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

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

plasma

membrane

150 nm

nonstructural

NS1 (139)

NS2 (124)

- inhibit Type I IFN induction - inhibit Type I IFN signaling - activate PI3K and NF-B - inhibit apoptosis

- viral transcription - RNA replication

M2-2 (90)

regulatory

inner envelope face

- assembly M (256) -

nucleocapsid-associated

M2-1 (194) - transcription processivity factor

- RNA-binding

- phosphoprotein

- polymerase

N (391)

P (241)

L (2165)

envelope spikes

G (298) - attachment

- neutralization and protective

antigen

- antibody decoy (secreted G)

- fractalkine mimic

- TLR antagonist

SH (64) - putative viroporin

- inhibits apoptosis

- fusion and entry

- neutralization and protective

antigen

- TLR4 agonist

F (574)

NS2 NS1 M2-1 M2-2

3´

G F SH M N P L

le

6 8 0 2 4 10 15 kb

tr

15,222 nt total

RSV Genome Organization and

Protein Functions

2

Disease Severity is Greatest in

Children <2.5 Months of Age

Boyce TG et al J Pediatr. 2000; 137:865

Other disease (23%)

CHD (5%)

BPD (3%)

Prematurity (12%)

Low-risk (53%)

0

10

20

30

40

50

60

Ja

n

Feb

Ma

r

Ap

r

Ma

y

Ju

n

Ju

l

Au

g

Se

p

Oct

No

v

De

c

Month of Birth

RS

V H

os

pit

ali

zati

on

s

pe

r 1

00

Ch

ild

ren

BPD

CHD

Other disease

<=28 wk

29-<33 wk

33-<36 wk

Low-risk

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 – High frequency of severe disease (filoviruses)

– Persistent infection (HSV, HIV, HCV)

– Reinfection is common (RSV, HIV)

• Alteration or evasion of host immune response – 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 – High frequency of severe disease (filoviruses)

– Persistent infection (HSV, HIV, HCV)

– Reinfection is common (RSV, HIV)

• Alteration or evasion of host immune response – 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)

5 Graham & Walker in The Immune Response to Infection, 2011

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

7 Graham et al. Clinical Pharmacology and Therapeutics 2009

No Efficacy –

Serious Adverse

Effects

Low/No Efficacy –

No Immediate

Safety Concerns

No Efficacy –

Inappropriate

Immune Response

Efficacy unknown –

Currently in

Clinical Testing

Efficacious

Formalin-inactivated

alum-precipitated

whole virus

Subunit vaccine

G protein –

streptococcal

conjugate

Subunit vaccine

F glycoprotein in

alum in adults

Various live

attenuated RSV

nasally in children

Live virus vaccine

delivered IM in

children

BPIV-RSV live

chimeric virus nasally

None

Overview of RSV

Vaccine Clinical Development

8

Live attenuated RSV

nasally in children

rA2cp248/404/1030/ΔSH

ΔM2-2

Post-fusion F Rosettes

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

Correlates of FI-RSV

Vaccine-Enhanced Illness

Johnson et al. J Virol 2004; 78:6024

% E

os

ino

ph

ils

in

BA

L

0

5

10

15

20

25

30

35

40

45

FI-Vero FI-rRSV wt

FI-rRSV

DG

FI-rRSV Gep-

FI-r RSV

DSH Graham et al. JI 1993;151:2032

Tang et al. Vaccine 1997;15:597

Properties to Avoid

• Antibodies with poor NT activity → Immune complex deposition

• CD4+ Th2-biased response → Allergic inflammation

Polack et al. J Exp Med 2002; 196:859

10

Options for Vaccine Evaluation

F

G

SH

Internal

Multiple

Neonate (<2 mo) Infants and children (>6 mo) • Sero-negative • Sero-positive

Siblings and parents of neonates Young adult women • Pregnant women • Women of child-bearing age

Elderly (>65 yr)

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

Whole-inactivated RSV

Platforms Antigens Delivery Target Populations

11

Respiratory tract Parenteral Other mucosal site

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

Efficacy

Somatic mutation - ++

Dendritic cell and APC maturation - ++

Clearance of maternally-derived antibody - ++

No longer breast-feeding - +

Safety

Idiosyncratic apnea and other rare adverse events + -

Small airway size ++ -

Relative Th2 bias ++ -

13 13

RSV Vaccine Pipeline

Product Sponsor Type of Vaccine Target Antigen Target population Phase

Sanofi RSV vaccine Sanofi Subunit F, G, M protein Elderly patients Phase II

BBG2na Queen’s Univ Belfast Subunit G n/a Phase II

MEDI-559 MedImmune Live-attenuated Whole virus Infants and children Phase I-IIa

MEDI-534 MedImmune Live chimeric F Protein Infants Phase I-IIa

MEDI ΔM2-2 & others NIAID +/- MedImmune Live-attenuated Whole virus Adults, infants and children Phase I

Novavax RSV Novavax Nanoparticle F Protein n/a Phase I

Sendai-RSV chimera St. Jude’s Live chimeric F n/a Pre-clinical

RSV vaccine Merck/Nobilon Single-cycle Whole virus n/a Pre-clinical

NanoBio RSV Nanobio/Merck Inactivated Whole virus n/a Pre-clinical

MVA-BN RSV Bavarian Nordic Vector Subunit Adult high risk patients Pre-clinical

GenVec RSV GenVec Vector F Children and infants Pre-clinical

Universal RSV Crucell/J&J Vector Subunit Infants and elderly Pre-clinical

RSV vac_Oka Okairos Vector F-N-M2-1 n/a Pre-clinical

VEE-F Alphavax Vector F n/a Pre-clinical

RNA replicon Novartis Vector-RNA F n/a Pre-clinical

Mymetics RSV Mymetics VLP-Virosome Multiple Elderly patients Pre-clinical

TechnoVax Technovax VLP Multiple n/a Pre-clinical

SynGem Mucosis VLP-lactococcus F n/a Pre-clinical

RSV VLP Vac LigoCyte VLP F n/a Pre-clinical

F protein Novartis Subunit F n/a Pre-clinical

RSV vaccine GSK Subunit F Pediatric Pre-clinical

AMV601 / RespiVac AmVac Subunit n/a Pre-clinical

PEV4 Pevion Subunit F n/a Pre-clinical

Epitope-scaffold U. Wash/ TSRI) Epitope-scaffold F epitope Pediatric and at-risk adults Pre-clinical

SHe Ghent/Immunovaccine Subunit SH n/a Pre-clinical

T4-214 TI Pharma n/a Pre-clinical

TWi RSV vaccine TWi Biotech n/a Pre-clinical

Sources: Company Website, Fierce Vaccines, RSV 2012 Symposium, Clinicaltrials.gov

14

Whole-inactivated virus

WT or attenuated virus

Naked

DNA or RNA

Vectors

VLPs or

virosomes

Comparing Product Concepts Based on

Immunological Concepts

15

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 -

++ I & II + - nasal +

++ I & II + - nasal or IM +

Recombinant,

or chimeric

viruses

Protein subunits

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

Prefusion

Receptor

Delivery of nucleocapsid and genome

Postfusion

Prehairpin

Target cell cytoplasm

17

*

* HR2 TM FP HR1

Organization of RSV F Glycoprotein

• 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 anti-parallel six-helix bundle in post-fusion state.

• F1 has a cysteine-rich domain. C-linked palmitylation

Disulfide bond

Cysteine

Infection inhibiting peptide

Unique to RSV

Heptad repeat

Transmembrane domain

*

Known or potential furin cleavage site

Signal peptide

F1 F2

69 212 313 322 333 343 358 367 382 393 416 422 439 550 1 574 37 21

70 116 126 500 27

Fusion peptide

N-linked glycosylation

Neutralizing antibody epitope

18

New Technologies Have Made an RSV

Vaccine Possible

Discovery of immunity Molecular

biology

10

12

14

16

0

2

4

6

8

1800 1820 1840 1860 1880 1900 2020 2040 1920 1940 1960 1980 2000 2060

Animal Models

B & T cell biology

Delivery devices

Genomics

Glycobiology

Informatics

Manufacturing

Nanobiology

Proteomics

Structural Biology

Vector biology

2080

Potential areas for new

technical advances

HPV

Rotavirus

Varicella

Japanese

encephalitis

Hepatitis A

Hepatitis B

Rubella

Mumps

Adenovirus

Measles

Poliovirus

Influenza

Yellow fever

Rabies

Smallpox

Major Conceptual and Technological Advances Viral Vaccines

Cell culture

19

RSV ?

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

21

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

Questions

22