Evaluation of Salmonella enterica serovar Typhimurium Vaccines in the Context of Immunosenescence

Abstract

Non-typhoidal Salmonella (NTS) is responsible for a high burden of foodborne infections and deaths worldwide. In the United States, NTS infections are the leading cause of hospitalizations and deaths due to foodborne illnesses, and older adults (≥65 years) are disproportionately affected by Salmonella infections. Due to this public health concern, we have developed a live attenuated vaccine, CVD 1926 (I77 ΔguaBA ΔclpP ΔpipA ΔhtrA), against Salmonella enterica serovar Typhimurium, a common serovar of NTS. The effects of age on parenteral vaccination are well documented, however, how advanced age impacts oral vaccine responses is less understood. In this dissertation, systemic and mucosal immune responses to CVD 1926 were evaluated in adult (six-to-eight-week-old) and aged (18-month-old) mice. We demonstrated that aged mice immunized with CVD 1926 failed to reduce bacterial burden upon challenge with wild-type S. Typhimurium, which was associated with lower vaccine-induced antibody titers and weaker T cell responses. Notably, characteristics of a successful mucosal vaccine response were weak in aged mice, suggesting that mucosal responses to oral vaccines decrease with advanced age. In efforts to develop a NTS vaccine that is effective for older adults, two vaccine approaches were evaluated: (i) a novel live-attenuated vaccine strain, CVD 1926 ΔsteD and (ii) heterologous prime boost strategy involving a mucosal prime with CVD 1926 that was followed by a parenteral boost with a conjugate S. Typhimurium vaccine. SteD is a Salmonella effector that suppresses CD4+ T cell responses during infection with wild-type S. Typhimurium. Using in vitro and in vivo assays, we demonstrated that CVD 1926 ΔsteD immunization elicits enhanced MHC-II expression, increased flagellin-specific CD4+ T cells, robust serum IgG and fecal IgA responses, and protection against S. Typhimurium colonization of the spleen, cecum, and small intestine upon challenge in aged mice. While the heterologous prime boost strategy induced robust Salmonella-specific antibody responses in aged mice, only modest protection against S. Typhimurium colonization was observed, suggesting that this vaccination approach cannot overcome immunosenescence. Taken together, these studies identify the age-associated deficits in mucosal vaccine responses and presents a promising prototype vaccine strain that may be effective for older adults.