N. meningitidis is an important cause of meningitis and sepsis. Conventional approaches to develop a vaccine for prevention of disease caused by capsular group B strains, which account for 30-80% of all cases, have been largely unsuccessful, and therefore there is a need for the identification of new vaccine candidates. To date, all candidate antigens have been identified using organisms grown in artificial media or on epithelial or endothelial cell monolayers. Little is known, however, about the gene expression profile of N. meningitidis during infection in vivo. Our hypothesis is that N. meningitidis grown in the infant rat model of bacteremia or in human whole blood will show specific genes that are up-regulated or activated compared to those expressed in artificial culture. Furthermore, genes that are up-regulated during invasive infection that encode novel proteins that are conserved in N. meningitidis, and that are predicted to be surface-accessible, will be promising vaccine candidates. We propose to use quantitative real-time PCR to study the temporal gene expression profile of N. meningitidis isolated from the bloodstream of infected infant rats and from the human blood infection model at different time-points, and also to compare the respective expression profiles with those of bacteria grown in broth. We will evaluate the immunogenicity of the recombinant proteins as purified His-tagged or GST-fusion proteins, and as """"""""native"""""""" proteins in E. coli outer membrane vesicles. Antisera from immunized mice will be analyzed by ELISA, FACS, serum bactericidal activity, and passive protection in the infant rat model. The proposed studies may identify new antigens capable of eliciting broadly protective antibody for prevention of N. meningitidis disease, including group B strains for which there is currently no vaccine available. Also, characterization of gene expression in an in vivo model will lead to a better understanding of meningococcal pathogenesis. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI061533-02
Application #
6897257
Study Section
Special Emphasis Panel (ZRG1-IDM-N (90))
Program Officer
Taylor, Christopher E,
Project Start
2004-06-01
Project End
2006-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
2
Fiscal Year
2005
Total Cost
$240,150
Indirect Cost
Name
Children's Hospital & Res Ctr at Oakland
Department
Type
DUNS #
076536184
City
Oakland
State
CA
Country
United States
Zip Code
94609
Granoff, Dan M (2010) Review of meningococcal group B vaccines. Clin Infect Dis 50 Suppl 2:S54-65
Pajon, Rolando; Beernink, Peter T; Harrison, Lee H et al. (2010) Frequency of factor H-binding protein modular groups and susceptibility to cross-reactive bactericidal activity in invasive meningococcal isolates. Vaccine 28:2122-9
Welsch, Jo Anne; Ram, Sanjay; Koeberling, Oliver et al. (2008) Complement-dependent synergistic bactericidal activity of antibodies against factor H-binding protein, a sparsely distributed meningococcal vaccine antigen. J Infect Dis 197:1053-61
Flitter, Becca A; Ismail, Adil; Vu, David et al. (2007) Group A antibody persistence five years after meningococcal polysaccharide vaccination in the Sudan. Hum Vaccin 3:135-8
Welsch, Jo Anne; Granoff, Dan (2007) Immunity to Neisseria meningitidis group B in adults despite lack of serum bactericidal antibody. Clin Vaccine Immunol 14:1596-602
Beernink, Peter T; Leipus, Arunas; Granoff, Dan M (2006) Rapid genetic grouping of factor h-binding protein (genome-derived neisserial antigen 1870), a promising group B meningococcal vaccine candidate. Clin Vaccine Immunol 13:758-63
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
Hou, Victor C; Koeberling, Oliver; Welsch, Jo Anne et al. (2005) Protective antibody responses elicited by a meningococcal outer membrane vesicle vaccine with overexpressed genome-derived neisserial antigen 1870. J Infect Dis 192:580-90