Current HIV Vaccine Research (James Kublin)

8/4/2019 Current HIV Vaccine Research (James Kublin)

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

Panel 5: Current HIVVaccine ResearchClinical Research

James Kublin, MD, MPH

Executive Director, HVTN

Journalist-2-Journalist Program

Bangkok, ThailandSeptember 12th, 2011


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Even a vaccine with low efficacy and limited coverage can impactthe epidemic and play a role in preventing future infections

Potential Impact of a VaccineGoogle: health affairs stover

The Impact Of An AIDS Vaccine InDeveloping Countries: A New Model

And Initial ResultsJohn Stover, Lori Bollinger, Robert Hecht, Clara Williams andEva RocaHealth Affairs 26(4):1147-1158 (2007)


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A general vaccinationstrategy 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 10years = +$27,900,000,000

Potential Impact of a Vaccine

The potential impact of a moderatelyeffective HIV vaccine with rapidly waningprotection in South Africa and Thailand.Andersson KM, Stover J. Vaccine. 2011 Aug18;29(36):6092-9. Epub 2011 Jun 22.


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HVTN Portfolio Outline

Fundamental Vaccinology and InnateImmunity

Memory and Mucosal Immunity

NHP Clinical Early Stage InvestigatorScholar Awards

First in humans and novel combinations andadjuvants

Head-to-Head Comparisons Later Phase Trials - Efficacy Cohort Development Studies of Infected Participants


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Clinical Research

Laboratory

Analytic/Design

Clinical Research Achievements

Low

Ad5 Titer

Med

Ad5 Titer

Med

Ad5 Titer

Up-regulated Down-regulated*p


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Timeline of HIV vaccine efficacy trials

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


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HVTN 078 Amendment


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HVTN 086 SAAVI/Novartis

To characterize and rank the vaccine regimens

Identify the best performing vaccine regimen based on HIV-specificneutralizing antibody responses following vaccination with Novartissubtype 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 6Group 1 38 MVA-C MVA-C gp140 gp140

8 Placebo Placebo Placebo Placebo

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


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


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 (1.45109pfu); gp140 (100 g)


9/23Corey L et al. Sci Transl Med 2011;3:79ps13-79ps13Published by AAAS

Adaptive designs accelerate vaccine development


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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 infection2-monthly for a maximum of 36 months

Hypothetical Schema of a 2-Vaccine Arm vs. Placebo Trial

Study ArmNumberSubjects

Month 0 Month 1 Month 3 Month 6 Month 12

Vaccine 1 2150 NYVAC NYVAC NYVAC + prot NYVAC + prot NYVAC + prot

Vaccine 2 2150 DNA DNA NYVAC + prot NYVAC + prot NYVAC + prot

Placebo 2150 Placebo Placebo Placebo Placebo Placebo

Total 6450


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Research Trial Duration for EachVaccine 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

VEhalved during first 6 mo

HIV testing bi-monthly

for up to 36 mo

Maximum of 134 HIV infections

for one vaccine regimen + placebo


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Objectives of the Design

Primary objective:

For each vaccine regimen, evaluate VE against infections diagnosedwithin 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 forpositive 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 AIDSendpoints

Exploratory objectives:

Several, including behavioral assessments with emphasison PrEP use


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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 forVE(0-18) > 0%

Premise: The vaccine will not confer greater efficacy for

exposures more distal from the immunization series


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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.


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Immune Correlates Analysis

Goal: Expeditiously evaluate priority immunologicalparameters as immune correlates of protection

For each vaccine not weeded out for non-efficacy ~6 months beforethe projected final analysis of VE(0-18), begin measurements on

vaccine arm infected cases to date and frequency matcheduninfected vaccine recipients

Such vaccines have VE(0-18) estimates at least 25% and meritinitiation of the immune correlates analysis

Design the trial to offer any vaccine showing efficacy on VE(0-18) toall placebo recipients at study close-out (36 months)

Measure vaccine-induced immune responses for the vaccinatedplacebo recipients, which is useful for evaluating immune

surrogates


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Filling in the Immunological Space


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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

S l i ( ) f


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Sample sizes (per arm) fortesting VE=40% vs. VE=0% forrange 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 26003.0% 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


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

HVTN/CHAVI NHP EarlyStage Investigator

Scholar Award

Funding Pilot Studies to Advance Non-HumanPrimate Models in Support of HIV Vaccines

Clinical Research


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2011 Scholars Cohort 3

Keith

Reeves

Wendy

Yeh

Carolina

Herrera

Afam

Okoye

New England

Primate ResearchCenter

Beth Israel

DeaconessMedical Center

St. George's,

University ofLondon

Oregon Health

and ScienceUniversity

Shaunna

Shen

Lu-Ann

Pozzi

Duke

University

New England

Primate ResearchCenter


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Thanks

Peter Gilbert

Larry Corey

Julie McElrath Glenda Gray

Georgia Tomaras

Jerome Kim


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Informs readers about thescience of the HVTN, themanagement of the Networks

many multilateralcollaborations, and ouroutstanding clinical sites.

Current issue includes articleson Epitope Mapping, AdaptiveTrial Design, and ExploringBarriers and Facilitators in theRecruitment of TransgenderWomen.

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Documents

Current HIV Vaccine Research (James Kublin)