Group A meningococci cause massive epidemics of meningitis and sepsis in sub-Saharan Africa. Compared to other bacterial polysaccharides (PS), group A has a number of unusual properties including being highly immunogenic in infants, and priming for booster antibody responses. Also, depending on the age of the person, or antigenic stimulus (natural exposure to group A or cross-reacting organisms, or conjugated vs. unconjugated PS vaccination), the PS can elicit bactericidal or non-bactericidal group A anticapsular antibodies. The role of non-bactericidal group A anticapsular antibodies in protection against group A disease is unknown, and the molecular basis for differences in antibody functional activity are poorly understood. Our hypothesis is that differences in antibody avidity and/or fine antigenic specificity, dictated by the structure of the antibody paratope, underlie these disparities in antibody functional activity. In this proposal we will characterize naturally acquired and vaccine-induced group A anticapsular antibodies from persons of different ages living in North America or sub-Saharan Africa, two areas of the world with vastly different risks of exposure to group A meningococci. Passive antibody protective activity will be measured in an animal model of group A bacteremia that will be developed. To define the V region genes utilized by the human antibody response to group A PS, and to determine the extent of hypermutation, we will perform combinatorial repertoire cloning and expression library analyses of group A PS-specific Fab fragments. This approach will be complemented by limited amino acid sequencing of VH and VL regions of clonally purified anticapsular antibodies and determination of V region genes by mass fingerprint analysis by MALDI-TOF mass spectroscopy of H and L chains separated by 2D gels. Together, these studies will elucidate the molecular basis by which human antibodies recognize group A PS, and will identify the mechanisms underlying the age- and vaccine-related disparities in antibody protective activity. The results may lead to establishment of more reliable surrogates of protective immunity for assessment of the efficacy of new group A conjugate vaccines being developed for elimination of epidemic meningococcal disease in sub-Saharan Africa. Our proposed studies also will increase our knowledge of human antibody recognition of bacterial PS antigens in general, and explain why some anticapsular antibodies confer protection against encapsulated bacteria, while others do not.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI058122-01A1
Application #
6824998
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Taylor, Christopher E,
Project Start
2004-06-01
Project End
2008-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
1
Fiscal Year
2004
Total Cost
$504,141
Indirect Cost
Name
Children's Hospital & Res Ctr at Oakland
Department
Type
DUNS #
076536184
City
Oakland
State
CA
Country
United States
Zip Code
94609
Vu, David M; Wong, Tracy T; Granoff, Dan M (2011) Cooperative serum bactericidal activity between human antibodies to meningococcal factor H binding protein and neisserial heparin binding antigen. Vaccine 29:1968-73
Granoff, Dan M (2009) Relative importance of complement-mediated bactericidal and opsonic activity for protection against meningococcal disease. Vaccine 27 Suppl 2:B117-25
Madico, Guillermo; Welsch, Jo Anne; Lewis, Lisa A et al. (2006) The meningococcal vaccine candidate GNA1870 binds the complement regulatory protein factor H and enhances serum resistance. J Immunol 177:501-10
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
Vu, David M; de Boer, Alberdina W; Danzig, Lisa et al. (2006) Priming for immunologic memory in adults by meningococcal group C conjugate vaccination. Clin Vaccine Immunol 13:605-10
Vu, David M; Welsch, Jo Anne; Zuno-Mitchell, Patricia et al. (2006) Antibody persistence 3 years after immunization of adolescents with quadrivalent meningococcal conjugate vaccine. J Infect Dis 193:821-8
Vu, David M; Kelly, Dominic; Heath, Paul T et al. (2006) Effectiveness analyses may underestimate protection of infants after group C meningococcal immunization. J Infect Dis 194:231-7
Granoff, Dan M; Morgan, Amy; Welsch, Jo Anne (2005) Persistence of group C anticapsular antibodies two to three years after immunization with an investigational quadrivalent Neisseria meningitidis-diphtheria toxoid conjugate vaccine. Pediatr Infect Dis J 24:132-6
Granoff, Dan M; Morgan, Amy; Welsch, Jo Anne (2005) Immunogenicity of an investigational quadrivalent Neisseria meningitidis-diphtheria toxoid conjugate vaccine in 2-year old children. Vaccine 23:4307-14
Amir, Jacob; Louie, Lesile; Granoff, Dan M (2005) Naturally-acquired immunity to Neisseria meningitidis group A. Vaccine 23:977-83