Design of glycoconjugate vaccines against invasive African Salmonella enterica serovar Typhimurium

• Published in: Infection and immunity 2015-03, Vol.83 (3), p.996-1007
• Main Authors: Rondini, S, Micoli, F, Lanzilao, L, Gavini, M, Alfini, R, Brandt, C, Clare, S, Mastroeni, P, Saul, A, MacLennan, C A
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Bacterial - biosynthesis; Bacterial Proteins - genetics; Bacterial Proteins - immunology; Diphtheria Toxin - genetics; Diphtheria Toxin - immunology; Drug Design; Female; Glycoconjugates - administration & dosage; Glycoconjugates - chemistry; Glycoconjugates - immunology; Glycosylation; Human immunodeficiency virus; Humans; Liver - drug effects; Liver - immunology; Liver - microbiology; Mice; Mice, Inbred C57BL; Microbial Immunity and Vaccines; Mutation; O Antigens - chemistry; O Antigens - immunology; Recombinant Proteins - genetics; Recombinant Proteins - immunology; Salmonella enterica; Salmonella Infections, Animal - immunology; Salmonella Infections, Animal - microbiology; Salmonella Infections, Animal - prevention & control; Salmonella typhimurium; Salmonella typhimurium - drug effects; Salmonella typhimurium - immunology; Salmonella typhimurium - pathogenicity; Salmonella Vaccines - administration & dosage; Salmonella Vaccines - chemistry; Salmonella Vaccines - immunology; Spleen - drug effects; Spleen - immunology; Spleen - microbiology; Structure-Activity Relationship; Vaccination
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.03079-14

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.