Chimpanzee Adenovirus Vaccine Provides Multispecies Protection against Rift Valley Fever

Abstract

Rift Valley Fever virus (RVFV) causes recurrent outbreaks of acute life-threatening human and livestock illness in Africa and the Arabian Peninsula. No licensed vaccines are currently available for humans and those widely used in livestock have major safety concerns. A 'One Health' vaccine development approach, in which the same vaccine is co-developed for multiple susceptible species, is an attractive strategy for RVFV. Here, we utilized a replication-deficient chimpanzee adenovirus vaccine platform with an established human and livestock safety profile, ChAdOx1, to develop a vaccine for use against RVFV in both livestock and humans. We show that single-dose immunization with ChAdOx1-GnGc vaccine, encoding RVFV envelope glycoproteins, elicits high-titre RVFV-neutralizing antibody and provides solid protection against RVFV challenge in the most susceptible natural target species of the virus-sheep, goats and cattle. In addition we demonstrate induction of RVFV-neutralizing antibody by ChAdOx1-GnGc vaccination in dromedary camels, further illustrating the potency of replication-deficient chimpanzee adenovirus vaccine platforms. Thus, ChAdOx1-GnGc warrants evaluation in human clinical trials and could potentially address the unmet human and livestock vaccine needs.

Figure 1. ChAdOx1-GnGc vaccination protects sheep, goats and cattle against RVFV challenge.

Kaplan-Meier plots are used to infer vaccine-mediated protection using the primary endpoint of qRT-PCR detection of viraemia over a 14-day period following challenge (a, sheep; d, goats; g, cattle). Peak viraemia levels for each species are shown as relative plaque-forming units (pfu; bars represent means), estimated by extrapolation from a standard curve generated using serial dilutions of RNA isolated from the challenge virus and assayed using the same method as the test samples (b, sheep; e, goats; h, cattle). Rectal temperature data measured at the same time of day during post-challenge monitoring are shown by vaccine allocation (c, sheep; f, goats; i, cattle), presented as means and standard errors. The respective group sizes for each species are detailed in the Methods section.

Figure 2. ChAdOx1-GnGc elicits high-titre RVFV neutralizing antibody.

For each species means and standard errors of RVFV neutralizing antibody titres measured 28 days post-vaccination are shown in (a) and titres measured 14 days post-challenge are shown in (c). Pooled pre-challenge (b) and post-challenge (d) neutralizing antibody data from vaccinees (ChAdOx1-GnGc groups and Smithburn group) are shown, with each point representing an animal and bars representing the means and standard errors. Neutralizing antibody titres measured 28 days post-ChAdOx1-GnGc immunization in dromedary camels are shown in (b). All analyses are by the Kruskal-Wallis test, with Dunn’s correction for multiple comparisons between groups. The respective group sizes for each species are detailed in the Methods section. ns –not statistically significant (p > 0.05). The dashed line represents the detection limit of the assay.

Figure 3. ChAdOx1-GnGc elicits comparable RVFV neutralizing antibody titres in Kenyan and UK livestock.

Sheep and cattle in the UK were immunized with either ChAdOx1-GnGc (n = 4/species), ChAdOx1-GnGc with Matrix-Q™ (n = 4/species) or placebo (n = 3 sheep, n = 4 cattle) using the same vaccine dose and volumes as in studies in Kenya (see Methods). RVFV neutralizing antibody titres were then measured over a 3-month period before culling. As in the Kenyan studies, Matrix-Q™ did not enhance the magnitude of the response in either species across the study period and the range of titres across time points were comparable to those in sheep (Kruskal-Wallis test p = 0.6) and cattle (Kruskal-Wallis test p = 0.9) in Kenya. Black circles–ChAdOx1-GnGc, clear circles–ChAdOx1-GnGc with Matrix-Q™, grey circles–placebo. The dashed line represents the detection limit of the assay.