which of these vaccines can safely be administered.
According to the 2013 IDSA clinical practice guideline for
vaccination of the immunocompromised host, which one
of the following vaccines is best to recommend for this
patients brother?
A. The IPV, PCV13, Hib, and DTaP vaccines but not the
rotavirus vaccine.
B. The PCV13, Hib, rotavirus, and DTaP vaccines but
not the IPV vaccine.
75 Interactive Case: Immunology in Solid Organ Transplantation
 C. The IPV, PCV13, Hib, and DTaP vaccines but not the
rotavirus and IPV vaccines.
D. The IPV, PCV13, Hib, DTaP, and rotavirus vaccines,
but the patient should avoid handling her brothers
diapers for 1 month after vaccinations.
8. Three months ago, a 16-year-old white girl received a
bilateral lung transplant for end-stage lung disease
secondary to cystic fibrosis. Her medical history also
includes gastroesophageal reflux disease, pancreatic
insufficiency, and chronic kidney disease caused by a sig-
nificant history of aminoglycoside therapy. The patients
postoperative course was complicated by Aspergillus fla-
vus and Pseudomonas aeruginosa pneumonia. Five days
ago, she was readmitted to the hospital medical ICU for
acute-on-chronic respiratory failure requiring endotra-
cheal intubation and mechanical ventilation. She had
alveolar infiltrates suggestive of rejection. A transbron-
chial lung biopsy yesterday revealed acute AMR (acute
lung injury with neutrophil infiltration of the alveolar
septae with capillaritis and C4d deposition in the alveo-
lar capillaries). Furthermore, the Luminex assay revealed
strong de novo donor-specific antibodies to HLA-B44 and
DR53 (mean fluorescence intensity of 5649 and 7034,
respectively). The patients immunosuppressive regimen
includes tacrolimus 1.5 mg by mouth twice daily, myco-
phenolate sodium 720 mg by mouth twice daily, and
prednisone 15 mg by mouth once daily. The team decides
to treat the acute AMR episode with five plasmapheresis
sessions followed by immunoglobulin 100 mg/kg/dose
after the first four sessions and 1 g/kg/dose after the final
plasmapheresis session. Depending on her response, the
patient may also receive rituximab. When considering the
immunoglobulin preparation to select for therapy, which
one of the following stabilizing agents used in immuno-
globulin preparations is best to avoid in this patient?
A. Maltose.
B. Sucrose.
C. Glucose.
D. Proline.
9. A 12-year-old Hispanic girl with chronic liver disease sec-
ondary to autoimmune hepatitis (AIH) is hospitalized for
an AIH flare caused by medication nonadherence. The
patient and her grandmother, her primary caregiver, are
being seen for a preliver transplant pharmacotherapy
consultation. The patient has no other significant medical
or surgical history. She takes prednisone, azathioprine,
and phytonadione. Her vaccine records, reviewed as part
of her liver transplant evaluation, show the following:
Three doses of hepatitis B vaccine, with a recent
hepatitis B surface antibody of 100 mIU/mL
One dose of Tdap (tetanus, diphtheria, and acellular
pertussis) vaccine at 11 years of age
PedSAP 2016 Book 1 Immunology
One dose of PCV13 at 10 years of age
Three doses of Hib vaccine before 6 months of age
Four doses of inactive polio vaccine
One dose of meningococcal conjugate (MCV4)
vaccine
Two doses of MMR vaccine
Two doses of varicella vaccine
One dose of influenza vaccine during the most
recent influenza season
Three doses of human papillomavirus 4 vaccine
According to the 20152016 CDC immunization schedule
guidelines, which one of the following strategies is best to
ensure that this patient is up-to-date on vaccinations for
potential liver transplantation?
A. Patient is up-to-date on vaccinations.
B. Give meningococcal serotype group B vaccine.
C. Give PPSV23 (23-valent pneumococcal
polysaccharide vaccine).
D. Give cytomegalovirus (CMV) vaccine.
10. Yesterday morning, a 5-month-old Hispanic boy received
a deceased donor split liver transplant for biliary atresia.
He received induction with intravenous basiliximab and
is receiving a maintenance immunosuppressive regimen
of intravenous methylprednisolone and oral tacrolimus.
The transplant donor was a 12-year-old girl. The donor
was CMV IgG positive, and the recipient was CMV IgG
positive at transplantation. According to the 2013 Amer-
ican Society of Transplantation ID guideline, which one
of the following regimens would be the best strategy for
CMV prophylaxis in this patient?
A. Intravenous ganciclovir followed by conversion to
oral valganciclovir when he is considered stable.
B. Intravenous ganciclovir for 7 days followed by
conversion to oral ganciclovir.
C. Intravenous ganciclovir for 7 days followed by
conversion to oral acyclovir with pre-emptive
monitoring.
D. Intravenous cidofovir followed by conversion to oral
brincidofovir when he is considered stable.
76 Interactive Case: Immunology in Solid Organ Transplantation
Learner Chapter Evaluation: Interactive Case: Immunology in Solid Organ
Transplantation.
As you take the posttest for this chapter, also evaluate the
materials quality and usefulness, as well as the achievement
of learning objectives. Rate each item using this 5-point scale:
Strongly agree
Agree
Neutral
Disagree
Strongly disagree
1. The content of the chapter met my educational needs.
2. The content of the chapter satisfied my expectations.
3. The author presented the chapter content effectively.
4. The content of the chapter was relevant to my practice
and presented at the appropriate depth and scope.
5. The content of the chapter was objective and balanced.
6. The content of the chapter is free of bias, promotion, or
advertisement of commercial products.
7. The content of the chapter was useful to me.
8. The teaching and learning methods used in the chapter
were effective.
9. The active learning methods used in the chapter were
effective.
10. The learning assessment activities used in the chapter
were effective.
11. The chapter was effective overall.
PedSAP 2016 Book 1 Immunology
Use the 5-point scale to indicate whether this chapter pre-
pared you to accomplish the following learning objectives:
12. Evaluate the differences in vaccine considerations as
they apply to candidates for and recipients of solid organ
transplantation (SOT).
13. Develop a schedule for catch-up vaccinations for
patients with a SOT.
14. Design an appropriate strategy for providing vaccina-
tions to parents and siblings of a SOT recipient.
15. Devise a pharmacotherapeutic plan for SOT recipients
based on the individual patients endogenous and pas-
sively transferred antibody status.
16. Develop a plan for managing immunoglobulins and pre-
venting adverse effects using different immunoglobulin
preparations.
17. Please provide any specific comments related to any
perceptions of bias, promotion, or advertisement of
commercial products.
18. Please expand on any of your above responses, and/or
provide any additional comments regarding this chapter:
77 Interactive Case: Immunology in Solid Organ Transplantation
Translating Evidence into Practice:
Human Papillomavirus Vaccination
By Nathan Painter, Pharm.D., CDE; and Stephanie Mayne, MHS

Reviewed by Carlton K.K. Lee, Pharm.D., MPH; and Nicholas M. Fusco, Pharm.D., BCPS

LEARNING OBJECTIVES

1. Identify groups recommended by the Advisory Committee on Immunization Practices (ACIP) for human papillomavirus
(HPV) vaccination.
2. Analyze the impact of various decision support methods on HPV vaccination.
3. Evaluate the benefits of clinician- and family-focused decision support for decreasing missed opportunities for HPV
vaccination.

TRANSLATING EVIDENCE INTO

ABBREVIATIONS IN THIS CHAPTER
ACIP Advisory Committee on
Immunization Practices
CHOP Childrens Hospital of Philadelphia
DTaP Diphtheria, tetanus, and acellular
pertussis vaccine
EHR Electronic health record
HPV Human papillomavirus
HPV-1 Human papillomavirus vaccine
dose 1
HPV-2 Human papillomavirus vaccine
dose 2
HPV-3 Human papillomavirus vaccine
dose 3
HPV2 Bivalent HPV vaccine (Cervarix)
HPV9 9-valent HPV vaccine (Gardasil 9)
HPV4 Quadrivalent HPV vaccine
(Gardasil)
MCV Meningococcal vaccine
PCV12 Pneumococcal conjugate vaccine
PBRN Practice-based research network
PPSV23 Pneumococcal polysaccharide
vaccine
Tdap Tetanus, diphtheria, and acellular
pertussis vaccine
PRACTICE
Topic Article
Mayne SL, duRivage NE, Feemster KA, et al. Effect of
decision support on missed opportunities for human
papillomavirus vaccination. Am J Prev Med
2014;47:734-44.
On-demand Webcast
Click here to begin this PedSAP activity.
Click here to view a transcription of this recorded webcast.
REFERENCES
CDC. Epidemiology and Prevention of Vaccine-Preventable
Diseases, 13th ed. Washington, DC: Public Health
Foundation, 2015.
CDC. Human papillomavirus-associated cancersUnited
States, 2004-2008. Morb Mortal Wkly Rep 2012;61:258-61.
CDC. Human papillomavirus vaccination coverage among
adolescent girls, 20072012, and postlicensure vaccine
safety monitoring, 2006 2013United States. Morb
Mortal Wkly Rep 2013;62:591-5.
Fiks AG, Grundmeier RW, Mayne S, et al. Effectiveness of
decision support for families, clinicians, or both on HPV
vaccine receipt. Pediatrics 2013;131:1114-24.

Hughes CC, Jones AL, Feemster KA, et al. HPV vaccine deci-
sion making in pediatric primary care: a semi-structured
interview study. BMC Pediatr 2011;11:74.

PedSAP 2016 Book 1 Immunology 79 Translating Evidence into Practice: Human Papillomavirus Vaccination
Markowitz LE, Hariri S, Lin C, et al. Reduction in human
papillomavirus (HPV) prevalence among young women
following HPV vaccine introduction in the United States,
National Health and Nutrition Examination Surveys, 2003-
2010. J Infect Dis 2013;208:385-93.

Rand CM, Shone LP, Albertin C, et al. National health care

visit patterns of adolescents: implications for delivery
of new adolescent vaccines. Arch Pediatr Adolesc Med
2007;161:252-9.

Satterwhite CL, Torrone E, Meites E, et al. Sexually

transmitted infections among US women and men: prev-
alence and incidence estimates, 2008. Sex Transm Dis
2013;40:187-93.

Vadaparampil ST, Kahn JA, Salmon D, et al. Missed clini-

cal opportunities: provider recommendations for HPV
vaccination for 11-12 year old girls are limited. Vaccine
2011;29:8634-41.

Wong CA, Taylor JA, Wright JA, et al. Missed opportunities

for adolescent vaccination, 2006-2011. J Adolesc Health
2013;53:492-7.

PedSAP 2016 Book 1 Immunology 80 Translating Evidence into Practice: Human Papillomavirus Vaccination
Self-Assessment Questions
11. The HPV vaccine received an approved indication in
2006 to prevent HPV infections in female patients; this
was expanded in 2009 to cover male patients. Which one
of the following patient and product combinations best
meets the vaccination recommendations of the Advisory
Committee on Immunization Practices (ACIP)?
A. A 7-year-old girl, bivalent HPV vaccine (HPV2)
B. An 8-year-old boy, quadrivalent HPV vaccine (HPV4)
C. A 9-year-old girl, 9-valent HPV vaccine (HPV9)
D. A 10-year-old boy, HPV2
12. An 11-year-old girl presents to her pediatrician with
cough, runny nose, and mild fever for the past 34 days.
Her mother brought her to the office for these symptoms
and for a note excusing her from school because she has
missed several days. Which one of the following factors
places this girl most at risk of a missed opportunity to
administer the HPV vaccine?
A. She is currently not feeling well.
B. She is not at the appropriate age.
C. She is presenting for an acute visit.
D. Her physician may not recommend it.
13. Using the Recommended Immunization Schedule pub-
lished by the CDC and endorsed by ACIP, which one of
the following vaccines presents the best opportunity for
also administering the HPV vaccine?
A. PCV12
B. PPSV23
C. DTaP
D. Tdap
14. An 11-year-old boy presents to his pediatrician for a pre-
ventive visit. He has not previously received the HPV
vaccine. Which one of the following vaccines is most
appropriate to recommend for this patient at this time?
A. HPV4
B. HPV2
C. HPV9
D. HPV4 or HPV9
15. A researcher wants to determine the effectiveness of
an intervention to improve adolescent vaccination rates
targeted to clinicians within primary care practices.
The intervention involves implementation of a system
of electronic health record vaccine alerts. Which study
design would best answer this research question?
A. Observational cohort study
B. Cluster randomized controlled trial
PedSAP 2016 Book 1 Immunology
C. Randomized controlled trial with individual-level
randomization only
D. Cross-sectional study
Questions 1620 pertain to the following case.
The study by Mayne et al (Effect of decision support on missed
opportunities for human papillomavirus vaccination) aimed
to compare the impact of clinician- versus family-focused
decision support, none, or both on captured opportunities for
HPV vaccination.
16. Which one of the following statements best describes
the greatest limitation of the study?
A. Randomization of study practices and participants
was not stratified to provide balance between
groups.
B. Generalizability of the study may be limited because
the study was only conducted in Philadelphia and
the surrounding areas.
C. Statistical models did not control for patient,
clinician, and practice characteristics.
D. The demographic characteristics of the study
groups were very different.
17. According to the findings of the study, which one of the
following interventions will most likely improve rates of
captured opportunities for HPV vaccination?
A. Prompt families to visit an educational website
before office visits so that they can learn more about
the HPV vaccine.
B. Remind families that their child is due for the HPV
vaccine through phone calls before the visit.
C. Provide educational content, vaccine alerts, and
performance feedback to clinicians.
D. Provide text message reminders to families about
upcoming vaccinations.
18. Which one of the following statements most accurately
reflects the results of the study by Fiks et al that differed
from the results of the study by Mayne et al?
A. The family-focused intervention improved rates of
HPV vaccination for dose 1 only.
B. The family-focused intervention improved rates of
HPV vaccination for doses 2 and 3 only.
C. The family-focused intervention improved rates of
HPV vaccination for all 3 doses.
D. The family-focused intervention did not improve
rates of any HPV vaccination dose.
81 Translating Evidence into Practice: Human Papillomavirus Vaccination
19. Which one of the following statements best describes
the study findings regarding the effectiveness of clini-
cian-focused intervention in different practice settings?
A. The clinician intervention increased captured
opportunities for HPV 1 at preventive visits to a
greater extent at suburban practices than at urban
practices.
B. The clinician intervention increased captured
opportunities for HPV 1 at preventive visits to a
greater extent at urban practices than at suburban
practices.
C. The clinician intervention increased captured
opportunities for all three doses at acute visits at
suburban practices only.
D. The clinician intervention increased captured
opportunities for all three doses at both urban and
suburban practices.
20. In the study by Mayne et al, the researchers used mar-
ginal standardization to transform the logistic regression
model into standardized proportions. Which one of the
following is the most appropriate interpretation of the
standardized proportions?
A. The actual proportion of captured opportunities in
each study arm
B. The expected proportion of captured opportunities if
the entire sample was in the control group
C. The expected proportion of captured opportunities if
the entire sample received both interventions
D. The expected proportion of captured opportunities if
the entire sample was alternately subjected to each
intervention arm or monitored as a control group

PedSAP 2016 Book 1 Immunology 82 Translating Evidence into Practice: Human Papillomavirus Vaccination
Learner Chapter Evaluation: Translating Evidence into Practice:
Human Papillomavirus Vaccination.

As you take the posttest for this chapter, also evaluate the Use the 5-point scale to indicate whether this chapter pre-
materials quality and usefulness, as well as the achievement pared you to accomplish the following learning objectives:
of learning objectives. Rate each item using this 5-point scale:
30. Identify groups recommended by the Advisory

Strongly agree Committee on Immunization Practices (ACIP) for human
papillomavirus (HPV) vaccination.
Agree
Neutral 31. Analyze the impact of various decision support methods
Disagree on HPV vaccination.
Strongly disagree 32. Evaluate the benefits of clinician- and family-focused
decision support for decreasing missed opportunities
19. The content of the chapter met my educational needs. for HPV vaccination.

20. The content of the chapter satisfied my expectations. 33. Please provide any specific comments related to any
perceptions of bias, promotion, or advertisement of
21. The author presented the chapter content effectively. commercial products.
22. The content of the chapter was relevant to my practice 34. Please expand on any of your above responses, and/or
and presented at the appropriate depth and scope. provide any additional comments regarding this chapter:
23. The content of the chapter was objective and balanced.
24. The content of the chapter is free of bias, promotion, or
advertisement of commercial products.
25. The content of the chapter was useful to me.
26. The teaching and learning methods used in the chapter
were effective.
27. The active learning methods used in the chapter were
effective.
28. The learning assessment activities used in the chapter
were effective.
29. The chapter was effective overall.

PedSAP 2016 Book 1 Immunology 83 Translating Evidence into Practice: Human Papillomavirus Vaccination
Translating Evidence into Practice:
Vancomycin-Associated Nephrotoxicity
By Jennifer Le, Pharm.D., MAS, BCPS-AQ ID, FCCP, FASHP; and
Kristen Nichols, Pharm.D., BCPS-AQ ID, BCPPS

Reviewed by Susan McKamy Adams, Pharm.D., BCPS; and Melissa Ray, Pharm.D., BCPS

LEARNING OBJECTIVES

1. Analyze the vancomycin pharmacokinetic and pharmacodynamic exposure parameters associated with nephrotoxicity in
pediatric versus adult patients.
2. Assess the significance of three variables associated with vancomycin nephrotoxicity in pediatric patients, and evaluate
the strength of design of studies evaluating these variables.
3. Evaluate the risks, benefits, and practical implications of various vancomycin therapeutic drug monitoring strategies for
pediatric patients.
4. Apply current best evidence to optimize vancomycin dosing while minimizing nephrotoxicity in pediatric patients.

TRANSLATING EVIDENCE INTO PRACTICE

ABBREVIATIONS IN THIS FEATURE
AUC Area-under-curve
AUC0-24 Area-under-curve over 24 hours
BAL Broncho-alveolar lavage
CL Clearance
Cmax Peak or maximum concentration
Cmin Trough or minimum concentration
CXR Chest radiograph
IQR Interquartile range
Ke Elimination rate constant
PK Pharmacokinetics
CART Classification and regression tree
MRSA Methicillin-resistant
Staphylococcus aureus
NONMEM Non-linear mixed effects modeling
Q Every
RUL Right upper lobe
SMX/TMP Sulfamethoxazole/trimethoprim
Vd Volume of distribution
WT Weight
Topic Article
Topic Article: Le J, Ny P, Capparelli EVC, et al. Pharmacodynamic
characteristics of nephrotoxicity associated with vancomycin use
in children. J Ped Infect Dis 2015;4:e109-16.
On-demand Webcast
Click here to begin this PedSAP activity.
Click here to view a transcription of this recorded webcast.
REFERENCES
Akcan-Arikan A, Zappitelli M, Loftis LL, et al. Modified RIFLE cri-
teria in critically ill children with acute kidney injury. Kidney Int
2007;71:1028-35.
Anderson BJ, Holford NH. Mechanism-based concepts of size
and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol
2008;48:303-32.
Anderson BJ, Holford NH. Understanding dosing: children are small
adults, neonates are immature children. Arch Dis Childhood
2013;98:737-44.
Bosso JA, Nappi J, Rudisill C, et al. Relationship between vancomy-
cin trough concentrations and nephrotoxicity: a prospective
multicenter trial. Antimicrob Agents Chemother 2011;55:5475-9.

Bulitta JB, Landersdorfer CB, Huttner SJ, et al. Population phar-

macokinetic comparison and pharmacodynamic breakpoints of
ceftazidime in cystic fibrosis patients and healthy volunteers.
Antimicrob Agents Chemother 2010;54:1275-82.

PedSAP 2016 Book 1 Immunology 85 TranslatingEvidenceintoPractice:Vancomycin-AssociatedNephrotoxicity

Carreno JJ, Kenney RM, Lomaestro B. Vancomycin-
associated renal dysfunction: where are we now?
Pharmacotherapy 2014;34:1259-68.
Cies JJ, Shankar V. Nephrotoxicity in patients with vancomy-
cin trough concentrations of 15-20 mug/ml in a pediatric
ICU. Pharmacotherapy 2013;33:392-400.
Eiland LS, English TM, Eiland EH 3rd. Assessment of van-
comycin dosing and subsequent serum concentrations in
pediatric patients. Ann Pharmacother 2011;45:582-9.
Frymoyer A, Hersh AL, Coralic Z, et al. Prediction of van-
comycin pharmacodynamics in children with invasive
methicillin-resistant Staphylococcus aureus infections: a
Monte Carlo simulation. Clin Ther 2010;32:534-42.
Hidayat LK, Hsu DI, Quist R, et al. High-dose vancomycin
therapy for methicillin-resistant Staphylococcus aureus
infections: efficacy and toxicity. Arch Intern Med
2006;166:2138-44.
Jeffres MN, Isakow W, Doherty JA, et al. A retrospective anal-
ysis of possible renal toxicity associated with vancomycin
in patients with health care-associated methicillin-
resistant Staphylococcus aureus pneumonia. Clin Ther
2007;29:1107-15.
Knoderer CA, Nichols KR, Lyon KC, et al. Are elevated van-
comycin serum trough concentrations achieved within the
first 7 days of therapy associated with acute kidney injury
in children? J Ped Infect Dis 2014;3:127-31.
Kralovicova K, Spanik S, Halko J, et al. Do vancomycin serum
levels predict failures of vancomycin therapy or nephrotox-
icity in cancer patients? J Chemother 1997;9:420-6.
Le J, Bradley JS, Murray W, et al. Improved vancomycin
dosing in children using area under the curve exposure.
Pediatr Infect Dis J 2013;32:e155-63.
Le J, Ngu B, Bradley JS, et al. Vancomycin monitoring in
children using bayesian estimation. Ther Drug Monit
2014;36:510-8.
Le J, Vaida F, Nguyen E, et al. Population-based pharma-
cokinetic modeling of vancomycin in children with renal
insufficiency. J Pharmacol Clin Toxicol 2014;2:1017-26.
Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guide-
lines by the infectious diseases society of america for the
treatment of methicillin-resistant Staphylococcus aureus
infections in adults and children: executive summary. Clin
Infect Dis 2011;52:285-92.
Lodise TP, Lomaestro B, Graves J, et al. Larger vancomy-
cin doses (at least 4 g per day) are associated with an
increased incidence of nephrotoxicity. Antimicrob Agents
Chemother 2008;52:1330-6.
Lodise TP, Patel N, Lomaestro BM, et al. Relationship
between initial vancomycin concentration-time profile and
nephrotoxicity among hospitalized patients. Clin Infect Dis
2009;49:507-14.
PedSAP 2016 Book 1 Immunology
Mahmood I. Prediction of drug clearance in children: impact
of allometric exponents, body weight, and age. Ther Drug
Monit 2007;29:271-8.
Marsot A, Boulamery A, Bruguerolle B, et al. Vancomycin:
a review of population pharmacokinetic analyses. Clin
Pharmacokinet 2012;51:1-13.
McKamy S, Hernandez E, Jahng M, et al. Incidence and risk
factors influencing the development of vancomycin neph-
rotoxicity in children. J Pediatr 2011;158:422-6.
Neely MN, Youn G, Jones B, et al. Are vancomycin trough
concentrations adequate for optimal dosing? Antimicrob
Agents Chemother 2014;58:309-16.
Pai MP, Neely M, Rodvold KA, et al. Innovative approaches
to optimizing the delivery of vancomycin in individual
patients. Adv Drug Deliv Rev 2014;77:50-7.
Patel K, Crumby AS, Maples HD. Balancing vancomycin effi-
cacy and nephrotoxicity: should we be aiming for trough
or AUC/MIC? Paediatr Drugs 2015;17:97-103.
Pottel H, Mottaghy FM, Zaman Z, et al. On the relationship
between glomerular filtration rate and serum creatinine in
children. Pediatr Nephrol 2010;25:927-34.
Pottel H, Vrydags N, Mahieu B, et al. Establishing age/sex
related serum creatinine reference intervals from hospi-
tal laboratory data based on different statistical methods.
Clin Chim Acta 2008;396:49-55.
Ragab AR, Al-Mazroua MK, Al-Harony MA. Incidence and
predisposing factors of vancomycin-induced nephrotoxic-
ity in children. Infect Dis Ther 2013;2:37-46.
Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic
monitoring of vancomycin in adult patients: a consen-
sus review of the American Society of Health-System
Pharmacists, the Infectious Diseases Society of America,
and the Society of Infectious Diseases Pharmacists. Am J
Health Syst Pharm 2009;66:82-98.
Schumacher GE, Barr JT. Bayesian approaches in pharma-
cokinetic decision making. Clin Pharm 1984;3:525-30.
Spiegelhalter DJ, Myles JP, Jones DR, et al. Bayesian meth-
ods in health technology assessment: a review. Health
Technol Assess 2000;4:1-130.
Totapally BR, Machado J, Lee H, et al. Acute kidney injury
during vancomycin therapy in critically ill children.
Pharmacotherapy 2013;33:598-602.
van Hal SJ, Lodise TP, Paterson DL. The clinical signifi-
cance of vancomycin minimum inhibitory concentration in
Staphylococcus aureus infections: a systematic review and
meta-analysis. Clin Infect Dis 2012;54:755-71.
86 TranslatingEvidenceintoPractice:Vancomycin-AssociatedNephrotoxicity
Self-Assessment Questions
21. According to studies of children and adults, which one
of the following is most likely to be associated with van-
comycin nephrotoxicity?
A. Trough concentration of 10 mcg/mL or greater
B. Dosage 60 mg/kg/day in children (or greater than 4
g/day in adults)
C. AUC over 24 hours of 600 mcg-hr/mL or greater
D. Therapy duration of more than 1 week
22. As a peer reviewer for a medical journal, you are critically
evaluating a submitted manuscript. The pharmacoki-
netic-pharmacodynamic study used population-based
modeling and post hoc Bayesian analysis to estimate
individual patient peak and trough concentrations.
Which one of the following statements best describes
the type of data needed to conduct the bayesian analysis
in this study?
A. Educated guess of inter- and intra-subject variability
for clearance
B. Published population-based values for clearance
and volume of distribution
C. Patient-specific dosing history and predicted serum
concentrations
D. Known pharmacokinetic parameters and measured
drug concentrations
23. An 8-year-old boy (height 52 inches, weight 57 lb) is
admitted to the hospital for a health careassociated
pneumonia with possible empyema. He has no signifi-
cant medical history except cephalexin use for a skin
infection 1 month before admission. He is current on his
routine childhood immunizations. On admission, sputum
and blood cultures were obtained, and he was initiated
on vancomycin 400 mg intravenously every 6 hours
and tobramycin 200 mg intravenously every 24 hours.
On hospital day 2, he experienced respiratory distress
requiring admission to the pediatric ICU for close moni-
toring. After 8 days of antibiotic therapy, the patients SCr
increased from 0.6 mg/dL (baseline on admission day) to
1.3 mg/dL. His SCr was 1.21.4 mg/dL for 3 days before
it declined, returning to normal values after 7 days. After
the third dose of vancomycin therapy, the measured true
trough concentration was 16 mcg/mL, and AUC over 24
hours was 815 mcg-hr/mL. According to the multivari-
ate regression analysis in the presented journal article,
which one of the following risk factors most likely indi-
cates nephrotoxicity in this patient?
A. Concomitant use of tobramycin, trough concentration
of 10 mcg/mL or greater, and vancomycin therapy for
more than 1 week
B. Recent cephalexin use, AUC over 24 hours of 800
mcg-hr/mL or greater, and stay in the pediatric ICU
PedSAP 2016 Book 1 Immunology
C. Concomitant use of tobramycin, AUC over 24 hours of
800 mcg-hr/mL or greater, and stay in the pediatric ICU
D. Stay in the pediatric ICU, dose of 60 mg/kg/day or
greater, and trough concentration of 15 mcg/mL
or greater
24. You are designing a multicenter study to evaluate fac-
tors associated with ototoxicity in hospitalized children
receiving vancomycin therapy. You would like to explore
10 variables of interest (including both categorical and
continuous variables) using a non-parametric test to
create a model that predicts the dichotomized outcome
of ototoxicity. Through this analysis, you will construct
a diagram that visually represents decisions to show
the most important factors associated with ototoxicity.
When statistically significant, breakpoints will be derived
for continuous variables. Which one of the following best
describes this type of analysis?
A. Classification and regression tree
B. Kaplan-Meier
C. Univariate regression modeling
D. Cox regression analysis
25. Given the methods presented in the journal article, which
one of the following best describes the analysis method
and program used for the population-based pharmacoki-
netic modeling that capitalized on the use of sparse data?
A. Bayesian estimation
B. Classification and regression tree
C. Kaplan-Meier
D. Non-linear mixed effects
Questions 2628 pertain to the following case.
C.K. is a 10-year-old boy (height 56 inches, weight 36 kg) with
a history of mitral stenosis, recent fatigue, and fevers. During
hospital admission, he receives a diagnosis of infective endo-
carditis. C.K.s blood cultures are positive for MRSA by S.
aureus and mecA rapid diagnostic tests; traditional culture
and susceptibility results are pending. C.K. is initiated on van-
comycin therapy for the treatment of his MRSA endocarditis.
26. To assess C.K.s vancomycin exposure at steady state,
which one of the following most accurately describes
when it would be best to obtain plasma vancomycin
concentrations?
A. 1 hour after the end of a 1-hour infusion
B. Just before a dose
C. After the distribution phase and just before the next
dose to calculate AUC0-24 by the clearance method
D. Every hour to calculate AUC0-24 by the trapezoidal
method
87 TranslatingEvidenceintoPractice:Vancomycin-AssociatedNephrotoxicity
27. Susceptibility testing for C.K.s S. aureus isolate shows
a vancomycin MIC of 2 mg/L. Which one of the follow-
ing AUC0-24 exposures would best target the treatment
of C.K.s endocarditis, and which is the potential nephro-
toxic risk of this exposure?
A. 400 mg-hr/L or greater, no increased risk
B. 400 mg-hr/L or greater, increased risk
C. 800 mg-hr/L or greater, no increased risk
D. 800 mg-hr/L or greater, increased risk
28. Every 6 hours, C.K. receives vancomycin 540 mg infused
over 1 hour. His SCr is 0.59 mg/dL. Which one of the fol-
lowing best describes C.K.s patient-specific AUC0-24?
30. Which one of the following is best to recommend for
J.M. to optimally balance the need for minimum effec-
tive vancomycin exposure with the assessed risk of
nephrotoxicity?
A. Decrease the dose to achieve an AUC target of 200
799 mg-hr/L.
B. Continue the current dose to achieve an AUC target
of 400 mg-hr/L or greater.
C. Increase the dose to achieve an AUC target of 800
mg-hr/L or greater.
D. Substitute another antibiotic for vancomycin
because the desired AUC is 800 mg-hr/L or greater.

Day Time Dose (mg) Concentration (mg/L)

0500, 1100,
1 540
1700, 2300
0500, 1100,
2 540
1700, 2300
3 0500, 1100 540
3 0730 26
3 1045 13.7

A. 135 mg-hr/L
B. 350 mg-hr/L
C. 540 mg-hr/L
D. 720 mg-hr/L

Questions 29 and 30 pertain to the following case.

J.M. is a 6-year-old boy (weight 22 kg) with acute hematoge-

nous osteomyelitis of the right femur. Initial surgical bone
and blood cultures show S. aureus resistant to oxacillin and
clindamycin but susceptible to vancomycin (MIC of 0.5 mg/L
or less). J.M. has been receiving vancomycin 550 mg intra-
venously every 6 hours based on previous therapeutic drug
monitoring. On day 9 of treatment, J.M.s repeat blood cul-
tures remain negative; he is afebrile, with decreased pain, and
he can walk about the unit with some assistance. His CRP
has decreased from 21.9 mg/L to 8 mg/L. Serum vancomy-
cin concentrations at 3 hours and 6 hours after the start of a
1-hour infusion are 35 mg/L and 17.6 mg/L.
29. Which one of the following is the best assessment of
J.M.s vancomycin exposure related to efficacy and
nephrotoxicity?
A. Exposure is adequate to treat infection without
significant risk of nephrotoxicity.
B. Both trough concentration and AUC indicate
unnecessary risk of nephrotoxicity.
C. The trough concentration, but not the AUC, indicates
unnecessary risk of nephrotoxicity.
D. The AUC, but not the trough concentration,
increases the risk of nephrotoxicity within an
acceptable range.

PedSAP 2016 Book 1 Immunology 88 TranslatingEvidenceintoPractice:Vancomycin-AssociatedNephrotoxicity

Learner Chapter Evaluation: Translating Evidence into Practice:
Vancomycin Toxicity.

As you take the posttest for this chapter, also evaluate the Questions 5254 apply to the entire learning module.
materials quality and usefulness, as well as the achievement
of learning objectives. Rate each item using this 5-point scale: 52. How long did it take you to read the instructional materi-
als in this module?
Strongly agree 53. How long did it take you to read and answer the assess-
Agree ment questions in this module?
Neutral 5 4. Please provide any additional comments you may have
Disagree regarding this module:
Strongly disagree

35. The content of the chapter met my educational needs.

36. The content of the chapter satisfied my expectations.
37. The author presented the chapter content effectively.
38. The content of the chapter was relevant to my practice
and presented at the appropriate depth and scope.
39. The content of the chapter was objective and balanced.
4 0. The content of the chapter is free of bias, promotion, or
advertisement of commercial products.
41. The content of the chapter was useful to me.
42. The teaching and learning methods used in the chapter
were effective.
4 3. The active learning methods used in the chapter were
effective.
4 4. The learning assessment activities used in the chapter
were effective.
45. The chapter was effective overall.

Use the 5-point scale to indicate whether this chapter pre-

pared you to accomplish the following learning objectives:

46. Analyze the vancomycin pharmacokinetic (PK) and

pharmacodynamic exposure parameters associated
with nephrotoxicity in pediatric versus adult patients.
47. Assess the significance of three variables associated
with vancomycin nephrotoxicity in pediatric patients,
and evaluate the strength of design of studies evaluat-
ing these variables.
4 8. Evaluate the risks, benefits, and practical implications of
various vancomycin therapeutic drug monitoring strate-
gies for pediatric patients.

49. Apply current best evidence to optimize vancomycin
dosing while minimizing nephrotoxicity in pediatric
patients.
50. Please provide any specific comments related to any
perceptions of bias, promotion, or advertisement of
commercial products.
51. Please expand on any of your above responses, and/or
provide any additional comments regarding this chapter:

PedSAP 2016 Book 1 Immunology 89 TranslatingEvidenceintoPractice:Vancomycin-AssociatedNephrotoxicity

PedSAP 2016-2018 Releases

Title Release Date BCPPS Test Deadline ACPE Test Deadline

Immunology May 16, 2016 September 15, 2016 May 14, 2019

Pediatric Critical Care September 15, 2016 January 17, 2017 September 14, 2019

Research Ethics/
January 17, 2017 May 15, 2017 January 14, 2020
Study Design

Pediatric Emergencies May 15, 2017 September 15, 2017 May 14, 2020

Sedation and
September 15, 2017 January 16, 2018 September 14, 2020
Analgesia

Pediatric Oncology January 16, 2018 May 15, 2018 January 14, 2021

Fluids/Electrolytes/ May 15, 2018 September 17, 2018 May 14, 2021
Nutrition

Neonatal and Pediatric September 17, 2018 January 15, 2019 September 14, 2021
Sepsis

PedSAP Pricing ACCP Members Nonmembers

Single Book $65 $90

Any Three or More Books $50/book $70/book

Full Series
$260 $355
(eight books)

*Appropriate shipping charges will apply.

This book is one release from the American College of Clinical Pharmacys 2016-2018 Pediatric Self-Assessment Program (PedSAP).

Releases are available singly or as an eight-book series over 3 years. Topics for the series are designed to cover the content outline

for the Board Certified Pediatric Pharmacy Specialist examination administered by the Board of Pharmacy Specialties.

For specific faculty, chapter titles, and available continuing pharmacy education contact hours, go to www.accp.com/bookstore.

To order, contact the

American College of Clinical Pharmacy,
13000 W. 87th St. Parkway, Lenexa, KS 66215
Voice: (913) 492-3311 / Fax: (913) 492-0088
Online Bookstore: www.accp.com/bookstore
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