Introduction. Recent Rift Valley fever (RVF) epidemiology in eastern Africa region is characterized by widening geographic range and increasing frequency of small disease clusters. Here we conducted studies in southwestern (SW) Uganda region that has since 2016 reported increasing RVF activities. Methods. A 22-month long hospital-based study in three districts of SW Uganda targeting patients with acute febrile illness (AFI) or unexplained bleeding was followed by a cross-sectional population-based human-animal survey. We then estimated RVFV force of infection (FOI) and yearly cases using the age-structured seroprevalence data and conducted genomic phylodynamic modelling of RVFV isolates. Results. Overall RVF prevalence was 10.5% (205 of 1,968) among febrile or hemorrhagic cases, including 5% with acute (PCR or IgM positive) infection, averaging 5 cases per month. Community-based serosurvey recorded prevalence of 11.8% (88 of 743) among humans and 14.6% (347 of 2,383) in livestock. Expected yearly human RVF cases were 314-2,111 per 1,369 km2 in SW Uganda versus 0-711 in comparable regions of Kenya and Tanzania. Viral genomic studies identified RVFV lineage C, sub-clade C.2.2, as the circulating strain in SW Uganda since 2019. Lineage C strain has undergone recent rapid evolution and clonal expansion resulting in four sub-clades, C.1.1, C.1.2, C.2.1, and C.2.2, that are more adept at establishing endemicity in new territories. Conclusions. We demonstrate an atypical RVF hyperendemic region in SW Uganda characterized by sustained human clinical RVF cases, unusually high population prevalence, and high number of expected yearly human cases, associated in part with emergence of new RVFV sub-lineages.

The authors have declared no competing interest.

Funding for this project was provided by the US National Institute of Allergy and Infectious Disease/National Institutes of Health (NIAID/NIH) grants number U01AI151799 through the Centre for Research in Emerging Infectious Diseases-East and Central Africa (CREID-ECA). Genomic work in Dr Samuel Oyolas laboratory was supported by the Global Health EDCTP3 (Grant Agreement no. 101103171) Joint Undertaking and its members as well as Bill and Melinda Gates Foundation and the Rockefeller Foundation. Laboratory testing at UVRI was supported by US Centers for Disease Control and Prevention through a grant to the institute. Silvia Situma received training support from the NIH/Fogarty International Centers D43 training grant number D43TW011519 awarded to Washington State University and University of Nairobi. John Schieffelin was supported by NIAID/NIH grant number 5U01AI151812 through the West Africa Research Network in Infectious Diseases (WARN-ID).

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:

Ethical approvals for this study were provided by the Uganda Virus Research Institute Research Ethics Committee (Study Number GC/127/849) and the Uganda National Council for Science and Technology (Study Number HS1713ES).

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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors