Novel RSV Vaccines Under
Development
Barney S. Graham, M.D., Ph.D.
Achievements and Future Challenges in the
Surveillance of Respiratory Viruses
San Jose, Costa Rica
January 30, 2013
Vaccine
Research
Center
National Institute of Allergy and
Infectious Diseases
National Institutes of Health
Department of Health and Human
Services
For more information:
1-866-833-LIFE
vrc.nih.gov
VRCforLIFE@mail.nih.gov
RSV Genome Organization and
Protein Functions
le
P
NS1 NS2 N
F
M SH G
M2-1 M2-2
L
3´
tr
15,222 nt total
0
2
4
8
6
10
plasma
membrane
15 kb
envelope spikes
G (298) - attachment
nonstructural
NS1 (139) - inhibit Type I IFN
induction
NS2 (124) - inhibit Type I IFN
signaling
- activate PI3K and
NF-B
- inhibit apoptosis
150 nm
nucleocapsid-associated
regulatory
M2-2 (90)
- viral transcription 
- RNA replication 
N (391) - RNA-binding
P (241) - phosphoprotein
L (2165) - polymerase
M2-1 (194) - transcription processivity
factor
- neutralization and protective
antigen
- antibody decoy (secreted G)
- fractalkine mimic
- TLR antagonist
F (574) - fusion and entry
- neutralization and protective
antigen
- TLR4 agonist
SH (64) - putative viroporin
- inhibits apoptosis
inner envelope face
M (256) - assembly
2
Disease Severity is Greatest in
Children <2.5 Months of Age
Boyce TG et al J Pediatr. 2000; 137:865
40
30
20
<=28 wk
29-<33 wk
10
33-<36 wk
Low-risk
Dec
Nov
Oct
Sep
Aug
Jul
Jun
May
Apr
0
Mar
CHD (5%)
BPD (3%)
CHD
Other disease
Feb
Low-risk (53%)
BPD
50
Jan
Prematurity (12%)
RSV Hospitalizations
per 100 Children
60
Other disease (23%)
Month of Birth
Biological challenges for vaccination
•
•
•
•
•
Relatively weak induction of cellular responses
Reduced capacity for somatic mutation of antibody
Presence of maternal antibody
Frequent reinfection
Legacy of vaccine-enhanced disease
3
Biological Factors Associated
with Difficult Vaccine Targets
•
Infection is not easily controlled by natural immunity
–
–
–
•
Alteration or evasion of host immune response
–
–
•
•
•
•
•
High frequency of severe disease (filoviruses)
Persistent infection (HSV, HIV, HCV)
Reinfection is common (RSV, HIV)
Interference with innate and adaptive immunity
Integration, sequestration, and immune sanctuaries
Significant genetic variation or multiple serotypes
Site of initial infection is major target organ for disease
Animal models do no recapitulate pathogenesis of human disease
Critical role for T cell-mediated immunity (HIV, HCV)
Delay between infection and induction of cellular immunity (HCV)
Graham & Walker in The Immune Response to Infection, 2011
4
Biological Factors Associated
with Difficult Vaccine Targets
•
Infection is not easily controlled by natural immunity
–
–
–
•
Alteration or evasion of host immune response
–
–
•
•
•
•
•
High frequency of severe disease (filoviruses)
Persistent infection (HSV, HIV, HCV)
Reinfection is common (RSV, HIV)
Interference with innate and adaptive immunity
Integration, sequestration, and immune sanctuaries
Significant genetic variation or multiple serotypes
Site of initial infection is major target organ for disease
Animal models do no recapitulate pathogenesis of human disease
Critical role for T cell-mediated immunity (HIV, HCV)
Delay between infection and induction of cellular immunity (HCV)
Graham & Walker in The Immune Response to Infection, 2011
5
Factors that Diminish Incentives for
Industrial Vaccine Development
• Concern about safety
– RSV
• Concern about achieving efficacy
– HIV, RSV
• Sporadic or biodefense threats without a dependable
commercial market
– Ebola/Marburg
– New emerging viral diseases
Graham et al. Clinical Pharmacology and Therapeutics 2009
6
Factors that Diminish Incentives for
Industrial Vaccine Development
• Concern about safety
– RSV
• Concern about achieving efficacy
– HIV, RSV
• Sporadic or biodefense threats without a dependable
commercial market
– Ebola/Marburg
– New emerging viral diseases
Graham et al. Clinical Pharmacology and Therapeutics 2009
7
Overview of RSV
Vaccine Clinical Development
No Efficacy –
Serious Adverse
Effects
Formalin-inactivated
alum-precipitated
whole virus
No Efficacy –
Low/No Efficacy –
Inappropriate
No Immediate
Immune Response Safety Concerns
Subunit vaccine
G protein –
streptococcal
conjugate
Subunit vaccine
F glycoprotein in
alum in adults
Various live
attenuated RSV
nasally in children
Efficacy unknown –
Currently in
Clinical Testing
Live attenuated RSV
nasally in children
rA2cp248/404/1030/ΔSH
ΔM2-2
Efficacious
None
Post-fusion F Rosettes
Live virus vaccine
delivered IM in
children
BPIV-RSV live
chimeric virus nasally
8
FI-RSV Vaccine-Enhanced Disease
Vaccine n
Infected (%)
Hospitalized (%)
Deaths
FI- RSV 31
20 (65)
16 (80)
2
FI-PIV-1 40
21 (53)
1 (5)
0
Kim et al. Am J Epidemiol 1969;89:422
9
% Eosinophils in BAL
Correlates of FI-RSV
Vaccine-Enhanced Illness
45
40
35
30
25
20
15
10
5
0
FI-Vero
Graham et al. JI 1993;151:2032
Tang et al. Vaccine 1997;15:597
FI-rRSV
wt
FI-rRSV FI-rRSV FI-r RSV
GepDG
DSH
Johnson et al. J Virol 2004; 78:6024
Polack et al. J Exp Med
2002; 196:859
Properties to Avoid
• Antibodies with poor NT activity → Immune complex deposition
• CD4+ Th2-biased response → Allergic inflammation
10
Options for Vaccine Evaluation
Platforms
Live-attenuated
•
•
RSV
chimeric paramyxovirus vectors
Gene-based vectors
•
•
•
Nucleic acid – DNA or RNA
Replication defective
Replication competent
Subunit or particle-based
•
•
•
•
•
Purified protein
Virus-like particle
Virosome
Nanoparticle
Peptides
Antigens
Delivery
Target Populations
F
Respiratory tract
Neonate (<2 mo)
G
Parenteral
Infants and children (>6 mo)
SH
Internal
Multiple
Other mucosal site
•
•
Sero-negative
Sero-positive
Siblings and parents of
neonates
Young adult women
•
•
Pregnant women
Women of child-bearing age
Elderly (>65 yr)
Whole-inactivated RSV
11
11
Considerations for Immunizing
RSV-Naïve Infants
• Opportunity to prevent or delay first RSV infection
– Reduced primary morbidity
– Reduced childhood wheezing
• Opportunity to establish future immune response patterns
(antibody specificity and T cell phenotype)
– Improved immunity against reinfection
• Target age is critical
– Peak age of hospitalization ~2.5 mo
– ~50% of hospitalization occur >6 mo
– If incidence is ~60% in first year, ~70% are RSV-naïve at 6 mo
12
12
Selecting Target Age for
Initiating Vaccination
<4 mo
>6 mo
Somatic mutation
-
++
Dendritic cell and APC maturation
-
++
Clearance of maternally-derived antibody
-
++
No longer breast-feeding
-
+
Idiosyncratic apnea and other rare adverse events
+
-
Small airway size
++
-
Relative Th2 bias
++
-
Efficacy
Safety
13
13
RSV Vaccine Pipeline
Product
Sanofi RSV vaccine
BBG2na
MEDI-559
MEDI-534
MEDI ΔM2-2 & others
Novavax RSV
Sendai-RSV chimera
RSV vaccine
NanoBio RSV
MVA-BN RSV
GenVec RSV
Universal RSV
RSV vac_Oka
VEE-F
RNA replicon
Mymetics RSV
TechnoVax
SynGem
RSV VLP Vac
F protein
RSV vaccine
AMV601 / RespiVac
PEV4
Epitope-scaffold
SHe
T4-214
TWi RSV vaccine
Sponsor
Sanofi
Queen’s Univ Belfast
MedImmune
MedImmune
NIAID +/- MedImmune
Novavax
St. Jude’s
Merck/Nobilon
Nanobio/Merck
Bavarian Nordic
GenVec
Crucell/J&J
Okairos
Alphavax
Novartis
Mymetics
Technovax
Mucosis
LigoCyte
Novartis
GSK
AmVac
Pevion
U. Wash/ TSRI)
Ghent/Immunovaccine
TI Pharma
TWi Biotech
Type of Vaccine
Subunit
Subunit
Live-attenuated
Live chimeric
Live-attenuated
Nanoparticle
Live chimeric
Single-cycle
Inactivated
Vector
Vector
Vector
Vector
Vector
Vector-RNA
VLP-Virosome
VLP
VLP-lactococcus
VLP
Subunit
Subunit
Subunit
Subunit
Epitope-scaffold
Subunit
Target Antigen
F, G, M protein
G
Whole virus
F Protein
Whole virus
F Protein
F
Whole virus
Whole virus
Subunit
F
Subunit
F-N-M2-1
F
F
Multiple
Multiple
F
F
F
F
F
F epitope
SH
Sources: Company Website, Fierce Vaccines, RSV 2012 Symposium, Clinicaltrials.gov
Target population
Elderly patients
n/a
Infants and children
Infants
Adults, infants and children
n/a
n/a
n/a
n/a
Adult high risk patients
Children and infants
Infants and elderly
n/a
n/a
n/a
Elderly patients
n/a
n/a
n/a
n/a
Pediatric
n/a
n/a
Pediatric and at-risk adults
n/a
n/a
n/a
Phase
Phase II
Phase II
Phase I-IIa
Phase I-IIa
Phase I
Phase I
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
Pre-clinical
14
Comparing Product Concepts Based on
Immunological Concepts
Native F
or G
MHC
pathway
CD8 T cell
induction
IL-4
Delivery
route
Replication
competence
-
II
-
++
IM
-
++/-
II
-
+/-
IM
-
++
II +/- I
+/-
-/+
IM
-
++
I & II
++
-
IM or nasal
- or +
++
I & II
+
-
IM
-
Recombinant,
or chimeric
viruses
++
I & II
+
-
nasal
+
WT or attenuated virus
++
I & II
+
-
nasal or IM
+
Whole-inactivated virus
Protein subunits
VLPs or
virosomes
Vectors
Naked
DNA or RNA
15
Passive Prophylaxis with Synagis
•Humanized mouse monoclonal antibody
•Monthly injections reduce hospitalizations by 50%
•Licensed for select high-risk infants
•Demonstrates neutralizing antibodies
against the F glycoprotein are protective
Shane Storey, Nat Rev Drug Discovery (2010) 9, 15-16
16
Vaccine Antigen Selection:
Rationale for Choosing F
Reasons for choosing F:
• Target of Synagis
• Higher sequence conservation than G
• Unlike G, F is absolutely required for virus entry
Target cell
cytoplasm
Receptor
Prefusion
Postfusion
Prehairpin
Delivery of
nucleocapsid and genome
17
Organization of RSV F Glycoprotein
F2
*
27
F1
70
116 126
500
FP HR1
1
21
*
37
69
*
HR2 TM
212
Unique to RSV
313 322 333 343 358 367 382 393 416 422 439
•
Signal peptide
Fusion peptide
Heptad repeat
Transmembrane domain
Cysteine
Disulfide bond
N-linked glycosylation
•
574
Type I integral membrane protein essential for
RSV entry and cell-to-cell fusion
Primary target for neutralizing antibody.
•
•
•
pH-independent class I viral fusion protein
Multiple furin cleavage sites
Two heptad repeat regions that form an antiparallel six-helix bundle in post-fusion state.
•
F1 has a cysteine-rich domain.
C-linked palmitylation
Known or potential furin cleavage site
550
Neutralizing antibody epitope
Infection inhibiting peptide
18
New Technologies Have Made an RSV
Vaccine Possible
Viral Vaccines
Major Conceptual and Technological Advances
Cell
Molecular Potential areas for new
culture biology
technical advances
Discovery of immunity
16
RSV ?
HPV
Rotavirus
14
Varicella
Japanese
12
encephalitis
Hepatitis A
10
Hepatitis B
Rubella
8
Mumps
Adenovirus
6
Measles
Poliovirus
4
Influenza
Yellow fever
2
Rabies
Smallpox
Animal Models
B & T cell biology
Delivery devices
Genomics
Glycobiology
Informatics
Manufacturing
Nanobiology
Proteomics
Structural Biology
Vector biology
0
1800
1820 1840
1860
1880
1900 1920
1940
1960 1980
2000
2020
2040
2060 2080
19
Summary
•
There is a robust pipeline of candidate RSV vaccines and antigen design is being
facilitated by atomic structure
•
We need RSV-devoted NGO involvement for advocacy, advancing candidates, and
coordination of public-private partnerships
•
Developing clinical trial infrastructure through North-South partnerships would
facilitate clinical development
•
The regulatory process will be facilitated if we avoid generic terms for new
vaccine platforms and describe them by immunological and biophysical
properties
•
For RSV-naïve infants it may be best to achieve licensure first in children >6 mo of
age
– Expand safety database
– Perform studies to evaluate herd (neonatal) immunity
– Develop mathematical transmission models to refine timing and schedule for vaccination
– Consider passive-active approaches
20
Viral Pathogenesis Laboratory
Sung-Han Kim, Syed Moin, Barney Graham, Kaitlyn Morabito, Azad Kumar, Kevin Graepel, Kayvon
Modjarrad, Man Chen, Tracy Ruckwardt, Allison Malloy, Jason McLellan, Jie Liu, Erez Bar-Haim
21
Questions
22