RV144 – One Year Later

Jerome H. Kim, MD
Deputy Director (Science), US Military HIV Research Program (MHRP)
Walter Reed Army Institute of Research
HIV Vaccines Project Manager
U.S. Army Medical Research and Materiel Command

AIDS Vaccine 2010

Atlanta, GA
27 Sept 2010

27 September 2010
 Past HIV Vaccine Concepts
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.

2003 2005 2007 2009

2003: AIDSVAX 2007: STEP-PHAMBILI 2009: RV144

STUDIES STUDIES Sanofi ALVAC prime,
VaxGen Env gp120 Merck Ad5-Gag/Pol/Nef A
Cellular Immunity I
Humoral Immunity
D
• P •Phase IIb study in high-risk
S
h subjects in North/South America
as •Elicited cellular immunity by IFN-
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A
e γ ELISPOT assays
III •No efficacy, possible increased
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Advancing HIV vaccine
hi candidates to efficacy trials will accelerate progress in 0
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the field,h-bringing us closer to an effective global vaccine. o
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2 sk 27 Septemberst
2010
 RV144: HIV-1 Prime-Boost Vaccine Trial 3

Trial Description Vaccine Regimen

RV144: A Phase III Trial of Aventis Pasteur Live • Prime: ALVAC® HIV (vCP1521)
Recombinant ALVAC-HIV (vCP1521) Priming With VaxGen • Schedule: 0, 1, 3, 6 mo
gp120 B/E (AIDSVAX® B/E) Boosting in HIV-uninfected Thai • subtype B (LAI) gag/pro
Adults • subtype E (92TH023) env; gp41-TM (LAI)
Sponsor
• Boost: AIDSVAX® B/E
Surgeon General, US Army; IND is held by USAMMDA; • Schedule: 3, 6 mo
MHRP and USAMC-AFRIMS execute for Sponsor • subtype B (MN) gp120 env
• subtype E gp120 env

Clinical Development Stage

 Phase IIb (Test of Concept, TOC) Trial

Co-Development Partners
 Ministry of Public Health (MOPH), Thailand
Vaccine Trials Centre, Mahidol University
Data 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

27 September 2010
 Trial Scrapbook: Infrastructure

Vaccine Distribution Klaeng District

Center (VDC) Health Center Hospital

Clinical Site 200: Trial Registry and

Si Racha Repository Center AFRIMS HIV Lab

27 September 2010
 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 screened
16,402 volunteers enrolled
16,395 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)
27 September 2010
 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
27 September 2010
 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
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.

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
27 September 2010
 Vaccination and Follow-up Schedule

HIV test,
risk assessment and counseling

0.5 1 2 3 (time in years)

6-month vaccination 3 years of follow-up (every 6 mo.)

schedule

ALVAC®-HIV (vCP1521) priming at week 0, 4, 12, 24

AIDSVAX® B/E gp120 boosting at week 12, 24

27 September 2010
From Screening to Vaccination

26,676 Initial Screen

128 Not Referred

26,548 HIV Test

418 HIV seropositive
8,780 Discontinued

Up to 45-days
17,350 Clinic Screen
984 Ineligible
422 TB/Other Disease
341 Female Reproductive
66 Unavailable for 3.5 years
16,402 Randomized 119 Other
7 Baseline
HIV PCR Positive

16,395 Infection Free

8,197 8,198
Vaccine Placebo
27 September 2010
 Definition of Analytical Methods

16,402 Randomized Intent-to-Treat (ITT)

7 Baseline
HIV PCR Positive

16,395 Infection Free

8,197 8,198 Modified Intent-to-Treat

Vaccine Placebo (mITT)

6,176 6,366
All doses on All doses on Per Protocol (PP)
schedule schedule

27 September 2010
 Efficacy by PP, ITT, and mITT


Per Protocol Modified ITT ITT

 36,720 person-years  52,985 person-years  52,985 person-
 86 infections 125 infections years
• Vaccine: 36 • Vaccine: 51 132 infections
• Placebo: 50 • Placebo: 74 • 7 prevalent
 VE: 26.2%, p=0.16  VE: 31.2%, p=0.04 • Vaccine: 56
 95% CI: -13.3, 51.9  adj. 95% CI: 1.1, 52.1 • Placebo: 76
 VE: 26.4%, p=0.08
 95% CI: -4.0, 47.9
27 September 2010
 Vaccine Efficacy Highest Early

(Kaplan-Meier-based estimates)
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

VE @ 12 months = 60%
(Cox PH, 95% CI 22, 80)

27 September 2010
 Co-primary Endpoint 2:
No difference in post-infection setpoint viral load

Mean Setpoint Viral Load

Vaccine recipients: 4.3 log10
Placebo recipients: 4.2 log10
p = 0.24

27 September 2010
No difference in post-infection CD4+ T cell count

Mean CD4 T cell count @ notification and

verification visits
Vaccine: 554.7/ul (SE = 38.0)
Placebo: 567.5/ul (SE = 27.2)
p = NS

27 September 2010
 RV144 Outcomes and Key Considerations
Salient Result
Regimen modestly prevented infection, with
a vaccine efficacy point of 31.2%; efficacy
greatest in lowest-risk groups.
Vaccine efficacy appears to be early and non-
durable.
Vaccine efficacy was observed in a
monophyletic (clade E) population.
Vaccination did not affect viral load or CD4 T-
cell count in infected subjects.
Immunological responses detected in vaccine
recipients included:
•transient induction of binding antibody;
•high early ADCC titers (later declined);
•CD4 T-cell responses.
16
Considerations and Implications
• Conditions may have permitted observation of
a modest effect with a weak vaccine.
• Vaccine may not be relevant to high-risk groups.
• A booster dose might be necessary to improve
durability and potency.
• Will different vaccines need to be developed for
different regions based on subtype?
• Mechanism for protection is distinct from the
mechanism for viral load control.
• Stronger CD8 response may reduce VL.
• 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.
27 September 2010
 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

27 September 2010
 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?

27 September 2010
 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

27 September 2010
 Laboratory: Post-RV144 Research Summary

 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

Scientific Steering
Committee

Humoral & Innate

Cellular Immunity Host Genetics Animal Models
Immunity

27 September 2010
 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.

27 September 2010
Correlates of Protection

Vaccination

Vaccinated - Protected Vaccinated – Infected

WHAT PROTECTS THE

VACCINATED – PROTECTED?

27 September 2010
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
27 September 2010
 Viral Sieve Effect
VACCINE INDUCED
VIRUSES IMMUNE
BREAKTHROUGH
RESPONSES VIRUS

Compare sequence of
breakthrough viruses in
vaccine and placebo
27 September 2010
 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?

27 September 2010
RV144 – The Second Year

27 September 2010
 MHRP Product Development Plan
MHRP vaccine development strategy emphasizes regional
and global approaches.

1 BUILDING ON RV144
REGIONAL VACCINE STRATEGY
Building 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.

DIVERSIFYING AND REFINING THE PORTFOLIO

2
GLOBAL 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.
27 September 2010
 Regional Pox-Protein Product Development Plan

SE Asia
MSM, high-risk
Phase IIb Objective: Demonstrate
Licensure in efficacy in target population to
Thailand achieve public health impact

Thailand Partners/Funders: US Army,

RV152, RV305, RV306 Thai Gov’t, NIH, sanofi pasteur
Trials are
RV144i laboratory prime-boost
studies regimens
Objective: RSA and Southern Africa with
RV144 Heterosexual, high-risk secondary
Determine a correlate of
Follow-on boost
protection for use in Objective: Translate vaccine to
Studies future trials; optimize
Phase IIb high-risk groups with greater
the regimen viral diversity
Efficacy
Partners/Funders: US Partners/Funders: Gates, NIH,
Army, Thai Gov’t, NIH, HVTN, sanofi pasteur, Novartis
sanofi pasteur, BMGF RSA, etc.

2010 2011 2012 2013 2014 2015 2016 2017

29 27 September 2010
 Diversifying and Refining the Portfolio*:
A Global Vaccine Strategy

Phase I: Multi-clade (A/C/E) or mosaic (M1/M2) inserts

Safety and
Trials are
immunogenicity
prime-boost
regimens Phase IIa: DNA/MVA vs
with Ad26/MVA for epitope and
additional clade breadth and
protein magnitude of immune
boost based response
on RV144 2- or 3-arm
data Phase IIb efficacy trial with
Efficacy##: common placebo
group

2011 2012 2013 2014 2015 2016 2017

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.
# . month delay in access to one of the two concepts, the products would proceed separately in Phase IIb
If there is a >12
30 (i.e. 2 two-arm studies). 27 September 2010
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.
Local Support

Global Advocacy
27 September 2010
 RV144: Progress Towards Global HIV Vaccine

“…a watershed event in the effort to find a

vaccine to prevent the AIDS virus…”
“The 50 Best Inventions of
2009; #8 Top Inventions,
#2 Medical Breakthroughs”

“A lot of people thought we would never “AIDS Vaccine Protects 1/3 of

be able to report a story like this ... So this Trial Volunteers”
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”

27 September 2010
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