Subunit and synthetic AIDS vaccines will require the use of adjuvants to boost their immunogenicity, especially to induce potent cell-mediated responses. Alum, the only adjuvant approved for human use, is less than ideal.
The aim of this proposal is to study the ability of a highly purified carbohydrate -- an immunomodulatory algal glucan, AG -- to serve as an adjuvant in enhancing the immune response of animals to proteins that exhibit low immunogenicity, and to elucidate the mechanism by which adjuvanticity occurs. The investigators can produce pure forms of this new glucan form Euglena gracilis in high yield, and have obtained preliminary evidence of AG's value as an adjuvant and of its high therapeutic index. In the studies proposed herein, they will administer mixtures of various forms of AG, or alum, with subunit antigens of HIV-1, including gp120, gp160, and synthetic peptide 254-274, 303-330, 428-443, and 584-609 of gp120 to rabbits to determine the anti-HIV-1 neutralizing antibody titers, and to mice gain insights into antigen-induced lymphocyte activation and cytotoxic T-lymphocyte (CTL) development. Because of the lack of an adequate and convenient animal model for studying protection against HIV-1 infection, they will first assess the adjuvanticity of AG in a murine herpes simplex virus type 1 model. They will evaluate the adjuvant potential of various forms of Ag by examining the humoral and cell-mediated immune responses in vitro and determining the success of immunization with antigen/AG conjugates in challenges in mice. Specifically, they will determine serum-neutralizing antibody titers, antigen-induced lymphocyte proliferation an II-2 production, CTL development, and protection from HSV challenge in vivo. These studies with the HSV model should permit the applicants to select the preferred forms of AG for use as adjuvants. They will next confirm the adjuvanticity of the AG in HIV-1 studies and optimize HIV-antigen /AG conjugates. Another objective of the proposal is to study the mechanism by which AG enhances immunity. This work will focus on the effect of Ag on antigen uptake and presentation by macrophages. Although immunopotentiation towards HIV is their immediate objective, the investigators expect that the outcome of this work will help them understand how various forms of AG enhance the immune response. This information will in turn help design AG-based adjuvants for use with future HIV-1 vaccines as well as a wide range of antigens to confer protective immunity against a number of infectious agents.
| Mohagheghpour, N; Dawson, M; Hobbs, P et al. (1995) Glucans as immunological adjuvants. Adv Exp Med Biol 383:13-22 |
