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RSV Vaccine Development

1 .

Acknowledgements

GSK/Okairos

Ripley Ballou

Jean-Francois Toussaint

Novavax

Greg Glenn

MedImmune

Filip Dubovsky

NIAID/NIH/VRC

Barney Graham

NIAID/NIH/LID

Peter Collins

Ursula Buchholz

.

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Ferolla FM et al. Am J Respir Crit Care Med. 2013 May 1;187(9):983-90.

Burden of RSV Extends Beyond Early Infancy

Obstacles to Successful

RSV Vaccine Development

Peak of severe pediatric disease in early infancy

suppression of the immune response by maternal Ab

Heterogenous at-risk populations require different vaccines:

Newborns

Older infants and young children

Elderly

Imperfect animal models; adult challenge not highly relevant

for pediatric disease

Specter of enhanced disease

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Enhanced RSV Disease following

FI-RSV

• Formalin-inactivated RSV (FI-RSV) developed in the

early 1960s

• Vaccine administered to RSV seropositive toddlers and

RSV naive infants

• The vaccine did not harm the toddlers, but when the

infants later encountered wild-type (live) RSV, they

experienced severe (enhanced) disease. Two (ages 14

and 16 months) died.

Kapikian et al. Am J Epidemiol 1969;89:1699 Kim et al. Am J Epidemiol 1969;89:422-434

0

20

40

60

80

100

vaccinees controls

Potentiation of RSV LRI following formalin inactivated vaccine

% RSV infected% hospitalized

% o

f sub

jects

en

rolled

at

CH

C

Adapted from Kim et al., Am J Epidemiol 89:422-434, 1969

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RSV Vaccines in Development: 2004

RSV F protein

Subunit

Live-

Attenuated

RSV F-based antigenRSV F protein

University of

Saskatchewan

RSV

NanoBio

MERCK

SH protein

Ghent University

MARKET APPROVED

PHASE IIIPHASE IIPHASE IPRECLINICAL

Medi-RSV ΔM2-2

LID/NIAID/NIH

Medi-559, RSV

LID/NIAID/NIH

RSV ΔNS2 Δ1313

LID/NIAID/NIH

Peptide microparticle

Particle-

BasedVLP

Virosome

Virosome

VLPBLP

VLP

University of

Pittsburgh

University of

Pittsburgh

Mucosis

Nucleic

Acid

Whole-

Inactivated

Gene-

Based

Vectors

Alphavirus

Sendai virus

MVA

Adenovirus

BAVARIAN NORDIC

Adenovirus/MVA

Alphavirus

Sendai virus

Medi-534, RSV/PIV3

DNARNA

RSV F protein

Subunit

Wyeth Wyeth Wyeth

(n=3)

VLP

Subunit

Live-

Attenuated

RSV

PHASE 3PHASE 1PRECLINICAL

Medi-RSV ΔM2-2

NIH/NIAID/LID

Medi-559, RSV

Nucleic

Acid

Gene-based

VectorsAlphavirus

Sendai virus

MVA

BAVARIAN NORDIC

Alphavirus

RNA DNA

NanoBio

VLP

Agilvax

VLP

University of

Massachusetts

VLPVirosome

RSV G protein

University

of Georgia

DPX-RSV

Adenovirus

RuenHuei

Biopharma

MARKET APPROVED

Adenovirus/MVA

DNA

Fraunhofer

VLP

VLP

Mucosis

VLP

Combination

Whole-

Inactivated

Updated: July 8, 2014

Particle-

based

RSV F protein

RSV F protein

RSV peptides

PeptiVir

DNA+protein combo

Fudan

University

SH protein

RSV

Codagenix

Peptide

microparticle

RSV cps2

NIH/NIAID/LID

RSV ΔNS2 Δ1313

NIH/NIAID/LID

RSV F protein

University

of Illinois

DNA prime,

Protein boost

RSV F protein

University

of

Saskatchewan

RSV F Nanoparticle

PHASE 2

RSV F protein

Instituto de

Salud Carlos III

VLP

Takeda

Vaccines

RSV

RNA

Adenovirus

SeV/RSVDelta-G RSV

BCG

Pontificia Universidad Católica

de Chile

RSV pre-F protein

NIH/

NIAID/VRC

VLP

RSV peptides

Renaptys

Adenovirus

University of

Pittsburg

Adenovirus

Crucell

RSV F protein

MVA

VLP

Georgia State

University

RSV Vaccine Snapshot

Source http://sites.path.org/vaccinedevelopment/respiratory-syncytial-virus-rsv/

(n=51)

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>1 RSV vaccine type needed; >1 PPC

• Maternal immunization

– Subunit and other nonreplicating vaccines

• Passive prophylaxis

– Next generation RSV F mAbs

VLPs, virosomes (?)

• Infant immunization

– Live vaccines

Maternal RSV Immunization:

RSV F is the primary target

• RSV has 2 major surface glycoproteins:

– RSV F binds to nucleolin on cell surface; mediates virus/cell

membrane fusion and cell/cell fusion

• Most neutralizing antibody is directed against the RSV fusion

(F) surface glycoprotein

• RSV F more highly conserved

between RSV A/ B subgroups than RSV G

• RSV F is therefore the primary antigenic

target for a maternal RSV vaccine

.

F

G

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RSV F Vaccines in Development

Prefusion F

Developer Phase

GSK 1

NIAID/NIH/VRC Preclinical 1

Ins. Salud San Carlos III preclinical

Postfusion F

11 © 2009, Johns Hopkins University. All rights reserved.

Developer Phase

NovaVax 2

MedImmune 1 (elderly)

Novartis/GSK preclinical

U. Illinois preclinical

U. Saskatchewan preclinical

Postfusion F has the palivizumab epitope,

but prefusion F has the majority of neut

epitopes recognized by human sera

12 © 2009, Johns Hopkins University. All rights reserved.

McLellan JS et al. J. Virol. 2011;85:7788-7796

McLellan JS et al. Science 2013;340:1113-1117

Swanson K A et al. PNAS 2011;108:9619-9624

Antigenic site 0

Postfusion Postfusion Prefusion

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Functional form of RSV F in pre-triggered conformation

Candidate RSV vaccine is stabilized native F trimer

Postfusion F in 6-helix bundle conformation

Stabilization Triggering

RSV Prefusion F Structure (Science April 2013)

RSV Vaccine Design (Science November 2013)

RSV Postfusion F Structure (JVI 2011)

Stablization of antigenic site on conformationally

authentic protein results in potent vaccine antigen

Loss or preservation of neutralization sensitive site on

the native F trimer

Prefusion RSV F vaccine (NIH) enhances antibody response in preclinical trials

J S McLellan et al. Science 2013;342:592-598

Published by AAAS

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GSK RSV Maternal vaccine candidate - Ph1 study

• Canada

• Schedule: 1 dose

• N = 128 Men aged 18-44y (16/group)

• 2 step staggered design with safety review by iSRC

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1. Safety/reactogenicity- incl. 12m follow-up 2. Immunogenicity (humoral) – incl. 12m follow-up

Study design/groups:

PreF+Alum

10 µg PreF

30 µg PreF

60 µg PreF

Non-Adj. PreF

10 µg PreF

30 µg PreF

60 µg PreF

Placebo (2 gps)

Saline

GSK Proprietary information

GSK’s proprietary PreF antigen designed to adopt Prefusion conformation

(http://www.clinicaltrials.gov/ct2/show/study/NCT01905215)

• 1- and 2-dose groups are pooled (identical at Day 28)

• 60 and 90µg groups are pooled to show overall impact of alum adjuvant at Day 28

• Peak GMT log2 10.0-10.5

Novavax M201: Safety and immunogenicity of RSV F

nanoparticle vaccine in women of childbearing age

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RSV F-protein Nanoparticle Vaccine

Candidate: Clinical Development Plans

Maternal Immunization (120 mcg F + 0.4 mg Alum; single dose)

• M203 in Pregnant women, 3rd trimester (FSI: Late 2014)

– POC for transfer of maternal antibodies to infants

• M204 in Pregnant women, 3rd trimester (FSI: ~2015)

– Efficacy: Prevention of medically attended RSV+ illness

• M301 in Pregnant women

– Pivotal efficacy study: Prevention of medically attended RSV+ illness

Pediatric Immunization

• P101 in seropositive 2-5 year olds, FSI Q4 2014

Elderly – New Development Plan

• E201 in Elderly, FSI Q4 2014

• Potential next trial, Phase 3/licensure trial

Infant RSV Immunization: Live Vaccines

• Live-attenuated (native RSV)

– cps2 (MedImmune, NIH/NIAID/LID; JHU CIR, IMPAACT)

– ΔNS2Δ1313 (NIH/NIAID/LID; JHU CIR)

– ΔM2-2 (MedImmune, NIH/NIAID/LID; JHU CIR)

– Codon-deoptimized (Codagenix, Emory)

– ΔG + G (Intravac)

• Live-vectored

– Sendai virus (St Jude’s)

– BCG expressing RSV NP or M2 (Pontifica U Catolica de Chile)

• Gene-based vectors

– ChAd3/MVA boost (Okairos)

– Other adenoviruses (Crucell, RuenHuei, Ruhr-Universitat Bochum, U Pittsburgh/Baylor, AmVac)

– Other MVA (Bavarian Nordic, Emergent Biosolutions)

– Alphavirus (Vanderbilt, Alphavax)

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Gene-based vector vaccines

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Open label dose escalation study in healthy adults (NCT01805921)

Experimental groups

1. PanAd3-RSV IM / MVA-RSV IM

2. PanAd3-RSV IM / PanAd3-RSV IM

3. PanAd3-RSV IN / MVA-RSV IM

4. PanAd3-RSV IN / PanAd3-RSV IM

Doses

PanAd3-RSV: Low 5 x 109 and High 5 x 1010 vp

MVA-RSV: Low 1 x 107 and High 1 x 108 pfu

GSK/Okairos RSV Paediatric vaccine candidate

20 GSK Proprietary information

GSK/Okairos ChAd & MVA encoding RSV F, N & M2-1 proteins

10 volunteers/group (2 & 8 volunteers at low & high dose)

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Live-attenuated vaccines

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RSV cps2 and ΔNS2Δ1313

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• Codon-stabilized version of the previously evaluated RSV 248/404/1030/ΔSH

• Phase I evaluation being completed in 51 RSV-seronegative infants and

children (NCT1852266, NCT 1968083)

cps2

• Deletion of the NS2 gene (IFN antagonist) and 1313 codon in L gene

• Phase I evaluation: completely restricted in replication in RSV-seropositive

children (n=15); currently being evaluated in RSV-seronegative children (n=60)

NCT1893554

ΔNS2Δ1313

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3' 5' M2 NS 1 NS 2 N P M S H G F L

l

RSV MEDI ΔM2-2: a novel rRSV

deletion mutant

(MedImmune/ LID, NIAID) • M2-2 is an RNA regulatory factor

• Deletion of M2-2 results in:

• decreased RNA replication

• increased transcription and antigen

expression1 (more Ag/ virion)

1. Bermingham A Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11259-64.

RSV MEDI ΔM2-2

• Phase I trial completed in 15 adults (open label), 15 RSV-

seropositive and 30 RSV-seronegative infants and children

(placebo controlled)

• Non-infectious in adults and RSV seropositive children

• Highly restricted in replication in RSV seronegative children

(mean peak titer 1.5 log10 pfu/mL), yet substantial increases in

RSV PRNT in 95% (19/20) vaccinees

• Further development of Δ M2-2 mutant viruses ongoing

.

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Some clinical trial considerations

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Clinical endpoints:

Define appropriate parameters for a

variety of clinical settings

• Hospitalization and medically-attended lower respiratory tract illness

(MA-LRI) have been used as endpoints for trials of palivizumab and

motavizumab in high-resource countries

• These outcomes may not be sufficiently sensitive or appropriate for

low-resource settings

• Definitions used in global studies of the

pediatric impact of influenza vaccines may be

useful, but will need to be modified

.

www.savethechildren.org.uk

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Clinical endpoints: some examples

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Study Primary Outcomes in Infants

Maternal Influenza Immunization1 Respiratory Illness with Fever (RIF)2

Maternal RSV immunization Tachypnea ? Difficulty breathing? Hypoxia?

1. Zaman K et al. N Engl J Med 2008; 359:1555-1564

2. RIF= T>38.0 and runny nose, congestion, cough, difficulty breathing or swallowing (maternal report)

Consider potential efficacy determinants in

low-resource settings

• In resource limited settings, RSV exposure, disease, and

vaccine efficacy may be influenced by

– Crowding

– Limited access to water

– Indoor air pollution

• Maternal illnesses that may affect transplacental transmission

of antibody

– HIV

– Hypergammaglobulinemia

– Placental malaria

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