title: Development of a glycoconjugate vaccine to prevent invasive Salmonella Typhimurium infections in sub-Saharan Africa.
abstract: Invasive infections associated with non-typhoidal Salmonella (NTS) serovars Enteritidis (SE), Typhimurium (STm) and monophasic variant 1,4,[5],12:i:- are a major health problem in infants and young children in sub-Saharan Africa, and currently, there are no approved human NTS vaccines. NTS O-polysaccharides and flagellin proteins are protective antigens in animal models of invasive NTS infection. Conjugates of SE core and O-polysaccharide (COPS) chemically linked to SE flagellin have enhanced the anti-COPS immune response and protected mice against fatal challenge with a Malian SE blood isolate. We report herein the development of a STm glycoconjugate vaccine comprised of STm COPS conjugated to the homologous serovar phase 1 flagellin protein (FliC) with assessment of the role of COPS O-acetyls for functional immunity. Sun-type COPS conjugates linked through the polysaccharide reducing end to FliC were more immunogenic and protective in mice challenged with a Malian STm blood isolate than multipoint lattice conjugates (>95% vaccine efficacy [VE] versus 30-43% VE). Immunization with de-O-acetylated STm-COPS conjugated to CRM197 provided significant but reduced protection against STm challenge compared to mice immunized with native STm-COPS:CRM197 (63-74% VE versus 100% VE). Although OPS O-acetyls were highly immunogenic, post-vaccination sera that contained various O-acetyl epitope-specific antibody profiles displayed similar in vitro bactericidal activity when equivalent titers of anti-COPS IgG were assayed. In-silico molecular modeling further indicated that STm OPS forms a single dominant conformation, irrespective of O-acetylation, in which O-acetyls extend outward and are highly solvent exposed. These preclinical results establish important quality attributes for an STm vaccine that could be co-formulated with an SE-COPS:FliC glycoconjugate as a bivalent NTS vaccine for use in sub-Saharan Africa.
authors.affiliation: Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, United States of America.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States of America.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Baliban
authors.affiliation: University of Maryland Computer-Aided Drug Design Center and Department of Pharmaceutical Sciences, School of Pharmacy, Baltimore, MD, United States of America.
authors.forename: Mingjun
authors.initials: M
authors.lastname: Yang
authors.affiliation: Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, United States of America.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States of America.
authors.forename: Girish
authors.initials: G
authors.lastname: Ramachandran
authors.affiliation: Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, United States of America.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States of America.
authors.forename: Brittany
authors.initials: B
authors.lastname: Curtis
authors.affiliation: Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, United States of America.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States of America.
authors.forename: Surekha
authors.initials: S
authors.lastname: Shridhar
authors.affiliation: Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, United States of America.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States of America.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Laufer
authors.affiliation: Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, United States of America.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States of America.
authors.forename: Jin Y
authors.initials: JY
authors.lastname: Wang
authors.affiliation: Fina Biosolutions, Rockville, MD, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Van Druff
authors.affiliation: Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, United States of America.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States of America.
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Higginson
authors.affiliation: Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, United States of America.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States of America.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Hegerle
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, United States of America.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Varney
authors.affiliation: Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, United States of America.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States of America.
authors.forename: James E
authors.initials: JE
authors.lastname: Galen
authors.affiliation: Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, United States of America.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States of America.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Tennant
authors.affiliation: Fina Biosolutions, Rockville, MD, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lees
authors.affiliation: University of Maryland Computer-Aided Drug Design Center and Department of Pharmaceutical Sciences, School of Pharmacy, Baltimore, MD, United States of America.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: MacKerell
authors.affiliation: Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, United States of America.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States of America.|Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, United States of America.
authors.forename: Myron M
authors.initials: MM
authors.lastname: Levine
authors.affiliation: Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, United States of America.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States of America.
authors.forename: Raphael
authors.initials: R
authors.lastname: Simon
mesh_terms: D017954:Africa South of the Sahara; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D005408:Flagellin / Q000276:immunology / Q000627:therapeutic use; D006001:Glycoconjugates / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D051379:Mice; D019081:O Antigens / Q000276:immunology / Q000627:therapeutic use; D012044:Regression Analysis; D012480:Salmonella Infections / Q000276:immunology / Q000517:prevention & control*; D022562:Salmonella Vaccines / Q000276:immunology / Q000627:therapeutic use*; D012486:Salmonella typhimurium; D014613:Vaccines, Attenuated / Q000276:immunology / Q000627:therapeutic use
chemical_list: D000907:Antibodies, Bacterial; D006001:Glycoconjugates; D007074:Immunoglobulin G; D019081:O Antigens; D022562:Salmonella Vaccines; D014613:Vaccines, Attenuated; D005408:Flagellin