23 July 20121

RV144: Clinical Development Plans

IAS 2012, Washington, DC USA

The views expressed are those of the presenter and should not be construed to represent the positions of the U.S. Army or DoD

Nelson L. Michael, M.D., Ph.DColonel, Medical Corps, U.S. Army

DirectorUS Military HIV Research Program (MHRP)Walter Reed Army Institute of Research

23 July 20122

Past HIV Vaccine Concepts

2

2003: AIDSVAX 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/Nef

Cellular 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 boostHumoral and Cellular

Immunity• 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.

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.

23 July 20123NEJM 361:2209 (03 Dec 09)

23 July 20124

RV 144 demonstrated efficacy

for HIV acquisition

N=16,39551 vaccine, 74 placebo HIV infectedEst. VE = 31% 95% CI 1-51% (p=0.04)

Rerks-Ngarm et al. (2009, NEJM)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Years

Prob

abili

ty o

f HIV

Infe

ction

(%)

Placebo

Vaccine

C. Modified Intention-to-Treat Analysis*

23 July 20125

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

23 July 20126

What we would want next Extend the observation of early 60% efficacy by increasing the durability of

immune responses Additional vaccine boosts Improved adjuvants Improved vaccines

Elucidate correlates of risk of infection. Adequately powered studies Adequate sample collections

Public health implementation--establish protection in higher incidence populations (additional boosts/improved adjuvants) Heterosexuals in sub-Saharan Africa MSM in Africa and Asia

23 July 20127

RV 144 correlates of risk—a teaser

23 July 20128

RV 144 Correlates Discovery Effort

RV144 Steering CommitteeScientific

Steering Committee

ProductDevelopment AdvisoryGroup

Humoral & Innate Immunity

Cellular Immunity

HostGenetics

AnimalModels

Scientific Advisory Groups

MHRP - DAIDS Steering Committee

PA H Steering Committee

ADVISORY GROUPS

Clinical Development

Correlates

23 July 20129NEJM 366:1275 (05 Apr 2012)

23 July 201210

Multivariate Logistic Regression: Quantitative Variables

Variable Relative risk P-value Q-value

IgA Binding to Envelope Panel 1.54 0.027 0.08

IgG Avidity A244 gp120 0.81 0.37 0.56

ADCC AE.HIV-1 Infected CD4 Cells 0.92 0.68 0.68

Tier 1 Neutralizing Antibodies 1.37 0.22 0.45

IgG Binding to gp70-V1V2 0.57 0.015 0.08

CD4+ T Cell Intracellular Cytokines 1.09 0.61 0.68

All 6 variables together in multivariate analysis, P=0.08Only a-Env IgA and IgG gp70:V1V2 binding, p = 0.009 (log reg), 0.012 (Cox)2 individual variables were significant:

gp70 V1V2 inversely correlates with infection [q = 0.08]Estimated 43% reduction in infection rate (per SD)

Plasma IgA directly correlates with infection [q = 0.08]Estimated 54% increase in infection rate (per SD)

23 July 201211

Is it V1V2 or both?

23 July 201212

Case control analysis of microarray shows trend to inverse correlation at tip of V2 and in CD4 binding site

23 July 201213

Sieve Analysis of RV144 Breakthrough Viruses supports importance of V2 loop

23 July 201214

Sieve Analysis of V2

Comparison of viruses from HIV-1 infected vaccine versus HIV-1 infected placebo recipients

These are not transmitted/founder viruses—the mean time to last negative visit was ~ 3 months.

V2 was a major focus of analysis.

Analysis—collaboration between Dr. Morgane Rolland (MHRP), Dr. Jim Mullins (UW), SCHARP

23 July 201215

Sequence variation in position 169

Edlefsen, SCHARP

23 July 201216

Sequence variation in position 181

Edlefsen, SCHARP

23 July 201217

Results: Sites 169 and 181 Separately

For each site, VE significantly differs against match vs. mismatched infection vaccine reduced infection rate 3.77 times more for 181-mm than 181-m

Positive VE for 169-matched infection and181-mismatched infection

The sieve analysis suggests that the vaccine selectively blocked acquisition with 169-matched and with 181-mismatched virus; but conferred no protection against 169-mismatched or 181-matched virus

Genotype No. Infections Est. VE 95% CI P-value169m 87 48% 18% to 66% 0.0036

169mm 23 -45% -258% to 33% 0.30181m 88 -20% -26% to 45% 0.38

181mm 22 78% 35% to 93% 0.0028

Genotypes No. Infections Est. HR / HR 95% CI P-value169mm/

169m87/23 2.73 1.08 to 6.92 0.034

181m/181mm

22/88 3.77 1.19 to 11.92 0.024

23 July 201218

Correlates of Risk of Infection WARNING—it is textbook (Stan Plotkin’s) knowledge that different

vaccines for the same pathogen can have different correlates of risk/protection.

Will correlate of risk for ALVAC-AIDSVAX B/E in RV 144 generalize to…. These products in Thai MSM? ALVAC-gp120 engineered for heterosexuals in Africa? Other HIV vaccines such as DNA/Ad5 (HVTN 505 phase IIb), Ad26-MVA,

etc?

We want all subsequent efficacy trials to seek correlates—now more than ever. This impacts clinical design.

23 July 201219

CollaboratorsDukeBart HaynesLarry LiaoGeorgia TomarasNathan VandergriftGarnett KelsoeDavid MontefioriThomas KeplerMarcella Sarzotti-KelsoeMunir Alam

Bill and Melinda Gates FoundationNina RussellFrancine McCutchan

HVTNPeter GilbertNicole FrahmJulie McElrath

UMDNJAbe Pinter

NYU/VA Susan Zolla-Pazner

HarvardJoseph SodroskiSteve HarrisonNorm Letvin

IHVGeorge LewisTony DeVico

NIH VRCGary NabelPeter KwongJohn MascolaMarie PanceraJason McLellan

Thai Ministry of Public Health

23 July 201220

Towards a Globally Effective HIV Vaccine

23 July 201221

MHRP’s Product Development Plan

21

REGIONAL VACCINE STRATEGYBuilding on the RV144 outcome and lessons learned, conduct efficacy trials of the prime-boost concept in:

a) Thai MSM populationsb) High-risk populations in Southern Africa

BUILDING ON RV1441

GLOBAL VACCINE STRATEGYPursuing 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 PORTFOLIO2

MHRP’s vaccine development strategy emphasizes regional and global approaches.

23 July 201222

Pox-Protein Public Private Partnership(NIAID-Gates led)

23 July 201223

Planned studies are mutually reinforcing and will amplify public

health impact and regional relevance.

23 May 2011

Precedent for vaccine

efficacy

Focus on regional

public health impact

Strategy for achieving potential licensure in target markets and having the broadest public health impact.

Future amplification of global reach

Mutually reinforcing studies strengthen and support public health benefit in target populations and the translation of the platform globally.

THAILANDHigh Risk MSM US/EUROPE

SOUTHEAST ASIA

Republic of South Africa (RSA)

High Risk Heterosexual

RV144

SOUTHERN AFRICA

23 July 201224

Timeline12 13 14 15 16 17 18

RV305

RV328

RV306

217-Vax (?)

RV348

Bridge Study

RV349Go/No-Go

23 July 201225

Short-term Development Objectives

Characterize vaccine immune responses using samples collected In sufficient amounts At the right times From systemic as well as mucosal sites

Improve magnitude and durability of vaccine-induced responses

23 July 201226

Research Strategy

Three Exploratory Phase II immunogenicity trials in Thailand

Collections: serum, plasma, cells, genital fluids Special collections: leukapheresis, gut biopsy, cervical

biopsy, bone marrow aspiration (except RV305) Broad array of humoral and cellular assays

23 July 201227

RV305 (RV144 extended boost study)

135+27=162

23 July 201228

RV306 (Intensive Immunogenicity)

404+56=460

23 July 201229

Bridging Study—from AIDSVAX/alum to delta 11/MF59

ALVAC-HIV prime as before

gp120 boost comparison: One B and one E, both gD negative, C1 delta 11 Novartis process and MF59 adjuvant Part A Open Label safety assessment in the U.S. for Novartis

product:

Wk 0 2 4 8 12 24 32 48

Gp N

A1 10 A A A/N A/N

A=ALVAC-HIV, N=Novartis rgp120B/E

23 July 201230

Bridging Study Part B Thailand—compare AIDSVAX/alum vs Novartis

gp120/MF59B Wk 0 2 4 8 12 24 32 48

Gp N

B1* 90 A A A/AVX A/AVX A/AVX

10 P P P/P P/P P/P

B2 90 A A A/N A/N A/N

10 P P P/P P/P P/P

B3 90 A A A/N A/N A/N

10 P P P/P P/P P/P

A=ALVAC-HIV, AVX=AIDSVAX B/E, N=Novartis rgp120B/E

*Possibly use RV306 samples

23 July 201231 31

Studies:RV144i immune correlates studiesRV305 protein boosting studyRV306 expanded immunogenicity study

Objective:Determine correlate of protectionfor use in future trials; optimize the regimen

Partners/Funders: US Army, Thai Gov’t, NIH, sanofi pasteur, BMGF

2010 2011 2012 2013 2014 2015 2016 2017

Ongoing RV144 Follow-up in Thailand

Population: MSM, high-riskProducts: ALVAC (sanofi) + gp120/MF59 (NVD)

Objective: Confirm result & demonstrate efficacy in target population with potential for licensure

Partners/Funders: US Army, Thai Gov’t, NIH, sanofi, BMGF?

Thailand ph2b

Population: Heterosexual, high-riskProducts: ALVAC (sanofi) + gp120/MF59 (NVD)

Objective: Extend result & translate vaccine to Africa, other high-risk groups

Partners/Funders: NIH, HVTN, sanofi, Novartis, BMGF, RSA?

Africa ph2b

Population: Heterosexual, high-riskProducts: DNA + NYVAC (sanofi) + gp140 (Polymun)/MF59 (NVD)

vs. NYVAC (sanofi) + gp140 (Polymun)/MF59 (NVD)

Objective: Extend results & accelerate evaluation of other products using adaptive trial design and first available protein

Partners/Funders: NIH, HVTN, sanofi pasteur, Novartis, BMGF

S. Africa ph2b

Licensure

ResearchCandidate selection

• ALVAC is default vector prime• Proteins boosts TBD• RV144 immune correlates• Immune grid• Cost, product availability

Pox-Protein Development Plan

23 July 201232

Ad26-MVA +/- proteinBarouch et al Nature 482:89-93 02 Feb 2012

23 July 201233 33

Nature 482, 89–93 (02 February 2012)

0

20

40

60

80

100

0 2 4 6 8

% U

ninf

ecte

d

Number of IR Challenges

DNA/MVAMVA/MVAAd26/MVAMVA/Ad26Sham

23 July 201234

MVA/Ad26 and Ad26/MVA Regimens Lower Early Setpoint Viral Loads Following SIVmac251 Infection

Log

SIV

RNA

2

3

4

5

6

7

8

9

0 20 40 60 80 100

418-08419-08420-08422-08423-08424-08425-08435-08MEAN

2

3

4

5

6

7

8

9

0 20 40 60 80 100

426-08434-08442-08443-08444-08452-08453-08454-08MEAN

2

3

4

5

6

7

8

9

0 20 40 60 80 100

440-08441-08445-08446-08447-08448-08449-08450-08MEAN 2

3

4

5

6

7

8

9

0 20 40 60 80 100

428-08430-08431-08433-08436-08437-08438-08439-08MEAN

Days Following Infection Days Following Infection Days Following Infection

Days Following Infection

Log

SIV

RNA

Sham MVA/MVA DNA/MVA

MVA/Ad26

5.75 6.095.47

4.55

2

3

4

5

6

7

8

9

0 20 40 60 80 100

409-08410-08411-08412-08413-08414-08416-08417-08MEAN

Days Following Infection

Ad26/MVA

3.83

3x resistance to infection4/8 : viremia blunted 1 log3/8 : rapid virologic control1/8 : persistently uninfected

23 July 201235

Protection Against Acquisition of IR SIVmac251 by Ad35/Ad26-SIVsmE543GagPolEnv Vaccine

0

20

40

60

80

100

0 2 4 6

% U

ninf

ecte

d

Number of IR Challenges

GagPol (N=16)GagPolEnv (N=16)Sham (N=8)

23 July 201236

Ad26-MVA correlates analysis

• Acquisition endpoint. • envelope binding antibody r= .79 p<.0001. • neutralization antibody r=.50 p=.0034• ADCC r=.38 p=.034 (trend)

• set point viral load endpoint, Many correlates (N=27);• prechallenge gag elispot count and gag elispot

breadth were both correlated (r=-.50 p=.006 and r=-.64 p=.0002, respectively) with the endpoint.

• peak envelope binding antibody r=-.70 followed by prechallenge neutralizing antibody r=.67.

23 July 201237

Summary RV 144 demonstrated that vaccines can provide HIV acquisition

protection.

Correlates of risk of infection were discovered in RV 144.

Correlates of risk of infection in Ad26-MVA (and other) vaccines have been discovered in NHP models.

We must educate (and remind) ourselves that correlates of risk may or may not generalize.

There is great value (but at a cost) to seek correlates of infection risk in future HIV vaccine trials.

Product development and scientific rationale must communicate with each other.

23 July 201238

AcknowledgementsSupported by:Collaboration for AIDS Vaccine Discovery Grant From the Bill and Melinda Gates Foundation

HVTN, DAIDS, NIAID

With Collaborations with the MHRP and Thai Ministry of Public HealthNational Institute of Allergy and Infectious Diseases (NIAID)National Institutes of Health (NIH)Division of AIDS (DAIDS)U.S. Department of Health and Human Services (HHS)

Center for HIV/AIDS Vaccine Immunology (CHAVI) # U19 AI067854-06

HVTN