Research Project
6695694
[unreadable] DESCRIPTION (provided by applicant): The first line of host defense occurs at the mucosal surfaces as the majority of pathogens invade the host through attachment, colonization and/or penetration of these membranes. The mucosal surface is inherently designed to prevent invasion of pathogenic organisms through the development of effective immunity. The potential to generate both a systemic and local immune response makes the mucosal system an attractive site for immunization. Mucosal immunization is associated with several significant advantages including low cost and ease of administration, a reduction in adverse side effects and more widespread acceptance. However, mucosal administration of protein and peptide antigens results in poor immune responses. Aluminum-based mineral salts are the only adjuvants currently approved for use in humans by the U.S. Food and Drug Administration. Although, they have an extensive safety record, aluminum compounds are considered poor mucosal adjuvants. Successful mucosal vaccination is therefore largely dependent on the development of safe, effective mucosal adjuvants and delivery systems that overcome these inherent difficulties. This can be considered the rate-limiting step in development of novel and improved vaccines. RxKinetix Inc. has developed a mucosal vaccine delivery system based on the non-ionic block copolymer, Pluronic (r) F127 (F127), combined with an immunostimulant. F127 has been widely used in a variety of pharmaceutical formulations for its surfactant and protein stabilizing properties without adverse effects. F127-based matrices are characterized by reverse thermogelation, a feature that allows a phase transition from liquid to gel upon reaching physiological temperatures. Therefore, F127 can be administered in liquid form and can act as sustained release depot at body temperature. We have evaluated the potential use of F127 as a component of both systemic and mucosal adjuvant/delivery vehicles by studying the immune response in mice to the antigens tetanus toxoid, diphtheria toxoid and anthrax recombinant protective antigen with F 127 in combination with selected immunomodulators. These studies indicated that IgG antibody responses were significantly enhanced by these adjuvant combinations as compared to antigens mixed with the immunomodulators alone. These enhanced effects suggest that F127 may potentially be synergistic with other immunomodulating agents. In this proposal we wish to expand our present repertoire of agents co-administered with F 127 to include the nontoxic B subunits of enterotoxinogenic Escherichia coli (EtxB) and cholera toxin (CtxB) and to compare them to the previously tested adjuvants. To this purpose we will test these adjuvants in combination with pneumococcal surface protein A, a clinically relevant vaccine candidate, as mucosal antigen. These studies will allow us to select the immunomodulator that is optimally synergistic with F127 and provide the necessary information to advance this product to Phase II studies. [unreadable] [unreadable]
