Live attenuated pediatric RSV vaccines

(NIAID program)
Peter L. Collins, PhD
National Institute of Allergy and Infectious Diseases
National Institutes of Health, USA
Immunostained RSV filaments on
the surface of a syncytium

Infant with RSV disease

NIAID

Objective
Live RSV vaccines to be given to RSV-nave infants
- Based on RSV strain A2 (subgroup A)
- Intranasal administration

Two live RSV vaccine approaches

Live-attenuated strains of RSV (in part with MedImmune)
Live-attenuated HPIV1, 2, and 3 as vectors to express RSV
antigen from an added gene

Can rational design (reverse genetics) provide improved candidates?

Live-attenuated and live-vectored RSV vaccines

Advantages
Free of RSV disease enhancement seen with inactivated and subunit RSV vaccines
- Formalin-inactivated RSV: 80% hospitalization rate, 9% mortality
- Also observed with purified RSV subunits in experimental animals
- Not observed with live-attenuated and live-vectored vaccines
IN administration, needle-free, direct stimulation of local as well as systemic immunity
- E.g., secretory antibodies; lung-resident memory T cells
- Greater restriction of transmission
Adjuvant-free; a single dose is substantially immunogenic
More amenable to achieving rapid protection early in life
Broad stimulation of innate, cellular, humoral immunity

Live vaccines give broader, more effective immunity in virus-nave recipients

Disadvantage
Infectious agent: must attenuate but retain immunogenicity

Three attenuated RSV strains in clinical studies

M2-2

NS1 NS2

SH

M2

Deletion of RNA regulatory protein yields increased gene transcription, decreased genome
replication

Increased antigen expression may increase immunogenicity

Expect gene deletion to be highly stable

cps2

NS1 NS2

SH

M2
cp

cp
cp cp
(stabilized version of
SH
248
1030
404
rA2cp248/404/1030SH,
stabilized
of Karron et al, 2005) Attenuation mainly involves temperature sensitivity point mutations

cp

Highly temperature sensitive, provides increased restriction in LRT

Increased genetic/phenotypic stability, but still an issue

NS21313

NS1 NS2

SH

M2

L
1313

NS2

Deletion of IFN antagonist may provide increased immunogenicity

NS2 also appears to be a virulence factor

Liesman et al, J Clin Invest 2014

Deletion of L residue 1313 confers a moderate ts phenotype

Deletions yield increased stability

I1314L

HPIV1, 2, and 3 as vectors for RSV-F protein

e.g. B/HPIV3
RSV F

HN

Bovine backbone with human F and HN genes

Advantages compared to attenuated RSV strains
Provides bivalent HPIV + RSV vaccine; increase breadth of protection against RT disease
HPIVs replicate in vitro to titers 10- to 100-fold greater than RSV

Avoids the physical instability of RSV

Can express forms of RSV F designed for greater immunogenicity but are
non-functional (i.e., stabilized pre-fusion F; post-fusion F)
Provided better boosts in rodents than re-dosing with an attenuated RSV
Attenuated HPIVs may be less reactogenic than attenuated RSV

Disadvantage: provides only 1 RSV antigen

Modified versions of RSV F (into B/HPIV3)

Jason McLellan
Barney Graham
Peter Kwong

(all GeneArt-codon-optimized, HEK)

S155C

S290C

DS
(pre-fusion)
DS-Cav1
(pre-fusion)

RSV F protein
S155C

S190F V270L
S290C

FP
TM, CT

Post-fusion

CT
CT
TM

CT

TM, CT from BPIV3 F protein

TM CT

S155C

S290C

CT

DS CT
TM CT

DS TM CT
S155C

DS-Cav1 CT
DS-Cav1 TM CT

S190F V270L
S290C

TM

CT

Rhesus study
S155C

S290C

DS
(pre-fusion)
DS-Cav1
(pre-fusion)

N=5

RSV F protein
S155C

S190F V270L
S290C

FP
TM, CT

Post-fusion

CT

Plus: unmodified
F protein control

CT
TM

CT

N=5

TM CT

S155C

S290C

CT

DS CT

TM CT

DS TM CT
S155C

DS-Cav1 CT
DS-Cav1 TM CT

N=4

S190F V270L
S290C

TM

CT

The epidemiology of the HPIVs suggest optimal times of vector use

HPIV3-based
vector

HPIV1-, 2-based
vectors

HPIV1, 2
HPIV3
RSV
0

10 11

12 15

Attenuated RSV strain

Seasonal?

18

21

24

age
(months)

Contributors to the present clinical studies:

LID/NIAID
Ulla Buchholz
Cindy Luongo
Shirin Munir
Bo Liang
Lijuan Yang
Tom McCarty
Sonja Surman
Emerito AmaroCarambot

LID alumni
Brian Murphy
Steve Whitehead

VRC/NIAID
Jason McLellan
Barney Graham
Peter Kwong

Center for Immunization

Research, Johns Hopkins
Ruth Karron
Betty Schappell
Bhavin Thumar
Karen Loehr
Et al.

IMPAACT
(International Maternal,
Pediatric, Adolescent,
AIDS Clinical Trials Group)
Coleen Cunningham
Betsy McFarland
George Siberry
Devasena
Gnanashanmugam
Et al.

Seattle Childrens Hospital

Janet Englund

MedImmune

NIAID Comparative
Medicine Branch

NIAID RCHSPB (DCR)

Clinical study participants

and their families