HIV vaccine research: The way forward

National Institute of Allergy and Infectious Diseases, National Institutes of Health, 31 Center Drive, Bethesda, MD 20892, USA.
Science (Impact Factor: 31.48). 07/2008; 321(5888):530-2. DOI: 10.1126/science.1161000
Source: PubMed

ABSTRACT The need to broaden research directed at answering fundamental questions in HIV vaccine discovery through laboratory, nonhuman primate (NHP), and clinical research has recently been emphasized. In addition, the importance of attracting and retaining young researchers, developing better NHP models, and more closely linking NHP and clinical research is being stressed. In an era of a level budget for biomedical research at the U.S. National Institutes of Health (NIH), HIV/AIDS vaccine research efforts will need to be carefully prioritized such that resources to energize HIV vaccine discovery can be identified. This article summarizes progress and challenges in HIV vaccine research, the priorities arising from a recent summit at NIAID, and the actions needed, some already under way, to address those priorities.

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Available from: Dennis R Burton, Aug 13, 2015
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    • "More than 65 % of these individuals live in sub-Saharan Africa (UNAIDS 2011). There is currently no effective vaccine against HIV despite promising initial results (Fauci et al. 2008; Dolgin 2010; Walker and Burton 2010). There is also no cure, although the latest generation of antiretroviral drugs can slow the disease and improve quality of life. "
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    ABSTRACT: Monoclonal antibodies (mAbs) that neutralize human immunodeficiency virus (HIV) can be used as microbicides to help prevent the spread of HIV in human populations. As an industry standard, HIV-neutralizing mAbs are produced as recombinant proteins in mammalian cells, but the high manufacturing costs and limited capacity reduce the ability of target populations in developing countries to gain access to these potentially life-saving medicines. Plants offer a more cost-effective and deployable production platform because they can be grown inexpensively and on a large scale in the region where the products are required. Here we show that the maize-derived HIV-neutralizing mAb 2F5 is assembled correctly in planta and binds to its antigen with the same affinity as 2F5 produced in mammalian cells. Although 2F5 has been produced at high levels in non-plant platforms, the yield in maize seeds is lower than previously achieved with another HIV-neutralizing mAb, 2G12. This suggests that the intrinsic properties of the antibody (e.g. sensitivity to specific proteases) and the environment provided by the production host (e.g. the relative abundance of different proteases, potential transgene silencing) may combine to limit the accumulation of some antibodies on a case-by-case basis.
    Plant Molecular Biology 09/2012; 80(4-5):477-88. DOI:10.1007/s11103-012-9962-6 · 4.07 Impact Factor
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    • "Humoral immunity in particular exerts substantial pressure on the gp120 HIV-1 envelope surface protein, leading to escape from the autologous neutralizing antibody (NAb) response by introducing specific mutations and/or compensatory substitutions in the env gene (Blish et al., 2008; Duenas-Decamp and Clapham, 2010; Duenas-Decamp et al., 2008, 2009; Gray et al., 2007b, 2008; O'Rourke et al., 2010; O'Rourke et al., 2009; Rong et al., 2007a,b, 2009; Shen et al., 2010). While an AIDS vaccine is urgently needed, lack of understanding of how to precisely elicit potent and cross-reactive neutralizing antibodies (NAbs) poses a major hurdle to vaccine development (Barouch, 2008; Fauci et al., 2008; Walker and Burton, 2010). HIV-1 has evolved mechanisms to overcome neutralization by autologous antibodies during the natural course of infection wherein Env goes through substantial genetic drift due to antibody pressure giving rise to neutralization escape variants (Blay et al., 2006; Korber and Gnanakaran, 2009; Korber et al., 2001; Lynch et al., 2009; Zhang et al., 2010). "
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    ABSTRACT: Identification of vulnerability in the HIV-1 envelope (Env) will aid in Env-based vaccine design. We recently found an HIV-1 clade C Env clone (4-2.J45) amplified from a recently infected Indian patient showing exceptional neutralization sensitivity to autologous plasma in contrast to other autologous Envs obtained at the same time point. By constructing chimeric Envs and fine mapping between sensitive and resistant Env clones, we found that substitution of highly conserved isoleucine (I) with methionine (M) (ATA to ATG) at position 424 in the C4 domain conferred enhanced neutralization sensitivity of Env-pseudotyped viruses to autologous and heterologous plasma antibodies. When tested against monoclonal antibodies targeting different sites in gp120 and gp41, Envs expressing M424 showed significant sensitivity to anti-V3 monoclonal antibodies and modestly to sCD4 and b12. Substitution of I424M in unrelated Envs also showed similar neutralization phenotype, indicating that M424 in C4 region induces exposure of neutralizing epitopes particularly in CD4 binding sites and V3 loop.
    Virology 08/2011; 418(2):123-32. DOI:10.1016/j.virol.2011.07.015 · 3.28 Impact Factor
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    • "In a preventive HIV vaccine efficacy trial, the usual primary objective is to assess vaccine efficacy (V E) to prevent HIV infection, where typically V E is defined as one minus the hazard ratio (vaccine/placebo) of the failure event. However, it may be quite difficult to achieve an efficacious vaccine due to genetic variation of HIV (Fauci et al., 2008). The study population is exposed to many genetic types of circulating HIVs but the vaccine only contains antigens based on one or a few strains, and the vaccine protection is likely to be lower against strains that are not in the vaccine or that have greater genetic distance from the strain(s) in the vaccine (Gilbert et al., 1999). "
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    ABSTRACT:   An objective of randomized placebo-controlled preventive HIV vaccine efficacy trials is to assess the relationship between the vaccine effect to prevent infection and the genetic distance of the exposing HIV to the HIV strain represented in the vaccine construct. Motivated by this objective, recently a mark-specific proportional hazards (PH) model with a continuum of competing risks has been studied, where the genetic distance of the transmitting strain is the continuous ‘mark’ defined and observable only in failures. A high percentage of genetic marks of interest may be missing for a variety of reasons, predominantly because rapid evolution of HIV sequences after transmission before a blood sample is drawn from which HIV sequences are measured. This research investigates the stratified mark-specific PH model with missing marks where the baseline functions may vary with strata. We develop two consistent estimation approaches, the first based on the inverse probability weighted complete-case (IPW) technique, and the second based on augmenting the IPW estimator by incorporating auxiliary information predictive of the mark. We investigate the asymptotic properties and finite-sample performance of the two estimators, and show that the augmented IPW estimator, which satisfies a double robustness property, is more efficient.
    Scandinavian Journal of Statistics 06/2011; 39(1):34 - 52. DOI:10.1111/j.1467-9469.2011.00746.x · 1.06 Impact Factor
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