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

PLoS Negl Trop Dis. 2017 Apr 7;11(4):e0005493. doi: 10.1371/journal.pntd.0005493. eCollection 2017 Apr.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Africa South of the Sahara
  • Animals
  • Antibodies, Bacterial / blood
  • Disease Models, Animal
  • Female
  • Flagellin / immunology
  • Flagellin / therapeutic use
  • Glycoconjugates / immunology
  • Glycoconjugates / therapeutic use
  • Humans
  • Immunoglobulin G / blood
  • Mice
  • O Antigens / immunology
  • O Antigens / therapeutic use
  • Regression Analysis
  • Salmonella Infections / immunology
  • Salmonella Infections / prevention & control*
  • Salmonella Vaccines / immunology
  • Salmonella Vaccines / therapeutic use*
  • Salmonella typhimurium*
  • Vaccines, Attenuated / immunology
  • Vaccines, Attenuated / therapeutic use


  • Antibodies, Bacterial
  • Glycoconjugates
  • Immunoglobulin G
  • O Antigens
  • Salmonella Vaccines
  • Vaccines, Attenuated
  • Flagellin