title: Design of glycoconjugate vaccines against invasive African Salmonella enterica serovar Typhimurium.
abstract: Nontyphoidal salmonellae, particularly Salmonella enterica serovar Typhimurium, are a major cause of invasive disease in Africa, affecting mainly young children and HIV-infected individuals. Glycoconjugate vaccines provide a safe and reliable strategy against invasive polysaccharide-encapsulated pathogens, and lipopolysaccharide (LPS) is a target of protective immune responses. With the aim of designing an effective vaccine against S. Typhimurium, we have synthesized different glycoconjugates, by linking O-antigen and core sugars (OAg) of LPS to the nontoxic mutant of diphtheria toxin (CRM(197)). The OAg-CRM(197) conjugates varied in (i) OAg source, with three S. Typhimurium strains used for OAg extraction, producing OAg with differences in structural specificities, (ii) OAg chain length, and (iii) OAg/CRM(197) ratio. All glycoconjugates were compared for immunogenicity and ability to induce serum bactericidal activity in mice. In vivo enhancement of bacterial clearance was assessed for a selected S. Typhimurium glycoconjugate by challenge with live Salmonella. We found that the largest anti-OAg antibody responses were elicited by (i) vaccines synthesized from OAg with the highest glucosylation levels, (ii) OAg composed of mixed- or medium-molecular-weight populations, and (iii) a lower OAg/CRM(197) ratio. In addition, we found that bactericidal activity can be influenced by S. Typhimurium OAg strain, most likely as a result of differences in OAg O-acetylation and glucosylation. Finally, we confirmed that mice immunized with the selected OAg-conjugate were protected against S. Typhimurium colonization of the spleen and liver. In conclusion, our findings indicate that differences in the design of OAg-based glycoconjugate vaccines against invasive African S. Typhimurium can have profound effects on immunogenicity and therefore optimal vaccine design requires careful consideration.
authors.affiliation: Novartis Vaccines Institute for Global Health, Siena, Italy simona.rondini@novartis.com.
authors.forename: S
authors.initials: S
authors.lastname: Rondini
authors.affiliation: Novartis Vaccines Institute for Global Health, Siena, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Micoli
authors.affiliation: Novartis Vaccines Institute for Global Health, Siena, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Lanzilao
authors.affiliation: Novartis Vaccines and Diagnostics, Siena, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Gavini
authors.affiliation: Novartis Vaccines Institute for Global Health, Siena, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Alfini
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: C
authors.initials: C
authors.lastname: Brandt
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Clare
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: P
authors.initials: P
authors.lastname: Mastroeni
authors.affiliation: Novartis Vaccines Institute for Global Health, Siena, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Saul
authors.affiliation: Novartis Vaccines Institute for Global Health, Siena, Italy.
authors.forename: C A
authors.initials: CA
authors.lastname: MacLennan
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D004167:Diphtheria Toxin / Q000235:genetics / Q000276:immunology; D015195:Drug Design; D005260:Female; D006001:Glycoconjugates / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D006031:Glycosylation; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D019081:O Antigens / Q000737:chemistry / Q000276:immunology*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D012481:Salmonella Infections, Animal / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D022562:Salmonella Vaccines / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000276:immunology / Q000472:pathogenicity; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D013329:Structure-Activity Relationship; D014611:Vaccination
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D004167:Diphtheria Toxin; D006001:Glycoconjugates; D019081:O Antigens; D011994:Recombinant Proteins; D022562:Salmonella Vaccines