Showing papers by "Jorge Flores published in 2008"

The Use of Nonhuman Primate Models in HIV Vaccine Development

Abstract: 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 vaccine-mediated 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 disease progression in NHP studies is the best surrogate measure of vaccine efficacy that can be used in preclinical assessments of vaccine approaches. An assumption that underlies the current approach to HIV-1 vaccine testing has been that vaccine immunogenicity is an essential surrogate measure of vaccine efficacy but, as noted above, the validity of this assumption is unknown. Some HIV-1 vaccine candidates have moved into phase I clinical testing with positive immune responses in NHPs, but without challenge data (Figure 1). Others have been tested only in rodents, whose immune responses have not reliably predicted either the consistency or level of immune responses in people. Overall, many HIV-1 vaccine candidates that are immunogenic in animals have elicited only weak and/or transient immune responses in humans. Critically, only a very few vaccine candidates have demonstrated any efficacy in NHP challenge models using pathogenic SIV isolates, the model that best recapitulates the key features of HIV-1 infection and pathogenesis according to the following criteria: (1) persistent, progressive systemic infection after experimental inoculation; (2) use of the CCR5 coreceptor; (3) acute depletion of memory CD4+ T cells, especially from mucosal sites; and (4) establishment of an initially disease-free plateau phase in the majority of animals, followed by (5) progression to AIDS over a period of several months to years. The key requirements, relevance, and limitations of specific NHP models for evaluating HIV-1 vaccine candidates have recently been reviewed in detail [1–10]. Figure 1 Current Preclinical Testing Strategy for Candidate HIV-1 Vaccines It is important to recognize that, in the past, there has been a reluctance to give NHP models any “gatekeeper” status in the HIV-1 vaccine testing pathway, out of concern that potentially effective HIV-1 vaccine candidates might thereby be missed. Specific concerns include the imperfect (albeit close) recapitulation by the SIV-infected macaque model of HIV-1 infection of humans, and the possibility that some experimental challenges used in NHP models might be more stringent than is relevant for typical transmissions of HIV-1 between humans. The last few years, however, have seen the development of vaccines that are more consistently immunogenic in NHPs. Hence, identifying immunogens with increased immunogenicity and screening out those vaccine candidates likely to have low efficacy has now become a much higher priority element of the preclinical HIV-1 vaccine evaluation process. The cost and the regulatory requirements associated with the manufacture of vaccines for human clinical trials are additional factors; specifically, the number of HIV-1 vaccine candidates now available for phase I testing has increased, resulting in the need to develop cost-effective strategies to filter the vaccine pipeline. Thus, the role of NHP models in the process of selecting HIV-1 vaccines for clinical trials is now being reconsidered.

Improving defences at the portal of HIV entry: mucosal and innate immunity.

Abstract: The authors discuss the key scientific issues in mucosal and innate immunity related to immune protection against HIV infection.

Broadening inclusion of vulnerable populations in HIV vaccine trials

Abstract: The urgent need for a preventive HIV vaccine, as well as the complexities of its development, calls for timely and reinforced efforts to ensure vaccine licensure for use in a broad range of at-risk populations from the outset. Such an integrated strategy to HIV vaccine development should include infants of HIV-infected women, adolescents and injection drug users. A safe and effective HIV vaccine licensed for use in these populations, in addition to sexually active adults, would probably have the most timely and profound impact on the HIV/AIDS pandemic. Advanced clinical development of HIV vaccines in these vulnerable populations imposes particular scientific, operational and ethical challenges. Recent developments, including the early termination of a Phase IIb trial, present additional previously unanticipated challenges.