RV 144: The Thai Phase III Trial
and
Development of a Globally-Effective,
Multi-Clade HIV Vaccine
Dr. Merlin Robb
Deputy Director, Clinical Research
US Military HIV Research Program (MHRP)
Walter Reed Army Institute of Research
HIV Vaccine: Quo Vadis
AIDS 2010
20 July 2010
MHRP
Objectives
2

Overview of RV144 outcomes
• Post-hoc hypothesis generating analyses

Update on ongoing research efforts
• Correlates research

Product development plans for a
globally-effective HIV vaccine
7 June 2010
RV 144
Vaccination and Follow-up Schedule
HIV test,
risk assessment and counseling
0.5
6-month vaccination
schedule
1
2
3 years of follow-up (every 6 mo.)
ALVAC®-HIV (vCP1521) priming at week 0, 4, 12, 24
AIDSVAX® B/E gp120 boosting at week 12, 24
3
(time in years)
RV 144
Vaccine Efficacy Appears Highest 6-12 months
3.5 years after first vaccination: Protective Efficacy = 31.2%
P = 0.04 95% CI: 1.1 – 52.1%
No effect on viral load
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%
VE @ 12 months = 60% (Cox PH, 95% CI 22, 80)
Anti-gp120 Reciprocal Mean Geometric Titers1
VISIT
2 WEEKS POST
VACCINE (V8)
24 WEEKS POST
VACCINE (V9)
AFRIMS
VRC
FOLD
FOLD
DECREASE DECREASE
(8:9 – A)
(8:9- V)
AFRIMS
VRC
AFRIMS
VRC
A244
12450
2377
1300
240
9.58
9.90
MN
27820
3771
2326
367
11.96
10.28
ANTIGEN
1Courtesy
of Dr. Rick Koup, May 2010
RV 144
Baseline Risk-stratified Treatment Effects (mITT)
Caveats:
• Overall incidence was low
• Risk was primarily heterosexual in low prevalence setting
• 90% of infections subtype E
Vaccine
Placebo
Treatment Effect
N
Endpoints
PY Rate %
N
Endpoints
PY Rate %
Efficacy
95% CI
Low
3,865
17
0.135
3,924
29
0.227
40.4%
-8.5,
67.2
Medium
2,369
12
0.157
2,292
22
0.299
47.6%
-6.0,
74.0
High
1,963
22
0.349
1,982
23
0.364
3.7%
-72.7,
46.3
VE for each risk category was statistically similar
RV 144
Baseline versus cumulative risk
Risk Assessment
Risk : Treatment Interaction
Baseline risk (pre-hoc analysis)
p = 0.21
“Ever” high / not ever high
p = 0.008
This may reflect the transient protective effect of the vaccine regimen
rather than imply protection only in “lower risk” individuals
RV 144
RV 144 lessons

Protection from infection possible
• No or minimal primary neutralizing antibody
• Limited CD8 T cell immunity
• Other immune effectors play a role

Protection seems greatest early and in low risk participants
• Boosting may improve overall efficacy
• Studies must consider risk variable

Mode of transmission
 Frequency of exposure
 Dose per exposure
8
7 June 2010
RV 144
Ongoing RV 144 Research

November 2009
• Immunogenicity studies
• HIV virus characterization

May 2010: Correlates Pilot Studies begin
• Collaboration with 30 US and international researchers
• Using RV144 samples

Humoral and Innate Immunity
 T-cell immunity
 Host Genetics
 Animal Models
9
7 June 2010
MHRP
Goal: Globally Effective HIV Vaccine
Effective in high-risk
populations
Multi-clade protection
against acquisition
GLOBALLY EFFECTIVE
HIV VACCINE
Durable, safe and
effective
Globally
accessible
Corollary: Efficacy trials are the only way to determine a correlate of immunity
and establish a rational basis for HIV vaccine development.
10
MHRP
Vaccine Strategy: Guiding Principles

Reasonable concepts
•
•

Evaluate these in efficient efficacy trials
•
•
•
11
Distinct from those previously tested, and
Best represent the concept
Leverage a diversity of approaches
Build incrementally on past successes
Minimize risk
7 June 2010
MHRP
Product Development Plan
Parallel product development pathways toward a globally effective HIV vaccine.
BUILDING ON RV144
1
REGIONAL VACCINE STRATEGY
Building on the RV144 regimen
2
DIVERSIFYING AND REFINING
THE PORTFOLIO
APPROACH
Phase IIb efficacy trial with extended
ALVAC/protein boosts, shorter follow-up:
a) MSM Thai population
b) High-risk heterosexuals in RSA
APPROACH
• Multi-clade populations for study
GLOBAL VACCINE STRATEGY
Pursuing diverse approaches toward
a globally effective vaccine.
• Increase CD8 potency
• Improve humoral response
• Add primary neutralizing AB
7 June 2010
MHRP
Vaccine Downselection
 A known correlate (unlikely) would guide downselection
 In the absence of a correlate:
•
If products generate similar immune responses,
strongest response will be selected
•
If products generate distinct immune response,
both concepts should be considered
 Practical considerations inform selection:
•
13
Availability, complexity, and cost
7 June 2010
MHRP
A Balanced Strategy
1
BUILDING ON RV144:
A Regional Vaccine Strategy
2
DIVERSIFYING AND REFINING
THE PORTFOLIO:
A Global Vaccine Strategy
Objective:
minimize risk and maximize the likelihood of
achieving an effective HIV vaccine.
14
7 June 2010