Genetic heterogeneity in the Salmonella Typhi Vi capsule locus: A population genomic study from Fiji

Typhoid fever is endemic in many parts of the world and remains a major public health concern in tropical and sub-tropical developing nations, including Fiji. To address high rates of typhoid fever, the Northern Division of Fiji is implementing a mass vaccination with typhoid conjugate vaccine (Vi-polysaccharide conjugated to tetanus toxoid) as a public health control measure in 2023. In this study we define the genomic epidemiology of S. Typhi in the Northern Division prior to island-wide vaccination, sequencing 85% (n=419) of the total cases from the Northern Division and Central Divisions of Fiji that occurred in the period 2017-2019. We found elevated rates of nucleotide polymorphisms in tviD and tviE genes (responsible for Vi-polysaccharide synthesis) relative to core genome levels within the Fiji endemic S. Typhi genotype 4.2. Expansion of these findings within a globally representative database of 12,382 S. Typhi (86 genotyphi clusters) showed evidence of convergent evolution of the same tviE mutations across the S. Typhi population, indicating that tvi selection has occurred both independently and globally. The functional impact of tvi mutations on the Vi-capsular structure and other phenotypic characteristics are presently unknown, yet commonly occurring tviE polymorphisms localise adjacent to predicted active site residues when overlayed against the predicted TviE protein structure. Given the central role of the Vi-polysaccharide in S. Typhi biology and vaccination, further integrated epidemiological, genomic, and phenotypic surveillance is required to determine the spread and functional implications of these mutations.