Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial

Buchbinder, Susan P; Mehrotra, Devan V; Duerr, Ann; Fitzgerald, Daniel W; Mogg, Robin; Li, David; Gilbert, Peter B; Lama, Javier R; Marmor, Michael; del Rio, Carlos; McElrath, M Juliana; Casimiro, Danilo R; Gottesdiener, Keith M; Chodakewitz, Jeffrey A; Corey, Lawrence; Robertson, Michael N

doi:10.1016/s0140-6736(08)61591-3

Cited by 1,713HIV Research and TreatmentHIV/AIDS Research and InterventionsSARS-CoV-2 and COVID-19 Research

Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial

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Buchbinder, Susan P, Mehrotra, Devan V, Duerr, Ann, Fitzgerald, Daniel W, Mogg, Robin, Li, David, Gilbert, Peter B, Lama, Javier R +8 more·2008·The Lancet

DOI 10.1016/s0140-6736(08)61591-3PMC PMC2721012

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Abstract

Background Observational data and non-human primate challenge studies suggest that cell-mediated immune responses might provide control of HIV replication. The Step Study directly assessed the efficacy of a cell-mediated immunity vaccine to protect against HIV-1 infection or change in early plasma HIV-1 levels. Methods We undertook a double-blind, phase II, test-of-concept study at 34 sites in North America, the Caribbean, South America, and Australia. We randomly assigned 3000 HIV-1-seronegative participants by computer-generated assignments to receive three injections of MRKAd5 HIV-1 gag/pol/nef vaccine (n=1494) or placebo (n=1506). Randomisation was prestratified by sex, adenovirus type 5 (Ad5) antibody titre at baseline, and study site. Primary objective was a reduction in HIV-1 acquisition rates (tested every 6 months) or a decrease in HIV-1 viral-load setpoint (early plasma HIV-1 RNA measured 3 months after HIV-1 diagnosis). Analyses were per protocol and modified intention to treat. The study was stopped early because it unexpectedly met the prespecified futility boundaries at the first interim analysis. This study is registered with ClinicalTrials.gov, number NCT00095576. Findings In a prespecified interim analysis in participants with baseline Ad5 antibody titre 200 or less, 24 (3%) of 741 vaccine recipients became HIV-1 infected versus 21 (3%) of 762 placebo recipients (hazard ratio [HR] 1.2 [95% CI 0.6-2.2]). All but one infection occurred in men. The corresponding geometric mean plasma HIV-1 RNA was comparable in infected male vaccine and placebo recipients (4.61 vs 4.41 log(10) copies per mL, one tailed p value for potential benefit 0.66). The vaccine elicited interferon-gamma ELISPOT responses in 75% (267) of the 25% random sample of all vaccine recipients (including both low and high Ad5 antibody titres) on whose specimens this testing was done (n=354). In exploratory analyses of all study volunteers, irrespective of baseline Ad5 antibody titre, the HR of HIV-1 infection between vaccine and placebo recipients was higher in Ad5 seropositive men (HR 2.3 [95% CI 1.2-4.3]) and uncircumcised men (3.8 [1.5-9.3]), but was not increased in Ad5 seronegative (1.0 [0.5-1.9]) or circumcised (1.0 [0.6-1.7]) men. Interpretation This cell-mediated immunity vaccine did not prevent HIV-1 infection or reduce early viral level. Mechanisms for insufficient efficacy of the vaccine and the increased HIV-1 infection rates in subgroups of vaccine recipients are being explored.

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“In the long term, a strategy involving homologous prime–boost with identical viral-vectored vaccines may be limited by anti-vector immunity12,91,92.”
From Immunological mechanisms of vaccine-induced protection against COVID-19 in humans (2021) · cites this paper as [92]
Gam-COVID-Vac uses different adenovirus vectors for each dose, which circumvents anti-vector immunity that could inhibit anti-S responses, as seen with Ad5-nCoV and non-COVID-19 adenovirus-based vaccines.
“This may be, in part, due to the fact that Gam-COVID-Vac uses different adenovirus vectors for each dose (adenovirus 26 for dose one and adenovirus 5 for dose two), thus circumventing the potential problem of anti-vector immunity that could inhibit anti-S responses, as has been identified for Ad5-nCoV (refs12,91) (Table 1) and non-COVID-19 adenovirus-based vaccines92.”
From Immunological mechanisms of vaccine-induced protection against COVID-19 in humans (2021) · cites this paper as [92]

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Authors: Buchbinder, S. P., Mehrotra, D. V., Duerr, A., Fitzgerald, D. W., Mogg, R., Li, D., Gilbert, P. B., Lama, J. R., Marmor, M., del Rio, C., McElrath, M. J., Casimiro, D. R., Gottesdiener, K. M., Chodakewitz, J. A., Corey, L., & Robertson, M. N.
Affiliations: San Francisco Department of Public Health (US)
Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Fred Hutch Cancer Center (US)
Cornell University (US)
Asociación Civil Impacta Salud y Educación (PE)
NYU Langone Health (US)
ORCID: Buchbinder, Susan P
Mehrotra, Devan V
Duerr, Ann
Fitzgerald, Daniel W
Mogg, Robin
Gilbert, Peter B
Lama, Javier R
Marmor, Michael
McElrath, M Juliana
Gottesdiener, Keith M
Corey, Lawrence
Robertson, Michael N
Venue: The Lancet
Publisher: Elsevier BV
Published: 2008-11
Volume: 372
Issue: 9653
Pages: 1881-1893
ISSN: 0099-5355 (ISSN-L)
0140-6736
DOI: 10.1016/s0140-6736(08)61591-3
PMC: PMC2721012
OpenAlex: W2153670011
Cited by: 1,713
References: 44
Citations by year: 2026: 25 · 2025: 22 · 2024: 51 · 2023: 47 · 2022: 56 · 2021: 74 · 2020: 59 · 2019: 64 · 2018: 49 · 2017: 94 · 2016: 108 · 2015: 98 · 2014: 171 · 2013: 135 · 2012: 162
FWCI: 51.90
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: The Lancet (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (UL1TR000454, 5m01rr000079-42)
National Institute of Allergy and Infectious Diseases (P30AI050409, UM1AI069496)
National Center for Research Resources (M01-RR000079)
National Center for Advancing Translational Sciences
Topics: Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
Health Sciences › Medicine › Infectious Diseases › HIV/AIDS Research and Interventions
Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Keywords: HIV-1 vaccine, cell-mediated immunity, adenovirus type 5, HIV-1 acquisition, interferon-gamma, vaccine efficacy, futility, STEP study, early HIV-1 infection
MeSH terms: Adolescent, Adult, Double-Blind Method, Female, Humans, Immunity, Cellular, Male, Middle Aged, Risk Factors, Sexual Behavior, HIV Antigens, HIV-1, HIV Infections, Proportional Hazards Models, AIDS Vaccines, Young Adult

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Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial

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