Transcript
Page 1: 2012 USPHS Scientific and Training  Symposium

20 June 20121

Strengthening Health Systems through the Nigerian Ministry

of Defense—U.S. Department of Defense Walter Reed Program Nigeria Partnership

2012 USPHS Scientific and Training Symposium

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

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Towards a Globally Effective HIV Vaccine:

The role for Nigeria

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MHRP’s Product Development Plan

4

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.

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Pox-Protein

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20 June 20126NEJM 361:2209 (03 Dec 09)

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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*

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

the durability of such protection (additional boosts) Heterosexual risk groups in Asia

Ensure that we can elucidate correlates/surrogates of protection with more appropriate sample collection.

Establish protection in higher incidence populations (additional boosts) Heterosexuals in sub-Saharan Africa MSM in Africa and Asia

Page 10: 2012 USPHS Scientific and Training  Symposium

20 June 201210NEJM 366:1275 (05 Apr 2012)

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Comparison of Infection Rate and Vaccine Efficacy Between Vaccine and Placebo Recipients in the RV144

ALVAC-HIV, AIDSVAX B/E TrialV1V2 Antibodies High V1V2

Antibodies,Increased

Vaccine Efficacy

Low V1V2 Antibodies,

Same Infection Rate as Placebos

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IgA Magnitude and Breadth AntibodiesHigh IgA

Antibodies,No Efficacy,

Same Infection Rate as Placebo

—No Enhancement

Low IgA, Increased

Vaccine Efficacy

Comparison of Infection Rate and Vaccine Efficacy Between Vaccinees and Placebo Recipients in the RV144

ALVAC-HIV, AIDSVAX B/E Trial

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Sequence variation in position 169

Edlefsen, SCHARP

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Sequence variation in position 181

Edlefsen, SCHARP

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Summary The case control correlates data suggest 2 hypotheses:

Binding to gp70:V1V2 correlates inversely with HIV infection rate? • A244 and MN V2 crown linear peptides show similar effects• Linear epitope microarray data suggest V2 effect

Anti-Env IgA M-B correlates directly with HIV infection rate

Sieve analysis suggests a V2 effect

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Planned studies are mutually reinforcing and will amplify public

health impact and regional relevance.

16 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

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The pox-protein approach is regional

Will we have to tailor vaccines for multiple sub-epidemics?

What will be the inducement to industry to support such an approach?

There are significant public health challenges with regional vaccine approaches.

What about Nigeria, and the rest of West Africa, with a dominance of pure subtype G and A/G recombinant HIV infections?

Can we make a universal HIV vaccine?

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

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Nature 482, 89–93 (02 February 2012)

0

20

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60

80

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0 2 4 6 8

% U

ninf

ecte

d

Number of IR Challenges

DNA/MVAMVA/MVAAd26/MVAMVA/Ad26Sham

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

Log

SIV

RNA

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0 20 40 60 80 100

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

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0 20 40 60 80 100

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

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

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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

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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

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

0

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0 2 4 6

% U

ninf

ecte

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Number of IR Challenges

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

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Ad26-MVA correlates analysis

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

• 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 antibodyr=.67.

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Increment 2: Pathway to a Global HIV Vaccine

23

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 IIa: DNA/MVA vs Ad26/MVA (Ad35) for

epitope and clade breadth and magnitude of immune

response

Phase IIbEfficacy#:

2- or 3-arm efficacy trial with common placebo group

A successful outcome will yield a mosaic or multi-clade vaccine effective in high-risk populations. Commercial partners have yet to be identified and may

restrict development and access to products.

.

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

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How to prepare Nigeria for HIV vaccine studies?

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Preparing Nigeria for HIV Vaccine Development

Recognize a public health gap—Feb 2004

Take risk—July 2004

Recognize that you are in someone else’s country and never forget it—Jan 2005 (Bolingo)

Develop durable and inclusive frameworks (steering committees, EPIC)

Deliver prevention, care and treatment first (PEPFAR)

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Preparing Nigeria for HIV Vaccine Development—2

Find champions (Drs. Orits, Njoku, Idoko)

Give the champions protegees—Jide, Ayemoba, Umar

Build a laboratory that serves service delivery, then research (Mogadishu)

Assess risk, prevalence and subtypes (RV 230)

Community engagement from the inception (GPP version 2.0)

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Preparing Nigeria for HIV Vaccine Development—3

Work with partners (IHV, Harvard, Pop Council, Heartland Alliance, CDC, USAID, etc)

Focus on key populations—MSM, CSW (high incidence)

Engage with major stake holders (NIH, Gates) but do not vex them….let them see you take risk

Advocate…UNAIDS, AVAC, AAVP

South-south partnerships within MHRP

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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


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