Multivalent vaccines for invasive <i>Salmonella</i> disease: need, rationale, and immunological foundations

<i>Salmonella enterica</i> infections are a major cause of morbidity and mortality worldwide, especially in sub-Saharan Africa and in the Asian continent, and are increasingly associated with antimicrobial resistance. <i>Salmonella enterica</i> serovars Typhi and Paratyphi A, B, and C cause enteric fever, while non-typhoidal <i>Salmonella</i> serovars (usually Typhimurium and Enteritidis) cause mainly gastroenteritis which can lead to systemic infections. Vaccines are only licensed against <i>S</i>. Typhi, but different combinations are in clinical development to prevent <i>S</i>. Typhi and <i>S</i>. Paratyphi A or <i>S</i>. Typhi and non-typhoidal <i>Salmonella</i>. Here, we describe elements of the pathogenesis of and immunity to <i>Salmonella</i> that are critical to guide the rational design of vaccines. We highlight how the choice of appropriate immunogenic and protective antigens would be essential to achieve the maximum coverage of serovars in a multivalent <i>Salmonella</i> vaccine. The principal vaccines under development at the preclinical and clinical stages are described, together with considerations on the technical and clinical feasibility of moving combination vaccines toward licensure.