The HVTN is supported by National Institute of Allergy and Infectious Diseases (NIAID). Panel 5: Current HIV Vaccine Research Clinical Research James Kublin, MD, MPH Executive Director, HVTN Journalist-2-Journalist Program Bangkok, Thailand September 12 th, 2011

Even a vaccine with low efficacy and limited coverage can impact the epidemic and play a role in preventing future infections Potential Impact of a Vaccine Google: health affairs stover The Impact Of An AIDS Vaccine In Developing Countries: A New Model And Initial Results John Stover, Lori Bollinger, Robert Hecht, Clara Williams and Eva Roca Health Affairs 26(4): (2007)

 A general vaccination strategy in South Africa between 2020 and % of the population, prevents 3.0M infections  36% of expected infections  requiring only 39 vaccinations/infection averted.  Treatment for HIV in RSA ~$930 (R6500) second line therapy ~$1,716 (R12,000); third line therapy ~$5,148 (R36,000).  Treatment costs over 10 years = +$27,900,000,000 Potential Impact of a Vaccine The potential impact of a moderately effective HIV vaccine with rapidly waning protection in South Africa and Thailand. Andersson KM, Stover J. Vaccine Aug 18;29(36): Epub 2011 Jun 22.

HVTN Portfolio Outline  Fundamental Vaccinology and Innate Immunity  Memory and Mucosal Immunity  NHP – Clinical – Early Stage Investigator Scholar Awards  First in humans and novel combinations and adjuvants  Head-to-Head Comparisons  Later Phase Trials - Efficacy  Cohort Development  Studies of Infected Participants

 Clinical Research  Laboratory  Analytic/Design Clinical Research Achievements Low Ad5 Titer Med Ad5 Titer Med Ad5 Titer Up-regulated Down-regulated *p<10 -6, 1 way ANOVA

Timeline of HIV vaccine efficacy trials Corey L et al. Sci Transl Med 2011;3:79ps13-79ps13

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HVTN 086 SAAVI/Novartis  To characterize and rank the vaccine regimens  Identify the best performing vaccine regimen based on HIV-specific neutralizing antibody responses following vaccination with Novartis subtype C gp140/MF59 vaccine As a concurrent or sequential boost to SAAVI MVA-C prime As a concurrent boost with SAAVI MVA-C after SAAVI DNA-C2 prime Study arm Number participantsMonth 0Month 1Month 3Month 6 Group 1 38MVA-C gp140 8Placebo Group 2 38MVA-C + gp140PlaceboMVA-C + gp140Placebo 8 Group 3 38DNA-C2 MVA-C 8Placebo Group 4 38DNA-C2 MVA-C + gp140 8Placebo Total 184 (152 vaccine / 32 placebo) Doses: DNA-C2 (4mg); MVA-C (1.45×10 9 pfu); gp140 (100 μg)

Corey L et al. Sci Transl Med 2011;3:79ps13-79ps13 Published by AAAS Adaptive designs accelerate vaccine development

Trial Example Schema  2 vaccine regimens vs. a shared placebo group  Examples of upcoming vaccines include ALVAC, NYVAC, DNAs, gp120, MVAs, Ad26, Ad35, immunoprophylaxis, etc.  HIV negative subjects enrolled and tested for HIV infection 2-monthly for a maximum of 36 months

Research Trial Duration for Each Vaccine Arm 12 Assumptions: N = 2,150 / group Annual sero-incidence in placebo group = 3% Annual rate of loss to follow-up = 5% 18 mo enrollment period Avg enrollment = 391 per mo halved during first 3 mo Vaccination regimen completed at 12 mo VE halved during first 6 mo HIV testing bi-monthly for up to 36 mo Maximum of 134 HIV infections for one vaccine regimen + placebo

Objectives of the Design  Primary objective: For each vaccine regimen, evaluate VE against infections diagnosed within 18 months of randomization [i.e., VE(0-18)]  Secondary objectives: 1.To evaluate durability of VE out to 36 months for each regimen showing reliable evidence for positive VE(0-18) 2.To expeditiously and rigorously evaluate immune correlates of protection if any of the vaccine regimens show reliable evidence for positive VE(0-18), including sieve analysis 3.To compare VE between the 2 vaccine regimens 4.To evaluate vaccine effects on HIV-1 progression for 18 months post- diagnosis, including viral load, CD4+ T cell count, HAART, and AIDS endpoints  Exploratory objectives: Several, including behavioral assessments with emphasis on PrEP use

Research Trial Divided into 2 Stages  A 2-stage design separately for each vaccine regimen: Stage 1 evaluates VE(0-18) Stage 2 evaluates longer-term VE(t), and occurs if, and only if, the trial provides reliable evidence for VE(0-18) > 0%  Premise: The vaccine will not confer greater efficacy for exposures more distal from the immunization series

Application of Monitoring Plan to RV144 Proposed Design Est. VE(0-18), 95% CI, 2-sided p-value: 49%, 32% to 82%, p=0.006.

Immune Correlates Analysis  Goal: Expeditiously evaluate priority immunological parameters as “immune correlates of protection”  For each vaccine not weeded out for non-efficacy ~6 months before the projected final analysis of VE(0-18), begin measurements on vaccine arm infected cases to date and frequency matched uninfected vaccine recipients Such vaccines have VE(0-18) estimates at least 25% and merit initiation of the immune correlates analysis  Design the trial to offer any vaccine showing efficacy on VE(0-18) to all placebo recipients at study close-out (36 months) Measure vaccine-induced immune responses for the vaccinated placebo recipients, which is useful for evaluating immune surrogates

Filling in the Immunological Space

Cost Drivers for Phase 2b Studies  Cost drivers Sample size – determined by:  vaccine efficacy  duration of follow-up  incidence Number of injections Frequency of visits PBMC time points Number of clinical sites  Site and Lab Capacity Square feet Footsteps Hands and hoods - PBMCs

Sample sizes (per arm) for testing VE=40% vs. VE=0% for range of infection rates * Testing VE=40% vs. VE=0% Annual incidence placebo armVE(0-18)VE(0-24) 2.0% % % % % % % % % * Testing done as in Gilbert et al.’s phase 2b design manuscript, using all of their assumptions except modifying the placebo incidence

The HVTN is supported by National Institute of Allergy and Infectious Diseases (NIAID). HVTN/CHAVI NHP Early Stage Investigator Scholar Award Funding Pilot Studies to Advance Non-Human Primate Models in Support of HIV Vaccines Clinical Research

2011 Scholars – Cohort 3 Keith Reeves Wendy Yeh Carolina Herrera Afam Okoye New England Primate Research Center Beth Israel Deaconess Medical Center St. George's, University of London Oregon Health and Science University Shaunna Shen Lu-Ann Pozzi Duke University New England Primate Research Center

Thanks  Peter Gilbert  Larry Corey  Julie McElrath  Glenda Gray  Georgia Tomaras  Jerome Kim

 Informs readers about the science of the HVTN, the management of the Network’s many multilateral collaborations, and our outstanding clinical sites.  Current issue includes articles on Epitope Mapping, Adaptive Trial Design, and Exploring Barriers and Facilitators in the Recruitment of Transgender Women. HVTN.org/Science/HVTNews