Alpha-Like Proteins in Immunity to Group B Streptococcus

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Infection by group B streptococci (GBS) is a leading cause of neonatal morbidity and mortality. Infants lacking sufficient humoral immunity who are exposed perinatally to this organism through the birth canal or via ascending maternal infection are at risk for developing disease at a rate of up to 1.8/1000 live births. Death or serious neurologic sequelae occur in many affected infants.
Historically, serotypes Ia, Ib, II, and III have been most prevalent among disease cases; recently, type V has emerged as an important disease-causing strain.</p>
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Prevention of neonatal GBS disease through maternal immunization is a promising area of active investigation. Although antibody to type-specific capsular polysaccharides is protective, a vaccine composed of type III polysaccharide alone elicited suboptimal immunity. </p>
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Recent attention has focused on the development of a capsular polysaccharide-GBS surface protein conjugate vaccine as a means of providing both an enhanced immune response and protection against a variety of serotypes.
Although relatively little is known about GBS surface proteins, previous work has demonstrated the presence of distinct protein antigens on GBS strains of various serotypes which share the properties of a ladder-like pattern on Western blot and resistance to trypsin degradation. Several of these proteins elicit protective immunity in animal models. One or more of these proteins may be an ideal candidate for a conjugate vaccine. </p>
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A major scientific goal of this project is to purify and characterize related proteins from two emerging GBS serotypes, type V and type VIII. Preliminary work has demonstrated the presence of these proteins. </p>
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Purification will be optimized using traditional methods of protein chemistry. Characterization of these antigens will be achieved at the biochemical, immunochemical, and genetic level. This work will lead to a better understanding of the potential role in virulence or immunity of this family of proteins, and will enable identification of a candidate protein for a conjugate vaccine. </p>
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The further scientific goal of this project is to construct a polysaccharide-conjugate vaccine using one or more of these proteins coupled to type III polysaccharide. The training aim of this project is to prepare the applicant for a career in vaccine science by providing the background and skills in protein chemistry, immunology, and molecular genetics which are fundamental to the development of vaccines. </p>
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Phase Il of this award will emphasize the broad training of the applicant in the areas outlined above. This will be accomplished through didactic training as well as through bench work directed at optimization of purification of these antigens, development of monoclonal antibodies, identification of protective antigens through animal studies, and development of a type V and type VIII GBS DNA library.</p>
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During Phase II, the applicant will undertake sequencing of the genes encoding these proteins and synthesis of the recombinant protein-polysaccharide vaccine.</p>