The Use of Nonhuman Primate Models in HIV Vaccine Development

In April 2006, the National Institute of Allergy and Infectious Disease (NIAID)-funded HIV Vaccine Trials Network and the NIAID Division of AIDS sponsored a workshop at which nonhuman primate (NHP) researchers and clinical trial scientists with HIV vaccine research expertise discussed how to more effectively use NHPs for evaluating HIV-1 vaccine candidates. This workshop precipitated a broad discussion on what types of NHP studies should be targeted in the critical preclinical pathway for HIV-1 vaccine candidates, especially those designed to elicit HIV-1-specific T cell responses. This paper describes the two-stage NHP screening strategy for T cell–based HIV-1 vaccines that emerged from discussions among the authors during the past year and a half. While conceived prior to the recent release of results for the phase IIB trial (STEP Study) of the Merck replication-incompetent adenovirus serotype 5 (Ad5)-HIV gag/pol/nef vaccine, we think the approach outlined below will be particularly useful for preclinical evaluation of vaccine candidates in the current vaccine pipeline for two reasons. First, the proposed strategy will eliminate suboptimal vaccine candidates early in the testing process (i.e., before initiation of phase I clinical trials). Second, the strategy would provide comparative immune response data in NHPs and humans for each promising HIV-1 vaccine product, information that could help the design of future vaccine candidates. The most rigorous approach to judging the potential efficacy of HIV-1 vaccine candidates in NHP models is to determine if prototype vaccine candidates can protect the animals from the uncontrolled replication of a virulent challenge virus that recapitulates the pathogenic effects of HIV-1 in humans. At present, the most extensively studied HIV-1 vaccines are intended primarily to induce T cell immunity. While binding antibodies are reliably detected, if neutralizing antibodies are detected they are usually of low titer and narrow in their breadth. The primary expected outcome for T cell vaccines is the control of viral replication after experimental challenge with simian immunodeficiency virus (SIV) in NHPs or natural infection with HIV-1 in humans. This control should result in reduced viral load in plasma or tissue and preservation of CD4+ T cell counts, thereby preventing or delaying progression to AIDS. Progress toward developing an AIDS vaccine has been hampered by the lack of clarity about what host immune responses are required to prevent HIV-1 transmission or protect against disease progression. An immune correlate of HIV-1 vaccinemediated protection can only be identified after analysis of the results from one or more efficacy trials of effective vaccine(s). There are clear examples of vaccines that are capable of providing modest control of viral replication after SIV challenge of macaques. No single immune effector function, however, has been consistently associated with these vaccine-mediated effects. Thus, at present, protection against The Use of Nonhuman Primate Models in HIV Vaccine Development