9th Conference on Retroviruses and Opportunistic Infections Seattle, Washington - February 24 -February 28, 2002

Conf Retroviruses Opportunistic Infect 2002 Feb 24-28;9:abstract no. L5
Emilio Emini for the Merck HIV-1 Vaccine Research Team
Merck Res. Labs., West Point, PA

BACKGROUND: The importance of the host cellular immune response for control of HIV-1 infection in seropositive humans is well-established. Although a prophylactic vaccine to prevent HIV-1 infection should preferably elicit both antiviral cellular and humoral immune responses, an immunogen that consistently induces broadly reactive anti-HIV-1 neutralizing antibodies has yet to be defined. Therefore, a substantial effort is currently focused on the development and assessment of immunogens that can elicit specific cellular immunity.

METHODS: Evaluation of the anti-HIV-1 cellular immune response in seropositive humans showed that the quantitatively strongest responses are directed against the gag, pol, and nef gene products. In addition, evaluation of these responses in human populations infected with different clades of the virus suggests that much of the cellular immune response can be directed across clades. Our research efforts have concentrated on the use of replication-defective adenoviral type 5 vectors for inducing specific cellular immunity. In comparative non-human primate studies, adenoviral vectors expressing the HIV-1 gag gene have proven to be particularly effective in eliciting both gag-specific CD8+ cytotoxic and CD4⁺ helper cellular responses. Preexisting humoral immunity to the vector could be overcome either through the use of a high vector dose or by priming the immune response using a "naked" DNA vector that also expressed gag. Rhesus monkeys immunized with an SIV gag-expressing adenoviral vector experienced a substantially attenuated SHIV infection with long-term suppression of virus replication following intravenous challenge with a large SHIV inoculum. Prototypic DNA and adenoviral type 5 vector vaccines expressing a consensus clade B HIV-1 gag gene are currently in phase I clinical trials to assess safety and immunogenicity.

RESULTS: These studies, performed in both HIV-1 seronegative and seropositive volunteers, involve assessment of escalating doses of the adenoviral vector vaccine used for both priming and boosting, as well as for boosting following priming with the DNA vector vaccine. The data obtained from these studies will provide an estimation of the adenoviral vector's immunogenicity in humans, and whether any immunogenicity suppression that may be mediated by preexisting anti-vector immunity can be overcome. The data will also provide information regarding the breadth of the elicited cellular response; a broad response is essential to provide a barrier to HIV-1 immune evasion that may result from selection of altered antigenic determinants. An early appraisal of potential cross-clade responses will also be obtained.

CONCLUSIONS: The results of the phase I studies will eventually be used to guide the composition and dose of the vaccine that will be studied in phase II trials for expanded assessment of immunogenicity in HIV-1 uninfected humans and for assessment of therapeutic potential in HIV-1 seropositive individuals.

020224
L5

Copyright © 2002 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.