Genomic insights into the impact of typhoid conjugate vaccine introduction and the COVID-19 pandemic on Salmonella Typhi and Paratyphi A in Nepal
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Background
Enteric fever, caused by Salmonella enterica serovars Typhi and Paratyphi A, remains a major concern in low-and middle-income countries, with treatment increasingly complicated by antimicrobial resistance. Typhoid conjugate vaccines (TCVs) offer a promising intervention, but their impact on circulating lineages and population structure remains poorly understood. Nepal introduced a nationwide TCV programme in April 2022, shortly after the COVID-19 pandemic disrupted healthcare delivery and surveillance.
Methods
We sequenced 350 S . Typhi and 114 S . Paratyphi A isolates collected in Nepal between 2018 and 2024 and analyzed them alongside1,796 previously published Nepal genomes (2005-2018). We characterized genotype distribution, antimicrobial resistance determinants, phylogenetic relationships and lineage-specific phylodynamics across three epidemiological periods: pre-pandemic (before 2020), pandemic/pre-vaccine (2020–2022), and post-vaccine introduction (2022–2024).
Results
Sixteen S . Typhi genotypes were identified, dominated by 4.3.1.2 (28%), 3.3.2 (20.3%) and 3.3.1 (16.9%); S . Paratyphi A was dominated by genotypes 2.4.3 (57.0%) and 2.4.2 (25.4%). Multidrug resistance was rare, but fluoroquinolone non-susceptibility was widespread (70.6% of S . Typhi; 99.1% of S . Paratyphi A), with high-level resistance confined to a single S . Typhi 4.3.1.2.1 clade dating to 2008. Phylodynamic reconstruction revealed asymmetric lineage trajectories: S . Typhi H58 contracted sharply during the pandemic, lineage 3.3 contracted specifically post-TCV, and S . Paratyphi A (not vaccine-targeted) showed only a modest pandemic-era decline. Post-TCV, the age distribution of cases shifted older and the adult genotype mix shifted toward lineage 3.3. We found no evidence of vaccine-driven escape at the Vi capsule or O-antigen in Nepal or across a cross-country cohort.
Conclusions
Both S . Typhi and S . Paratyphi A populations in Nepal underwent recent declines in effective population size, coinciding with the COVID-19 pandemic and TCV introduction. Persistent fluoroquinolone resistance, particularly among S . Paratyphi A, underscores ongoing AMR challenges and highlights the need for expanded vaccine strategies targeting both pathogens.
Author Summary
Enteric fever, caused by the bacteria Salmonella Typhi and Salmonella Paratyphi A, remains a major cause of illness across South Asia, and its treatment is increasingly threatened by antibiotic resistance. Typhoid conjugate vaccines (TCVs) can prevent typhoid, but they do not protect against Paratyphi A, and their effect on the bacterial populations circulating in a community is not well understood. Nepal introduced TCV nationwide in 2022, shortly after the COVID-19 pandemic disrupted daily life and healthcare. We sequenced the whole genomes of S . Typhi and Paratyphi A collected in Nepal between 2018 and 2024 and combined them with previously published genomes to reconstruct how these populations changed over time. Different lineages declined at different times: one major typhoid lineage shrank during the pandemic, whereas another declined specifically after vaccine introduction. S . Paratyphi A, which the vaccine does not target, changed little and served as a natural comparator. Resistance to fluoroquinolone antibiotics remained widespread. Our findings illustrate how vaccination and large-scale social disruption can reshape the populations that cause enteric fever, and they support expanding vaccines to also cover S . Paratyphi A.
