Effect of rAd5-Vector HIV-1 Preventive Vaccines on HIV-1 Acquisition: A Participant-Level Meta-Analysis of Randomized Trials.
BACKGROUND
Three phase 2b, double-blind, placebo-controlled, randomized efficacy trials have tested recombinant Adenovirus serotype-5 (rAd5)-vector preventive HIV-1 vaccines: MRKAd5 HIV-1 gag/pol/nef in Step and Phambili, and DNA/rAd5 HIV-1 env/gag/pol in HVTN505. Due to efficacy futility observed at the first interim analysis in Step and HVTN505, participants of all three studies were unblinded to their vaccination assignments during the study but continued follow-up. Rigorous meta-analysis can provide crucial information to advise the future utility of rAd5-vector vaccines.


METHODS
We included participant-level data from all three efficacy trials, and three Phase 1-2 trials evaluating the HVTN505 vaccine regimen. We predefined two co-primary analysis cohorts for assessing the vaccine effect on HIV-1 acquisition. The modified-intention-to-treat (MITT) cohort included all randomly assigned participants HIV-1 uninfected at study entry, who received at least the first vaccine/placebo, and the Ad5 cohort included MITT participants who received at least one dose of rAd5-HIV vaccine or rAd5-placebo. Multivariable Cox regression models were used to estimate hazard ratios (HRs) of HIV-1 infection (vaccine vs. placebo) and evaluate HR variation across vaccine regimens, time since vaccination, and subgroups using interaction tests.


RESULTS
Results are similar for the MITT and Ad5 cohorts; we summarize MITT cohort results. Pooled across the efficacy trials, over all follow-up time 403 (n = 224 vaccine; n = 179 placebo) of 6266 MITT participants acquired HIV-1, with a non-significantly higher incidence in vaccine recipients (HR 1.21, 95% CI 0.99-1.48, P = 0.06). The HRs significantly differed by vaccine regimen (interaction P = 0.03; MRKAd5 HR 1.41, 95% CI 1.11-1.78, P = 0.005 vs. DNA/rAd5 HR 0.88, 95% CI 0.61-1.26, P = 0.48). Results were similar when including the Phase 1-2 trials. Exploratory analyses based on the efficacy trials supported that the MRKAd5 vaccine-increased risk was concentrated in Ad5-positive or uncircumcised men early in follow-up, and in Ad5-negative or circumcised men later. Overall, MRKAd5 vaccine-increased risk was evident across subgroups except in circumcised Ad5-negative men (HR 0.97, 95% CI 0.58-1.63, P = 0.91); there was little evidence that the DNA/rAd5 vaccine, that was tested in this subgroup, increased risk (HR 0.88, 95% CI 0.61-1.26, P = 0.48). When restricting the analysis of Step and Phambili to follow-up time before unblinding, 114 (n = 65 vaccine; n = 49 placebo) of 3770 MITT participants acquired HIV-1, with a non-significantly higher incidence in MRKAd5 vaccine recipients (HR 1.30, 95% CI 0.89-1.14, P = 0.18).
The data support increased risk of HIV-1 infection by MRKAd5 over all follow-up time, but do not support increased risk of HIV-1 infection by DNA/rAd5. This study provides a rationale for including monitoring plans enabling detection of increased susceptibility to infection in HIV-1 at-risk populations.
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Yunda
Y
Huang
National Institute of Allergy and Infectious Diseases and Biostatistics Research Branch, National Institutes of Health, Bethesda, MD, United States of America.
Dean
D
Follmann
Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
Martha
M
Nason
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Lily
L
Zhang
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Ying
Y
Huang
Merck Research Laboratories, North Wales, PA, United States of America.
Devan V
DV
Mehrotra
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Zoe
Z
Moodie
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Barbara
B
Metch
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Holly
H
Janes
Infectious Disease Division, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States of America.
Michael C
MC
Keefer
Aurum Institute for Health Research, Johannesburg, South Africa.
Gavin
G
Churchyard
HJF HIV Program, US Military HIV Research Program, Bethesda, MD, United States of America.
Merlin L
ML
Robb
Research and Development, International AIDS Vaccine Initiative, New York, New York, United States of America.
Patricia E
PE
Fast
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Ann
A
Duerr
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
M Juliana
MJ
McElrath
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Lawrence
L
Corey
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD, United States of America.
John R
JR
Mascola
Viral Pathogenesis Laboratory, National Institute of Allergy and Infectious Diseases, Bethesda, MD, United States of America.
Barney S
BS
Graham
Division of Infectious Diseases, Department of Medicine, Columbia University, New York, New York, United States of America.
Magdalena E
ME
Sobieszczyk
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
James G
JG
Kublin
Infectious Disease Clinical Research, Merck, Philadelphia, Pennsylvania, United States of America.
Michael
M
Robertson
Division of Infectious Diseases, Department of Medicine, Columbia University, New York, New York, United States of America.
Scott M
SM
Hammer
University of the Witwatersrand, Johannesburg, South Africa.
Glenda E
GE
Gray
Bridge HIV, San Francisco Department of Public Health, San Francisco, CA, United States of America.
Susan P
SP
Buchbinder
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Peter B
PB
Gilbert
D016915:AIDS Vaccines / Q000235:genetics* / Q000627:therapeutic use*; D000260:Adenoviruses, Human / Q000235:genetics*; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D015658:HIV Infections / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D016032:Randomized Controlled Trials as Topic; D019444:Vaccines, DNA / Q000235:genetics / Q000627:therapeutic use; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics
D016915:AIDS Vaccines; D019444:Vaccines, DNA; D054299:env Gene Products, Human Immunodeficiency Virus; D054301:gag Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D054302:pol Gene Products, Human Immunodeficiency Virus