Global diversity and antimicrobial resistance of typhoid fever pathogens: insights from 13,000 Salmonella Typhi genomes

The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks twenty-one years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000), and provides a detailed overview of global genotype and antimicrobial resistance (AMR) distribution and temporal trends, generated using open analysis platforms (GenoTyphi and Pathogenwatch). Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show potential of travel-associated data to provide informal “sentinel” surveillance for such locations. The data indicate ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020), but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. The Consortium’s aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies. ### Competing Interest Statement All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf. NAF chairs the Wellcome Surveillance and Epidemiology of Drug Resistant Infections (SEDRIC) group, which has a focus on antimicrobial resistance, and has no financial interests to declare. AJP is chair of the UK Department of Health and Social Care's (DHSC) Joint Committee on Vaccination and Immunisation (JCVI) but does not take part in the JCVI COVID-19 committee. He was a member of WHO SAGE until 2022. AJP's employer, Oxford University has entered into a partnership with AstraZeneca for development of a COVID-19 vaccine. AJP has provided advice to Shionogi & Co., Ltd on development of a COVID19 vaccine. KMN receives grant support from the Bill and Melinda Gates Foundation for TyVAC (the Typhoid Vaccine Acceleration Consortium). IB has consulted for BlueDot, a social benefit corporation that tracks the spread of emerging infectious diseases. All other authors had no competing interests to declare. ### Funding Statement This study did not receive direct funding. ZAD received funding from the European Union′s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681. MAC is affiliated to the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Genomics and Enabling Data at University of Warwick in partnership with the UK Health Security Agency (UKHSA), in collaboration with University of Cambridge and Oxford. The views expressed are those of the author(s) and not necessarily those of the NIHR, the Department of Health and Social Care, the UKHSA, or the U.S. Centers for Disease Control and Prevention. RAK, TM and GT were supported by the Bill & Melinda Gates Foundation (BMGF) grant OPP1217121 and the BBSRC Institute Strategic Programme BB/R012504/1 and its constituent project BBS/E/F/000PR10348. SB was supported by a Wellcome Trust Senior Fellowship. MML was supported by the Bill and Melinda Gates Foundation grants OPP1194582, INV-029806, and OPP1161058. MJS was supported by National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) (grant F30AI156973) and BMGF (OPP1194582/INV-000049). JRA, IB, SS, DOG, FNQ, SS, AMT, KV, JI, SPL, DT, JS, JCS, SI, RS received support from BMGF (grant INV-008335/OPP1113007). KMN receives support from BMGF (grant OPP1151153). IB reports funding from the Canadian Institutes of Health Research. SS notes support from BMGF (grant INV-042340) and Child Health Research Foundation. PT has received funding from the Wellcome Trust (grants 222156 and 220211). NAF is a National Institute for Health and Care Research (NIHR) Professor of Global Health. AJP acknowledges funding support from the WHO and Gavi, the Vaccine Alliance. DMA notes support from the NIHR Global Health Research Unit on Genomic Surveillance of AMR. RSH is a NIHR Senior Investigator. AMS is supported by the SEQAFRICA project, funded by the Department of Health and Social Care′s Fleming Fund using UK aid. INO acknowledges support from the UK NIHR Global Health Research Unit on Genomic Surveillance of Antimicrobial Resistance Consortium Award NIHR (project 16/136/111), the UK Medical Research Council/ Department for International Development African Research Leaders Award: (MR/L00464X/), and a Calestous Juma Fellowship from the Bill and Melinda Gates Foundation (INV-036234). DAR has received support from NIH, NIAID, and the United States Department of Health and Human Services (grant U19AI110820). AK has been supported by ICMR, India. CMP has received funding through a Joint Global Health Trials Scheme (MR/TOO5033/1) and acknowledges funding from the Department for Health and Social Care, the Department for International Development/Global Challenges Research Fund, the UK Medical Research Council, and the Wellcome Trust. JC acknowledges support from the ANLIS Malbran and the Ministry of Health, Argentina. FXW and EN acknowledge funding support from the Institut Pasteur and Santé Publique France. GAM acknowledges support from BMGF (grant OPP1020327). RKL and VS recognize funding from NIHR (grant 16\_136\_111) and the Wellcome Trust (grant 206194). SK recognises support from the NIH (grant R01AI099525). RRB, SJL, JS, and ARG note funding support from BMGF. RFB has received support from BMGF and the NIH. GT and RK are supported by BMGF (grant OPP1217121) and the BBSRC Institute Strategic Programme BB/R012504/1 and its constituent project BBS/E/F/000PR10348. FM reports funding from BMGF (OPPGH5231 and OPP1127988). ST was supported by (BMGF INV-018979). DTP was supported by a Wellcome International Training Fellowship (grant 222983/Z/21/Z). KS and DJP note support from the Wellcome Trust. BW has received support from the US Food and Drug Administration. JAC received support from US National Institutes of Health grants U01AI062563, R01TW009237, and R01AI121378, and Bill & Melinda Gates Foundation grants OPPGH5231, OPP1558210, and OPP1151153. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Each contributing study or surveillance programme obtained local ethical and governance approvals, as reported in the primary publication for each dataset. For this study, inclusion of data that were not yet in the public domain by August 2021 was approved by the Observational / Interventions Research Ethics Committee of the London School of Hygiene and Tropical Medicine (ref #26408), on the basis of details provided on the local ethical approvals for sample and data collection I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data analysed during this study are publicly accessible. Raw Illumina sequence reads have been submitted to the European Nucleotide Archive (ENA), and individual sequence accession numbers are listed in Table S2. The full set of n=13,000 genome assemblies generated for this study are available for download from FigShare: doi 10.26180/21431883. All assemblies of suitable quality (n=12,849) are included in the online platform Pathogenwatch (https://pathogen.watch/organisms/styphi), where they can be interactively explored and included in user-driven comparative analyses. All underlying code developed for data analysis is freely available at https://github.com/katholt/TyphoidGenomicsConsortiumWG1.