High diversity amongst African Treponema pallidum genomes provides a window into global transmission dynamics of syphilis: A genomic epidemiology study

Background: Global syphilis rates have risen dramatically since the early 2000s. Genomes can be used to inform rational control and intervention strategies by enhancing surveillance and ensuring vaccines have broad global utility. However, although >1000 Treponema pallidum genomes are now available from high-income countries, genomic data from Africa remain limited. Methods: We combined samples from 1198 participants recruited into a genital ulcer aetiology study in Botswana, Ghana, Uganda and Zimbabwe (collected 2022-2023) with 276 samples from national syphilis surveillance in South Africa to generate 147 novel African T. pallidum genomes (collected 2006-2023). Combining these with 167 publicly available African genomes and 1062 genomes from 24 non-African countries, we performed contextual population genomic analyses to understand the T. pallidum genomic diversity and transmission within and between African countries and the rest of the world. Findings: Contrasting with previous studies showing global circulation of highly similar T. pallidum, we found remarkable diversity amongst African T. pallidum. Of 56 sublineages, 20 were exclusively found amongst 6 African countries, 31 were found amongst 24 non-African countries, and 5 were found in both. Sublineage sharing between Africa and the rest of the world was rare, with 83.8% of African syphilis caused by locally circulating sublineages. Only 20.1% of African syphilis was resistant to macrolides (global average = 68.6%); where resistance occurred, this was strongly linked to introduction of global sublineages into Africa. Interpretation: African T. pallidum is characterised by locally circulating strains not found globally. Since sublineage sharing between countries is low, cataloguing African T. pallidum diversity will require intense local sampling in many countries. These findings will inform ongoing strategies for genomic surveillance and vaccine design, whilst contributing to our understanding of the spread of antimicrobial resistance in Africa, enabling refined treatment guidelines based on local data. Funding: Wellcome and the Gates Foundation.