RV 144 - AIDS 2010

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