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Ebola Virus Vaccine Development

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Ebola Virus Vaccine Development Dale and Betty Bumpers Vaccine Research Center National Institute of Allergy and Infectious Diseases National Institutes of Health Department of Health and Human Services Ebola Virus Vaccine Development Nancy J. Sullivan, Ph.D. Chief, Biodefense Research Section, VRC, NIAID, NIH Les Pensieres, Fondation Merieux Conference Center January 12, 2015 Early Experimental Approaches to Vaccines Against Ebolavirus Killed virus (MBG) vaccine Enhanced disease in guinea pigs Recombinant protein (insect cells) Partial protection in guinea pigs (MBG) No protection in primates Have filoviruses evolved mechanisms to evade humoral immunity? Challenges for Protective Humoral Immunity Against Ebolavirus Pleomorphic (length 14,000nm) and high density glycoprotein…accessible? Stable virion, lethal infection with few particles Broad tropism and multi-organ distribution Rapid internalization via macropinocytosis and use of intracellular receptor Vaccine-Induced Immune Protection Against Ebolavirus Infection DNA/rAd EBOV GP Weeks 0 4 8 20 32 VP30 VP24 L VP40 GP 5’ NP VP35 3’ rAd EBOV IR Overlap Trailer Leader IR Overlap• IRDNA/rAd5Edit Overlap demonstrates proof of principle for vaccine Site protection of macaquesWeeks 0 4 • Single shot rAd5 vaccine provides rapid protection Plasmid DNA Replication-defective rAd 100 NHP: Cynomolgus macaques BSL4, n=4 per group 50 EBOV: IM challenge % Survival 1000 PFU Mortality at 6-9 days 0 No vaccine DNA/rAd5 rAd5 (n>50*) (n=8) (n=23*) Sullivan et al., Nature 2000, 2003 Pathway to Licensure for Ebola and Marburg Vaccines Nature Rev Microbiol., 2009 VRC Filovirus Vaccine Clinical Trial History Year / n= Study Vector Insert Outcome Phase Product/ Placebo 5/2 Safe 2003 Ebola (Z+S) VRC 204 DNA 8/2 Immunogenic Phase I ∆TM GP 8/2 No rapid protection in NHP Safe 2006 Ebola (Z+S) 12/4 VRC 205 Ad5 Immunogenic Phase I PM GP 12/4 Sub-optimal NHP protection Ebola (Z+S) WT GP Safe 2008 VRC 206 DNA 20 Immunogenic Phase I Marburg (A) No rapid protection in NHP WT GP Ebola (Z+S) WT GP Safe 2009 90/6 RV 247 DNA Immunogenic Phase IB Marburg (A) No rapid protection in NHP WT GP Safe 2014 Ebola (Z+S) VRC 207 cAd3 20 Immunogenic Phase I WT GP Rapid protection in NHP * numbers of subjects that received Ebola vaccine are shown in bold Optimization of Vaccine Dose (rAd5 GP/NP) Challenge: Experimental groups: 28 days post-immunization n=3 cynomolgus macaques per group 1000 PFU Ebola Zaire Vaccine dose escalation 1-log increments 100 Vaccine Dose 1012 80 101 1 1010 60 109 Control 40 PercentSurvival 20 0 0 1 2 Week s PLoS Medicine 2006 Preliminary Identification of Immune Correlate for rAd5-GP/NP Vaccine Protection Survivors CD8+ T-cell Antibody Fatalities 2.5 25000 2.0 20000 1.5 +) a - 15000 GP IgG GP - 1.0 Anti 10000 CD8+ (TNF CD8+ (percent positive) (percent 0.5 (Reciprocal Endpoint Dilution Titer) Dilution Endpoint (Reciprocal 5000 0.0 0 Vaccine Dose (Particle Units) PLoS Medicine 2006 ELISA IgG Against EBOV GP is an Immune Correlate of Protection (rAd5 Vaccines - NHP) 1700 3700 Odds ratio >100 p = 0.005 Ebola challenge dose > 100x LD99 (parenteral exposure) Sullivan et al, 2009, Nat. Rev. Micro. Immune Correlate of Protection Evidence that T Cells are Needed for Uniform Protection by rAd5-GP Vaccine 1. Cross protection against Ebola Bundibugyo with Ebola Zaire GP vaccine achieved in the absence of Bundi-specific Ab 2. Passive Ab transfer does not protect naïve NHP, and CD8 depletion eliminates protective immunity in vaccinated NHP Anti-Zaire ELISA IgG (GP) is a nCoP IgG ELISA GP Anti-Bundi V4: EBOV RNA+ Efficacy of Rare Serotype Human rAds for Protection Against Ebola virus in Macaques 1 0 0 7 5 5 0 % Survival % Survival 2 5 Ab = 1700 Ab = 1300 0 1010 1010 1011 1010 1011 Ad5 Ad35 Ad26 Journal of Virology, 2011 Do Lower Ad26 and Ad35 T-cell Responses Explain Reduced Protection? CD4 CD8 0 .4 0 .5 0 .4 0 .3 + 0 .3 0 .2 0 .2 Cytokine 0 .1 0 .1 (% Memory Subset) Memory (% 0 .0 0 .0 Ad5 Ad26 Ad35 Ad5 Ad26 Ad35 CD4 and CD8 responses as high as rAd5 Qualitatively Distinct Cytokine Secretion Patterns That Define Functional T-cell Responses (12-Color Flow Cytometry) IFN-g IFN-g IFN-g TNF-a IL-2 IFN-g TNF-a Each combination (subset) is functionally distinct CD8 T-Cell Functional Quality Associated with rAd Vector Vaccines in Macaques 3+ 3+ 3+ 3+ 2+ 1+ 2+ 1+ 1+ 1+ 2+ 2+ rAd26 rAd35 rAd5 ChAd3 TNF/IFNg “Effector” 3+ 2+ 1+ Selection of Alternative Adenovirus Vectors For an Ebolavirus Vaccine B Ad35 Ad34 Ad11 Ad50 Ad4 ChAd30 ChAd63 100 Ad16 E Ad7 52 100 Ad3 C7 ChAd20 100 100 99 AdC68 100 100 100 Ad5 93 98 ChAd6 100 Ad24 100 100 57 C 54 Ad48 ChAd3 100 97 62 100 37 92 71 98 100 Ad49 Ad10 D Ad6 Ad26 Ad43 Ad2 Ad37 Ad41 Ad18 Ad40 Ad12 F A Acute and Durable Protection by ChAds Vaccinate ChAd Ebola Ebolavirus Ebolavirus GP challenge challenge (n = 4/group) Weeks: 0 1 2 3 4 5 9-12 months (Ab, ICS) Is a prime-boost vaccine better for generating durable protective immunity? Acute Protection Durable Protection 1 0 0 1 0 0 8 0 8 0 l l a a v v i i v 6 0 v 6 0 r r u u S S 4 0 4 0 % % 2 0 2 0 0 0 rAd5 ChAd3 ChAd63 ChAd3 ChAd3 ChAd63 1010 VP 1010 VP 1010 VP 1011 VP 1010 VP 1010 VP Prime-Boost Vaccination to Generate Durable Protective Immunity Inserts: GP(Z) + GP(S), codon-optimized ChAd3: To generate rapid protection MVA: Pox vectors generate strong CD4 T-cell response needed for long-term CD8 memory ChAd/MVA Prime: Boost: Ebolavirus ChAd 1010 MVA 108 Challenge 10 months 0 4 8 12 Peak Memory Weeks Quality of MVA-Boosted CD8+ T-cell Responses Boost: Prime: (n=4/group) Ebolavirus 10 8 ChAd 10 PU MVA 10 Challenge Weeks: 0 4 8 10-12 9-12 months Week 4 Week 10-12 Week 38 3+ TNF/IFNg ChAd3 ChAd63 ChAd3 ChAd63 ChAd3 ChAd63 “Memory” MVA boosts memory CD8 with either ChAd3 or ChAd63 prime ChAd3 exceeds ChAd63 for maintenance of TNF/IFNg effectors Relative Potency of ChAd3/MVA and ChAd63/MVA for Induction of Durable Protection Against Ebola Challenge Protection (10 months post vaccine) 1 0 0 8 0 6 0 4 0 % Survival % Survival % 2 0 0 No vaccine ChAd3/MVA ChAd63/MVA Effector and memory CD8+ T cells associate with long term protection ChAd3/MVA established as lead candidate for Phase I clinical testing Ebola Bivalent and Monovalent Vaccines Bivalent Monovalent 1. Bulk cAd3 cAd3 1. Bulk cAd3 cAd3 GP Zaire GP Sudan GP Zaire GP Sudan 2. Vialed 2. Vialed 1:1 Ratio Zaire only 3. Bivalent, cAd3-EBO 3. Monovalent, cAd3-EBOZ Julie Ledgerwood Ebola Vaccine Clinical Trial Schema A Phase I, Open-Label, Dose-Escalation Clinical Trial VRC 207 Study Schema Group Subjects Day 0 1 10 cAd3-EBO at 2x1010 PU 2 10 cAd3-EBO at 2x1011 PU Total 20 IM Injections in 1 mL volume with needle and syringe Julie Ledgerwood Ebola Vaccine Safety Data • Well tolerated • No Serious Adverse Events • Low incidence of fever • 0% (0/10) at 2x1010 • 20% (2/10) at 2x1011 Julie Ledgerwood Ebola Vaccine Antibody Response in Humans Z a ir e S u d a n 1 0 0 0 0 1 0 0 0 0 ) ) 0 0 9 9 C 1 0 0 0 C 1 0 0 0 E E ( ( A A S S I I L L E E 1 0 0 1 0 0 P P G G 1 0 1 0 2 4 2 4 2 4 2 4 k k k k k k k k e e e e e e e e e e e e e e e e W W W W W W W W 1 0 1 1 1 0 1 1 G ro u p 1 : 2 x 1 0 P U G ro u p 2 : 2 x 1 0 P U G ro u p 1 : 2 x 1 0 P U G ro u p 2 : 2 x 1 0 P U GMT 331 2037 279 936 at Week 4 (158-695) (1007-4118) (154-505) (433-2021) Ledgerwood, et al. NEJM 2014 Confidential, Unpublished data GP-S Specific GP-Z Specific ** *** *** * *** *** *** CD4 Ebola 0.Vaccine4 T-Cell Responses in HumansMe mory t e s T Cells b u S f 0.2 o % CD8 Memory T Cells , e s n 0.0 GP-S Specific GP-Z Specific o , p e 1.5 s ** ** ** * ** ** * e s 1.5 ** ** ** * ** ** * R n CD8 o e n p i t Memory s k e e o s 1.0 t 1.0 T Cells R y b C u e l n S a i t f k o o o T 0.5 t 0.5 y % C l a t 0.0 o T 0.0 Week: 0 2 4 0 2 4 Week: 0 2 4 0 2 4 10 11 10 11 Week: D0ose:2 2x104 0 2x102 4 WeDoseek:: 02x102 4 2x100 2 4 Dose: 2x1010 2x1011 Dose: 2x1010 2x1011 Ledgerwood, et al. NEJM 2014 JulieConfidential, Ledgerwood Unpublished data Ebola Vaccine Induces Polyfunctional T-Cells In Human Subjects CD4 T Cells CD8 T Cells IFN IL2 TNF + + + – + + + – + + + – – – + – + – – – + IFN+ TNF+ 2x1010 2x1011 Dose 2x1010 2x1011 Polyfunctional CD8 T cell responses resemble protected NHP responses (Stanley et al, Nat Med 2014) Ledgerwood, et al.
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