Characterisation of the protective immune response to Rift Valley fever virus after natural exposure or vaccination with ChAdOx1 RVF

Rift Valley fever virus is a single stranded RNA Phlebovirus. Spread by numerous species of mosquito, it is predominantly a disease of livestock including sheep, goats and cattle. Disease is characterised by extremely high mortality in young animals and abortions in pregnant animals, with significant impacts on food security and the wider economy. Spill over into humans results in a wide spectrum of disease from self-limiting febrile illness to haemorrhagic fever and death. RVFV is endemic throughout multiple countries in Africa. Current livestock vaccines have significant drawbacks and due to a lack of licenced human vaccines or therapeutics, RVF is considered a priority pathogen for the development of countermeasures by the WHO and OIE. A safe, effective and cheap vaccine that protects livestock and humans against RVF disease would be invaluable. This thesis seeks to advance this goal on several fronts by facilitating the development of a leading RVF vaccine candidate, ChAdOx1 RVF, co-developed for use in livestock and humans. Firstly, I provide much needed data on the naturally acquired, and likely protective, immune response towards RVFV in Kenyan adults. Showing long-lasting antibodies target both glycoproteins, Gn and Gc, with the former as the principle target of the long-lived neutralising antibody response. I then analysed the factors influencing successful manufacture of ChAdOx1 RVF which has allowed the vaccine to be produced for critical livestock and human trials, improving our understanding of construct design, genetic- and thermo- stability of this vector. I show that neutralising antibodies, strongly associated with protection, were induced in the first humans vaccinated with ChAdOx1 RVF. Characterisation of the cellular and humoral response in livestock then provides important context for the vaccine’s proven ability to elicit protective immunity in multiple target species. Finally, I explore the possibility of improving the utility of the RVF vaccine in livestock by creating a bivalent vaccine which targets an additional disease, Peste-des-petits ruminants. The extremely high efficacy of ChAdOx1 RVF in livestock, including during pregnancy, and the induction of neutralising antibodies in humans is extremely encouraging. ChAdOx1 RVF has the potential to become a vital countermeasure against RVF outbreaks, significantly improving animal and public health from a disease with pandemic potential.