Neisseria meningitidis (Nm) is a major cause of meningitis and septicemia. Serogroup B (NmB) strains account for 30 to 80 percent of invasive disease in different populations. Capsular polysaccharide-protein conjugate vaccines are available against all of the major serogroups except for NmB, which cross-reacts with host antigens. A protein antigen-based vaccine (referred to as 4CMenB) that targets NmB strains recently was licensed in Europe. However, failure of 4CMenB vaccination to decrease asymptomatic NmB carriage was instrumental in a preliminary decision by policy makers not to recommend routine vaccination in the UK. While considerable data indicate that glycoconjugate vaccines prevent both invasive disease and decrease nasopharyngeal colonization, there are important gaps in knowledge about the underlying mechanisms, and how protein-based vaccines can be improved to decrease carriage more effectively. Our hypotheses are that improving serum antibody quantity and quality (i.e, avidity, breadth of epitope reactivity, and functional activity) and/or targeting additional antigens, will increase the ability of NmB vaccine to decrease carriage. The major challenges that impede investigation of these questions are, 1) the specificity of Nm for the human host, and 2) the lack of appropriate in vitro and in vivo models. For example, human CEACAM1 specifically mediates adhesion of Nm to airway epithelial cells, and human complement factor H (fH) specifically down-regulates complement activation and permits meningococci to evade bacteriolysis in humans. Our laboratory has developed a broadly protective meningococcal native outer membrane vesicle vaccine (NOMV) from mutants with genetically attenuated endotoxin and over-expressed factor H binding protein (fHbp). Data indicate that the quality of the antibody responses to fHbp when over-expressed in an NOMV vaccine is greater than to recombinant fHbp vaccines. To determine the effect of NOMV-fHbp immunization on carriage, and to identify additional antigens that might be added to the vaccine to decrease carriage, we propose to: 1) develop in vitro airway models of meningococcal colonization, 2) generate a transgenic mouse model of human colonization that expresses both human CEACAM1 and human fH, and 3) use these model systems to evaluate the ability our NOMV-fHbp vaccine and new antigens to prevent colonization. The results will increase our understanding of the mechanisms by which vaccination decreases meningococcal carriage, and will further development of a broadly protective serogroup B meningococcal vaccine that prevents both invasive disease and asymptomatic carriage.
Limiting meningococcal carriage is an important feature for vaccines for prevention of transmission and disease in large populations. This proposal aims to develop further a broadly protective serogroup B vaccine created by our laboratory by investigating whether it can also prevent carriage, and whether the vaccine can be improved to prevent carriage. These goals will be accomplished by developing novel in vitro and in vivo models to measure effects of vaccination on carriage, and testing whether the addition of new antigens enhances protection against carriage.
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|Lewis, Lisa A; Vu, David M; Vasudhev, Shreekant et al. (2013) Factor H-dependent alternative pathway inhibition mediated by porin B contributes to virulence of Neisseria meningitidis. MBio 4:e00339-13|
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|Rossi, Raffaella; Granoff, Dan M; Beernink, Peter T (2013) Meningococcal factor H-binding protein vaccines with decreased binding to human complement factor H have enhanced immunogenicity in human factor H transgenic mice. Vaccine 31:5451-7|
|Granoff, Dan M; Ram, Sanjay; Beernink, Peter T (2013) Does binding of complement factor H to the meningococcal vaccine antigen, factor H binding protein, decrease protective serum antibody responses? Clin Vaccine Immunol 20:1099-107|
|Granoff, Dan M (2013) Commentary: European Medicines Agency recommends approval of a broadly protective vaccine against serogroup B meningococcal disease. Pediatr Infect Dis J 32:372-3|
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