Although the use of vaccines to combat infectious diseases has greatly improved human health, they are poorly immunogenic and requires multiple doses for protection. As such, vaccines are co-administered with an adjuvant to enhance immunity. Numerous classes of vaccine adjuvants have been developed and showed the desired immune response over the past several decades. Unfortunately, only a few adjuvants are considered to be sufficiently potent and clinically liable for use in humans. Alum, a mixture of aluminum hydroxide and phosphate salts, remains the dominant adjuvant with extensive safety record approved for use in human vaccination. In efforts to discover new adjuvants, an unusual class of carbohydrates, zwitterionic polysaccharides (ZPSs), containing both negative and positive charge motifs in their repeating units, were found to activate CD4+ T-cell-dependent immune responses and modulate host cytokine responses to bacterial infection. ZPSs when co-administered with antigen tetanus toxoid increase the specific antibody tier, illustrating their capacity to serve as potential vaccine adjuvants in vivo. One of the best characterized ZPSs is zwitterionic polysaccharide PS A1, isolated from capsular Bacteroides fragilis. Studies showed that glycoconjugates, generated from conjugation of PS A1 to tumor-associated mucin antigen TN, elicits high titer antibodies that are specific and selective for the TN hapten. Despite the promise of PS A1 as a potential adjuvant, obtaining it from natural sources is a complicated process of extraction and purification that results in the production of minute, relatively impure quantities and could alter its structure. Since FDA has strict regulation regarding the purity and quality of vaccine adjuvants for use in humans, a synthetic source must be developed for PS A1 to be utilized as a clinically relevant adjuvant. The main goal of this proposal will address these challenges through the chemical synthesis of natural and non-natural PS A1 oligosaccharides with defined repeating units utilizing our recently developed nickel-catalyzed ?-glycosylation methodologies. This proposed effort will deliver defined PS A1 molecules in high purity without batch-to-batch variation and provide tools for studying their roles as adjuvants and exploring structure-relationship activity (SAR) studies. 1
The success of vaccination requires the generation of a strong immune response to the inoculated antigens able to provide long-term protective immunity against infectious diseases. To accomplish this goal often requires the addition of vaccine adjuvants, substances that do not induce immune response against themselves, but significantly enhance the immunogenicity of co-administered antigens. The goal of this proposal involves the development of carbohydrate immunostimulants which hold promise of yield novel vaccine adjuvants for use in humans to combat a variety of infectious diseases. 1
