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V accine R esearch C enter

V accine R esearch C enter. National Institute of Allergy and Infectious Diseases National Institutes of Health Department of Health and Human Services. HVTN 505: Objectives and Timelines Barney S. Graham, MD, PhD XIX International AIDS Conference

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V accine R esearch C enter

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  1. Vaccine Research Center National Institute of Allergy and Infectious Diseases National Institutes of Health Department of Health and Human Services HVTN 505: Objectives and Timelines Barney S. Graham, MD, PhD XIX International AIDS Conference Workshop on Correlates of Immunity in Vaccine Research July 23, 2012 For more information: 1-866-833-LIFE vrc.nih.gov VRCforLIFE@mail.nih.gov

  2. The Goals of Vaccination Measures of Vaccine Efficacy (VE) • Individuals • To prevent infection • To prevent disease • To control or reduce disease • Population • To prevent transmission to susceptible individuals • To control epidemic spread of infection VEs VEp VEi

  3. Viral Interaction with Individual Host and Population Factors required to maintain an epidemic Elements of host immunity Exposure Susceptible host Attachment Physical barriers or Pre-existing antibody Invasion or resistance Transmission Innate response Evasion or abortive replication Adaptive response Persistence or clearance Individual Points where vaccination can influence an epidemic Population

  4. Ro =  c  D Ro = reproductive rate of agent in a population  = transmission efficiency c = rate of partner change or new exposures D = duration of infectious period Ro Vaccine-induced T cell response reduces virus load and shedding Vaccine-induced antibody reduces transmission efficiency c D  Reduced exposure risk How can vaccines impact an epidemic? If R0 < 1 epidemic will contract If R0 >1 epidemic will expand

  5. What is an immunological correlate? • Correlate - An immune response (biomarker) that is statistically correlated with a clinical outcome • Correlate of risk (CoR) - Statistically correlated with the rate of HIV infection in the vaccine group (Qin et al., JID, 2007) • Correlate of protection (CoP) - Statistically correlated with vaccine efficacy in the vaccine and placebo groups (Plotkin and Gilbert, CID, 2012) • nCoP: nonmechanisticCoPis an immune response indirectly associated with protection mCoP: mechanistic CoP is an immune response causally responsible for protection • Surrogate – an immune response that can be used as a substitute endpoint for clinical efficacy • Specific - Predictive of VE for a particular vaccine platform or study population • General - Predictive of VE in different settings (e.g., across vaccine platforms, study populations, viral populations, or species) 5

  6. Why is it important to identify immune correlates? Conventional trial progression Trial Design Data Analysis Data Analysis New Trial Design Outcome Randomization Randomization Typically small number of study groups Adaptive trial design Modifiy: Size Populations Primary outcome Randomization or allocation Real- Time Data Analysis Trial Design Data Analysis Outcome Randomization Could start with multiple study groups and continuously roll in additional groups The key for adaptive vaccine trials to gain efficiency is to analyze study endpoints while accrual is ongoing. This is possible for vaccine studies using a surrogate endpoint based on the identification of an immune correlate, but not if the endpoint is infection since it is likely that sufficient data would not be available until accrual is completed. Koup, Graham, Douek. Nature Reviews Immunology 2011; 11:65-70. 6

  7. How do adaptive immune responses control virus infection? Isolated virion Virus-infected cell Latency or extracellular sequestration Antibody +++ - +/- T cells - +++ -

  8. Brief History of HIV Vaccines gp160/gp120 subunits Poxvirus vector + protein rAd5-gag/pol/nef DNA/rAd5-Env/gag/pol/nef Pivotal basic & clinical research discoveries Antibody Relative focus on vaccine effector mechanisms CD8 T cells

  9. HIV Vaccine Efficacy Trial Outcomes Schedule (months) Rate of Infection (%) Efficacy Vaccine Placebo 0 1 2 3 6 5.7 5.8 0 VaxGen RV144 + + 0.6 0.9 ↓ 31.2% (p=.04) Step 7.3 5.0 ↑ 31.5% (NS) 1st interim analysis 3Q2013 ? HVTN 505

  10. HVTN 505 rAd5 Env A Env B Env C gag/pol B 0 1 2 12 Months 3 6 9 CMV-R promoter Env A Env B Env C gag B pol B nef B

  11. Phase 2b, Randomized, Placebo-Controlled Test-of Concept Trial to Evaluate the Safety and Efficacy of a Multiclade HIV-1 DNA Plasmid Vaccine Followed by a Multiclade Recombinant Adenoviral Vector Vaccine in HIV-Uninfected, Adenovirus Type 5 Neutralizing Antibody Negative, Circumcised Men and Male-to-Female Transgender Persons Who Have Sex with Men Short Title: VRC DNA/rAd5 Multiclade, Multigene HIV-1 Vaccine Regimen in HIV(-) MSM Version 3.0 Principal Investigator - Scott M. Hammer, M.D. HVTN 505

  12. HVTN 505: Vaccination Schedule • 80% power to detect 50% reduction in HIV-1 acquisition • 93% power to detect 1 log10 reduction in setpoint VL if VE=0; 84% power if VE=50%

  13. HVTN 505: Primary EndpointsWeek 28 (4 weeks post-boost) through Month 24 Post-infection diagnosis visit schedule VL setpoint = average of all values between week 10 and 20 after diagnosis study visit and prior to ART initiation Weeks 0 2 4 6 8 10 12 14 16 20 24 Diagnosis of HIV Infection Acquisition (VE) endpoint VL endpoint

  14. HVTN 505 Enrollment through July 7, 2012 Average enrollment over past 40 weeks (since Oct 1,2011) = 14.6 ppts/wk

  15. Non-Efficacy Stopping Boundary: VE(24) Note that a final analysis point estimate of VE(24)=36% (31:46 vaccinee:placebo distribution of infections) would have P<0.05. Peter Gilbert

  16. What will we learn from HVTN 505? • Is the rate of HIV acquisition reduced by >50%? • Is mean VL reduced by >1 log10 genome copy/ml? • Is there a sieve effect or selective escape from vaccine-induced antibody or T cell responses in breakthrough viruses? • Is there an immune correlate of protection?

  17. HVTN 505 Timeline Final analysis Interim analysis Future trials will compete with other preventive approaches CAPRISA 004 TDF microbicide gel 39% efficacy CDC 4370 TDF/FTC PrEP in IVDU – Thailand VOICE – TDF oral &TDF gel microbicide – South & East Africa – stopped early HPTN 052 – Treatment of discordant couples – global - 96% efficacy FEM-PrEP TDF/FTC – Africa – stopped early – no efficacy Partners PrEP TDF/FTC – East Africa - 62-73% efficacy CDC 4940 TDF/FTC PrEP in heterosexuals – Botswana - 63% efficacy iPrEx TDF/FTC PrEP – Americas – 44% efficacy MSM

  18. Considerations in Choosing Endpoints for the Correlates Analysis • Strength of association between the immune response and the rate of HIV infection in vaccinees • Dynamic range of the immune response in vaccinees • Precision of assay for measuring functionally relevant response • Number of Week 28+ infected vaccinees • The correlates analysis is based on comparing infected vaccinees with control vaccinees who are not infected

  19. HVTN 505: Scientific Planning • Preparation for correlates analysis • Marker Working Group established to direct and prioritize activities (Scott Hammer and Peter Gilbert co-Chairs) • Pilot studies to down-select assays for immune correlates not used in RV144 • Confirm specificity and sensitivity, background levels, controls of assays to be used • Real-time analysis • Sequencing of breakthrough viral isolates • Selected humoral and cellular immune studies • TDF/FTC levels • Mucosal studies have been added to last 1/3 of subjects • Optional rectal secretion and semen sampling for antibody and cytokine analysis

  20. Scaffolded gp70-V1V2 Protein alpha4,beta7 interaction motif V2 V1 V1V2 HIV-1 V1V2 His6 gp70 Scaffold: Murine leukemia Virus gp70 Pinter A, et al. Vaccine 16:1903, 1998

  21. Prototypic Antibodies for Broad Neutralization of HIV-1 gp120inner domain gp120 outer domain V1V2/glycan (aa160N-165I) V3/glycan (aa332N) membrane proximal domain + lipid CD4 binding site (aa368D) bridging sheet McLellan, Ofek, Zhou, Zhu, Kwong

  22. Transmission bottleneck is point of greatest vulnerability Blood or mucosal exposure Regional spread 18-72 hours Systemic Dissemination between 4 and 12 days Latency Infection of immunoprivileged sites & sequestration

  23. Study population is important Blood No physical barrier, abundant target cells IVDU Rectal mucosa Weak physical barrier, many target cells MSM Cervical/vaginal mucosa Strong physical barrier, sparse target cells Thai general population

  24. HVTN 505 Protocol Team Chair: Scott Hammer Co-Chairs: Magdalena Sobieszczyk & Michael Yin Protocol Team Leader: Shelly Karuna Biostatisticians: Peter Gilbert, Holly Janes, Doug Grove & Amy Krambrink DAIDS Medical Officers:Chuka Anude & Elizabeth Adams VRC Developer Representatives: Barney Graham & Mary Enama VRC Immunologist: Richard Koup Core Medical Monitor: Shelly Karuna HVTN Laboratory Program: John Hural & Julie McElrath Clinical Trials Manager:Shelly Mahilum Protocol Development Coordinator: Carter Bentley SDMC Senior Project Manager: Drienna Holman SDMC Project Manager: Diana Lynn SDMC Clinical Affairs: Pat Farrell DAIDS Pharmacist: Ana Martinez DAIDS Regulatory Affairs: Michelle Conan-Cibotti HVTN Regulatory Affairs : Renee Holt HVTN Pharmacist: Jan Johannessen Community Ed Unit Representative: Gail Broder Communications: Jim Maynard Community Engagement: Steve Wakefield Community Educators/Recruiters: Coco Alinsug & Jason Roberts CAB Members:Rick Church & Rich Trevino Clinic Coordinator: Steven Chang Clinical Trials Manager HVTN Investigators: Susan Buchbinder, Mike Keefer, Beryl Koblin, & Mark Mulligan Technical Editor:Adi Ferrara

  25. Vaccine Research Center National Institute of Allergy and Infectious Diseases National Institutes of Health 1-866-833-LIFE www.vrc.nih.gov vaccines@nih.gov

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