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

• Published in: PLoS neglected tropical diseases 2017-04, Vol.11 (4), p.e0005493
• Main Authors: Baliban, Scott M, Yang, Mingjun, Ramachandran, Girish, Curtis, Brittany, Shridhar, Surekha, Laufer, Rachel S, Wang, Jin Y, Van Druff, John, Higginson, Ellen E, Hegerle, Nicolas, Varney, Kristen M, Galen, James E, Tennant, Sharon M, Lees, Andrew, MacKerell, Jr, Alexander D, Levine, Myron M, Simon, Raphael
• Format: Article
• Language: English
• Subjects: Acetylation; Africa South of the Sahara; Animal models; Animals; Antibodies; Antibodies, Bacterial - blood; Antibody response; Antigen (tumor-associated); Antigens; Assaying; Attenuation; Backbone; Bacteria; Bactericidal activity; Biochemistry; Biology and Life Sciences; Blood; CAD; Children; Computation; Computer aided design; Computer applications; Conjugate vaccines; Crosslinking; Disease Models, Animal; Dosage and administration; Drug development; Epitopes; Exposure; Female; Flagellin; Flagellin - immunology; Flagellin - therapeutic use; Glycoconjugates - immunology; Glycoconjugates - therapeutic use; Homology; Humans; Immune response; Immune system; Immunization; Immunogenicity; Immunoglobulin A; Immunoglobulin G; Immunoglobulin G - blood; Immunology; Infants; Infectious diseases; Invasive fish; Invasive species; Medicine; Medicine and Health Sciences; Mice; Molecular biology; Molecular modelling; Monoclonal antibodies; O Antigens - immunology; O Antigens - therapeutic use; Pharmaceutical sciences; Pharmacy; Phosphates; Pneumonia; Polysaccharides; Prevention; Properties (attributes); Proteins; Public health; Reagents; Regression Analysis; Research and Analysis Methods; Saccharides; Salmonella; Salmonella Infections - immunology; Salmonella Infections - prevention & control; Salmonella typhimurium; Salmonella Vaccines - immunology; Salmonella Vaccines - therapeutic use; Salmonellosis; Streptococcus infections; Structural analysis; Sun; Tropical diseases; Vaccine efficacy; Vaccines; Vaccines, Attenuated - immunology; Vaccines, Attenuated - therapeutic use; Wheelchairs
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0005493

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.