HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis.
BACKGROUND
In the Step Study, the MRKAd5 HIV-1 gag/pol/nef vaccine did not reduce plasma viraemia after infection, and HIV-1 incidence was higher in vaccine-treated than in placebo-treated men with pre-existing adenovirus serotype 5 (Ad5) immunity. We assessed vaccine-induced immunity and its potential contributions to infection risk.


METHODS
To assess immunogenicity, we characterised HIV-specific T cells ex vivo with validated interferon-gamma ELISPOT and intracellular cytokine staining assays, using a case-cohort design. To establish effects of vaccine and pre-existing Ad5 immunity on infection risk, we undertook flow cytometric studies to measure Ad5-specific T cells and circulating activated (Ki-67+/BcL-2(lo)) CD4+ T cells expressing CCR5.


RESULTS
We detected interferon-gamma-secreting HIV-specific T cells (range 163/10(6) to 686/10(6) peripheral blood mononuclear cells) ex vivo by ELISPOT in 77% (258/354) of people receiving vaccine; 218 of 354 (62%) recognised two to three HIV proteins. We identified HIV-specific CD4+ T cells by intracellular cytokine staining in 58 of 142 (41%) people. In those with reactive CD4+ T cells, the median percentage of CD4+ T cells expressing interleukin 2 was 88%, and the median co-expression of interferon gamma or tumor necrosis factor alpha (TNFalpha), or both, was 72%. We noted HIV-specific CD8+ T cells (range 0.4-1.0%) in 117 of 160 (73%) participants, expressing predominantly either interferon gamma alone or with TNFalpha. Vaccine-induced HIV-specific immunity, including response rate, magnitude, and cytokine profile, did not differ between vaccinated male cases (before infection) and non-cases. Ad5-specific T cells were lower in cases than in non-cases in several subgroup analyses. The percentage of circulating Ki-67+BcL-2(lo)/CCR5+CD4+ T cells did not differ between cases and non-cases.


CONCLUSIONS
Consistent with previous trials, the MRKAd5 HIV-1 gag/pol/nef vaccine was highly immunogenic for inducing HIV-specific CD8+ T cells. Our findings suggest that future candidate vaccines have to elicit responses that either exceed in magnitude or differ in breadth or function from those recorded in this trial.
McElrath
M Juliana
MJ
Vaccine and Infectious Disease Institute and the HIV Vaccine Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Medicine, The University of Washington, Seattle, WA, USA; Department of Laboratory Medicine, The University of Washington, Seattle, WA, USA. Electronic address: jmcelrat@fhcrc.org.
De Rosa
Stephen C
SC
Vaccine and Infectious Disease Institute and the HIV Vaccine Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Laboratory Medicine, The University of Washington, Seattle, WA, USA.
Moodie
Zoe
Z
Vaccine and Infectious Disease Institute and the HIV Vaccine Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Dubey
Sheri
S
Merck Research Laboratories, West Point, PA, USA.
Kierstead
Lisa
L
Merck Research Laboratories, West Point, PA, USA.
Janes
Holly
H
Vaccine and Infectious Disease Institute and the HIV Vaccine Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Defawe
Olivier D
OD
Vaccine and Infectious Disease Institute and the HIV Vaccine Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Carter
Donald K
DK
Vaccine and Infectious Disease Institute and the HIV Vaccine Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Hural
John
J
Vaccine and Infectious Disease Institute and the HIV Vaccine Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Akondy
Rama
R
Emory Vaccine Center, Emory University, Atlanta, GA, USA.
Buchbinder
Susan P
SP
HIV Research Section, San Francisco Department of Public Health, San Francisco, CA, USA.
Robertson
Michael N
MN
Merck Research Laboratories, West Point, PA, USA.
Mehrotra
Devan V
DV
Merck Research Laboratories, West Point, PA, USA.
Self
Steven G
SG
Vaccine and Infectious Disease Institute and the HIV Vaccine Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Biostatistics, The University of Washington, Seattle, WA, USA.
Corey
Lawrence
L
Vaccine and Infectious Disease Institute and the HIV Vaccine Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Medicine, The University of Washington, Seattle, WA, USA; Department of Laboratory Medicine, The University of Washington, Seattle, WA, USA.
Shiver
John W
JW
Merck Research Laboratories, West Point, PA, USA.
Casimiro
Danilo R
DR
Merck Research Laboratories, West Point, PA, USA.
D016915:AIDS Vaccines / Q000276:immunology* / Q000627:therapeutic use*; D005260:Female; D015488:HIV Antigens / Q000145:classification / Q000187:drug effects / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D008297:Male; D015337:Multicenter Studies as Topic; D016032:Randomized Controlled Trials as Topic; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D016915:AIDS Vaccines; D015488:HIV Antigens