Pediatric Cell-Mediated Immune System and Response to Ty21a Typhoid Vaccination Compared to Adults

Abstract

Typhoid fever is a life-threatening disease caused by the human-restricted pathogen Salmonella enterica serovar Typhi (S. Typhi). The oral live-attenuated Ty21a typhoid vaccine protects against this severe disease by eliciting robust, multifunctional cell mediated immunity (CMI), shown to be associated with protection in wild-type S. Typhi challenge studies. Ty21a induces S. Typhi-responsive CD8+ and CD4+ T cells but little is known about the response to this vaccine in children. To address this important gap in knowledge, we have used mass cytometry to analyze pediatric and adult pre- and post-Ty21a vaccination T cells with both an HLA-E restricted and an autologous S. Typhi-antigen presentation model. Here, using conventional supervised analytical tools, we show adult T cells are more multifunctional at baseline than those obtained from children. Moreover, pediatric and adult T cells respond similarly to Ty21a vaccination, but adult responders remain more multifunctional. The use of the unsupervised dimensionality reduction tools allowed us to confirm these findings, as well as to identify increases and decreases in well-defined specific CD4+ and CD8+ T cell populations that were not possible to uncover using the conventional gating strategies. These findings evidenced age-associated maturation of multifunctional S. Typhi-responsive T cell populations, including those which have previously shown to be associated with protection from, and/or delayed onset of, typhoid disease. Further, in depth analysis of control stimulation conditions also found age-associated multifunctional T cell heterogeneity. These findings are likely to play an important role in improving pediatric vaccination strategies against S. Typhi and other enteric pathogens.