Promising first results in human clinical trial of Rift Valley fever vaccine

Rift Valley fever virus, a pathogen to ruminants, camelids, and humans, is an emerging mosquito-borne bunyavirus currently endemic to Africa and the Arabian Peninsula. Although animals are primarily infected via mosquito bites, humans mainly become infected following contact with infected tissues or fluids of infected animals. “There is an urgent need for adequate countermeasures, especially for humans, because effective therapeutics or vaccines are not yet available”, explains Paul Wichgers Schreur of Wageningen Bioveterinary Research (WBVR, part of Wageningen University & Research). WBVR is the leading partner in the CEPI funded LARISSA* consortium that develops the live-attenuated hRVFV-4s vaccine beyond initial proof of concept. This vaccine was shown to be safe and efficacious in various rodent and ruminant animal models including pregnant sheep. Safety was also confirmed in a non-human primate marmoset model and in reversion to virulence studies with lambs. In 2022 the safety, tolerability, and immunogenicity of the hRVFV-4s vaccine was subsequently assessed in humans for the first time as a next step in the vaccine development.

Human trial

Between August and December, 2022, 75 healthy participants aged between 18 and 45 years, were vaccinated with various doses of hRVFV-4s in a first-in-human, single-centre, randomised, double-blind, placebo-controlled trial in Belgium.

None of the vaccinated participants reported serious adverse events or severe vaccine-related adverse events. Pain at the injection site was most frequently reported as solicited local adverse event. Besides this, headache and fatigue were reported as solicited systemic adverse events. No vaccine virus RNA was detected in any of the blood, saliva, urine, and semen samples.

Rift Valley fever virus nucleocapsid antibody responses were detected in most vaccinated participants irrespective of the administered dose (43 of 60 (72%). In contrast, a clear dose-response relationship was observed for neutralising antibodies on day 28 with four (20%) of 20 participants responding in the low-dose group, 13 (65%) of 20 responding

in the medium-dose group, and all participants (20 [100%] of 20) responding in the high-dose group. Consistent with the antibody responses, cellular immune responses against the nucleocapsid protein were detected in all dose groups, whereas a more dose-dependent response was observed for the Gn and Gc surface glycoproteins. Neutralising antibody titres declined over time, whereas nucleocapsid antibody responses remained relatively stable for at least 6 months.

Outcome

The hRVFV-4s vaccine showed a favourable safety profile, showed good tolerability, and induced a strong humoral and cellular immune response in healthy individuals. Given these promising outcomes, further evaluation of the vaccine in populations at highest risk for Rift Valley fever is warranted.

* This study was done within the LARISSA project and was funded by the Coalition for Epidemic Preparedness Innovations (CEPI) with support from the EU Horizon 2020 programme.