title: Mucosal vaccination against serogroup B meningococci: induction of bactericidal antibodies and cellular immunity following intranasal immunization with NadA of Neisseria meningitidis and mutants of Escherichia coli heat-labile enterotoxin.
abstract: Conjugated polysaccharide vaccines protect against serogroup C meningococci. However, this approach cannot be applied to serogroup B, which is still a major cause of meningitis. We evaluated the immunogenicity of three surface-exposed proteins from serogroup B Neisseria meningitidis (App, NhhA, and NadA) identified during whole-genome sequencing. Mice were immunized intranasally with individual proteins in the presence of wild-type Escherichia coli heat-labile enterotoxin (LTwt), LTR72, a partially inactivated mutant, or LTK63, a completely nontoxic mutant, as the adjuvant. Each of the meningococcal proteins induced significant cellular responses; NhhA and NadA induced strong antibody responses, but only NadA induced bactericidal antibody when administered intranasally with mucosal adjuvants. In addition, immunoglobulin A and bactericidal antibodies were detected in the respiratory tract following intranasal delivery of NadA. Analysis of antigen-specific cytokine production by T cells from immunized mice revealed that intranasal immunization with NadA alone failed to generate detectable cellular immune responses. In contrast, LTK63, LTR72, and LTwt significantly augmented NadA-specific gamma interferon, interleukin-4 (IL-4), IL-5, and IL-10 production by spleen and lymph node cells, suggesting that both Th1 and Th2 cells were induced in vivo. The strongest cellular responses and highest bactericidal antibody titers were generated with LTR72 as the adjuvant. These findings demonstrate that the quality and magnitude of the immune responses generated by mucosal vaccines are influenced by the antigen as well as the adjuvant and suggest that nasal delivery of NadA with mucosal adjuvants has considerable potential in the development of a mucosal vaccine against serogroup B meningococci.
authors.affiliation: Centre for Molecular Microbiology and Infection, Department of Biological Sciences, Imperial College of Science, Technology and Medicine, London, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Bowe
authors.forename: Ed C
authors.initials: EC
authors.lastname: Lavelle
authors.forename: Edel A
authors.initials: EA
authors.lastname: McNeela
authors.forename: Christine
authors.initials: C
authors.lastname: Hale
authors.forename: Simon
authors.initials: S
authors.lastname: Clare
authors.forename: Beatrice
authors.initials: B
authors.lastname: Arico
authors.forename: Marzia M
authors.initials: MM
authors.lastname: Giuliani
authors.forename: Aaron
authors.initials: A
authors.lastname: Rae
authors.forename: Alan
authors.initials: A
authors.lastname: Huett
authors.forename: Rino
authors.initials: R
authors.lastname: Rappuoli
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
mesh_terms: D000818:Animals; D004768:Enterotoxins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D004926:Escherichia coli / Q000276:immunology*; D018928:Immunity, Mucosal / Q000276:immunology*; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000187:drug effects / Q000276:immunology; D051379:Mice; D009345:Neisseria meningitidis / Q000276:immunology*; D012137:Respiratory System / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D014612:Vaccines / Q000276:immunology* / Q000494:pharmacology
chemical_list: D004768:Enterotoxins; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D014612:Vaccines