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Lancet. 2008 Nov 29;372(9653):1894-1905. doi: 10.1016/S0140-6736(08)61592-5. Epub 2008 Nov 13.

HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis.

Author information

1
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.
2
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.
3
Vaccine and Infectious Disease Institute and the HIV Vaccine Trials Network, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
4
Merck Research Laboratories, West Point, PA, USA.
5
Emory Vaccine Center, Emory University, Atlanta, GA, USA.
6
HIV Research Section, San Francisco Department of Public Health, San Francisco, CA, USA.
7
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.
8
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.

Abstract

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.

FINDINGS:

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.

INTERPRETATION:

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.

PMID:
19012957
PMCID:
PMC2774110
DOI:
10.1016/S0140-6736(08)61592-5
[Indexed for MEDLINE]
Free PMC Article

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