Design of Maximally Immunogenic Vaccines from Synthetic Peptides Linked to Polymer Carriers.

摘要

Considerable and encouraging progress has been made in fulfilling the aims set forth in our original research proposal. Using relevant peptides from the circumsporozoite coat protein of P.falciparum and P.bergei, we have successfully constructed peptide-polymer conjugate of optimal immunogenicity in mice. We chose dextran as the carrier polymer of choice after experimenting with a number of carriers of different chemical and physical characteristics. The molecular parameters crucial for the construction of the immunogen were determined. These involved using a dextran carrier molecule of optimum molecular mass coupled to peptide in such a way as to yield an optimum peptide density and valence per molecule. Importantly, as we originally proposed, these conjugates were immunogenic without the use of adjuvants. The constructed antigenic conjugates were essentially of the T-cell independent type, and gave rise primarily to antibody of the IgM isotype. Building on the information gained from the determination of the optimal molecular characteristics necessary for peptide-dextran conjugates to stimulate IgM responses, we next concentrated on stimulating IgG antibody responses. This was done because protective, neutralizing antibodies are often IgG isotypes of higher affinity. We synthesized the polyproteins poly-BSA and poly-OVA for use as carriers. By themselves, these polyproteins induced IgG as well as IgM responses and immunogenicity increased with increasing multiplicity of protein. Injection protocols were optimized so as to yield maximal immunogenicity using the lowest doses feasible.