Walter Reed Army Institute of Research (WRAIR)

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1 Walter Reed Army Institute of Research (WRAIR) PUBLIC PRIVATE PARTNERSHIPS IN HIV (AND OTHER) VACCINE RESEARCH & DEVELOPMENT NELSON L. MICHAEL, M.D., PH.D. COLONEL, MEDICAL CORPS, U.S. ARMY DIRECTOR, MILITARY HIV RESEARCH PROGRAM 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.

2 Government, Pharma, Academia, Civil Society Pharmaceutical companies can substantially execute product development when the return on investment is high, sustained, and reliable. For many tropical diseases, this is not the case (HIV, malaria, dengue, MERS, Ebola, Zika, etc.) Innovation from academia, de-risking from government, pharma s expertise in products, and community trust (civil society) are all critical in making countermeasures to many of the world s greatest infectious disease threats. 2

3 HIV Vaccines for Prevention CANARYPOX VECTOR PRIME, GP120 PROTEIN BOOST STRATEGY

4 HIV Vaccine Efficacy Trials To Date No NOTE: Phambili (HVTN 503) began to explore a regimen similar to STEP in South Africa (not shown) 4

5 Thai Phase III HIV Vaccine Trial (RV144) Summary 1.0 Modified Intention-to-Treat Analysis* 0.9 Probability of HIV Infection (%) Placebo Vaccine Years Early (VE = 60%)effect wanes (Robb et al, Lancet ID 2012) bnab decreases rapidly (Rerks-Ngarm et al, NEJM 2009) 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. 5

6 T Cell Correlate Cytokine response (IL-10, IL- 13) from Env stimulated PBMC Polyfunctional CD4+ T cell (CD40L, IL-2, IL-4, IFN- and TNF- ) and (CD40L, IL-2 and IL-4) (Haynes et al. NEJM 2012; Lin et al. Nature Biotechnology 2015) Prior Observations: Complex Immune Correlates of HIV-1 Risk in RV144 Host Genetics and Antibodies IgG, IgG3, nab, Avidity and Fc RIIC SNP IgA/ HLA A*02 allele IgA/ HLA II DQB1*06 IgG/ HLA II DPB1*13 (Li et al. JCI 2014; Gartland et al. JV 2014; Prentice et al. Sci.Trans Med. 2015) Tomaras, Haynes Vaccines 2014, 2(1), Tomaras, Plotkin Immunological Reviews 2016, In Press V2 Correlate V1V2 IgG, V1V2 IgG Breadth V2 Linear AE hotspot V1V2 IgG3 (Haynes et al. NEJM 2012; Gottardo et al. Plos One 2013; Zolla-Pazner et al. Plos One 2014; Yates, Tomara; Chung, Alter et al. Sci. Trans. Med 2014; Chung et al. Cell 2015) IgA Correlate IgA Env Score IgA A. OOMSA gp140 CF IgA. A1 Congp140 IgA C1 IgA Non-Vaccine Strains IgA/IgG ratio (Haynes et al. NEJM 2012; Tomaras, Ferrari et al. PNAS 2013) Antibody Interactions Low IgA/ ADCC Low IgA/ nab Low IgA/ IgG Env Avidity IgG3/ ADCC IgG3/IgG1 (Haynes et al. NEJM 2012; Tomaras, Ferrari et al. PNAS 2013; Yates;Chung et al. Sci. Trans. Med 2014; Chung et al. Cell 2015) Virus Sieve Analysis and Antibodies V2 Sieve (and V2 mabs dependent on 169K) Genetic distance from Vaccine strain /IgG and IgG3 V1V2 correlates (Rolland et al. Nature 2012; Liao et al. Immunity 2012; Gilbert et al. Statistics in Biosciences 2016)

7 2010 Formation of the P5 Partnership Purpose: To build on RV144 data and ultimately license a poxprotein based HIV vaccine with the potential for broad and timely public health impact. Strategy: Developed a partnership to extend the RV144 concept to Clade C regions of the world. Use expert committees to select the strains and then use company expertise to manufacture these vaccines for immunogenicity, safety and efficacy.

8 Construction of the P5 Clade C Vaccine Regimen Construct ALVAC-HIV-C (vcp2438) Construct Bivalent Subtype C gp120/mf59 Add Booster at 12 and now 18 months Optimize regimen for regional relevance, increased potency, and durability

9 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. 9

10 HVTN Strategy for the Phase 3 Program HVTN 097 Designed to evaluate RV144 vaccine regimen in RSA and compare immunogenicity to that in Thailand HVTN 100 A standard phase 1 trial of the Clade C products to decide whether to proceed to an efficacy trial HVTN 702 A Pivotal Efficacy Trial assessing efficacy and safety

11 HVTN 702 Group N* Primary vaccine regimen Boosters Month 0 Month 1 Month 3 Month 6 Month 12 Month ALVAC-HIV (vcp2438) ALVAC-HIV (vcp2438) ALVAC-HIV (vcp2438) + Bivalent Subtype C gp120/mf59 ALVAC-HIV (vcp2438)+ Bivalent Subtype C gp120/mf59 ALVAC-HIV (vcp2438) + Bivalent Subtype C gp120/mf59 ALVAC-HIV (vcp2438) + Bivalent Subtype C gp120/mf Placebo Placebo Placebo + Placebo Placebo + Placebo Placebo + Placebo Placebo + Placebo Total 5400 Estimated Total Study duration 72 months: Stage 1: 60 months-18 months for enrolment, 24 months of follow-up for HIV-1 uninfected individuals, 18 months follow up for HIV-1 infected individuals) Stage 2: an additional 12 months of follow up for uninfected individuals

12 HVTN 702 A pivotal phase 2b/3 multi-site, randomized, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of ALVAC-HIV (vcp2438) and Bivalent Subtype C gp120/mf59 in preventing HIV-1 infection in adults in South Africa Started Nov. 1, 2016 in RSA 1600 enrolled

13 HIV Vaccines for Prevention ADENOVIRUS TYPE 26, MODIFIED VACCINIA ANKARA, GP140 STRATEGY

14 Proof-of-Concept Studies in Non-Human Primates Heterologous vector-based prime-boost regimens delivering SIV or HIV-mosaic antigens afford partial protection against SIVmac251 and SHIV-SF162P3 repetitive intra-rectal challenges Barouch DH, Michael NL et al. Barouch DH, Michael NL et al. 100 Ad26/MVA % Uninfected Ad35/Ad26 Sham (N=1 28 weeks post final immunization 40 weeks post final immunization Number of IR Challenges SIVmac251 SHIV-SF162P3 Ad26/MV A Per-Exposure Risk Reduction 83% 12% Full Protection after 6 challenges -- Property of Janssen - Do not distribute-- Per-Exposure Risk Reduction Ad26/MVA 90% 16% Full Protection after 6 challenges 14

15 Ad26/MVA/Protein Mosaic HIV Vaccine Different HIV-1 clades dominate in different geographic regions Adolescents (11-17 years) /Adults (18-65 years) in endemic countries and populations at risk in Western world Vectors that elicit optimal immune responses Low seroprevalent Ad26 Ad26.HIV-Gag-Pol Ad26.HIV-Env (MVA.HIV-Gag-Pol-Env) Mosaic inserts for global coverage (Gag-Pol-Env) Trimeric env protein for improved humoral immunity Dan H Barouch et al, 2013 Dan H Barouch et al., 2010 Designed for protection against all HIV subtypes 15 15

16 The Ad26/Ad26+gp140 HIV Vaccine Regimen Provides Substantial Protection Against SHIV SF162P3 Challenges in Non-Human Primates Percent uninfected week post first challenge Lead regimen *Statistically significant vs Sham in a Cox proportional hazard model and Log-rank test; Statistically significant vs Sham in a 2-sided Fisher s exact test -- Property of Janssen - Do not distribute-- 16

17 Binding antibodies to HIV Env together with HIV Env specific T cells correlated with protection in NHP SHIV SF162P3 challenge study wk28 Env ELISA (log10) Infection status at Challenge #3 Uninfected Infected Shaded colors and diagonal lines indicate the probability of infection modeled on combined ELISpot and ELISA responses In addition functional antibodies, as assessed by ADCP, were found to correlate with protection, as has been observed in previous studies and are considered supportive wk26 ELISpot (log10) Model based on groups boosted with Ad26, or Ad26+gp140, or gp Property of Janssen - Do not distribute-- 17

18 Government, Pharma, Academia, Civil Society United States Army/Department of Defense National Institute of Allergy and Infectious Diseases Beth Israel Deaconess Medical Center (Harvard) Janssen/Johnson & Johnson Gates Foundation IAVI (USAID) HIV Vaccine Trials Network (global academic/usg) Southern African nations, advocacy groups 18

19 HIV-V-A004 Trial Design: a multicenter, randomized, parallel group, placebo-controlled, double-blind clinical trial in healthy HIV-uninfected adults Primary endpoint for immunogenicity 3rd vaccination + 4 weeks (Week 28) Group N Day 0 (Baseline) Week 12 Week 24 Week 48 Booster 1 50 Ad26 Ad26 Ad26 + gp140 HD Ad26 + gp140 HD 2 50 Ad26 Ad26 Ad26 + gp140 LD Ad26 + gp140 LD 3 50 Ad26 Ad26 Ad26 Ad Ad26 Ad26 MVA + gp140 HD MVA + gp140 HD 5 50 Ad26 Ad26 MVA + gp140 LD MVA + gp140 LD 6 50 Ad26 Ad26 MVA MVA 7 50 Ad26 Ad26 gp140 HD gp140 HD 8 50 Placebo Placebo Placebo Placebo Label used in tables and figures Ad26/Ad26 + gp140 HD Ad26/Ad26 + gp140 LD Ad26/Ad26 12 month follow-up Ad26/MVA + gp140 HD Ad26/MVA + gp140 LD Ad26/MVA Ad26/gp140 HD Placebo/Placebo Ad26= Ad26.Mos.HIV MVA= MVA-Mos gp140 HD= gp140 DP (250 mcg + adjuvant) gp140 LD= gp140 DP (50 mcg + adjuvant) weeks Property of Janssen - Do not distribute-- 19

20 Criteria Endpoint Target (LL of 95% CI) APPROA CH Post 3rd Go/No Go criteria towards PoC based on APPROACH Lead Regimen Results post 3 rd APPROACH APPROA CH Post 4th TRAVER SE Results post 4 th APPROACH Humoral Cellular Env boost IgG binding responses on clade C Env ADCP responses to Clade C Env Elispot responses to at least one ENV peptide pool* IgG to clade C Env of Ad/Ad+Env over Ad/Ad >90% (>77%) 100% (93%) 100% (92%) >56% (>40%) 72% (%) 80% (65%) >50% (>35%) 77% (62%) 83% (68%) >1.5 fold 5.5 fold(3.5) 6.9 fold (4.5) >2.15 log10 cpte Env ELISPOT OR >3.8 log10 Clade C gp140 ELISA post 3 rd : post 4 th : >60% >75% 94% 93% Magnitude Subjects should be above BOTH response thresholds post 3 rd : post 4 th : >40% >60% 64% 80% 20

21 Proof-of-Concept Study HPX2008/HVTN 705 Design: Multicenter, randomized, parallel group, placebo-controlled, double-blind clinical trial Countries: South Africa, Zambia, Zimbabwe, Malawi, Mozambique (up to 26 sites) Population: Sexually active HIV-1 uninfected women (born female), age years N=2,600 Women 1:1 randomization +/- 14 months recruitment Vaccine Stage 2 (24-36) Placebo Stage 2 (24-36) Mo. 7 Wk 28 (PP infections) Mo. 24 Wk years Mo. 36 Wk years Stage 1 : Month 0 to Month 24 ends when the last subject reaches 24 months post 1 st vaccination (1 yr post last vaccination) Stage 2 : Month 24 to Month 36 ends when the last subject reaches 36 months post 2 nd vaccination (2 yrs post last vaccination) -- Property of Janssen - Do not distribute-- 21

22 HIV Vaccines for Prevention FOR THE FIRST TIME IN NINE YEARS, MORE THAN ONE HIV VACCINE EFFICACY STUDY IS ONGOING!

23 Clinical Evaluation of Ebola Vaccine Candidates

24 Early MHRP/WRAIR Ebola Research in Africa: US Military, NIAID HIV vaccine research infrastructure in Uganda leveraged in 2009 to conduct first Ebola vaccine clinical trial in Africa 24

25 West African Ebola Outbreak Highlights gaps in global public health response, available countermeasures WRAIR responds... 25

26 Ebola Vaccine Testing - US WRAIR CTC Completed Phase I trial of VSV-EBOV vaccine candidate in 2014 Agile: Initiated study within 11 weeks Leveraged established expertise and capabilities Showed vaccine was safe, generates immune response MHRP diagnostics lab optimized Ebola assays to support vaccine trial regulatory requirements Conducted in collaboration with NIH, other DoD, WHO and corporate partners 26 26

27 Leveraging Cross Program Collaboration 01 April

28 Efficacy Signal: hand off to Merck, WHO, Governments of Norway, Guinea, MSF UNCLASSIFIED 28 28

29 New Clinical Trials Capability in W. Africa Inaugural site initiation training, WRP-N CRC Walter Reed Program Nigeria Clinical Research Centre established in Abuja Enrolls 331 participants in RV 429: GSK sponsored phase II trial of monovalent cad3-eboz in African Adults Study complete, product safe, well tolerated. Publication pending 29

30 MHRP/WRAIR African Clinical Trials Network 30

31 RV456/EBL2003 A Randomized, Observer-blind, Placebo-controlled, Two-part, Phase 2 Study to Evaluate the Safety, Tolerability and Immunogenicity of Two Prime-boost Regimens of the Candidate Prophylactic Vaccines for Ebola Ad26.ZEBOV and MVA-BN-Filo Ongoing study exploring an alternative to rvsv-zebov: Janssen Pharma, US Military, Governments of Uganda, Tanzania, Kenya, Nigeria, and Mozambique

32 MERS CoV A First-in-Human Vaccine Trial KAYVON MODJARRAD, M.D., PH.D. DIRECTOR, EMERGING INFECTIOUS DISEASE THREATS MILITARY HIV RESEARCH PROGRAM

33 Déjà vu SARS-CoV MERS-CoV

34 Epidemiology MERS CoV first identified in Sep 2012 in Saudi Arabia, but retrospectively diagnosed from an April 2012 nosocomial outbreak in Jordan (NAMRU-3) Korea cases, 36 deaths >2066 cases > 720 deaths 27 countries 34

35 First-in-Human MERS Vaccine Middle East Respiratory Syndrome Viral respiratory disease, fatality 36% Given global deployments, military personnel are at especially high risk in the Arabian and Korean Peninsulas February 2016: WRAIR began Phase I trial of MERS-CoV vaccine candidate, the first for use in humans December 2017: Study results being analyzed and submitted as 1 st published results of a MERS vaccine 35

36 Vaccine Candidates Focus on Spike (S) Interacts with DPP4 (CD26) as entry receptor G Lu et al. Nature 2013 Q Wang et al Cell Host Microbe

37 GLS-5300: A Synthetic Consensus MERS CoV DNA Vaccine Plasmid DNA encodes S protein of MERS CoV GenBank sequences through August 2015 In situ production in muscle Key Differentiators GLS-5300 induces B and T cell immunity Multiple reactive epitopes spanning full S Highly immunogenic in mice, NHPs, camels Binding Ab end-point titers ~1:50,000 ELISPOT: 1,000 4,000 SFU per 10 6 PBMC pvax1 Spike 37

38 MERS CoV DNA Vaccine Protects Monkeys 3 log viral load reduction recovered from lungs No histopathology in vaccinated animals Vaccinating rhesus macaques protected from disease

39 Phase I Study Design Open label, dose-ranging, single site (WRAIR) Healthy adults (18 50), BMI < 35 3 dose schedule, IM Electroporation 66 of 75 participants completed 3 doses No safety signals Last visit Sep 2017 Key immunogenicity at 2 an 12 weeks post vaccination series Follow up through 1 year

40 Summary Priority pathogen with pandemic potential that has no licensed countermeasure. DNA vaccine with efficacy in NHPs tested in a first-in-human trial at WRAIR. Irrespective of dose, a 3 injection series is safe and immunogenic. Additional immunogenicity testing and identification of a protective surrogate are pending Dose-sparing intradermal regimens are advancing to human trials The investigators have adhered to the policies for protection of human subjects as prescribed in AR

41 Acknowledgments WRAIR/MHRP Nelson Michael Stephen Thomas Merlin Robb Amy Castellano Kristin Mills Janice Darden GeneOne LifeScience Inc Joel Maslow Young Park Celine Remiglio Christine Roberts Funding from the Defense Health Agency Laval University Gary Kobinger Trina Racine Wistar Institute David Weiner Lab 41

42 Walter Reed Army Institute of Research (WRAIR) PROSPECTS FOR A ZIKA VACCINE 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.

43 Zika virus (ZIKV) Another flavor of flavivirus 43

44 Flavivirus Structure Dengue virus Zika virus 44

45 Spread of Zika Virus: Adapted from Weaver S, Antiviral Res, ? >Decades Ago? 2013 Outbreaks Serologic evidence Virus detection/confirmed human case

46 46

47 Zika virus vaccines intense interest 47

48 Zika Vaccine Landscape 48

49 Zika Vaccine (ZPIV) Rapid Countermeasure Development 9 months from bench to clinic! Proven Vaccine Platform Successfully developed licensed vaccine for Japanese Encephalitis, another flavivirus Early Zika Detection Bio surveillance in South East Asia aided vaccine design In-house Capabilities Developed and produced 1,500 doses for clinical testing 49

50 Phase I Clinical Trials of ZPIV First vaccination at WRAIR: 09 November 2016 WRAIR Silver Spring, MD Previous flavivirus immunity Saint Louis University (SLU) Center for Vaccine Development Dose optimization Harvard BIDMC Boston, MA Accelerated schedule SLU Center for Vaccine Development Puerto Rico Natural flavivirus immunity NIH Vaccine Research Center Bethesda, MD DNA vaccine prime, ZPIV boost In 9 months, WRAIR went from vaccine concept to clinical testing 50

51 ZPIV was well tolerated 51

52 ZPIV was immunogenic 52

53 Mice were protected by ZPIV challenge by hyperimmune IgG from ZPIV vaccinees 53

54 Publication of Interim Analysis 4 December st inactivated Zika vaccine human trial results published Safe, immunogenic, reaching threshold of animal efficacy 1 st Zika vaccine to demonstrate a correlate of protection in humans 54

55 ACKNOWLEDGEMENTS WRAIR (Gov) BIDMC (Aca) NIAID (Gov) St. Louis Univ. (Aca) Kayvon Modjarrad Karen Peterson Stephen Thomas* Rick Jarman Rafael De La Barrara Ken Eckels Deborah Whitmer Merlin Robb Leyi Lin Trevor Crowell Erica Sondergaard Kristin Mills Anne Basil Melissa Walsh Veronica Tonwe Dan Barouch Katy Stephenson Peter Abbink Rafael Larocca Jessica Ansel Andrew Hall Sabrina Tan Stephen Walsh Christina Bricault Michael Boyd Sanofi Pasteur (Pr) Jim Tartaglia Jon Heinrichs Sanjay Gurunathan Matt Bonaparte Nick Johnston Tony Fauci John Mascola Hilary Marston Bob Eisinger Barney Graham Robert Johnston Cristina Cassetti EMMES (Pr) Peter Dawson Jill Barrett Jason Thompson Sarah George Dan Hoft Jan Tennant Keith Meyer James Bryan Karla Mosby Azra Blazevic MRMC (Gov) George Ludwig Wendy Sammons-Jackson Ken Bertram Mike Kozar Bob Charles Greg Gillette Barry Datlof * SUNY-Upstate 55

56 Government, Pharma, Academia, Civil Society Pharmaceutical companies can substantially execute product development when the return on investment is high, sustained, and reliable. For many tropical diseases, this is not the case (HIV, malaria, dengue, MERS, Ebola, Zika, etc.) Innovation from academia, de-risking from government, pharma s expertise in products, and community trust (civil society) are all critical in making countermeasures to many of the world s greatest infectious disease threats. 56

57 US Military HIV Research Program Soldier Health. World Health. 57