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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
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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)
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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.
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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
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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
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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-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)
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Corey 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 infection 2-monthly for a maximum of 36 months
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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
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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
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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 for VE(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 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
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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
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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
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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
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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
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Thanks
Peter Gilbert Larry Corey Julie McElrath Glenda Gray Georgia Tomaras Jerome Kim
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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