There remains an urgent need to develop vaccines to prevent meningococcal infection. The aim of this application is to assess the efficacy of protein vaccine candidates that have been demonstrated to be involved in meningococcal carriage. We have recently identified ten genes required for colonisation of the human host. Mutants lacking these genes fail to colonise the nasopharyngeal explant model, which expresses the diversity of cell types and environments the bacterium encounters during the early stage of infection. Three of the genes are predicted to encode novel surface expressed proteins. We will examine the vaccine candidacy of these surface expressed proteins involved in colonisation. We will generate polyclonal antibodies against each candidate, and determine whether any candidate elicits bactericidal antibody responses. Next the conservation of vaccine candidates will be assessed in a panel of characterised meningococcal isolates, and we will determine whether the candidates are recognised by individuals during the course of meningococcal infection by performing immunoblots using sera from convalescent patients. Finally, to evaluate the protective efficacy of the candidates, each will be examined for its ability to induce protective immunity against live bacterial challenge in a murine model.
This proposal leads directly from a currently funded Meningitis Research Foundation project, and seeks to apply recently obtained knowledge on meningococcal carriage to the development of vaccines.
Results from this study have been published in scientific journals as follows:
Sun YH, Exley R, Li Y, Goulding D, Tang CM.
Identification and characterization of genes required for competence in Neisseria meningitidis.
J Bacteriol 2005 May;187(9):3273-6.
Exley RM, Shaw J, Mowe E, Sun YH, West NP, Williamson M, Botto M, Smith H, Tang CM.
Available carbon source influences the resistance of Neisseria meningitides against complement.
J Exp Med 2005 May 16;201(10):1637-45.
Sun YH, Li Y, Exley RM, Winterbotham M, Ison CA, Smith H, Tang CM.
Identification of novel antigens that protect against systemic meningococcal infection.
Vaccine 2005 Jul 14;23(32):4136-41.
Li Y, Winterbotham M, Mowe E, Gorringe AR, Tang CM,
Immunization with live Neisseria lactamica protects mice against meningococcal challenge and can elicit serum bactericidal antibodies.
Infect Immun 2006 Nov;74(11):6348-55. Epub 2006 Sep 11.
Schneider MC, Exley RM, Chan H, Feavers IM, Kang YH, Sim RB, Tang CM.
Functional significance of factor H binding to Neisseria meningitidis.
J Immunol 2006 Jun 15;176(12):7566-75.
Carpenter EP, Corbett A, Thomson H, Adacha J, Jenson K, Bergeron J, Kasampalidis I, Exley R, Winterbotham M, Tang CM, Baldwin GS, Freemont P. AP endonuclease paralogues with distinct activities in DNA repair and bacterial pathogenesis
EMBO J 2007 Feb 22; [Epub ahead of print].