Lessons from Failure—Preparing for Future HIV‐1 Vaccine Efficacy Trials

The Journal of Infectious Diseases (Impact Factor: 6). 04/2005; 191(5):647-9. DOI: 10.1086/428406
Source: PubMed
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    • "Montefiori, personal communication). Interestingly, in Vax004 (clade B gp120MN and gp120GNE8), the vaccine induced robust gp120 binding and neutralization antibody levels to the Tier 1 strain HIV-1 MN, but neutralization breadth for Tier 2 HIV-1 isolates was weak and sporadic, consistent with the lack of observed protection (Gilbert et al., 2005; Graham and Mascola, 2005). "
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    ABSTRACT: Recent findings have brought optimism that development of a successful human immunodeficiency virus type-1 (HIV-1) vaccine lies within reach. Studies of early events in HIV-1 infection have revealed when and where HIV-1 is potentially vulnerable to vaccine-targeted immune responses. With technical advances in human antibody production, clues about how antibodies recognize HIV-1 envelope proteins have uncovered new targets for immunogen design. A recent vaccine regimen has shown modest efficacy against HIV-1 acquisition. However, inducing long-term T and B cell memory and coping with HIV-1 diversity remain high priorities. Mediators of innate immunity may play pivotal roles in blocking infection and shaping immunity; vaccine strategies to capture these activities are under investigation. Challenges remain in integrating basic, preclinical and clinical research to improve predictions of types of immunity associated with vaccine efficacy, to apply these insights to immunogen design, and to accelerate evaluation of vaccine efficacy in persons at-risk for infection.
    Immunity 10/2010; 33(4):542-54. DOI:10.1016/j.immuni.2010.09.011 · 21.56 Impact Factor
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    • "and/or reducing virus replication and progression to disease [1] [2]. However, both approaches have failed at inducing any type of protection [3] [4]. "
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    ABSTRACT: The native HIV-1 Tat protein was chosen as vaccine candidate for phase I clinical trials in both uninfected ( identifier: NCT00529698) and infected volunteers ( identifier: NCT00505401). The rationale was based on the role of Tat in the natural infection and AIDS pathogenesis, on the association of Tat-specific immune responses with the asymptomatic stage and slow-progression rate as well as on its sequence conservation among HIV clades ( The parallel conduction in the same clinical centers of randomized, double blind, placebo-controlled phase I studies both in healthy, immunologically competent adults and in HIV-infected, clinically asymptomatic, individuals represents a unique occasion to compare the vaccine-induced immune response in both the preventive and therapeutic setting. In both studies, the same lot of the native Tat protein was administered 5 times, every four weeks, subcute (SC) with alum adjuvant or intradermic (ID), in the absence of adjuvant, at 7.5 microg, 15 microg or 30 microg doses, respectively. The primary and secondary endpoints of these studies were the safety and immunogenicity of the vaccine candidate, respectively. The study lasted 52 weeks and monitoring was conducted for on additional 3 years. The results of both studies indicated that the Tat vaccine is safe and well tolerated both locally and systemically and it is highly immunogenic at all the dosages and by both routes of administration. Vaccination with Tat induced a balanced immune response in uninfected and infected individuals. In particular, therapeutic immunization induced functional antibodies and partially reverted the marked Th1 polarization of anti-Tat immunity seen in natural infection, and elicited a more balanced Th1/Th2 immune response. Further, the number of CD4 T cells correlated positively with anti-Tat antibody titers. Based on these results, a phase II study is ongoing in infected drug-treated individuals (
    Reviews on Recent Clinical Trials 09/2009; 4(3):195-204. DOI:10.2174/157488709789957529 · 1.07 Impact Factor
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    • "If more data including both placebo and vaccinated recipients confirm that selection pressure differs between viruses infecting these three races, deciphering the genetic determinants of these differences should become a public-health priority. Indeed, our results highlight the need for selecting a broader representation of volunteers, based on ethnicity, in the design of future HIV-1 vaccine studies and trials [19]. "
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    ABSTRACT: Differences in HIV-1 gp120 sequence variation were examined in North American volunteers who became infected during a phase III vaccine trial using the rgp120 vaccine. Molecular adaptation of the virus in vaccine and placebo recipients from different ethnic subgroups was compared by estimating the dN/dS ratios in viruses sampled from each individual using three different methods. ANOVA analyses detected significant differences in d(N)/d(S) ratios among races (P < 0.02). gp120 sequences from the black individuals showed higher mean d(N)/d(S) ratios for all estimators (1.24-1.45) than in other races (0.66-1.35), and several pairwise comparisons involving blacks remained significant (P < 0.05) after correction for multiple tests. In addition, black-placebo individuals showed significantly (P < 0.02) higher mean d(N)/d(S) ratios (1.3-1.66) than placebo individuals from the other races (0.65-1.56). These results suggest intrinsic differences among races in immune response and highlight the need for including multiple ethnicities in the design of future HIV-1 vaccine studies and trials.
    Retrovirology 07/2009; 6(1):67. DOI:10.1186/1742-4690-6-67 · 4.19 Impact Factor
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