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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
20 June 20122
20 June 20123
Towards a Globally Effective HIV Vaccine:
The role for Nigeria
20 June 20124
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.
20 June 20125
Pox-Protein
20 June 20126NEJM 361:2209 (03 Dec 09)
20 June 20127
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*
20 June 20128
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
20 June 20129
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
20 June 201210NEJM 366:1275 (05 Apr 2012)
20 June 201211
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
20 June 201212
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
20 June 201213
Sequence variation in position 169
Edlefsen, SCHARP
20 June 201214
Sequence variation in position 181
Edlefsen, SCHARP
20 June 201215
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
20 June 201216
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
20 June 201217
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?
20 June 201218
Ad26-MVA +/- proteinBarouch et al Nature 482:89-93 02 Feb 2012
20 June 201219 19
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
20 June 201220
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
20 June 201221
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)
20 June 201222
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.
20 June 201223
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
20 June 201224
How to prepare Nigeria for HIV vaccine studies?
20 June 201225
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)
20 June 201226
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)
20 June 201227
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
20 June 201228
20 June 201229
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