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Surface polysaccharides of pathogenic bacteria, including capsular polysaccharides (CP) and the O-specific polysaccharide (O-SP) of lipopolysaccharides (LPS), function both as essential virulence factors and protective antigens. Covalent binding of these saccharides to medically useful proteins to form conjugates increases their immunogenicity and confers T-cell dependence, making them suitable vaccines for infants and children. This project, previously directed by Dr. Rachel Schneerson, has evaluated the safety, immunogenicity and efficacy of several constructs of shigella vaccine. The O-SP of Shigella sonnei bound to recombinant non-toxic Pseudomonas aeruginosa exoprotein A (rEPA) had an efficacy of over 70 percent in young adults. This conjugate and that of S. flexneri 2a bound to the succinylated exoprotein A (rEPA-succ) were safe and induced IgG antibodies to the homologous LPS in 1- to 4-year-olds. A randomized, blinded, Phase 3 study of the conjugates in 1- to 4-year-olds, with each conjugate serving as a control for the other, showed the vaccines to be safe. Immunogenicity and efficacy of the S. sonnei conjugate were age-related with no efficacy in 1- to 2-year-olds but with about 70 percent in 3- to 4-year-olds.<P> As with previously tested constructs, fold increases in antibody levels were similar to those for adults, but the actual achieved levels were lower. There were too few cases of S. flexneri 2a infection for statistical analysis. Protection from non-vaccine types of S. flexneri, in S. flexneri 2a conjugate recipients, was noticed, including S. flexneri type 6, the most common isolate during the study. The overall efficacy of S. flexneri 2a vaccine against all S. flexneri non-type 2a was 44.9%, and against type 6 alone was 51.7%; both these values were not statistically significant.The applicability of this approach to S. flexneri types 2a and 6 and S. dysenteriae type 1 has been investigated. <P>The structures isolated from these bacteria containing core plus 1-4 O-SP (O-SPC) as repeat units (RU), were analyzed by NMR and mass spectroscopy. The first RU attached to the core of S.flexneri 2a and 6 LPSs were different from the following RUs in their O-acetylation and/or glycosylation. Conjugates of core plus more than 1 RU were needed to induce LPS antibodies in mice. These antibody levels were comparable to those induced by the full length O-SP conjugates. In S. dysenteriae type 1, the first RU was identical to the following RUs, with the exception that the GlcNAc was bound to the core in the beta-configuration, while in all other RUs it was in the alpha-configuration. In spite of this difference, conjugates of S. dysenteriae type 1 core with 1, 2 or 3 RUs induced LPS antibodies in mice with levels similar to those induced by the synthetic S. dysenteriae type 1 saccharide conjugates and statistically higher than those of the full size O-SP conjugates. O-SPC conjugates are easy to prepare, characterize, and standardize. <P>More highly immunogenic vaccine candidates were prepared using the model of synthetic S. dysenteriae type 1 saccharides-protein conjugates. Low molecular mass O-SP-core (O-SPC) fragments containing an average of 3-4 repeat units of S. sonnei O-SP were isolated and bound to the recombinant non-toxic exoprotein B of Clostridium difficile. Levels of IgG anti-S. sonnei LPS induced by these conjugates in young outbred mice were significantly higher than those induced by the full-length O-SP conjugates.<P> A clinical lot of this vaccine candidate was prepared and its safety and immunogenicity were evaluated in healthy adults in Israel. Sixty adult volunteers meeting the inclusion criteria have been vaccinated. No adverse reactions were noted. Blood samples were collected at pre-, one week, and 4 weeks-post injection from all vaccinees (180 blood samples in total). The last blood sampling at 26-week post-injection will be completed by the end of November 2012. Antibody assays will be completed 2 months later and analyses and writing of the final report will take another 2-3 months.

Schneerson, Rachel
DHHS/NIH - National Institute of Child Health and Human Development
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