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 12th, 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 RocaHealth Affairs 26(4):1147-1158 (2007)

A general vaccination strategy in South Africa between 2020 and 2030 60% 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. 2011 Aug 18;29(36):6092-9. 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

6hr

24hr

72hr

168h

r6h

r24

hr72

hr16

8hr

6hr

24hr

72hr

168h

r6h

r24

hr72

hr16

8hr

6hr

24hr

72hr

168h

r6h

r24

hr72

hr16

8hr

6hr

24hr

72hr

168h

r6h

r24

hr72

hr16

8hr

6hr

24hr

72hr

168h

r6h

r24

hr72

hr16

8hr

071-056 071-008 071-046 071-015071-35 071-048 071-044 071-050 071-025 071-052

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

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 arm

Number participants Month 0 Month 1 Month 3 Month 6

Group 1 38 MVA-C MVA-C gp140 gp1408 Placebo Placebo Placebo Placebo

Group 2 38 MVA-C + gp140 Placebo MVA-C + gp140 Placebo8 Placebo Placebo Placebo Placebo

Group 3 38 DNA-C2 DNA-C2 MVA-C MVA-C8 Placebo Placebo Placebo Placebo

Group 4 38 DNA-C2 DNA-C2 MVA-C + gp140 MVA-C + gp1408 Placebo Placebo Placebo Placebo

Total 184 (152 vaccine / 32 placebo)

Doses: DNA-C2 (4mg); MVA-C (1.45×109pfu); gp140 (100 μg)

Corey L et al. Sci Transl Med 2011;3:79ps13-79ps13Published 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 arm

VE(0-18) VE(0-24)

2.0% 4250 3225

2.5% 3400 2600

3.0% 2855 2175

3.5% 2450 1875

4.0% 2150 1650

4.5% 1920 1475

5.0% 1730 1325

5.5% 1575 1200

6.0% 1445 1100* 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 AwardFunding 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.

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