This application builds upon the investigators' prior experience developing live attenuated Salmonella-based mucosal vaccines for delivery of HIV antigens (Ag). Since most cases of HIV are sexually transmitted, mucosal immunity is likely to be critical in preventing infection. Salmonella is an attractive vaccine vector because it elicits potent mucosal and systemic immune responses to cloned foreign Ag in humans and in animal studies. Such vaccines also offer practical and financial advantages over parenterally administered vaccines. The primary objective of the proposed studies is to optimize an experimental murine system for mucosal immunization of mice using attenuated Salmonella which express subunits of HIV-1 envelope (env), demonstrated in preliminary studies to elicit both cellular and humoral mucosal responses to HIV. Env has been selected as an immunogen because it contains neutralizing determinants for primary HIV isolates.
The specific aims of the application are to carry out: (1) genetic modification of existing recombinant Salmonella-env vaccines to enhance immunogenicity - approaches will include modification of env expression regulation, modification of env compartmentalization, and evaluation of alternative genetic strategies of virulence attenuation; (2) evaluation of novel mucosal adjuvants - the applicants plan to assess coexpression of bacterial pili which target gut-associated lymphoid tissues, coadministration with E. coli heat-labile enterotoxin subunit, or co-administration with immunomodulatory retinoids, and (3) comparison of different routes and schedules of immunization - oral, intranasal, intravaginal, and intrarectal routes will be investigated, along with protocols which combine mucosal priming with parenteral boosting. In each of the of the proposed experiments, vaccines will be examined for their ability to elicit humoral and cellular immune responses to HIV and Salmonella epitopes in mucosal and systemic compartments. Mucosal immunization has been shown to mediate protection against polio, influenza and typhoid in humans. This proposal has been designed to identify promising effective strategies to augment mucosal immunity to HIV vaccines that will be suitable for subsequent evaluation in human studies.
| Diri, E; Lipsky, P E; Berggren, R E (2000) Emergence of systemic lupus erythematosus after initiation of highly active antiretroviral therapy for human immunodeficiency virus infection. J Rheumatol 27:2711-4 |
