A candidate glycoconjugate vaccine induces protective antibodies in the serum and intestinal secretions, antibody recall response and memory T cells and protects against both typhoidal and non-typhoidal Salmonella serovars

Abstract

Human <i>Salmonella</i> infections pose significant public health challenges globally, primarily due to low diagnostic yield of systemic infections, emerging and expanding antibiotic resistance of both the typhoidal and non-typhoidal <i>Salmonella</i> strains and the development of asymptomatic carrier state that functions as a reservoir of infection in the community. The limited long-term efficacy of the currently licensed typhoid vaccines, especially in smaller children and non-availability of vaccines against other <i>Salmonella</i> serovars necessitate active research towards developing a multivalent vaccine with wider coverage of protection against pathogenic <i>Salmonella</i> serovars. We had earlier reported immunogenicity and protective efficacy of a subunit vaccine containing a recombinant outer membrane protein (T2544) of <i>Salmonella</i> Typhi in a mouse model. This was achieved through the robust induction of serum IgG, mucosal secretory IgA and <i>Salmonella</i>-specific cytotoxic T cells as well as memory B and T cell response. Here, we report the development of a glycoconjugate vaccine, containing high molecular weight complexes of <i>Salmonella</i> Typhimurium O-specific polysaccharide (OSP) and recombinant T2544 that conferred simultaneous protection against <i>S.</i> Typhi, <i>S.</i> Paratyphi, <i>S.</i> Typhimurium and cross-protection against <i>S.</i> enteritidis in mice. Our findings corroborate with the published studies that suggested the potential of <i>Salmonella</i> OSP as a vaccine antigen. The role of serum antibodies in vaccine-mediated protection is suggested by rapid seroconversion with high titers of serum IgG and IgA, persistently elevated titers after primary immunization along with a strong antibody recall response with higher avidity serum IgG against both OSP and T2544 and significantly raised SBA titers of both primary and secondary antibodies against different <i>Salmonella</i> serovars. Elevated intestinal secretory IgA and bacterial motility inhibition by the secretory antibodies supported their role as well in vaccine-induced protection. Finally, robust induction of T effector memory response indicates long term efficacy of the candidate vaccine. The above findings coupled with protection of vaccinated animals against multiple clinical isolates confirm the suitability of OSP-rT2544 as a broad-spectrum candidate subunit vaccine against human infection due to typhoidal and non-typhoidal <i>Salmonella</i> serovars.