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Safety and efficacy of ChAdOx1 RVF vaccine against Rift Valley fever in pregnant sheep and goats.

ABSTRACT: Rift Valley fever virus (RVFV) is a zoonotic mosquito-borne virus that was first discovered in Kenya in 1930 and has since spread to become endemic in much of Africa and the Arabian Peninsula. Rift Valley fever (RVF) causes recurrent outbreaks of febrile illness associated with high levels of mortality and poor outcomes during pregnancy-including foetal malformations, spontaneous abortion and stillbirths-in livestock, and associated with miscarriage in humans. No vaccines are available for human use and those licensed for veterinary use have potential drawbacks, including residual virulence that may contraindicate their use in pregnancy. To address this gap, we previously developed a simian adenovirus vectored vaccine, ChAdOx1 RVF, that encodes RVFV envelope glycoproteins. ChAdOx1 RVF is fully protective against RVF in non-pregnant livestock and is also under development for human use. Here, we now demonstrate that when administered to pregnant sheep and goats, ChAdOx1 RVF is safe, elicits high titre RVFV neutralizing antibody, and provides protection against viraemia and foetal loss, although this protection is not as robust for the goats. In addition, we provide a description of RVFV challenge in pregnant goats and contrast this to the pathology observed in pregnant sheep. Together, our data further support the ongoing development of ChAdOx1 RVF vaccine for use in livestock and humans.

SUBMITTER: Stedman A

PROVIDER: S-EPMC6802222 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Safety and efficacy of ChAdOx1 RVF vaccine against Rift Valley fever in pregnant sheep and goats.

Stedman Anna A Wright Daniel D Wichgers Schreur Paul J PJ Clark Madeleine H A MHA Hill Adrian V S AVS Gilbert Sarah C SC Francis Michael J MJ van Keulen Lucien L Kortekaas Jeroen J Charleston Bryan B Warimwe George M GM

NPJ vaccines 20191018

Rift Valley fever virus (RVFV) is a zoonotic mosquito-borne virus that was first discovered in Kenya in 1930 and has since spread to become endemic in much of Africa and the Arabian Peninsula. Rift Valley fever (RVF) causes recurrent outbreaks of febrile illness associated with high levels of mortality and poor outcomes during pregnancy-including foetal malformations, spontaneous abortion and stillbirths-in livestock, and associated with miscarriage in humans. No vaccines are available for human ...[more]

PMID: 31646004

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Project description:Rift Valley fever (RVF) in ungulates and humans is caused by a mosquito-borne RVF phlebovirus (RVFV). Live attenuated vaccines are used in livestock (sheep and cattle) to control RVF in endemic regions during outbreaks. The ability of two or more different RVFV strains to reassort when co-infecting a host cell is a significant veterinary and public health concern due to the potential emergence of newly reassorted viruses, since reassortment of RVFVs has been documented in nature and in experimental infection studies. Due to the very limited information regarding the frequency and dynamics of RVFV reassortment, we evaluated the efficiency of RVFV reassortment in sheep, a natural host for this zoonotic pathogen. Co-infection experiments were performed, first in vitro in sheep-derived cells, and subsequently in vivo in sheep. Two RVFV co-infection groups were evaluated: group I consisted of co-infection with two wild-type (WT) RVFV strains, Kenya 128B-15 (Ken06) and Saudi Arabia SA01-1322 (SA01), while group II consisted of co-infection with the live attenuated virus (LAV) vaccine strain MP-12 and a WT strain, Ken06. In the in vitro experiments, the virus supernatants were collected 24 h post-infection. In the in vivo experiments, clinical signs were monitored, and blood and tissues were collected at various time points up to nine days post-challenge for analyses. Cell culture supernatants and samples from sheep were processed, and plaque-isolated viruses were genotyped to determine reassortment frequency. Our results show that RVFV reassortment is more efficient in co-infected sheep-derived cells compared to co-infected sheep. In vitro, the reassortment frequencies reached 37.9% for the group I co-infected cells and 25.4% for the group II co-infected cells. In contrast, we detected just 1.7% reassortant viruses from group I sheep co-infected with the two WT strains, while no reassortants were detected from group II sheep co-infected with the WT and LAV strains. The results indicate that RVFV reassortment occurs at a lower frequency in vivo in sheep when compared to in vitro conditions in sheep-derived cells. Further studies are needed to better understand the implications of RVFV reassortment in relation to virulence and transmission dynamics in the host and the vector. The knowledge learned from these studies on reassortment is important for understanding the dynamics of RVFV evolution.

Project description:Uganda has had repeated outbreaks of Rift Valley fever (RVF) since March 2016 when human and livestock cases were reported in Kabale after a long interval. The disease has a complex and poorly described transmission patterns which involves several mosquito vectors and mammalian hosts (including humans). We conducted a national serosurvey in livestock to determine RVF virus (RVFV) seroprevalence, risk factors, and to develop a risk map that could be used to guide risk-based surveillance and control measures. A total of 3,253 animals from 175 herds were sampled. Serum samples collected were screened at the National Animal Disease Diagnostics and Epidemiology Centre (NADDEC) using a competition multispecies anti-RVF IgG ELISA kit. Data obtained were analyzed using a Bayesian model that utilizes integrated nested Laplace approximation (INLA) and stochastic partial differential equation (SPDE) approaches to estimate posterior distributions of model parameters, and account for spatial autocorrelation. Variables considered included animal level factors (age, sex, species) and multiple environmental data including meteorological factors, soil types, and altitude. A risk map was generated by projecting fitted (mean) values, from a final model that had environmental factors onto a spatial grid that covered the entire domain. The overall RVFV seroprevalence was 11.3% (95% confidence interval: 10.2-12.3%). Higher RVFV seroprevalences were observed in older animals compared to the young, and cattle compared to sheep and goats. RVFV seroprevalence was also higher in areas that had (i) lower precipitation seasonality, (ii) haplic planosols, and (iii) lower cattle density. The risk map generated demonstrated that RVF virus was endemic in several regions including those that have not reported clinical outbreaks in the northeastern part of the country. This work has improved our understanding on spatial distribution of RVFV risk in the country as well as the expected burden of the disease in livestock.

Project description:Rift Valley fever virus (RVFV) is a mosquito-borne RNA virus of the Phlebovirus genus in the phenuviridae family. Its genome is trisegmented with small (S), medium (M) and large (L) fragments. In nature, the virus exists as a single serotype that is responsible for outbreaks of Rift Valley fever (RVF), a zoonotic disease that often occurs in Africa and the Middle East. RVFV genomes are thought to undergo both recombination and reassortment and investigations of these events is important for monitoring the emergence of virulent strains and understanding the evolutionary characteristics of this virus. The aim of this study was to characterize the genomes of RVFV isolates from cattle, sheep, and goats collected during an interepidemic period in Kenya between June 2016 and November 2021. A total of 691 serum samples from cattle (n = 144), goats (n = 185) and sheep (n = 362) were analysed at the Central Veterinary Laboratories. The competitive IgM-capture ELISA, was used to screen the samples; 205 samples (29.67%) tested positive for RVFV. Of the 205 positive samples, 42 (20.5%) were from cattle, 57 (27.8%) from goats, and 106 (51.7%) from sheep. All the IgM-positive samples were further analyzed by qPCR, and 24 (11.71%) tested positive with Ct values ranging from 14.788 to 38.286. Two samples, 201808HABDVS from sheep and 201810CML3DVS from cattle, had Ct values of less than 20.0 and yielded whole genome sequences with 96.8 and 96.4 coverage, respectively. There was no statistically significant evidence of recombination in any of the three segments and also phylogenetic analysis showed no evidence of reassortment in the two isolated RVFV segments when compared with other isolates of different lineages from previous outbreaks whose genomes are deposited in the GenBank. No evidence of reassortment leaves room for other factors to be the most probable contributors of change in virulence, pathogenicity and emergence of highly virulent strains of the RVFV.

Dataset Information

Safety and efficacy of ChAdOx1 RVF vaccine against Rift Valley fever in pregnant sheep and goats.

Publications

Safety and efficacy of ChAdOx1 RVF vaccine against Rift Valley fever in pregnant sheep and goats.

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