title: Monoclonal Antibodies of a Diverse Isotype Induced by an O-Antigen Glycoconjugate Vaccine Mediate In Vitro and In Vivo Killing of African Invasive Nontyphoidal Salmonella.
abstract: Nontyphoidal Salmonella (NTS), particularly Salmonella enterica serovars Typhimurium and Enteritidis, is responsible for a major global burden of invasive disease with high associated case-fatality rates. We recently reported the development of a candidate O-antigen-CRM197 glycoconjugate vaccine against S. Typhimurium. Here, using a panel of mouse monoclonal antibodies generated by the vaccine, we examined the relative efficiency of different antibody isotypes specific for the O:4 antigen of S. Typhimurium to effect in vitro and in vivo killing of the invasive African S. Typhimurium strain D23580. All O:4-specific antibody isotypes could mediate cell-free killing and phagocytosis of S. Typhimurium by mouse blood cells. Opsonization of Salmonella with O:4-specific IgA, IgG1, IgG2a, and IgG2b, but not IgM, resulted in cell-dependent bacterial killing. At high concentrations, O:4-specific antibodies inhibited both cell-free complement-mediated and cell-dependent opsonophagocytic killing of S. Typhimurium in vitro. Using passive immunization in mice, the O:4-specific antibodies provided in vivo functional activity by decreasing the bacterial load in the blood and tissues, with IgG2a and IgG2b being the most effective isotypes. In conclusion, an O-antigen-CRM197 glycoconjugate vaccine can induce O-antigen-specific antibodies of different isotypes that exert in vitro and in vivo killing of S. Typhimurium.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis, Singapore.
authors.forename: Yun Shan
authors.initials: YS
authors.lastname: Goh
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Clare
authors.affiliation: Sclavo Behring Vaccines Institute for Global Health, a GlaxoSmithKline Company, Siena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Micoli
authors.affiliation: Sclavo Behring Vaccines Institute for Global Health, a GlaxoSmithKline Company, Siena, Italy.
authors.forename: Allan
authors.initials: A
authors.lastname: Saul
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Pietro
authors.initials: P
authors.lastname: Mastroeni
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom calman.maclennan@ndm.ox.ac.uk.
authors.forename: Calman A
authors.initials: CA
authors.lastname: MacLennan
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019081:O Antigens / Q000276:immunology*; D012480:Salmonella Infections / Q000276:immunology; D022562:Salmonella Vaccines / Q000276:immunology*; D019779:Salmonella enterica / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D007132:Immunoglobulin Isotypes; D019081:O Antigens; D022562:Salmonella Vaccines