Current HIV Vaccine Research (James Kublin)
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Transcript of 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
8 Placebo Placebo Placebo Placebo
Group 3 38 DNA-C2 DNA-C2 MVA-C MVA-C
8 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 (1.45109pfu); gp140 (100 g)
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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.
HVTN.org/Science/HVTNews