Molecular correlates of vaccine-induced protection against typhoid fever.

Typhoid fever is caused by the Gram-negative bacterium Salmonella enterica serovar Typhi and poses a substantial public health burden worldwide. Vaccines have been developed based on the surface Vi-capsular polysaccharide of S. Typhi, this includes a plain-polysaccharide-based vaccine, ViPS, and a glycoconjugate vaccine, ViTCV. Previous studies have provided partial insight into the protective mechanisms of these Vi-derived vaccines. To understand immune responses to these vaccines and their vaccine-induced immunological protection, bulk RNA-sequencing (RNA-Seq) data were generated from blood samples obtained from adult human volunteers enrolled in a vaccine trial, who were then challenged with S. Typhi in a controlled human infection model (CHIM). Transcriptomic responses revealed strong differential molecular signatures between the two vaccines mostly driven by the upregulation in humoral immune signatures, including selective usage of immunoglobulin heavy chain variable region (IGHV) genes and more polarised clonal expansions. We describe several molecular correlates of protection against S. Typhi infection including clusters of B cell receptor (BCR) clonotypes associated with protection, with known binders of Vi-polysaccharide among these. Taken together, we report a series of contemporary analyses that reveal the transcriptomic signatures after vaccination and infectious challenge, while identifying molecular correlates of protection that may inform future vaccine design and assessment.