title: Impact of conjugation chemistry on the immunogenicity of S. Typhimurium conjugate vaccines.
abstract: Salmonella Typhimurium is major cause of invasive nontyphoidal Salmonella disease in Africa. Conjugation of S. Typhimurium O-antigen to an appropriate carrier protein constitutes a possible strategy for the development of a vaccine against this disease, for which no vaccines are currently available. The conjugation chemistry used is one of the parameters that can affect the immunogenicity of glycoconjugate vaccines. Herein different glycoconjugates were synthesized to investigate the impact of this variable on the immunogenicity of S. Typhimurium conjugate vaccines in mice, all with CRM₁₉₇ as carrier protein. Random derivatization along the O-antigen chain was compared with site-directed activation of the terminal KDO sugar residue of the core oligosaccharide. In particular, two different random approaches were used, based on the oxidation of the polysaccharide, which differently impact the structure and conformation of the O-antigen chain. For the selective conjugation methods, linkers of two different lengths were compared. When tested in mice, all conjugates induced anti-O-antigen IgG antibodies with serum bactericidal activity. Similar anti-O-antigen antibody levels were elicited independent of the chemistry used and a higher degree of saccharide derivatization did not impact negatively on the anti-O-antigen IgG response. Bactericidal activity of serum antibodies induced by selective conjugates was similar independent of the length of the spacer used. Random conjugates elicited antibodies with greater bactericidal activity than selective ones, and an inverse correlation was found between degree of O-antigen modification and antibody functional activity.
authors.affiliation: Novartis Vaccines Institute for Global Health, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Stefanetti
authors.affiliation: Novartis Vaccines Institute for Global Health, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Rondini
authors.affiliation: Novartis Vaccines Institute for Global Health, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Lanzilao
authors.affiliation: Novartis Vaccines Institute for Global Health, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Saul
authors.affiliation: Novartis Vaccines Institute for Global Health, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: C A
authors.initials: CA
authors.lastname: MacLennan
authors.affiliation: Novartis Vaccines Institute for Global Health, Via Fiorentina 1, 53100 Siena, Italy. Electronic address: francesca.micoli@novartis.com.
authors.forename: F
authors.initials: F
authors.lastname: Micoli
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D001426:Bacterial Proteins / Q000737:chemistry*; D005260:Female; D006001:Glycoconjugates / Q000737:chemistry* / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D019081:O Antigens / Q000737:chemistry* / Q000276:immunology; D022562:Salmonella Vaccines / Q000737:chemistry / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology; D058248:Serum Bactericidal Antibody Assay; D018074:Vaccines, Conjugate / Q000737:chemistry* / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D006001:Glycoconjugates; D007074:Immunoglobulin G; D019081:O Antigens; D022562:Salmonella Vaccines; D018074:Vaccines, Conjugate; C028581:CRM197 (non-toxic variant of diphtheria toxin)
keywords: CRM(197); Conjugation chemistry; Glycoconjugate; O-antigen; Salmonella Typhimurium; Vaccine