Development of a glycoconjugate vaccine to prevent invasive Salmonella Typhimurium infections in sub-Saharan Africa.

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TitleDevelopment of a glycoconjugate vaccine to prevent invasive Salmonella Typhimurium infections in sub-Saharan Africa.
Publication TypeJournal Article
Year of Publication2017
AuthorsBaliban, SM, Yang, M, Ramachandran, G, Curtis, B, Shridhar, S, Laufer, RS, Wang, JY, Van Druff, J, Higginson, EE, Hegerle, N, Varney, KM, Galen, JE, Tennant, SM, Lees, A, Mackerell, AD, Levine, MM, Simon, R
JournalPLoS Negl Trop Dis
Date Published2017 Apr
KeywordsAfrica South of the Sahara, Animals, Antibodies, Bacterial, Disease Models, Animal, Female, Flagellin, Glycoconjugates, Humans, Immunoglobulin G, Mice, O Antigens, Regression Analysis, Salmonella Infections, Salmonella typhimurium, Salmonella Vaccines, Vaccines, Attenuated

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.

Alternate JournalPLoS Negl Trop Dis
PubMed ID28388624
PubMed Central IDPMC5397072
Grant ListR01 AI110627 / AI / NIAID NIH HHS / United States