The typhoid Mary legacy: Genomic epidemiology uncovers contemporary carriage dynamics across two decades of enteric fever surveillance in England and Wales

Modern knowledge regarding 'healthy bacterial carriers' traces back to the legacy of typhoid Mary, who unknowingly infected >50 people with enteric fever. Yet, the intricacies of typhoidal Salmonella carriage, inclusive of Salmonella Typhi and Paratyphi A/B, remain largely unknown. Using data collected by the United Kingdom Health Security Agency's Salmonella reference laboratory and enhanced surveillance, we examined cases of enteric fever in England and Wales between 2004-2023, to track disease trends and identify carriers. In total, 8,297 cases of enteric fever were reported during the study period, including concerning rises post-pandemic that are not linked to emerging bacterial strains. 92% of cases reported travel, mainly to Southern Asia, and disease was most prevalent in more deprived communities. Around 2.7% of cases failed to clear after three weeks, constituting carriage, but only 0.1% persisted over a year. Odds of carriage were significantly increased in patients aged 81-90 (447%, p < 0.001) and in non-travel associated cases (64%, p = 0.025) while odds were significantly decreased in patients aged 21-30 (35%, p = 0.046) and in S. Paratyphi A infections (35%, p = 0.01). Isolates linked to carriage failed to cluster under specific lineages or genotypic clades, aside from a small S. Paratyphi B population potentially circulating locally in England. This study highlights increased prevalence of acute enteric fever infection in more deprived communities, and elevated risk of TS carriage in elderly patients and those without recent foreign travel. Our findings suggest host immune function likely plays a greater role in carriage risk than bacterial genotype. Given the lack of genetic signature for carriage, future research must focus on host factors influencing persistence, and repeat sampling post-antibiotic treatment should be implemented to identify 'modern day typhoid Marys' and reduce disease transmission.