Induction of Broad Immunity against Invasive Salmonella Disease by a Quadrivalent Combination Salmonella MAPS Vaccine Targeting Salmonella Enterica Serovars Typhimurium, Enteritidis, Typhi, and Paratyphi A.

Bloodstream infections in low- and middle-income countries (LMICs) are most frequently attributed to invasive Salmonella disease caused by four primary serovars of Salmonella enterica: Typhi, Paratyphi A, Typhimurium, and Enteritidis. We showed previously that a bivalent vaccine targeting S. Typhi and S. Paratyphi A using a Multiple Antigen-Presenting System (MAPS) induced functional antibodies against S. Typhi and S. Paratyphi. In the current study, we describe the preclinical development of a first candidate quadrivalent combination Salmonella vaccine with the potential to cover all four leading invasive Salmonella serotypes. We showed that the quadrivalent Salmonella MAPS vaccine, containing Vi from S. Typhi, O-specific Polysaccharide (OSP) from S. Paratyphi A, S. Enteritidis and S. Typhimurium, combined with the Salmonella-specific protein SseB, elicits robust and functional antibody responses to each of the components of the vaccine. Our data indicates that the application of MAPS technology to the development of vaccines targeting invasive forms of Salmonella is practical and merits additional consideration.

A Bivalent MAPS Vaccine Induces Protective Antibody Responses against Salmonella Typhi and Paratyphi A.

Infections by Salmonella Typhi and Paratyphi A strain are still a major cause of morbidity and mortality in developing countries. Generation of antibodies against the Vi capsular polysaccharide of S. Typhi via either pure polysaccharide or protein-polysaccharide conjugate is a very effective way to protect against S. Typhi. To date, there is no commercially available vaccine against S. Paratyphi A. The O-specific polysaccharide (OSP) has been generally considered a good vaccine target for Paratyphi A. Here, a bivalent vaccine against Vi and OSP was generated using the Multiple Antigen Presenting System (MAPS). Three different protein constructs, including CRM197, rEPA of Pseudomonas, and a pneumococcal fusion protein SP1500-SP0785, were fused to Rhizavidin (Rhavi) and evaluated their impact on immunogenicity when incorporated as fusion proteins affinity-bound to the two polysaccharides. We compared the antibody responses, antibody avidity, and cidal activity of sera post-immunization with monovalent vs. combination vaccines. We also wished to evaluate the generation of Vi-specific memory B cells in mice. We found little interference when combination vaccine was compared to monovalent vaccines with respect to antibody concentration and cidal activity of sera. Significant affinity maturation was noted for both Vi and OSP antigens. Thus, our preclinical results with a combination Vi- and OSP-MAPS vaccine strongly support the feasibility of this approach and its application of this approach to other important salmonella and Shigella species.