Rift Valley fever immuno-epidemiology, disease severity, and vaccine response among human populations in Uganda

BACKGROUND: Rift Valley fever (RVF) is a mosquito-borne viral infection of ruminants and humans in Africa and the Arabian Peninsula with potential for global spread. Knowledge gaps exist on the burden of RVF and disease manifestations, and currently no licensed vaccines exist for humans. This projectstudied the RVF seroprevalence, risk factors and disease manifestations, and assessed the response to the ChAdOx1 RVF candidate vaccine among humans in Uganda. METHODS: This research project involved four studies. Study 1 was a systematic review and meta-analysis of the RVF clinical manifestations in humans. Study 2 was a cross-sectional seroprevalence and risk factor assessment survey that analysed data and tested stored plasma specimens for RVF antibodies in Uganda. Study 3 analysed cross-sectional data and enrolled into 1 year follow up a cohort of RVF survivors to study the clinical manifestations and immune response to the wildtype virus infection in Uganda. Study 4 was a phase 1 safety and immunogenicity clinical trial of the novel ChAdOx1RVF vaccine among healthy adults in Uganda. RESULTS: RVF seroprevalence was high (10.2%; 95% confidence interval (CI) 8.6 - 12.1) and associated with age, ethnicity, and owning cattle and poultry. The systematic review and meta-analysis established nine clinical syndromes and that RVF causes 21% (95% CI 14 - 29) mortality, mostly among hospitalised patients. However, among cases reported to the Uganda health care system during the Uganda outbreaks of November 2017 to March 2020, 70% (n=28/40) were hospitalised, out of whom 64% (n=18/28) died. Survivors recovered without sequalae and developed high wellsustained IgG antibodies. Healthy adults administered the ChAdOx1RVF vaccine showed no safety concern and robust humoral and cellular immune responses were elicited. CONCLUSION: This PhD project provides insight into the exposure burden of RVF among populations at risk, the high mortality among hospitalised patients, and immune response among survivors in Uganda. It also provides encouraging results on the safety and immunogenicity of the ChAdOx1 RVF vaccine among humans. Interventions should be developed to prevent infections and improve patient outcomes.