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Review
. 2010 Sep;5(5):357-61.
doi: 10.1097/COH.0b013e32833d2d2b.

Overview of STEP and Phambili trial results: two phase IIb test-of-concept studies investigating the efficacy of MRK adenovirus type 5 gag/pol/nef subtype B HIV vaccine

Glenda Gray  1 , Susan Buchbinder, Ann Duerr
Affiliations
Review

Overview of STEP and Phambili trial results: two phase IIb test-of-concept studies investigating the efficacy of MRK adenovirus type 5 gag/pol/nef subtype B HIV vaccine

Glenda Gray et al. Curr Opin HIV AIDS. 2010 Sep.

Abstract

Purpose of review: Two phase IIb test-of-concept studies evaluated the replication-defective adenovirus type 5 (Ad5) vaccine MRK gag/pol/nef HIV vaccine to prevent infection or decrease early plasma viral load in disparate populations. The STEP study enrolled men and women in the Americas, Caribbean and Australia; the Phambili trial enrolled men and women in South Africa, where the modes of sexual transmission and HIV-1 risk, subtypes of HIV-1, and background Ad5 seroprevalence differed.

Recent findings: Vaccination in both studies were stopped, after the first interim efficacy analysis of the STEP study crossed predetermined nonefficacy boundaries. Neither trial demonstrated a decrease in HIV acquisition nor decreased early plasma viral load in vaccinees compared with placebo recipients. Post-hoc analyses of men enrolled in the STEP study showed a larger number of HIV infections in the subgroup of vaccinated men who were Ad5-seropositive and uncircumcised compared with a comparable placebo group. This was not demonstrated in the Phambili study, in which most men were heterosexual, whereas most in STEP were homosexual/bisexual. Further analysis of the STEP study has yet to explain the effect of Ad5 seroprevalence on increased HIV-1 susceptibility in men receiving the vaccine. However, promising vaccine effects on early viral control were seen, and the possibility of effects on early viral load set-point in women in Phambili was seen.

Summary: These trials have provided a number of lessons about the importance of clinical trials in the HIV vaccine discovery process, and insight into the type and level of immune response that will be required for control of viral replication.

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Figures

Figure 1
Figure 1. Viral load Setpoint by Treatment Arm in the Phambili study
The HIV viral load setpoint was defined as the geometric mean of viral load at assessed at ~2 months through ~3 months after detection of infection for individuals not taking antiretroviral therapy. Viral load in vacinees did not differ from that among placebo recipients. Hollow symbols indicate that viral load set-point is estimated as follows:

  1. Either month 2 or month 3 viral load is used

  2. If month 2 or month 3 are missing, 1 month post diagnosis is used

  3. If month 1-3 are missing, the average of the diagnostic samples are used

See this image and copyright information in PMC

References

    1. Patterson S, Papagatsias T, Benlahrech A. Use of adenovirus in vaccines for HIV. Handb Exp Pharmacol. 2009;(188):275–93. Review. PubMed PMID: 19031031. - PubMed

    2. Good overview of the rationale for the use of adenoviruses in vaccine research.

    1. Priddy FH, Brown D, Kublin J, et al. Safety and immunogenicity of a replication-incompetent adenovirus type 5 HIV-1 clade B gag/pol/nef vaccine in healthy adults. Clin Infect Dis. 2008 Jun 1;46(11):1769–81. - PubMed
    1. Catanzaro AT, Koup RA, Roederer M, et al. Phase 1 safety and immunogenicity evaluation of a multiclade HIV-1 candidate vaccine delivered by a replication-defective recombinant adenovirus vector. J Infect Dis. 2006 Dec 15;194(12):1638–49. Epub 2006 Nov 8. Erratum in: J Infect Dis. 2009 Oct 15;200(8):1352-3. - PMC - PubMed
    1. Buchbinder SP, Mehrotra DV, Duerr A, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet. 2008 Nov 29;372(9653):1881–93. - PMC - PubMed

    2. This article fully describes the Step study and its outcome. This was the first phase IIB test of concept study using this product and formed the basis of further exploratory research looking at the association of baseline status and HIV-1 infection.

    1. Barouch DH, Korber B. HIV-1 vaccine development after STEP. Annu Rev Med. 2010;61:153–67. Review. - PMC - PubMed

    2. Excellent review on vaccine development given the outcome of the Step study. This review is essential for clinicians who have an interest in HIV vaccine science.

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