title: Heat shock protein complex vaccines induce antibodies against Neisseria meningitidis via a MyD88-independent mechanism.
abstract: BACKGROUND
  Neisseria meningitidis are common colonizers of the human nasopharynx. In some circumstances, N. meningitidis becomes an opportunistic pathogen that invades tissues and causes meningitis. While a vaccine against a number of serogroups has been in effective use for many years, a vaccine against N. meningitidis group B has not yet been universally adopted. Bacterial heat shock protein complex (HSPC) vaccines comprise bacterial HSPs, purified with their chaperoned protein cargo. HSPC vaccines use the intrinsic adjuvant activity of their HSP, thought to act via Toll-like receptors (TLR), to induce an immune response against their cargo antigens. This study evaluated HSPC vaccines from N. meningitidis and the closely related commensal N. lactamica.
  
  
  RESULTS
  The protein composition of N. lactamica and N. meningitidis HSPCs were similar. Using human HEK293 cells we found that both HSPCs can induce an innate immune response via activation of TLR2. However, stimulation of TLR2 or TLR4 deficient murine splenocytes revealed that HSPCs can activate an innate immune response via multiple receptors. Vaccination of wildtype mice with the Neisseria HSPC induced a strong antibody response and a Th1-restricted T helper response. However, vaccination of mice deficient in the major TLR adaptor protein, MyD88, revealed that while the Th1 response to Neisseria HSPC requires MyD88, these vaccines unexpectedly induced an antigen-specific antibody response via a MyD88-independent mechanism.
  
  
  CONCLUSIONS
  N. lactamica and N. meningitidis HSPC vaccines both have potential utility for immunising against neisserial meningitis without the requirement for an exogenous adjuvant. The mode of action of these vaccines is highly complex, with HSPCs inducing immune responses via both MyD88-dependent and -independent mechanisms. In particular, these HSPC vaccines induced an antibody response without detectable T cell help.
authors.affiliation: Mucosal Immunology, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia; Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Science, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Jia Xi
authors.initials: JX
authors.lastname: Han
authors.affiliation: Mucosal Immunology, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia; Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Science, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Garrett Z
authors.initials: GZ
authors.lastname: Ng
authors.affiliation: ImmunoBiology Ltd., Babraham Research Campus, Babraham, Cambridge, UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Cecchini
authors.affiliation: Mucosal Immunology, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia; Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Science, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Yok Teng
authors.initials: YT
authors.lastname: Chionh
authors.affiliation: Mucosal Immunology, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia; Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Science, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Saeed
authors.affiliation: Division of Infectious Disease Control, Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Lisbeth M
authors.initials: LM
authors.lastname: Næss
authors.affiliation: ImmunoBiology Ltd., Babraham Research Campus, Babraham, Cambridge, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Joachim
authors.affiliation: ImmunoBiology Ltd., Babraham Research Campus, Babraham, Cambridge, UK.
authors.forename: Lucy E
authors.initials: LE
authors.lastname: Blandford
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3010, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Strugnell
authors.affiliation: ImmunoBiology Ltd., Babraham Research Campus, Babraham, Cambridge, UK.
authors.forename: Camilo A
authors.initials: CA
authors.lastname: Colaco
authors.affiliation: Mucosal Immunology, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia; Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Science, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: phil.sutton@mcri.edu.au.
authors.forename: Philip
authors.initials: P
authors.lastname: Sutton
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood*; D001426:Bacterial Proteins / Q000276:immunology; D001428:Bacterial Vaccines / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral; D007113:Immunity, Innate; D007074:Immunoglobulin G / Q000097:blood; D008585:Meningitis, Meningococcal / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D042806:Neisseria lactamica; D009345:Neisseria meningitidis; D020543:Proteome; D013154:Spleen / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D016207:Cytokines; D006360:Heat-Shock Proteins; D007074:Immunoglobulin G; D053594:Myeloid Differentiation Factor 88; D020543:Proteome; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4
keywords: Heat shock protein; Heat shock protein complex vaccine; Meningitis; Neisseria lactamica; Neisseria meningitidis