Conjugate-induced Polysaccharide Antibodies

Child Health And Human Development

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Abstract

Surface polysaccharides of Gram-negative enteric pathogens, in the form of capsule or lipopolysaccharide, are both essential virulence factors and protective antigens. The immunogenicity of these polysaccharides were enhanced by binding to carrier proteins. Sequential clinical studies in adults and in children in Vietnam, an area with a high attack rate of typhoid, showed that the capsular polysaccharide (Vi) conjugates bound to the recombinant Pseudomonas aeruginosa exoprotein A (rEPA) elicited high responses against typhi. In a Phase III trial, About 12,000 2-5 years old children injected with the conjugate vaccine showed no significant side reaction. The efficacy of Vi-rEPA was 89% after 48 months surveillance. Chidren in the pacebo group were given the conjugate vaccine 2.5 years later. Salmonella paratyphi A, the second most common cause of enteric fever in Southeast Asia, conjugate vaccine was found to be safe and immunogenic in adults, teenagers and then 2-4 year old children. In southeast China, cases of paratyphi A has exceeded those of typhi. A phase III clinical trial is planned. Escherichia coli O157, an emerging pathogen, causes hemolytic uremic syndrome in young children. Phase 1 study of E. coli O157 O-specific polysaccharide-rEPA conjugate demonstrated safety and immunogenicity in adult volunteers. The phase II study of E. coli O157 conjugate, 52 children 2-5 years old children were recruited. Children injected once or twice showed that the vaccine was safe. Preliminary immunogenicity data showed children responded uniformly with greater than 10 fold rise of anti-LPS IgG 6 weeks after the first injection. Non-toxic shiga toxin I and II are purified from mutant E. coli O157 and will be conjugated with O-specific polysaccharide for a bivalent vaccine. The major reservoir of E.coli O157 is cattle. LPS-protein conjugate showed to be immunogenic in cattle and a challenge study showed an inversed correlation between the serum anti-LPS IgG and the level of colonization of E. coli O157 at rectal. Vibrio cholera O1 and O139 are the major sero types in cholera infections. Conjugates synthesized with capsular polysaccharide of O139 and O-specific polysaccharide of LPS of O1 elicited vibriocidal antibodies in mice. Detoxified LPS from both Inaba and Ogawa serotypes have been used as a base for conjugate vaccine. In animal study, the conjugates elicited higher antibody level than LPS alone. A chemical synthesized O-specific polysaccharide for Ogawa will be prepared and conjugated to protein carrier. The immunogenicity of cholera vaccine prepared with naturally purified or chemically synthesized O-specific polysaccharide will be compared. Clinical trials of these conjugates are planned. One of the most common Salmonella infection in developed country is Salmonella typhimurium. Antibiotic resistant strains have been common in disease isolates. We have compared the O-specific polysaccharide structure of the most common and antibiotic resistant strains. The O-acetyl group on the abequose is found to be a major antigenic site and an immunodominant determinant. Strains that are O-acetyl positive reacted with antibodies from O-acetyl negative strains poorly. Selection of strains for vaccine preparation will therefore rely on the epidemiology survey and bacteriology identification. Campylobacter jejuli infection is one of the most common enteric infection in the US and around the world. The most common type in US is type 2. Campylobacter is microaerophilic and fermentation in liquid media has been difficult. Various media and fermentation conditions was studied and moderate growth in liquid media were observed. Chemical analysis showed that the surface polysaccharide contains keto and does not contain colominic acid. From the size and the staining properties, we concluded that the polysaccharide is an oligo LPS.