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VSV Consortium Overview and key questions being addressed in Phase 1 Trials Nelson L. Michael, M.D., Ph.D

Colonel, Medical Corps, U.S. Army

US Military HIV Research Program

Walter Reed Army Institute of Research

WHO Consultation: EVD Vaccines

Geneva, Switzerland

29 September 2014

The views expressed are those of the authors and should not be construed to

represent the positions of the U.S. Army or the Department of Defense.

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Preclinical rVSV vaccine development

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BioProtection

Systems

•Deletion of fusogenic VSV-G protein

•Substitution of Ebolavirus Zaire-strain Kikwit envelope protein

• 1-2 log reduction in titer relative to wild-type

• Eliminates VSV-G toxicity

•This vaccine vector is the PHAC construct that has been published previously

(i.e., Nature Med 2005, PLoS Pathogens 2007, Vaccine 2008,…)

•Highly characterized non-clinical product

VSV wt N P M G L

BPSC100

1 N P M ZEBOVGP L

BPSC1001: Vaccine Candidate

Recombinant VSV Vaccine Structure

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BioProtection

Systems

Filovirus

Vaccine

Vaccine

Efficacy

Mice/guinea pigs NHP

Marburg Musoke 100% 100%

Ebola Zaire 100% 100%

Ebola Sudan 100% 100%

Ebola Ivory Coast 100%

Prophylactic Vaccination Efficacy in NHPs

Survival after 1000 LD50 Challenge

IM vaccination/day 28 IM challenge

Reference: Geisbert,et al., J VIROLOGY, 2009, 83(14):7296–7304

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BioProtection

Systems

Multivalent VSV-filovirus vaccine

Reference: Geisbert et al., 2009 J

VIROLOGY, 83(14)_ 7296–7304

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BioProtection

Systems

Vaccine Efficacy via Multiple Routes

Routes of Administration

Vaccination Groups

2 x 107 pfu

Challenge

ZEBOV 1000 pfu

VSVΔG/MARVGP

Control

VSVΔG/ZEBOVGP

Cynomolgus

Macaques

IM = intramuscular

OR = oral

IN = intranasal

2/2

4/4

4/4

IM = intramuscular 0/2

Survival Viremia

Reference: Geisbert and Feldmann. 2011. J. Inf. Dis. 204:S1075–S1081.

0/2

0/2

0/4

0/4

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BioProtection

Systems

Correlates of immune protection

Analysis of protective effects

Vaccination

single dose by OR, IN, or IM route Immunological

Assay

B cell

ZEBOV GP-specific IgM, IgG, IgA produced VLP ELISA

Low neutralizing Ab titres with OR & IN routes Flow Cytometric

Neutralization Assay

T cell

ZEBOV GP-specific memory T cell responses Flow Cytometry

ZEBOV GP-specific PBMCs secrete IL-2 &

IFN-γ ELISPOT

All

cells

Prevents lymphocyte death during ZEBOV

infection Flow Cytometry

Reference: Alimonti et al., 2009. J. Immunology, 182, 128.16.,

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BioProtection

Systems

rVSV-based vaccines: Post-exposure efficacy in NHPs

Reference: Geisbert and Feldmann. 2011. J. Inf. Dis. 204:S1075–S1081.

Vaccination within 20-30 min of exposure

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BioProtection

Systems

Post-exposure therapeutic activity in rodents

2x105 pfu VSVG/ZEBOVGP

treatment either before or

after a 1000 LD50 MA-

ZEBOV infection (ip)

2x105 pfu VSVG/ZEBOVGP

treatment either before or

after a 1000 LD50 GA-ZEBOV

infection (ip)

Mice (n=5) 24 hrs prior

30 min after

24 hrs after

untreated

Guinea Pigs (n=6)

60 min after (83%)

24 hrs prior (66%)

24 hrs after (50%)

untreated

Vaccination up to 24 hrs after exposure

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WRAIR Phase 1 Trial:

Maryland, USA

A Phase 1 Randomized, Single-Center, Double-Blind, Placebo Controlled, Dose-Escalation Study to Evaluate the Safety and

Immunogenicity of the BPSC1001 Ebola Virus Vaccine Candidate in Healthy Adult Subjects

Protocol Number: WRAIR #2163

IND Number: 16131

Basic Inclusion Criteria

• Inclusion

– Healthy adults, aged 18 to 50 yrs (inclusive)

– Informed consent with test of understanding

– Effective contraception

– Willing to minimize blood and body fluid exposures for 7 days after vaccination

Basic Exclusion Criteria

• Exclusion

– Allergies, abnormal labs, Hepatitis, HIV, immunosuppression

– Prior exposure to filovirus or filovirus vaccine

– Prior exposure to VSV or VSV vectored vaccine

– High risk VSV exposure through occupation

– Contact with animals at risk of VSV infection (cattle, horses, etc)

– Likely to transmit to vulnerable individuals

Basic Exclusion Criteria

• Exclusion (cont)

– Receipt of vaccines within 14-30 days of injection

– Acute or chronic, clinically significant, medical conditions

– Recent blood product receipt or donation

BPSC1001 (rVSVΔG-ZEBOV-GP)

Cohort # Subjects * BPSC1001 Dose # Placebo Injections **

1 10 3x106 pfu 1

3 n/a 2

2 10 2x107 pfu 1

3 n/a 2

3 10 1x108 pfu 1

3 n/a 2

Total 39

* 3 control subjects per cohort ** Placebo injections given to all subjects

Group A 2 IP, 1 Placebo

Vaccination Day X X X

Group B 3 IP, 1 Placebo

Group C 5 IP, 1 Placebo

Days 0 1 2 …………… 8……………......15…………

SMC REVIEW

Immunization Timeline in Cohort

BPSC1001 (rVSVΔG-ZEBOV-GP)

Cohort Vaccination Viral PCR * Safety Labs (clinical)

** Immunology time

points

1 Day 0 Days 0, 1,3,7,14

Days 0, 1, 3, 7, 28, 180

Days 0, 7, 14, 28, 56, 84, 180

2 Day 0

3 Day 0

* Additional PCR if not negative x 2 time-points or as clinically indicated ** CBC, Chemistry, PT/PTT, Urine (blood, protein, glucose)

Endpoints

– Safety, tolerability • Solicited / unsolicited AEs

• SAEs

– Vaccine virus replication • Viremia (PCR)

• Detection of virus in urine, saliva (PCR)

– Immunogenicity • EBOV GP ELISA

• EBOV neutralizing Ab

• EBOV-specific antibody and cellular response (exploratory, subset)

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NIAID Div of Clinical Research (Lane)

Phase 1 Trial

WRAIR design + day 28 boost

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Drug Manufacture and Supplies

• GMP-compliant MSV and MCB are available and large enough to sustain manufacturing activity for several years

• Manufacturing process successfully executed at 10 L scale

• Multiple manufacturing runs at 30L scale scheduled through December with goal to reach 50 - 100,000 vials at 108 pfu/ml to be released from Q4 through Q1 2015

• Process development underway to increase to 250 L scale representing roughly 50,000 vials per lot

• Phase 1 studies include dose finding to determine available doses. Dose-sparing studies also pending in October 2014

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Phase 1 Trials under discussion

VEBCON Proposed Trial 1 Hamburg-Marburg

Group Dose N Vaccination Rx-AE-SAE Immunology time points

A 2 x 10 ^7 10 Day 0 14d-28d-180d Lab 0,1,2,7,56,84,180

0,7, 14, 28, 56,84, 180 B 5 x 10 ^7 10 Day 0

Sequential dose escalation Viremia, shedding days 1-7,14,28,56

VEBCON Proposed Trial 2 Lambarene Gabon and Kilifi Kenya

Group Dose N Vaccination Rx-AE-SAE Immunology time points

A 2 x 10 ^7 50 Day 0 14d-28d-6 mo Daily 7 days Lab 0,1,2,7,28, 56,84,180

0,7, 14, 28, 56, 84, 180

B 5 x 10 ^7 50 Day 0

Sequential dose escalation Viremia, shedding days 0,1,6,14

VEBCON Proposed Trial 3 Geneva

Group Dose N Vaccination Rx-AE-SAE Immunology time points

A 2 x 10 ^7 50 Day 0 14d-28d-6 mo 0,7, 14, 28, 90, 180, (356) B 5 x 10 ^7 50 Day 0

Randomized dose comparison Viremia, shedding days 0,1,3,7

Collaborators

U.S. Government

PHAC Clinical Trial Investigators

European & African

Consortium VEBCON

WHO

University Medical Center Hamburg-

Eppendorf

University of Marburg

University of Geneva

University of Tubingen

CERMEL, Gabon

KEMRI Wellcome Research Programme

NewLink

WRAIR/ DoD

NIAID