HIV vaccine development using recombinant coxsackieviruses

迄今为止，没有一种单一的疫苗策略能够引起所认为的全部免疫反应

To date, no single vaccine strategy is capable of eliciting the entire spectrum of immune responses deemed necessary for an effective HIV vaccine. The long-term goal of this study is to develop a new platform for creating recombinant vaccines, using a targeted epitope strategy, capable of inducing diverse HIV-specific immune responses. The overall hypothesis is that expression of targeted HIV epitopes, in appropriate immunological contexts, will elicit a wide range of immune responses. The advantage of a targeted epitope strategy is that expression of structurally constrained, conserved, immunogenic peptides in an HIV vaccine will minimize the problem of escape mutants. The proposed study is relevant for HIV vaccines because it describes proof-of-principle experiments to address two critical issues in vaccine development i.e.the need for diverse immune responses and the development of escape mutants. The proposal focuses on 1) Construction of CVB4/HIV recombinants that elicit gag p24-specific T helper cell responses, 2) Construction of a CVB4/HIV recombinant that elicits gag p24-specific CTL responses, 3) Construction of CVB4/HIV recombinants that elicit virus neutralizing antibodies, and 4) Evaluation of the immunogenicity of a cocktail of CVB4/HIV recombinants administered via the oral or intranasal route. The immunogenicity of recombinants expressing T helper cell epitopes will be evaluated using a T cell proliferation assay and the ELISPOT assay. The immunogenicity of recombinants expressing CTL epitopes will be monitored using the ELISPOT assay. The immunogenicity of recombinants expressing B cell epitopes will be assessed by ELISA and by a virus-neutralization assay. Recombinants that induce the strongest immune response in each category will be grouped to make a vaccine cocktail. Several adjuvants will be tested to identify adjuvants that enhance the breadth and strength of HIV-specific immune responses induced by the vaccine cocktail. Relevance to public health: A preventive vaccine is urgently needed to halt the global spread of HIV-1. Current vaccine candidates are promising in that they are able to induce some of the necessary immune responses. New vaccine strategies are needed to increase the repertoire of immune responses and to overcome the problem of escape mutants. The present proposal describes a new approach to augment HIV-specific immune responses and to minimize the problem of escape mutants.