rv144 one year later (jerome h. kim, m.d.)
TRANSCRIPT
RV144 – One Year Later
AIDS Vaccine 2010Atlanta, GA27 Sept 2010
Jerome H. Kim, MDDeputy Director (Science), US Military HIV Research Program (MHRP)Walter Reed Army Institute of Research
HIV Vaccines Project ManagerU.S. Army Medical Research and Materiel Command
27 September 2010
Past HIV Vaccine Concepts
2
2003: AIDSVAX STUDIES
VaxGen Env gp120Humoral Immunity
• Phase III studies in high-risk subjects in the US/Thailand
• Elicited type-specific Abs but not broadly reactive NAbs
• No efficacy
2003: AIDSVAX STUDIES
VaxGen Env gp120Humoral Immunity
• Phase III studies in high-risk subjects in the US/Thailand
• Elicited type-specific Abs but not broadly reactive NAbs
• No efficacy
2007: STEP-PHAMBILI STUDIES
Merck Ad5-Gag/Pol/NefCellular Immunity
•Phase IIb study in high-risk subjects in North/South America•Elicited cellular immunity by IFN-γ ELISPOT assays•No efficacy, possible increased HIV-1 acquisition
2007: STEP-PHAMBILI STUDIES
Merck Ad5-Gag/Pol/NefCellular Immunity
•Phase IIb study in high-risk subjects in North/South America•Elicited cellular immunity by IFN-γ ELISPOT assays•No efficacy, possible increased HIV-1 acquisition
2009: RV144Sanofi ALVAC prime,
AIDSVAX gp120 boost
Humoral and Cellular I
mmunity
• Phase III study in low-risk subjects in Thailand
• 31% reduction in HIV-1 acquisition with no viral load effect
2009: RV144Sanofi ALVAC prime,
AIDSVAX gp120 boost
Humoral and Cellular I
mmunity
• Phase III study in low-risk subjects in Thailand
• 31% reduction in HIV-1 acquisition with no viral load effect
2003 20072005 2009
Advancing HIV vaccine candidates to efficacy trials will accelerate progress in the field, bringing us closer to an effective global vaccine.
Advancing HIV vaccine candidates to efficacy trials will accelerate progress in the field, bringing us closer to an effective global vaccine.
Although only three concepts have undergone clinical efficacy testing to date, each HIV vaccine efficacy trial has yielded unexpected outcomes that have
transformed the HIV landscape.
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RV144: HIV-1 Prime-Boost Vaccine Trial
Trial DescriptionRV144: A Phase III Trial of Aventis Pasteur Live Recombinant ALVAC-HIV (vCP1521) Priming With VaxGen gp120 B/E (AIDSVAX® B/E) Boosting in HIV-uninfected Thai Adults
Co-Development Partners Ministry of Public Health (MOPH), Thailand
Vaccine Trials Centre, Mahidol UniversityData Management Unit, Mahidol University
Royal Thai Army Division of AIDS, National Institute of Allergy & Infectious Diseases (NIAID), NIH Global Solutions for Infectious Diseases (VaxGen) sanofi pasteur
SponsorSurgeon General, US Army; IND is held by USAMMDA; MHRP and USAMC-AFRIMS execute for Sponsor
Clinical Development Stage Phase IIb (Test of Concept, TOC) Trial
Vaccine Regimen
• Prime: ALVAC® HIV (vCP1521)• Schedule: 0, 1, 3, 6 mo • subtype B (LAI) gag/pro• subtype E (92TH023) env; gp41-TM (LAI)
• Boost: AIDSVAX® B/E• Schedule: 3, 6 mo • subtype B (MN) gp120 env• subtype E gp120 env
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Vaccine Distribution
Center (VDC) Health Center
Klaeng District Hospital
Trial Registry and Repository Center AFRIMS HIV Lab
Clinical Site 200:
Si Racha
Trial Scrapbook: Infrastructure
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RV144 Trial: Key Dates and Statistics
• Screening started: 24 Sep 2003 • First vaccination: 20 Oct 2003• Enrollment completed: 30 Dec 2005
60,000+ interested people 26,675 volunteers screened16,402 volunteers enrolled16,395 rec’d at least one dose (mITT)
• Enrollment completed: 30 Dec 2005• Vaccination completed: 31 Jul 2006• Interim Analysis (mITT): 18 Jul 2007• 2007 – 2009: Roadmaps and Access, and
Dossiers• Commitment to ensuring the study
participants would be first to learn of outcome regardless of result
• Presented to WHO-VAC, Enterprise, PAVE, AVRS
• Roadmap III consensus: 15 Dec 2008• Access Plan consensus: 29 Jul 2009
• Study completed: 30 June 2009
• Final Analysis Meeting: 10-11 Sep 2009
• Announcement: 24 Sep 2009• Presentation: 20 Oct 2009• Other statistics
– 52,985 mITT p-y of follow-up (final)
– 102,069 HIV EIA screening tests
– 104,900 vaccine vials shipped, 100% accountability
– 296,307 visits (final)– 641,157 specimens (plasma
and cells, final)– 1,163,267 CRF pages (final)
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RV144 Endpoints
Co-primary Endpoints To determine whether immunization with ALVAC-HIV (vCP1521) boosted by
AIDSVAX B/E gp120 protects Thai volunteers from HIV infection (Acquisition) 90.8% power to detect difference if true VE=50%
To determine the effect of immunization on viral load after intercurrent infection (Viral load) 80% power to detect a 0.39 log difference in VL setpoint (if VE = 50%) Mean of log viral load at first 3 planned assessments at/after serologic diagnosis
Secondary Endpoints
To determine the effect of immunization on CD4 cell count after intercurrent infection
To confirm the safety of this vaccine combination
To evaluate whether participation is associated with behavior change that increases the risk of HIV infection
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NEW ENGLAND JOURNAL OF MEDICINE
Detailed Results from RV 144 HIV Vaccine Trial
Published online on October 20; print on December 3
Results also presented at the 2009 AIDS Vaccine Conference in Paris
Phase III Prime-Boost Trial in Thailand
Phase III HIV Vaccine Trial
31.2 % effective
Safe vaccine regimen
A major step forward for HIV vaccines
Provides the first evidence that development of a safe and effective HIV vaccine is possible
On September 24, 2009, the trial sponsor—the U.S. Army Surgeon
General’s—announced that a vaccine regimen was modesty effective in
preventing HIV infection in humans.
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6-month vaccination schedule
6-month vaccination schedule 3 years of follow-up (every 6 mo.)3 years of follow-up (every 6 mo.)
0.5 1 2 3
ALVAC®-HIV (vCP1521) priming at week 0, 4, 12, 24
AIDSVAX® B/E gp120 boosting at week 12, 24
(time in years)
HIV test,risk assessment and counseling
HIV test,risk assessment and counseling
Vaccination and Follow-up Schedule
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From Screening to Vaccination
26,676 Initial Screen
26,548 HIV Test
17,350 Clinic Screen
16,402 Randomized
16,395 Infection Free
8,197 Vaccine
8,198 Placebo
128 Not Referred
418 HIV seropositive8,780 Discontinued
984 Ineligible422 TB/Other Disease341 Female Reproductive 66 Unavailable for 3.5 years119 Other
7 BaselineHIV PCR Positive
Up to 45-days
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16,402 Randomized16,402 Randomized
16,395 Infection Free16,395 Infection Free
8,197 Vaccine
8,198 Placebo
6,176All doses on
schedule
6,176All doses on
schedule
6,366All doses on
schedule
6,366All doses on
schedule
Intent-to-Treat (ITT)
Modified Intent-to-Treat (mITT)
Per Protocol (PP)
Definition of Analytical Methods
7 BaselineHIV PCR Positive
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Efficacy by PP, ITT, and mITT
Per Protocol 36,720 person-years 86 infections
• Vaccine: 36• Placebo: 50
VE: 26.2%, p=0.16 95% CI: -13.3, 51.9
Per Protocol 36,720 person-years 86 infections
• Vaccine: 36• Placebo: 50
VE: 26.2%, p=0.16 95% CI: -13.3, 51.9
Modified ITT52,985 person-years125 infections
• Vaccine: 51• Placebo: 74
VE: 31.2%, p=0.04 adj. 95% CI: 1.1, 52.1
Modified ITT52,985 person-years125 infections
• Vaccine: 51• Placebo: 74
VE: 31.2%, p=0.04 adj. 95% CI: 1.1, 52.1
ITT 52,985 person-years132 infections
• 7 prevalent• Vaccine: 56• Placebo: 76
VE: 26.4%, p=0.08 95% CI: -4.0, 47.9
ITT 52,985 person-years132 infections
• 7 prevalent• Vaccine: 56• Placebo: 76
VE: 26.4%, p=0.08 95% CI: -4.0, 47.9
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Vaccine Efficacy Highest Early
mITT PP
month Events Efficacy Events Efficacy
6 16 54% n/a n/a
12 42 60% 21 68%
18 67 44% 41 41%
24 82 36% 53 27%
30 95 36% 62 31%
Efficacy did not decrease with time in a statistically meaningful way
(Kaplan-Meier-based estimates)
VE @ 12 months = 60% (Cox PH, 95% CI 22, 80)
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Co-primary Endpoint 2: No difference in post-infection setpoint viral load
Mean Setpoint Viral LoadVaccine recipients: 4.3 log10
Placebo recipients: 4.2 log10
p = 0.24
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No difference in post-infection CD4+ T cell count
Mean CD4 T cell count @ notification and verification visitsVaccine: 554.7/ul (SE = 38.0)Placebo: 567.5/ul (SE = 27.2)p = NS
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Salient Result Considerations and Implications
Regimen modestly prevented infection, with a vaccine efficacy point of 31.2%; efficacy greatest in lowest-risk groups.
• Conditions may have permitted observation of a modest effect with a weak vaccine.• Vaccine may not be relevant to high-risk groups.
Vaccine efficacy appears to be early and non-durable.
• A booster dose might be necessary to improve durability and potency.
Vaccine efficacy was observed in a monophyletic (clade E) population.
• Will different vaccines need to be developed for different regions based on subtype?
Vaccination did not affect viral load or CD4 T-cell count in infected subjects.
• Mechanism for protection is distinct from the mechanism for viral load control.• Stronger CD8 response may reduce VL.
Immunological responses detected in vaccine recipients included:•transient induction of binding antibody;•high early ADCC titers (later declined);•CD4 T-cell responses.
• CD8 CTL responses and NAbs (as currently measured) do not appear critical to prevent infection in this study.• Identification of a correlate of protection may
be difficult due to limitations of samples and endpoints.
RV144 Outcomes and Key Considerations
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What we have learned—RV 144
Protection among low incidence heterosexual Thais, VE 31.2% at 42 months
No effect on post-infection viremia or CD4 count
Relatively monophyletic circulating variants CRF01_AE
Efficacy appears to be early and non-durable
Evoked binding Ab but not measurable, primary isolate Nab— BAb appeared early and decreased by > 10 fold over 6 months
CD4+ Env responses, but not CD8 responses
Correlate/surrogate studies limited by samples and endpoints
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The Impact of RV144
Protection against infection is possible
Protection against infection and reduction in post-infection viral load may be mediated by different immune mechanisms Design of the next set of HIV vaccines with stronger “killer
cell” responses or stronger or more balanced “killer” and “helper” responses
Adaptation of the animal model to account for prevention of infection – low dose rectal and vaginal challenges
Design of efficacy trials with “pox” and protein prime-boost combinations
What does this say about anti-HIV antibodies?
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RV144: The follow-up
Laboratory – pursuit of a laboratory correlate of protection
Clinical Development Pathway – building upon and extending the result of RV144 with the next set of clinical trials
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Laboratory: Post-RV144 Research Summary
Humoral & Innate Immunity Cellular Immunity Host Genetics Animal Models
Scientific Steering Committee
Effort led by the U.S. Military HIV Research Program (MHRP), NIAID, Gates Foundation and more than 30 U.S. and international collaborators
Intensive laboratory studies of the patient specimens in an effort to define the immune mechanisms (a “correlate” or “surrogate” mediating the protection against HIV infection
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RV144 Scientific Research Proposals
Proposal solicitation at Paris Meeting (20 Oct 2009) MHRP website, meetings 32 proposals approved
Core analysis studies: Scientific Working Groups and MHRP collaborations Humoral/innate, cellular immunity, host genetics, sequence
analysis as well as NHP studies
Additional outside research proposals: Universities, NIH, private industry Includes 4 international proposals 30 MTAs
Work is ongoing 27 September 2010
What is a Correlate / Surrogate of Protection?
Correlate of protection is a specific immune response against a vaccine that is closely related to protection against infection, disease, or other defined endpoint “Surrogate” of Infection
A correlate is an objective criterion for protection (ie, a lab assay) of individual vaccinees Practically, it permits licensure of a vaccine without efficacy
(Phase III) testing or permits the testing of combinations of vaccines.
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Correlates of Protection
Vaccinated – InfectedVaccinated – Infected
WHAT PROTECTS THE VACCINATED – PROTECTED?
WHAT PROTECTS THE VACCINATED – PROTECTED?
VaccinationVaccination
Vaccinated - ProtectedVaccinated - Protected
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What Might Protect Against Infection?
Antibody (Humoral) Broadly neutralizing antibody Type-specific neutralizing antibody Non-neutralizing antibody – ADCC?
Cellular Immune Responses CD8+ cytotoxic T cells? CD4 helper or cytotoxic T cells?
Host Genetic / Innate factors HLA Kir, Fc, Trim 5a, APOBEC Phagocytosis
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Viral Sieve Effect
VIRUSESVACCINE INDUCED
IMMUNERESPONSES
BREAKTHROUGHVIRUS
Compare sequence of breakthrough viruses in vaccine and placebo
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What do we learn from sieve analysis?
Sieve analysis identifies the viruses that break through the defenses established by vaccination Placebo recipients have the full range of viruses in the
community, vaccine recipients might have a smaller number of “breakthrough” viruses, with particular characteristics not common in placebo recipients
It may point out weaknesses in vaccine-induced immune response
Sieve analysis may also help us understand what parts of the virus are important for the establishment of infection or a needed for the earliest propagation of virus in infected persons Could we improve the vaccine to target the virus when it is
most vulnerable?
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RV144 – The Second Year
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MHRP Product Development Plan
REGIONAL VACCINE STRATEGYREGIONAL VACCINE STRATEGYBuilding on the RV144 outcome and lessons learned, conduct efficacy trials of the pox protein prime-boost
concept in:a)Thai MSM populations;b)High-risk populations in Southern Africa.
REGIONAL VACCINE STRATEGYREGIONAL VACCINE STRATEGYBuilding on the RV144 outcome and lessons learned, conduct efficacy trials of the pox protein prime-boost
concept in:a)Thai MSM populations;b)High-risk populations in Southern Africa.
BUILDING ON RV14411
GLOBAL VACCINE STRATEGYGLOBAL VACCINE STRATEGY
Pursuing diverse platforms (e.g. vectors, multi-valent constructs or mosaic inserts) that build on the prime-boost concept and readily translate to
multi-clade testing and a globally effective vaccine.
GLOBAL VACCINE STRATEGYGLOBAL VACCINE STRATEGY
Pursuing diverse platforms (e.g. vectors, multi-valent constructs or mosaic inserts) that build on the prime-boost concept and readily translate to
multi-clade testing and a globally effective vaccine.
DIVERSIFYING AND REFINING THE PORTFOLIO22
MHRP vaccine development strategy emphasizes regional and global approaches.
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2010 2011 2012 2013 2014 2015 2016 2017
Trials areprime-boost
regimenswith
secondaryboost
Phase IIbEfficacyPhase IIbEfficacy
RSA and Southern AfricaHeterosexual, high-risk
Objective: Translate vaccine to high-risk groups with greater viral diversity
Partners/Funders: Gates, NIH, HVTN, sanofi pasteur, Novartis RSA, etc.
RV144 Follow-onStudies
RV144 Follow-onStudies
ThailandRV152, RV305, RV306RV144i laboratory studies
Objective:Determine a correlate of protection for use in future trials; optimize the regimen
Partners/Funders: US Army, Thai Gov’t, NIH, sanofi pasteur, BMGF
Phase IIbLicensure in Thailand
Phase IIbLicensure in Thailand
SE AsiaMSM, high-risk
Objective: Demonstrate efficacy in target population to achieve public health impact
Partners/Funders: US Army, Thai Gov’t, NIH, sanofi pasteur
Regional Pox-Protein Product Development Plan
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Diversifying and Refining the Portfolio*:A Global Vaccine Strategy
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2011 2012 2013 2014 2015 2016 2017
Trials are prime-boost
regimens with
additional protein
boost based on RV144
data
Phase I: Safety and
immunogenicity
Phase I: Safety and
immunogenicity
Phase IIa: DNA/MVA vs Ad26/MVA for epitope and
clade breadth and magnitude of immune
response
Phase IIa: DNA/MVA vs Ad26/MVA for epitope and
clade breadth and magnitude of immune
response
Phase IIbEfficacy#: Phase IIbEfficacy#:
2- or 3-arm efficacy trial with common placebo group
Successful outcome -- mosaic or multi-clade vaccines effective in high-risk populations..
Successful outcome -- mosaic or multi-clade vaccines effective in high-risk populations..
.
N.B. Timelines may be reduced if studies are designed to integrate Ph IIa and IIb as a single “rolling” study*This timeline assumes use of an off-the-shelf protein, or no protein at all. An additional 1-2 years would be required if novel proteins are used.#If there is a >12 month delay in access to one of the two concepts, the products would proceed separately in Phase IIb (i.e. 2 two-arm studies).
Multi-clade (A/C/E) or mosaic (M1/M2) inserts
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Developing a Globally-Effective HIV Vaccine
The HIV vaccine research community should aim to develop and license a globally-effective HIV vaccine as efficiently as
possible.
Global Advocacy
Local Support
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RV144: Progress Towards Global HIV Vaccine
“…a watershed event in the effort to find a vaccine to prevent the AIDS virus…”
“A lot of people thought we would never be able to report a story like this ... So this is a potentially big deal.”
“HIV researchers say the results from a large trial in Thailand offer renewed optimism that an effective HIV vaccine is possible.”
“HIV Trial Provides Hope”
“AIDS Vaccine Protects 1/3 of Trial Volunteers”
“The 50 Best Inventions of 2009; #8 Top Inventions,
#2 Medical Breakthroughs”
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