Pneumococcal vaccination in adults Author Daniel M Musher, MD Section Editor John G Bartlett, MD Deputy Editor Anna R Thorner, MD Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Mar 2014. | This topic last updated: Jan 23, 2014. INTRODUCTION Pneumococcal infections, including pneumonia and invasive disease such as bacteremia and meningitis, are an important source of morbidity and mortality in children <1 year of age, older adults, and persons with conditions that affect their ability to make antibody to capsular polysaccharides (table 1) . Asplenia greatly increases the risk for overwhelming systemic infection, and cochlear implants increase the risk for central nervous system infection. Pneumococcal vaccination is recommended for all children, for adults who have a condition that places them at increased risk for pneumonia or invasive pneumococcal disease, and for all adults 65 years of age. The highest incidence of invasive pneumococcal disease in adults occurs in those with certain underlying conditions, such as HIV infection, as well as in adults 65 years of age and in children <2 years of age (table 1). The highest mortality rates occur in individuals 65 years of age, especially those who are elderly and in those who have significant comorbidities. (See "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia", section on 'Epidemiology' and "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia", section on 'Prognosis'.) The indications for, immunogenicity of, and efficacy and adverse reactions associated with pneumococcal vaccination in adults will be presented here. Pneumococcal vaccination in children and specific groups of high-risk adults is discussed in detail separately. (See "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children" and "Pneumococcal (Streptococcus pneumoniae) polysaccharide vaccines in children" and "Pneumococcal immunization in HIV-infected adults" and "Prevention of sepsis in the asplenic patient", section on 'Pneumococcal vaccine' and "Immunizations in solid organ transplant candidates and recipients", section on 'Pneumococcus' and "Immunizations in hematopoietic cell transplant candidates and recipients", section on 'Pneumococcus' and "Immunizations in patients with cancer", section on 'Pneumococcal vaccine' and "Immunizations for patients with chronic liver disease", section on 'Pneumococcal vaccine'

and "Immunizations in patients with end-stage renal disease", section on 'Pneumococcal vaccine'.) The microbiology, pathogenesis, epidemiology, clinical manifestations, diagnosis, and treatment of pneumococcal infections are also presented separately. (See "Microbiology and pathogenesis of Streptococcus pneumoniae" and "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia" and "Pneumococcal pneumonia in adults".) APPROACH TO VACCINATION Available vaccines The surface capsular polysaccharide of Streptococcus pneumoniae is the principal means by which these organisms resist ingestion and killing by phagocytic cells. Antibody to capsule greatly facilitates phagocytosis and killing. Capsular polysaccharide is the essential component of all pneumococcal vaccines that are currently available. More than 90 different pneumococcal capsular serotypes have been identified. (See "Microbiology and pathogenesis of Streptococcus pneumoniae", section on 'Capsule'.) Since it is not possible to include all of the serotypes in a pneumococcal vaccine, available vaccines contain capsular polysaccharides from serotypes that are most likely to cause invasive disease. Two types of pneumococcal vaccines are approved for use in the United States: Pneumococcal polysaccharide vaccine (PPSV23; Pneumovax or Pnu-Immune) consists of capsular material from 23 pneumococcal types (table 2), which have historically caused approximately 85 to 90 percent of cases of pneumococcal disease [1]. PPSV23 has been used in adults for decades but not in infants or toddlers under age two since polysaccharide antigens are poorly immunogenic in such individuals. Pneumococcal conjugate vaccine (PCV, initially marketed as a 7-valent vaccine, PCV7 [Prevnar or Prevnar 7], now replaced by PCV13 [Prevnar 13]) consists of capsular polysaccharides from the 13 most common types that cause disease, covalently linked to a non-toxic protein that is nearly identical to diphtheria toxin. This covalent linking to a protein renders the polysaccharide antigenic in infants and toddlers. Pneumococcal conjugate vaccines with different numbers of serotypes are produced in other parts of the world (table 2). Because of its excellent immunogenicity in infants and toddlers, PCV7 was adopted for

universal use in this age group beginning in 2000; since 2010, PCV13 has been recommended for infants and children in its place. Starting in 2012, PCV13 is also recommended for use in selected high-risk adults (table 3). The use of pneumococcal vaccines in infants and children is discussed in detail separately. (See "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children" and "Pneumococcal (Streptococcus pneumoniae) polysaccharide vaccines in children".) Indications The 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been recommended for many years in the United States for all adults 65 years of age and in younger patients who have a condition that increases the risk of invasive pneumococcal disease or pneumococcal pneumonia. Risk factors for invasive pneumococcal disease and pneumococcal pneumonia are discussed in detail separately. (See "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia", section on 'Epidemiology' and "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia", section on 'Risk factors for infection' and "Pneumococcal pneumonia in adults", section on 'Risk factors'.) In 2012, the United States Advisory Committee on Immunization Practices (ACIP) began recommending sequential administration of both PPSV23 and PCV13 for individuals aged 19 or older with functional or anatomic asplenia, an immunocompromising condition (eg, HIV infection, cancer), a cerebrospinal fluid leak, a cochlear implant, or advanced kidney disease [2]. ACIP recommendations for use of one or both kinds of vaccines are summarized in the Table (table 3). Specific recommendations for pneumococcal vaccination of hematopoietic cell transplant recipients are presented separately. (See "Immunizations in hematopoietic cell transplant candidates and recipients", section on 'Pneumococcus'.) In 2011, PCV13 was approved by the US Food and Drug Administration (FDA) for use in adults 50 years of age, based on studies showing that PCV13 stimulates good antibody responses in adults in this age group [3]. However, this vaccine has not been recommended by the ACIP for healthy adults [3]. PPSV23 In accordance with the ACIP, we recommend PPSV23 for all persons 65 years of age and for persons aged 19 to 64 years who are at increased risk for pneumococcal infection and/or serious complications of pneumococcal infection (table 3) [2,4]. Patients who should receive both PPSV23 and PCV13 are discussed below. (See 'PCV13 and PPSV23' below.)

Patients with the following underlying conditions should receive PPSV23 alone: Cigarette smoking Chronic heart disease, including congestive heart failure and cardiomyopathy, but excluding hypertension Chronic lung disease, including asthma and chronic obstructive pulmonary disease (see "Management of infection in acute exacerbations of chronic obstructive pulmonary disease") Diabetes mellitus Alcoholism Chronic liver disease (see "Immunizations for patients with chronic liver disease") Age 65 years The incidence of pneumococcal disease and the associated mortality are very low in adults under the age of 50. Both the incidence of pneumococcal disease and the mortality rate increase after age 50 and more sharply after age 65 [5]. All adults aged 65 years should receive a dose of PPSV23 even if they were vaccinated when they were <65 years of age; however, a minimum interval of five years between PPSV23 doses should be maintained [2,4]. (See 'Revaccination' below.) Although the ACIP has not made a recommendation about vaccinating any adult who has been diagnosed with invasive pneumococcal disease, we suggest that all such individuals receive PPSV23 even if they have not been diagnosed with one of the conditions listed above because they have proven themselves to be susceptible and infection with one serotype does not provide protection against other serotypes.

PCV13 and PPSV23 The ACIP recommends that both PCV13 and PPSV23 be given sequentially to adults who have the underlying conditions listed below (table 3) [2]. When practicable, PCV should be given first, followed by PPSV at eight weeks later. Persons who should receive both PCV13 and PPV23 given sequentially: Cerebrospinal fluid leak Cochlear implant Functional or anatomic asplenia, including sickle cell disease, other hemoglobinopathies, congenital asplenia, and acquired asplenia In the absence of antibody (most unvaccinated adults lack measurable antibody to most pneumococcal capsular polysaccharides), the only clearance of pneumococci from the bloodstream is by the spleen, and asplenic individuals are at risk for overwhelming pneumococcal infection. (See "Clinical features and management of sepsis in the asplenic patient", section on 'Role of the spleen in host defense' and "Prevention of sepsis in the asplenic patient".) Immunocompromise: Congenital or acquired immunodeficiency, including B or T lymphocyte deficiency, complement deficiencies (particularly C1, C2, C3, and C4 deficiencies), and phagocytic disorders (excluding chronic granulomatous disease) HIV infection (see "Pneumococcal immunization in HIVinfected adults", section on 'When to immunize') Chronic renal failure

 Nephrotic syndrome Leukemia Lymphoma Hodgkin disease Multiple myeloma Generalized malignancy Iatrogenic immunosuppression, including glucocorticoids or radiation Solid organ transplant As noted above, PCV13 is not recommended for healthy adults of any age. (See 'Indications' above.) Schedule for dual vaccination Individuals who have an indication to receive both PCV13 and PPSV23 should be vaccinated according to the following schedule [2]: For patients who have not previously received either PCV13 or PPSV23, a single dose of PCV13 should be given, followed by a dose of PPSV23 at least eight weeks later. For patients who have previously received one or more doses of PPSV23, a single dose of PCV13 should be given one or more

years after the last PPSV23 dose was received. For patients who require additional doses of PPSV23, the first such dose should be given no sooner than eight weeks after PCV13 and at least five years after the most recent dose of PPSV23. Administration Both pneumococcal vaccines are administered as a 0.5 mL dose. PCV13 should be given intramuscularly, whereas PPSV23 can be given either intramuscularly or subcutaneously. Intradermal administration can cause severe local reactions and should be avoided. Administration with other vaccines Either formulation of pneumococcal vaccine may be given concomitantly with other vaccines [6,7]. When more than one vaccine is given, they should be administered with different syringes and at different injection sites. Concurrent administration of PPSV23 with the influenza vaccine is safe and does not alter the effectiveness of either vaccine [8]. Coadministration of PPSV23 and the zoster vaccine does not alter the antibody response to PPSV23 [9]. Although such coadministration may reduce the immunogenicity of the zoster vaccine [6,9,10], in order to avoid introducing barriers to patients receiving indicated vaccines, the Centers for Disease Control and Prevention (CDC) recommends that PPSV23 and the zoster vaccine be administered at the same visit if the patient is eligible for both vaccines [11-13]. In patients who require both PPSV23 and PCV13, the two vaccines should be given at different times as outlined above; the schedule depends on which formulation was given first. (See 'Schedule for dual vaccination' above.) Revaccination For immunocompromised patients and individuals with functional or anatomic asplenia who are <65 years of age, the ACIP recommends only one single revaccination with PPSV23 5 years after the first dose (table 3) [2,4]. However, since asplenic patients are at particularly high risk for overwhelming pneumococcal infection, some authorities recommend regular revaccination at five- to six-year intervals [14,15]. (See "Prevention of sepsis in the asplenic patient", section on 'Revaccination in children and adults'.) All adults aged 65 years should receive a dose of PPSV23 even if they were vaccinated when they were <65 years of age; however, a minimum interval of five years between PPSV23 doses should be maintained [2,4].

The ACIP does not recommend routine revaccination of immunocompetent adults with PPSV23 because data on the efficacy of additional doses are insufficient. Some studies have raised concern that repeated vaccination with pneumococcal polysaccharide vaccines may lead to hyporesponsiveness [16], but this does not appear to be relevant if more than five years have passed since the previous dose [17-19]. Some data have shown that injection site reactions are more common after revaccination than after primary vaccination, but in most studies, such reactions were not severe, were self-limited, and tended to occur when the time between vaccinations was less than five years [20-22]. (See 'Adverse reactions' below.) At the present time, revaccination of adults with PCV13 is not recommended. OVERVIEW OF BENEFITS AND LIMITATIONS Preventing pneumococcal disease in older adults and those with certain underlying conditions is an important goal given the high burden of disease and associated morbidity and mortality in these populations [4]. Many (but not all) studies have demonstrated efficacy against invasive and noninvasive pneumococcal disease [23], such as bacteremia and meningitis, but both immunogenicity and efficacy are likely to be lower in elderly patients and immunocompromised hosts. The development of pneumococcal conjugate vaccines represents a major advance, and the universal use of such vaccines in infants has led to dramatic reductions in the incidence of pneumococcal disease. The herd effect has resulted in greater than a 90 percent decline in pneumococcal disease due to vaccine serotypes in older children who did not receive Prevnar and in adults (figure 1) [24,25]. The universal use of PCV7 has also led to a substantial reduction in hospitalizations for pneumonia in children and adults in the United States [26]. Preliminary data suggest that precisely the same decline in pneumonia due to vaccine serotypes is being observed with widespread use of PCV13, an observation that raises serious question about the potential benefits of using PCV13 routinely in adults. (See "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children", section on 'Efficacy and effectiveness' and "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia", section on 'Impact of childhood vaccination' and "Impact of universal infant immunization with pneumococcal (Streptococcus pneumoniae) conjugate vaccines in the United States".) There are few data on the efficacy of pneumococcal conjugate vaccines in specific high-risk groups, such as various immunocompromised populations. The most well-studied immunocompromised group has been HIV-infected patients in Africa, in whom the polysaccharide vaccine was not effective whereas the conjugate vaccine was effective

[27,28]. (See 'Efficacy' below and "Pneumococcal immunization in HIVinfected adults", section on 'Efficacy and immunogenicity of pneumococcal vaccination'.) An untoward effect of the widespread use of pneumococcal conjugate vaccines has been the emergence of "replacement strains," a term used to describe non-vaccine pneumococcal serotypes that have appeared as colonizers of the nasopharynx and as a cause of pneumococcal disease [29]. Replacement strains have emerged because pneumococcal conjugate vaccines stimulate mucosal immunity which, in turn, reduces nasopharyngeal carriage of vaccine serotypes. This reduction in carriage appears to create an ecologic niche for nonvaccine serotypes [30]. As an example, S. pneumoniae type 19A (not included in PCV7) emerged as a common cause of pneumococcal disease in children and adults a few years after this vaccine began being used in infants and toddlers (figure 1) [24,31]. (See "Impact of universal infant immunization with pneumococcal (Streptococcus pneumoniae) conjugate vaccines in the United States".) The recommendation to give both PPSV23 and PCV13 to high-risk adults is far more costly than recommending PPSV23 alone. In addition, adherence to a two-vaccine regimen is likely to be poorer than adherence to a one-vaccine regimen. Despite the strength of the recommendation, data supporting this approach are meager. A comparison of the properties of pneumococcal polysaccharide and conjugate vaccines is reviewed in the Table (table 4). PNEUMOCOCCAL POLYSACCHARIDE VACCINES The pneumococcal polysaccharide vaccine (PPSV23; Pneumovax 23, PnuImmune) includes 23 purified capsular polysaccharide antigens (table 2). These serotypes were initially chosen because they represented 85 to 90 percent of the serotypes that cause invasive disease in the United States. In 2009, 60 to 76 percent of cases of invasive pneumococcal disease in adults in the United States were caused by PPSV23 serotypes [32]. Immunogenicity Successful vaccination is indicated by antigenspecific antibody responses within two to three weeks; the responses may not be consistent among all serotypes in PPSV23 and vary from one individual to another. Although important for epidemiologic studies, checking antibody responses after vaccination is rarely performed in individual subjects. (See "Assessing the immunologic response to vaccination".) The serum concentration of antibody that correlates with protection against pneumococcal disease has not been clearly defined. After healthy adults >50 years of age are vaccinated, antibody declines

rapidly over a one- to two-year period, persisting at low levels for 10 or more years [17,20,22,29]. Despite these observations, in a report from the Centers for Disease Control and Prevention's pneumococcal surveillance system, efficacy of the pneumococcal polysaccharide vaccine did not decline at seven or more years after vaccination [33]. Revaccination with PPSV23 induces persistent functional antibody response in healthy middle-aged and older adults [18,20]. Some studies have shown an inverse association between circulating antibody concentrations just before primary vaccination or revaccination and subsequent increase, consistent with other observations suggesting that it may be detrimental to revaccinate patients too soon following initial vaccination [22]. (See 'Revaccination' above.) Efficacy Several case-control studies, randomized trials, and metaanalyses have shown that the pneumococcal polysaccharide vaccine (PPSV) prevents pneumococcal disease. Some studies have suggested that PPSV protects against invasive infection (defined as pneumococcal disease with isolation of the infecting organisms from a normally sterile body site) but not from noninvasive (ie, nonbacteremic), pneumococcal pneumonia [23,30,34-44]. However, other studies have not demonstrated efficacy for preventing invasive or noninvasive disease [38,39,44-47] or for reducing mortality [23,48]. Most studies of elderly individuals have failed to show a reduction of all-cause pneumonia [43]. A population-based case control study showed that the immediate efficacy of PPSV declined as age increased, as did the duration of any observed effect [36]. The avidity of antibody for pneumococcal polysaccharide may diminish with age. Possible reasons for the conflicting results include the rarity of the outcomes being assessed (leading to a small number of events in studies) and the difficulty in accurately diagnosing pneumococcal pneumonia. In general, studies with more specific endpoints (eg, invasive pneumococcal disease caused by vaccine serotypes) have been more likely to demonstrate efficacy than studies with less specific endpoints (eg, nonbacteremic pneumococcal pneumonia, all-cause pneumonia, all-cause mortality) [30]. A 2013 systematic review and meta-analysis assessed the efficacy of PPSV for preventing invasive pneumococcal disease, all-cause pneumonia, and all-cause mortality in adults in 16 randomized trials; some of the individual meta-analyses included data from fewer than 16 trials [23]. The following results were observed: PPSV significantly reduced the risk of invasive pneumococcal disease (odds ratio [OR] 0.26, 95% CI 0.14-0.45).

 Among otherwise healthy individuals in low-income countries included in one trial, there was a significant reduction in invasive pneumococcal disease (OR 0.14, 95% CI 0.030.61). This group is considered to be at elevated risk of pneumococcal disease due to overcrowding and/or environmental factors. Among otherwise healthy individuals in high-income countries (many of whom were elderly), there was a significant reduction in invasive pneumococcal disease (OR 0.20, 95% CI 0.10-0.39). Among individuals with chronic diseases in high-income countries, there was no evidence of protective efficacy, but the analysis was underpowered to detect a significant difference between the vaccinated and control groups. The benefit of PPSV for preventing invasive pneumococcal disease was more pronounced when the analysis was limited to trials that assessed the incidence of disease caused by serotypes included in the vaccine (OR 0.18, 95% CI 0.10-0.31). PPSV was associated with reductions in both invasive (OR 0.26, 95% CI 0.15-0.46) and noninvasive pneumococcal pneumonia (OR 0.46, 95% CI 0.25-0.84). There was efficacy against all-cause pneumonia among individuals in low-income countries (OR 0.54, 95% CI 0.43-0.67) but not among individuals in high-income countries in either the general population or in adults with chronic illness. PPSV did not reduce all-cause mortality. A 2009 systematic review graded randomized trials based on statistical

criteria and retained only a few in their meta-analysis [44]. When the analysis was limited to trials of highest methodologic quality, efficacy of vaccination was not observed. However, their analysis gave disproportionate weight to two studies that relied on serologic techniques to diagnose pneumococcal pneumonia [45,46]. These serologic tests have been shown to be of questionable validity for diagnosing pneumococcal pneumonia [49]. The immunogenicity and efficacy of PPSV23 in patients with a specific risk factor is discussed in detail separately. (See "Pneumococcal immunization in HIV-infected adults", section on 'Efficacy and immunogenicity of pneumococcal vaccination' and "Immunizations in solid organ transplant candidates and recipients", section on 'Pneumococcus' and "Immunizations in patients with cancer", section on 'Pneumococcal vaccine' and "Immunizations in hematopoietic cell transplant candidates and recipients", section on 'Pneumococcus' and "Management of infection in acute exacerbations of chronic obstructive pulmonary disease", section on 'Vaccination' and "Immunizations in patients with end-stage renal disease", section on 'Pneumococcal vaccine' and "Immunizations for patients with chronic liver disease", section on 'Pneumococcal vaccine'.) Adverse reactions The most common adverse reactions to PPSV23 are injection site pain or tenderness (in 60 percent of vaccinees), swelling or induration (in 20 percent), and erythema (in 16 percent) [6]. These reactions usually persist for less than 48 hours. Moderate systemic reactions (eg, fever and myalgias) and more severe local reactions (eg, local induration) occur less commonly. (See "Pneumococcal polysaccharide vaccine (23-valent): Drug information".) As noted above, some studies have suggested that injection site reactions are more common after revaccination than after primary vaccination, but in most studies, such reactions were mild and selflimited [20-22]. One retrospective study showed no increase in medically attended adverse events among individuals who received three or more doses of PPSV23 compared with those who received one dose [50]. Healthcare providers should report suspected adverse events to the Vaccine Adverse Event Reporting System (VAERS). VAERS can be contacted via the VAERS web site or by telephone at 800-822-7967. Contraindications A severe allergic reaction (eg, anaphylaxis) to PPSV23, an exceedingly rare event, is an absolute contraindication to revaccination with PPSV23 [7]. (See "Pneumococcal polysaccharide vaccine (23-valent): Drug information".) PNEUMOCOCCAL CONJUGATE VACCINES Pneumococcal

protein-conjugate polysaccharide vaccines have a number of beneficial properties that polysaccharide vaccines lack (table 4). Children <2 years of age respond poorly to polysaccharide antigens. However, when a polysaccharide is covalently conjugated to a carrier protein, the resulting antigen is recognized as T celldependent, stimulating a good serum antibody response, mucosal immunity, and immunologic memory in children (including those <2 years) and adults. As a result of inducing a mucosal immune response and reducing nasopharyngeal colonization, pneumococcal conjugate vaccines cause herd protection, reducing rates of disease not only in vaccinated individuals but also in those who were not vaccinated, especially siblings and playmates, but also parents and other unvaccinated adults. The implementation of universal vaccination of infants in the United States with a pneumococcal conjugate vaccine beginning in 2000 has resulted in a dramatic decrease in invasive pneumococcal disease in both children and adults (figure 1). The efficacy of PCV13 in children is discussed in greater detail separately. (See "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children", section on 'Efficacy and effectiveness'.) A 7-valent pneumococcal conjugate vaccine, PCV7, which contained protein-conjugated capsular polysaccharides from the seven pneumococcal serotypes that most commonly infected children, was recommended for universal use in infants and toddlers in the United States beginning in 2000. This recommendation was followed by a dramatic decrease in invasive pneumococcal disease in both children and adults (figure 1). In 2010, a 13-valent pneumococcal conjugate vaccine, PCV13, which contains four additional common serotypes plus types 1 and 5 (table 2) that are of major significance in underdeveloped countries, was recommended in place of PCV7. Some European countries have used a 10-valent vaccine, and a 15-valent vaccine is in development. In 2009, 39 to 55 percent of cases of invasive pneumococcal disease in adults in the United States were caused by PCV13 serotypes [32]. In 2012, PCV13 began to be recommended for use in selected high-risk adults. (See 'Approach to vaccination' above and 'Available vaccines' above.) Immunogenicity The data from various studies comparing pneumococcal conjugate vaccines (PCV) with the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in adults show that the conjugate vaccines are at least as immunogenic as PPSV23 for the serotypes covered. A careful review of all studies published until 2011 found no definitive or consistent advantage of either vaccine [29].

A study in mice showed that PCV7 elicited an increase in serotypespecific memory B cell responses, whereas PPSV23 resulted in a decrease in memory B cell frequency, supporting the hypothesis that pneumococcal conjugate vaccines (but not polysaccharide vaccines) induce a T celldependent memory B cell response [51]. While it seems likely that pneumococcal conjugate vaccines induce a more persistent immune response than PPSV23, further studies are required to prove this [30]. Even if concentrations of serum antibody to capsular polysaccharides remain higher in recipients of conjugate than in recipients of polysaccharide vaccine, an efficacy study would be required to prove an advantage of conjugate vaccine because a protective antibody level has never been clearly defined. Immunologic priming Since pneumococcal conjugate vaccines stimulate memory B cells [51], it is possible that administration of such a vaccine may prime the immune system for an improved secondary immune response to a pneumococcal polysaccharide vaccine (PPSV) [30]. However, several trials have not shown that a prime-boost regimen with a pneumococcal conjugate vaccine followed by a pneumococcal polysaccharide vaccine enhances immunogenicity [52-56]. In one openlabel randomized trial, administration of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) six months prior to the 7-valent pneumococcal conjugate vaccine (PCV7) resulted in attenuated antibody concentrations compared with PCV7 alone [55]. Nevertheless, based on these considerations, the United States Advisory Committee on Immunization Practices (ACIP) recommends that patients with an indication for both vaccines should generally receive the conjugate vaccine first, followed eight weeks later by the polysaccharide vaccine, and patients who have already received polysaccharide vaccine first should wait one year before receiving conjugate vaccine. (See 'Schedule for dual vaccination' above.) Efficacy The only direct evidence for an advantage of PCV in adults at increased risk for pneumococcal disease comes from two randomized trials in HIV-infected patients, carried out at different times and in different African countries by the same group of investigators [27,28]. The first study showed that PPVS23 was no more protective than placebo against invasive pneumococcal disease; in fact, there even was a suggestion, albeit unexplained, of increased susceptibility to infection in the vaccinated group [28]. The second study showed that two doses of PCV7 greatly reduced the rate of invasive pneumococcal disease during the first year after vaccination (85 percent reduction); this effect was reduced to 25 percent protection in the second year after vaccination [27]. The overall rate of protection in two years after vaccination was 74 percent. The efficacy of pneumococcal conjugate vaccines in HIV-infected adults

is discussed in greater detail separately. (See "Pneumococcal immunization in HIV-infected adults".) Based largely on theoretical considerations and on results that may suggest slightly better responses of some adults to PCV versus PPSV, the ACIP has recommended PCV for adults who have certain underlying medical conditions (table 3). This recommendation was in the absence of data demonstrating clinical efficacy in adults and the lack of data regarding the full impact of routine PCV13 vaccination in children on the incidence of pneumococcal disease in adults [3]. The first of these issues is expected to be addressed in a trial in the Netherlands comparing PCV13 to placebo in 85,000 adults 65 years of age [57]. However, since this trial began concurrently with the recommendation to use PCV in infants in the Netherlands, it will not answer the question of whether its use in adults is efficacious in countries that routinely vaccinate infants [25]. Given the dramatic reduction in invasive pneumococcal disease observed in adults following the routine use of PCV in children in the United States due to the herd effect (figure 1), it is possible that vaccination of adults will not provide additional benefit. (See 'Overview of benefits and limitations' above.) An additional limitation of the Dutch trial is that since it is placebocontrolled, it will not directly answer the question of whether PCV13 provides better protection than PPSV23 [25]. As noted above, pneumococcal conjugate vaccines have proven to be highly effective in children. (See "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children", section on 'Efficacy and effectiveness'.) Adverse reactions As with PPSV, the most common adverse reactions with PCV13 include local reactions, such as erythema, swelling, and pain at the injection site, as well as systemic reactions, such as fatigue, headache, chills, rash, anorexia, myalgias, and arthralgias [7,58]. (See "Pneumococcal conjugate vaccine (13-valent): Drug information".) Healthcare providers should report suspected adverse events to the Vaccine Adverse Event Reporting System (VAERS). VAERS can be contacted via the VAERS web site or by telephone at 800-822-7967. Contraindications Severe allergic reaction (eg, anaphylaxis) to any component of PCV13 or any diphtheria toxoidcontaining vaccine is a contraindication to receiving PCV13 [7]. (See "Pneumococcal conjugate vaccine (13-valent): Drug information".) COST-EFFECTIVENESS A cost-effectiveness analysis has suggested that the use of PCV13 of adults using the existing indications

(ie, vaccination at age 65 years and at younger ages if comorbidities are present) would be more cost-effective than PPSV23, provided that the effectiveness of PCV13 at preventing nonbacteremic pneumococcal pneumonia is high ($28,900 versus $34,600 per quality-adjusted-lifeyear [QALY] gained, respectively) [59]. Important limitations of this study are that the authors relied on the meta-analysis of Huss et al [44] rather than that of Moberley et al [23] and developed their estimates based on the erroneous assumption that PPSV23 provides no protection against noninvasive pneumococcal infection. If the herd effect of PCV13 is as large as has been shown for PCV7 (and preliminary data suggest that it is), infection in adults due to strains contained in PCV13 will largely be eliminated, which will render the use of PCV in adults irrelevant and will greatly increase the cost per QALY. A more recent cost analysis from the United Kingdom [60] recognized the herd effect of conjugate vaccine, concluding that use of PCV13 in groups at risk for pneumococcal was not likely to be cost effective. INVESTIGATIONAL APPROACHES Existing pneumococcal vaccines utilize capsular polysaccharides as antigens. Vaccines cannot include all serotypes, replacement strains appear, and pneumococci readily acquire DNA from other microorganisms by transformation, giving them the ability to switch capsular serotypes. These facts have led to attempts to develop vaccines based on highly conserved proteins (eg, pneumolysin, histidine triad protein D, surface protein A), some of which are surface expressed and one of which (pneumolysin) is responsible for disease. Several such vaccines are in development [25,30,61]. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient information: Vaccines for adults (The Basics)" and "Patient information: Vaccines (The Basics)")

 Beyond the Basics topic (see "Patient information: Pneumonia prevention (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Pneumococcal infections, including pneumonia and invasive disease such as bacteremia and meningitis, remain an important source of morbidity and mortality in adults, especially among older adults (table 1), and those with certain conditions, including immunocompromise and asplenia. (See 'Introduction' above.) Two types of pneumococcal vaccines are approved for use in the United States: A pneumococcal polysaccharide vaccine (PPSV23; Pneumovax 23, Pnu-Immune) that includes 23 purified capsular polysaccharide antigens A pneumococcal protein-conjugate vaccine (PCV13; Prevnar 13) that includes capsular polysaccharide antigens covalently linked to a non-toxic protein that is nearly identical to diphtheria toxin (see 'Available vaccines' above) PPSV23 has been used in adults for decades in the United States but is not recommended for infants or toddlers under age two because it is poorly immunogenic in this age group. A 7-valent pneumococcal conjugate vaccine, PCV7, was recommended for universal use in infants and toddlers beginning in 2000; since 2010, a 13-valent pneumococcal conjugate vaccine, PCV13, has been recommended for infants and children in its place. In 2012, PCV13 began to be recommended for use in selected high-risk adults. (See 'Available vaccines' above.)

We recommend PPSV23 for all adults 65 years of age and in persons 19 to 64 years of age who have a condition that increases the risk of pneumococcal disease (Grade 1B). The indications for vaccination are summarized in the following Table (table 3). (See 'Indications' above.) We suggest PCV13 followed eight weeks later by PPSV23 for use in individuals aged 19 or older with functional or anatomic asplenia, an immunocompromising condition (eg, HIV infection, cancer), a cerebrospinal fluid leak, a cochlear implant, or advanced kidney disease (table 3) (Grade 2C). If such adults have already received PPSV23, at least one year should transpire before they are given PCV13. (See 'Indications' above and 'Schedule for dual vaccination' above.) PCV13 is not recommended for healthy adults of any age. (See 'Indications' above.) PPSV23 and PCV13 are administered intramuscularly as a 0.5 mL dose. They may be administered concurrently with other vaccines, such as the influenza vaccine, but at a separate site. However, PPSV23 and PCV13 should be administered at different times as outlined above; the schedule depends on which formulation was given first. (See 'Administration' above and 'Schedule for dual vaccination' above.) A single revaccination with PPSV23 is recommended in adults 65 years of age if they were vaccinated more than five years previously at a time when they were less than 65 years of age, and in immunocompromised patients, five years or more after the first dose. Some experts continue to recommend administration of PPSV23 every six to seven years for asplenic individuals. Revaccination with PCV13 is not recommended. (See 'Revaccination' above.) The strongest evidence for the benefit of PCV over PPSV23 in adults at increased risk for pneumococcal disease comes from

randomized trials in HIV-infected individuals in Africa, which demonstrated a reduction in invasive pneumococcal disease among individuals who received PCV7, but no reduction in recipients of PPSV23. (See 'Efficacy' above.) ACKNOWLEDGMENT The editorial staff at UpToDate Inc. would like to acknowledge Dr. Elaine Tuomanen and Dr. Patricia Hibberd, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1.Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1997; 46:1. 2.Centers for Disease Control and Prevention (CDC). Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2012; 61:816. 3.Centers for Disease Control and Prevention (CDC). Licensure of 13valent pneumococcal conjugate vaccine for adults aged 50 years and older. MMWR Morb Mortal Wkly Rep 2012; 61:394. 4.Centers for Disease Control and Prevention (CDC), Advisory Committee on Immunization Practices. Updated recommendations for prevention of invasive pneumococcal disease among adults using the 23-valent pneumococcal polysaccharide vaccine (PPSV23). MMWR Morb Mortal Wkly Rep 2010; 59:1102. 5.Centers for Disease Control and Prevention 2011. Active Bacterial Core Surveillance (ABCs) report, Emerging Infections Program Network Streptococcus pneumoniae, 2010. http://www.cdc.gov/abcs/reports-findings/survreports/spneu10orig.pdf (Accessed on March 21, 2013). 6.PNEUMOVAX 23 (pneumococcal vaccine polyvalent) sterile, liquid vaccine for intramuscular or subcutaneous injection - prescribing information. http://www.merck.com/product/usa/pi_circulars/p/pneumovax_23/ pneumovax_pi.pdf (Accessed on October 24, 2013). 7.Prevnar 13 prescribing information. http://www.fda.gov/downloads/biologicsbloodvaccines/vaccines/a pprovedproducts/ucm201669.pdf (Accessed on January 08, 2013). 8.Honkanen PO, Keistinen T, Kivel SL. Reactions following administration of influenza vaccine alone or with pneumococcal vaccine to the elderly. Arch Intern Med 1996; 156:205.

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