vsv consortium overview and key questions and key
TRANSCRIPT
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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