Inability to induce antibody which, neutralizes a spectrum of HIV isolates and mucosal immunity are widely recognized deficiencies of current vaccines for AIDS. This project combines the expertise and resources of six investigators at three universities and the Centers for Disease Control in collaboration with several companies in order to develop a rationale and practical procedures for addressing these limitations in order to develop improved vaccine adjuvant fori mutations for AIDS. The first short term goal (1 year) is to employ materials potentially usable in man to develop an antigen-adjuvant formulation to stimulate long lasting broadly cross reacting neutralizing antibody to HIV. We believe that this is possible because hyperimmunization of animals with glycosolated recombinant HIV gpl2O (SF-2) (Chiron) in strong adjuvants induces broadly cross reacting neutralizing antibody to conformational epitopes. Empty HIV virions (Therion) and whole killed HIV probably also contain such conformational epitopes. In previous studies, we developed nonionic block copolymers with detoxified RaLPS as potent adjuvants which influence the specificity, titer, isotype and duration of antibody responses. These materials will be used in several adjuvant formulations selected to influence thc specificity of antibody. Virus neutralization, syncytium inhibition and Western blots of multiple HIV strains (SF2, RF, MN, IIIB and fresh patient isolates) will be used to assess antibody responses. The second short term goal is to develop an adjuvant and delivery system for inducing mucosal immunity. We have shown that multiple (water-in-oil-in-water) emulsions containing copolymer L310 are effective vehicles for delivering native antigens to the lower intestinal tract and for inducing prolonged sIgA and systemic IgG and IgA antibody. They have the advantage that no denaturing solvents are used. Animals will be immunized with HIV antigens in multiple emulsions orally and in oral-parenteral combinations with and without cholera toxin to determine the optimal protocol for inducing mucosal sIgA and systemic IgG and IgA antibody. Long term goals are to continue basic research into new chemical entities, combinations and procedures to improve these responses. This will include efforts to enhance the titer and duration of neutralizing antibody, induce mucosal immunity in the genito-urinary tract, and induce cell mediated immunity against HIV. Finally studies of immunogenicity of the most promising adjuvants will be performed in hu-SCID-PBL mice.
| McNicholl, J M; Bond, K B; Ruhadze, E R et al. (1998) Enhancement of HIV type 1 vaccine immunogenicity by block copolymer adjuvants. I. Induction of high-titer, long-lasting, cross-reactive antibodies of broad isotype. AIDS Res Hum Retroviruses 14:1457-71 |
| Tomasi, M; Dertzbaugh, M T; Hearn, T et al. (1997) Strong mucosal adjuvanticity of cholera toxin within lipid particles of a new multiple emulsion delivery system for oral immunization. Eur J Immunol 27:2720-5 |
