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      Magnitude and Breadth of the Neutralizing Antibody Response in the RV144 and Vax003 HIV-1 Vaccine Efficacy Trials

      1 , 2 , 3 , 3 , 3 , 2 , 4 , 4 , 4 , 4 , 1 , 1 , 5 , 5 , 1 , 1 , 1 , 1 , 4 , 4 , 6 , 7 , 2 , 7 , 3 , 8 , 9 , 9 , 9 , 10 , 4 , 1 , 4 , 4

      The Journal of Infectious Diseases

      Oxford University Press

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          Background.  A recombinant canarypox vector expressing human immunodeficiency virus type 1 (HIV-1) Gag, Pro, and membrane-linked gp120 (vCP1521), combined with a bivalent gp120 protein boost (AIDSVAX B/E), provided modest protection against HIV-1 infection in a community-based population in Thailand (RV144 trial). No protection was observed in Thai injection drug users who received AIDSVAX B/E alone (Vax003 trial). We compared the neutralizing antibody response in these 2 trials.

          Methods.  Neutralization was assessed with tier 1 and tier 2 strains of virus in TZM-bl and A3R5 cells.

          Results.  Neutralization of several tier 1 viruses was detected in both RV144 and Vax003. Peak titers were higher in Vax003 and waned rapidly in both trials. The response in RV144 was targeted in part to V3 of gp120.vCP1521 priming plus 2 boosts with gp120 protein was superior to 2 gp120 protein inoculations alone, confirming a priming effect for vCP1521. Sporadic weak neutralization of tier 2 viruses was detected only in Vax003 and A3R5 cells.

          Conclusion.  The results suggest either that weak neutralizing antibody responses can be partially protective against HIV-1 in low-risk heterosexual populations or that the modest efficacy seen in RV144 was mediated by other immune responses, either alone or in combination with neutralizing antibodies.

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          Most cited references 32

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          The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens.

           T. Wyatt,  J Sodroski (1998)
          The human immunodeficiency virus-type 1 (HIV-1) envelope glycoproteins interact with receptors on the target cell and mediate virus entry by fusing the viral and cell membranes. The structure of the envelope glycoproteins has evolved to fulfill these functions while evading the neutralizing antibody response. An understanding of the viral strategies for immune evasion should guide attempts to improve the immunogenicity of the HIV-1 envelope glycoproteins and, ultimately, aid in HIV-1 vaccine development.
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            HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites.

            The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is dependent on its avoidance of antibody-mediated neutralization. The virus elicits abundant, envelope-directed antibodies that have little neutralization capacity. This lack of neutralization is paradoxical, given the functional conservation and exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are larger than the typical antibody footprint and should therefore be accessible for antibody binding. Because gp120-receptor interactions involve conformational reorganization, we measured the entropies of binding for 20 gp120-reactive antibodies. Here we show that recognition by receptor-binding-site antibodies induces conformational change. Correlation with neutralization potency and analysis of receptor-antibody thermodynamic cycles suggested a receptor-binding-site 'conformational masking' mechanism of neutralization escape. To understand how such an escape mechanism would be compatible with virus-receptor interactions, we tested a soluble dodecameric receptor molecule and found that it neutralized primary HIV-1 isolates with great potency, showing that simultaneous binding of viral envelope glycoproteins by multiple receptors creates sufficient avidity to compensate for such masking. Because this solution is available for cell-surface receptors but not for most antibodies, conformational masking enables HIV-1 to maintain receptor binding and simultaneously to resist neutralization.
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              HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis.

              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. 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. 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. 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.

                Author and article information

                J Infect Dis
                J. Infect. Dis
                The Journal of Infectious Diseases
                Oxford University Press
                1 August 2012
                25 May 2012
                25 May 2012
                : 206
                : 3
                : 431-441
                [1 ]Duke University Medical Center , Durham, North Carolina
                [3 ]Fred Hutchinson Cancer Research Center , Seattle, Washington
                [4 ]US Military HIV Research Program, Walter Reed Army Institute of Research , Rockville, Maryland
                [5 ]University of Alabama at Birmingham
                [8 ]Baskin School of Engineering, University of California, Santa Cruz
                [9 ]Global Solutions for Infectious Diseases, South San Francisco, California
                [2 ]Armed Forces Research Institute of Medical Sciences
                [6 ]Department of Disease Control, Ministry of Public Health
                [7 ]Faculty of Tropical Medicine, Mahidol University , Bangkok, Thailand
                [10 ]Sanofi-Pasteur, Toronto, Canada
                Author notes

                Presented in part: 12th Annual Meeting of the Institute of Human Virology, Calabria, Italy, 4–8 October 2010 and 5th Vaccine and International Society of Vaccine Annual Global Congress, Seattle, Washington, 2–4 October 2011.

                Correspondence: David C. Montefiori, PhD, Department of Surgery, Box 2926, Duke University Medical Center, Durham, NC 27710 ( monte@ 123456duke.edu ).
                © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 28
                Major Articles and Brief Reports

                Infectious disease & Microbiology


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