Rational design of anti-meningococcal polysaccharide conjugate vaccines.

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With the exception of group B meningococci, successful polysaccharide (capsule)-protein conjugate vaccines are available to prevent the most common causes of bacterial meningitis in humans. Due to the random coupling methods of conjugate vaccine production, a complete description of the molecular attributes of a successful vaccine has not been accomplished. We propose a rational method of conjugate vaccine production in which the structure of the immunodominant components of the protein carrier are preserved after coupling, and the valence and position of the carbohydrate units varied in a defined manner. Methods to accomplish this goal include cysteine mutagenesis (removal or addition), coupling through a spacer with low immunogenicity, and testing efficacy in the murine immunisation model. Direct assay of IgG and the bactericidal titer of the immune sera in the presence of complement will determine the protective antibody response. The immunogenic group C meningococcal capsule will serve as the positive test case. The relatively nonimmunogenic group B capsule will test whether polysaccharide valence or position of attachment to the carrier augments the immunological response. The results will provide an experimental scaffold for determining the molecular attributes of a successful vaccine and could lead to marked improvements in immunogenicity over vaccines that are currently being used to prevent bacterial meningitis.