Phase III HIV Vaccine TrialThailand

Strengthening Health Systems through the Nigerian Ministryof DefenseU.S. Department of Defense Walter Reed Program Nigeria Partnership2012 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 2012#1

20 June 2012#2Towards a Globally Effective HIV Vaccine:

The role for Nigeria

20 June 2012#3MHRPs Product Development Plan4REGIONAL VACCINE STRATEGYBuilding on the RV144 outcome and lessons learned, conduct efficacy trials of the prime-boost concept in:Thai MSM populationsHigh-risk populations in Southern AfricaBUILDING ON RV1441GLOBAL 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 PORTFOLIO2MHRPs vaccine development strategy emphasizes regional and global approaches.20 June 2012#4Pox-Protein20 June 2012#5

NEJM 361:2209 (03 Dec 09)20 June 2012#6RV 144 demonstrated efficacyfor HIV acquisitionN=16,39551 vaccine, 74 placebo HIV infectedEst. VE = 31% 95% CI 1-51% (p=0.04)

Rerks-Ngarm et al. (2009, NEJM)

0.00.51.01.52.02.53.03.51.00.90.80.70.60.50.40.30.20.10.0YearsProbability of HIV Infection (%)PlaceboVaccineC. Modified Intention-to-Treat Analysis*20 June 2012#What we have learnedRV 144Protection among low incidence heterosexual Thais, VE 31.2% at 42 monthsNo effect on post-infection viremia or CD4 countRelatively monophyletic circulating variants CRF01_AEEfficacy appears to be early and non-durableEvoked binding Ab but not measurable, primary isolate Nab BAb appeared early and decreased by > 10 fold over 6 monthsCD4+ Env responses, but not CD8 responsesCorrelate/surrogate studies limited by samples and endpoints20 June 2012#8RV144 was designed as a community-based, randomized, double-blind, placebo-controlled trial, with equal numbers of volunteers in each arm. As a community-based trial, volunteers were not selected based or randomized based on their risk behavior. The two key inclusion criteria were HIV uninfected and 18-30 years of age. We excluded volunteers who had a diagnosis of chronic disease, who were pregnant or who were breastfeeding. Six study injections were given in the first six months of the study, followed by HIV testing and risk counselling every six months for three years post-vaccination. Risk behavior was assessed by self-administered questionnaire at each visit. Volunteers therefore committed a total of 3.5 years to the study, and we commend and thank them for their dedication.What we would want nextExtend the observation of early 60% efficacy by increasing the durability of such protection (additional boosts)Heterosexual risk groups in AsiaEnsure 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 AfricaMSM in Africa and Asia

20 June 2012#9RV144 was designed as a community-based, randomized, double-blind, placebo-controlled trial, with equal numbers of volunteers in each arm. As a community-based trial, volunteers were not selected based or randomized based on their risk behavior. The two key inclusion criteria were HIV uninfected and 18-30 years of age. We excluded volunteers who had a diagnosis of chronic disease, who were pregnant or who were breastfeeding. Six study injections were given in the first six months of the study, followed by HIV testing and risk counselling every six months for three years post-vaccination. Risk behavior was assessed by self-administered questionnaire at each visit. Volunteers therefore committed a total of 3.5 years to the study, and we commend and thank them for their dedication.NEJM 366:1275 (05 Apr 2012)

20 June 2012#10

Comparison of Infection Rate and Vaccine Efficacy Between Vaccine and Placebo Recipients in the RV144 ALVAC-HIV, AIDSVAX B/E TrialV1V2 AntibodiesHigh V1V2 Antibodies,Increased Vaccine Efficacy Low V1V2 Antibodies,Same Infection Rate as Placebos 20 June 2012#

IgA Magnitude and Breadth AntibodiesHigh IgA Antibodies,No Efficacy, Same Infection Rate as PlaceboNo Enhancement Low IgA, Increased Vaccine EfficacyComparison of Infection Rate and Vaccine Efficacy Between Vaccinees and Placebo Recipients in the RV144 ALVAC-HIV, AIDSVAX B/E Trial20 June 2012#Sequence variation in position 169

Edlefsen, SCHARP20 June 2012#Sequence variation in position 181

Edlefsen, SCHARP20 June 2012#SummaryThe 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 effectsLinear epitope microarray data suggest V2 effectAnti-Env IgA M-B correlates directly with HIV infection rateSieve analysis suggests a V2 effect20 June 2012#Planned studies are mutually reinforcing and will amplify public health impact and regional relevance.16May 2011Precedent for vaccine efficacyFocus on regional public health impactStrategy for achieving potential licensure in target markets and having the broadest public health impact.

Future amplification of global reachMutually reinforcing studies strengthen and support public health benefit in target populations and the translation of the platform globally.THAILANDHigh Risk MSMUS/EUROPE

SOUTHEAST ASIARepublic of South Africa (RSA)High Risk HeterosexualRV144

SOUTHERN AFRICA

20 June 2012#Switch I and II16The pox-protein approach is regionalWill 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 2012#Ad26-MVA +/- protein

Barouch et al Nature 482:89-93 02 Feb 201220 June 2012#1819

Nature 482, 8993 (02 February 2012)

02040608010002468% Uninfected Number of IR ChallengesDNA/MVAMVA/MVAAd26/MVAMVA/Ad26Sham20 June 2012#MVA/Ad26 and Ad26/MVA Regimens Lower Early Setpoint Viral Loads Following SIVmac251 InfectionLog SIV RNA

Days Following InfectionDays Following InfectionDays Following InfectionDays Following InfectionLog SIV RNAShamMVA/MVADNA/MVAMVA/Ad265.756.095.474.55

Days Following InfectionAd26/MVA3.833x resistance to infection4/8 : viremia blunted 1 log3/8 : rapid virologic control1/8 : persistently uninfected20 June 2012#Protection Against Acquisition of IR SIVmac251 by Ad35/Ad26-SIVsmE543GagPolEnv Vaccine

20 June 2012#Ad26-MVA correlates analysis Acquisition endpoint. envelope binding antibody r= .79 p