A global multi-institutional Typhoid fever genomic surveillance network to improve global public health outcomes

Project Information

TyphiNET

Grant agreement ID: 845681

DOI

10.3030/845681

Project closed

EC signature date 25 April 2019

Start date 1 April 2020

End date 31 March 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 212 933,76

EU contribution

€ 212 933,76

Coordinated by

LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE ROYAL CHARTER
United Kingdom

Periodic Reporting for period 1 - TyphiNET (A global multi-institutional Typhoid fever genomic surveillance network to improve global public health outcomes)

Reporting period: 2020-04-01 to 2022-03-31

Summary of the context and overall objectives of the project

Globally there are ~10 million typhoid fever cases per year, resulting in >100,000 deaths from infection with the causative agent, Salmonella Typhi (Typhi). Antimicrobial therapy is the mainstay of typhoid fever control, and genomic epidemiology studies have revealed that drug resistance emerging in one country can rapidly spread to other neighbouring countries and intercontinentally. Genomic and phenotypic surveillance for typhoid and antimicrobial resistance (AMR) is therefore very important for disease control. TyphiNET aimed to develop innovative approaches for typhoid genomic surveillance through three main objectives: (1) to unlock data from travel-associated typhoid cases in high income countries that are adopting genomics for routine Salmonella surveillance; (2) to unlock data from project-based genomic surveillance in endemic areas; and (3) to develop an open access publicly available platform for synergising, visualising, and disseminating large scale genomic data sourced from sentinel and endemic area surveillance. TyphiNET outcomes are informative for the management of both endemic disease in low- and middle-income countries and travel-associated cases elsewhere, including providing region- and country-specific data to inform empirical antimicrobial choice and strategic targeting of control and intervention strategies.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The founding of the Global Typhoid Genomics Consortium (TGC; further details available at: https://www.typhoidgenomics.org/) was central to achieving TyphiNET project objectives. Through the contributions of a diverse community of >60 TGC members across >30 countries, >13,000 Typhi genome sequences were aggregated and analysed in terms of their genomic epidemiology parameters (prevalence of genotypes/lineages, resistance to specific antimicrobials, and transmission patterns) for different regions using data from travel-associated sentinel surveillance and from locally collected endemic area surveillance. These analyses revealed that for the 2010-2020 period the globally disseminated Typhi genotype H58 (4.3.1) frequently associated with AMR, remained common in Southern Asia (70%), Southeast Asia (47%), Southern Africa (66%) and Eastern Africa (93%), with non-H58 genotypes dominant in other regions e.g. 2.5.1 in Central Africa (76%), 3.1.1 in Western Africa (65%), 2.3.2 in Central America (56%). These data also revealed that Multidrug-resistance remains problematic across Sub-Saharan Africa, present at high frequencies in Eastern Africa (83%), Southern Africa (61%), and Western Africa (39%) compared to other geographic regions. Seventy-six percent of contemporaneous genomes carried resistance determinants to ciprofloxacin, and were distributed across a diverse range of geographies and pathogen genotypes. Phylodynamic analyses revealed multiple AMR emergence events and global transmission patterns of drug resistant genotypes. Examination of sequences from time-matched travel-associated and locally collected cases originating from endemic areas across South Asia and Melanesia revealed high levels of congruence for genotype (Spearman’s rank correlation 0.86 p=2.21e-13) and AMR (Spearman’s rank correlation r = 0.79 p= 0.00049) frequencies, suggesting that travel-associated cases are suitable for use in sentinel surveillance of countries where typhoid is endemic.

The TyphiNET online AMR surveillance dashboard (available at: http://typhi.net) was developed to make genome-derived metrics of public health utility available to a non-expert audience for the first time. The dashboard sources data from Typhi Pathogenwatch (http://pathogen.watch; populated with TGC data) and allows users to create interactive data visualisations of public health utility via any standard web browser. Users can interact with global maps showing worldwide frequencies of drug resistance and associated genotypes by country. Users can also interact with country-level summary plots allowing for the exploration of drug resistance trends over time, genotype frequency trends over time, resistance frequencies for different drug classes by genotype, and the molecular determinants (genes and mutations) driving AMR. All plots can be filtered by time period and data source (e.g. locally collected, or travel-associated data) and downloaded by the user. Reports of all plots generated as well as a line list of underlying genome-derived data can also be downloaded. The TyphiNET dashboard successfully reconstructs past changes in the population structure of public health relevance such as the emergence of extensively drug resistant (XDR) typhoid (resistant to all orally administered drugs except for azithromycin).

Published contributions:
• Dyson, Z. A., & Holt, K. E. (2021). Five years of GenoTyphi: updates to the global Salmonella Typhi genotyping framework. J Infect Dis, 224(Supplement_7), S775-S780.
• Dyson, Z. A., Malau, E., Horwood, P. F., Ford, R., Siba, V., Yoannes, M., ... & Holt, K. E. (2022). Whole genome sequence analysis of Salmonella Typhi in Papua New Guinea reveals an established population of genotype 2.1. 7 sensitive to antimicrobials. PLoS Negl Trop Dis, 16(3), e0010306.
• Kariuki, S./Dyson, Z. A., Mbae, C., Ngetich, R., Kavai, S. M., Wairimu, C., ... & Dougan, G. (2021). Multiple introductions of multidrug-resistant typhoid associated with acute infection and asymptomatic carriage, Kenya. eLife, 10, e67852.
• Argimón, S., Yeats, C. A., Goater, R. J., Abudahab, K., Taylor, B., Underwood, A., ... Dyson, Z.A. ... & Aanensen, D. M. (2021). A global resource for genomic predictions of antimicrobial resistance and surveillance of Salmonella Typhi at Pathogenwatch. Nat Commun, 12(1), 1-12.

Forthcoming publications:
• ’20 years of typhoid genomics’ manuscript (spanning the first Typhi genome sequence in 2001 to all TGC sequences aggregated in 2021)
• Manuscript describing the utility of including travel-associated cases in typhoid sentinel surveillance
• Manuscript describing the data sharing pipelines and utility of the TyphiNET dashboard
• Manuscript describing the technical software development of the TyphiNET dashboard

Findings disseminated at:
• 2022 Annual UK Microbiology Society Conference
• 2022 European Congress of Clinical Microbiology and Infectious Diseases
• 2022 Antimicrobial Resistance – Genomes, Big Data and Emerging Technologies conference
• 2022 International Symposium on Salmonella and Salmonellosis
• 2022 13th International Meeting on Microbial Epidemiological Markers
• 2021 International Conference on Typhoid & Other Invasive Salmonelloses
• 2021 American Society of Tropical Medicine & Hygiene Conference

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The formation of the TGC represents the first typhoid genomics consortium modelled around sharing of Typhi genome data for public health benefit with formal structures for governance and engagement with key stake holders. Through the TGC we have carried out the largest global genomic analysis of Typhi populations to date. Subsequently, TyphiNET has provided: (i) guidelines for the inclusion of travel-associated cases in routine typhoid surveillance; (ii) an updated global overview of typhoid populations with a focus on public health; and (iii) a routinely updated typhoid surveillance platform designed for a non-genomics audience. These contributions have the potential to guide future surveillance efforts in addition to empirical therapy and the strategic targeting of control and intervention strategies.

TyphiNET online antimicrobial resistance surveillance dashboard