Panel 5: Current HIV Vaccine Research Clinical Research

James Kublin, MD, MPH Executive Director, HVTN

Journalist-2-Journalist Program Bangkok, Thailand September 12th, 2011

The HVTN is supported by National Institute of Allergy and Infectious Diseases (NIAID).

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):1147-1158 (2007)

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

A general vaccination strategy in South Africa
between 2020 and 2030 60% of the population, prevents 3.0M infections

Treatment for HIV in RSA

36% of expected infections requiring only 39 vaccinations/infection averted.

The potential impact of a moderately effective HIV vaccine with rapidly waning protection in South Africa and Thailand. Andersson KM, Stover J. Vaccine. 2011 Aug 18;29(36):6092-9. Epub 2011 Jun 22.

Treatment costs over 10 years = +$27,900,000,000

~$930 (R6500) second line therapy ~$1,716 (R12,000); third line therapy ~$5,148 (R36,000).

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 Achievements

Clinical Research

Laboratory

Med Ad5 Titer

Low Med Ad5 Titer Titer Ad5

Analytic/Design

*p<10-6, 1 way ANOVA

Up-regulated Down-regulated

Timeline of HIV vaccine efficacy trials

Corey L et al. Sci Transl Med 2011;3:79ps13-79ps13

HVTN 078 Amendment

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 Number arm participants Group 1 38 8 38 Group 2 8 Group 3 38 8 38 Group 4 8 184 (152 vaccine / Total 32 placebo)

Month 0 MVA-C Placebo MVA-C + gp140 Placebo DNA-C2 Placebo DNA-C2 Placebo

Month 1 MVA-C Placebo Placebo Placebo DNA-C2 Placebo DNA-C2 Placebo

Month 3 gp140 Placebo MVA-C + gp140 Placebo MVA-C Placebo MVA-C + gp140 Placebo

Month 6 gp140 Placebo Placebo Placebo MVA-C Placebo MVA-C + gp140 Placebo

Doses: DNA-C2 (4mg); MVA-C (1.45109pfu); gp140 (100 g)

Adaptive designs accelerate vaccine development

Published by AAAS

Corey L et al. Sci Transl Med 2011;3:79ps13-79ps13

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. Hypothetical Schema of a 2-Vaccine Arm vs. Placebo Trial
Study Arm Vaccine 1 Vaccine 2 Placebo Total Number Subjects 2150 2150 2150 6450 Month 0 NYVAC DNA Month 1 NYVAC DNA Month 3 NYVAC + prot NYVAC + prot Month 6 NYVAC + prot NYVAC + prot Month 12 NYVAC + prot NYVAC + prot

Placebo

Placebo

Placebo

Placebo

Placebo

HIV negative subjects enrolled and tested for HIV infection 2-monthly for a maximum of 36 months

Research Trial Duration for Each Vaccine Arm

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 postdiagnosis, 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 arm VE(0-18) VE(0-24)

2.0%
2.5% 3.0% 3.5% 4.0% 4.5% 5.0% 5.5% 6.0%

4250
3400 2855 2450 2150 1920 1730 1575 1445

3225
2600 2175 1875 1650 1475 1325 1200 1100

* Testing done as in Gilbert et al.s phase 2b design manuscript, using all of their assumptions except modifying the placebo incidence

HVTN/CHAVI NHP Early Stage Investigator Scholar Award

Funding Pilot Studies to Advance Non-Human Primate Models in Support of HIV Vaccines Clinical Research

The HVTN is supported by National Institute of Allergy and Infectious Diseases (NIAID).

2011 Scholars Cohort 3

Keith Reeves

Carolina Herrera

Afam Okoye
Oregon Health and Science University

Wendy Yeh
Beth Israel Deaconess Medical Center

Lu-Ann Pozzi
New England Primate Research Center

Shaunna Shen
Duke University

New England St. George's, Primate Research University of Center London

Thanks

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

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