The long-term objective of this study is to increase our understanding of the immunologic properties of molecular mimetics of a bacterial polysaccharide that also is an autoantigen. Mimetics can act as antigens, bind to antibody receptors on B cells, and elicit serum antibody responses to the nominal antigen. Yet, little is understood about the properties of antigenic mimetics that contribute to their immunogenicity. Nor is much known about the quality of the antibody response with respect to conferring protection against a pathogen. Neisseria meningitidis group B (NmB) polysaccharide is an excellent model to investigate these questions. NmB is a major cause of meningitis and sepsis. The mechanism of protection is well defined (serum antibody), and reliable assays exist for measurement of antibody binding to the polysaccharide antigen, functional antibody against the bacteria, and passive protection in an infant rat model of bacteremia. Efforts to develop a NmB vaccine have been hampered by poor immunogenicity of the polysaccharide capsule, which cross-reacts with host polysialic acid. The PI's laboratory has prepared a panel of murine monoclonal antibodies (Mabs) that react with capsular polysaccharide epitopes on NmB that are distinct from host polysialic acid. These Mabs are bactericidal and confer passive protection in animal models. The PI's hypothesis is that mimetic antigens identified by these Mabs will be able to elicit protective anti-capsular antibody responses that are specific for the pathogen, avoiding the risk of autoantibody. Further, that the best mimetics will be those that adopt relatively stable conformations. To search for such mimetics, the PI proposes to screen phage libraries displaying independently folding peptides, or search for constrained protein mimetics within immunoglobulin scaffolds (single chain variable (ScFv) anti-idiotypes). The mimetics will be investigated for their ability to elicit anticapsular antibody responses. The Ig isotype, antibody functional activity to the bacteria, and immunoglobulin variable region gene usage in response to the mimetics, will be compared to that elicited by the nominal antigen. A central question will be whether a mimetic identified with a Mab that reacts specifically with encapsulated NmB strains, but not with host polysialic acid, will elicit protective antibody responses without autoantibody activity. Additional questions will be whether the repertoire of the antibody response to the mimetic is similar or different than that elicited by the nominal polysaccharide, and what effect, if any, the antibody repertoire may have on protection. Taken together, the data will provide important information on the properties of mimetic antigens with chemical structures that are distinct from that of the nominal polysaccharide antigen. The results also may identify new candidate molecules for inclusion in a future vaccine for prevention of NmB disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Bacteriology and Mycology Subcommittee 2 (BM)
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Taylor, Christopher E,
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Children's Hospital & Res Ctr at Oakland
United States
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Moe, Gregory R; Dave, Apurva; Granoff, Dan M (2006) Molecular analysis of anti-N-propionyl Neisseria meningitidis group B polysaccharide monoclonal antibodies. Mol Immunol 43:1424-31
Moe, Gregory R; Dave, Apurva; Granoff, Dan M (2005) Epitopes recognized by a nonautoreactive murine anti-N-propionyl meningococcal group B polysaccharide monoclonal antibody. Infect Immun 73:2123-8
Lottenbach, Kathleen R; Granoff, Dan M; Barenkamp, Stephen J et al. (2004) Safety and immunogenicity of haemophilus influenzae type B polysaccharide or conjugate vaccines in an elderly adult population. J Am Geriatr Soc 52:1883-7
Ismail, Adil A; Harris, Shannon L; Granoff, Dan M (2004) Serum group a anticapsular antibodies in a Sudanese population immunized with meningococcal polysaccharide vaccine during a group A epidemic. Pediatr Infect Dis J 23:748-55
Granoff, Dan M; Harris, Shannon L (2004) Protective activity of group C anticapsular antibodies elicited in two-year-olds by an investigational quadrivalent Neisseria meningitidis-diphtheria toxoid conjugate vaccine. Pediatr Infect Dis J 23:490-7
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Harris, Shannon L; Finn, Adam; Granoff, Dan M (2003) Disparity in functional activity between serum anticapsular antibodies induced in adults by immunization with an investigational group A and C Neisseria meningitidis-diphtheria toxoid conjugate vaccine and by a polysaccharide vaccine. Infect Immun 71:3402-8
Welsch, Jo Anne; Moe, Gregory R; Rossi, Raffaella et al. (2003) Antibody to genome-derived neisserial antigen 2132, a Neisseria meningitidis candidate vaccine, confers protection against bacteremia in the absence of complement-mediated bactericidal activity. J Infect Dis 188:1730-40
Jodar, Luis; LaForce, F Marc; Ceccarini, Costante et al. (2003) Meningococcal conjugate vaccine for Africa: a model for development of new vaccines for the poorest countries. Lancet 361:1902-4

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