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African horse sickness is a lethal viral disease of equids transmitted by biting midges of the Genus Culicoides . The disease is endemic to sub-Saharan Africa but outbreaks of high mortality and economic impact have occurred in the past in non-endemic regions of Africa, Asia and Southern Europe. Vaccination is critical for the control of this disease but only live attenuated vaccines are currently available. However, there are bio-safety concerns over the use of this type of vaccines, especially in non-endemic countries, and live attenuated vaccines do not have DIVA (Differentiation of Infected from Vaccinated Animals) capacity. In addition, large scale manufacturing of live attenuated vaccines of AHSV represents a significant environmental and health risk and level 3 bio-safety containment facilities are required for their production. A variety of different technologies have been investigated over the years to develop alternative AHSV vaccines, including the use of viral vaccine vectors such Modified Vaccinia Ankara virus (MVA). In previous studies we demonstrated that recombinant MVA expressing outer capsid protein AHSV-VP2 induced virus neutralising antibodies and protection against virulent challenge both in a mouse model and in the horse. However, AHSV-VP2 is antigenically variable and determines the existence of 9 different AHSV serotypes. Immunity against AHSV is serotype-specific and there is limited cross-reactivity between certain AHSV serotypes: 1 and 2, 3 and 7, 5 and 8, 6 and 9. In Africa, multiple serotypes circulate simultaneously and a polyvalent attenuated vaccine comprising different AHSV serotypes is used. We investigated the potential of a polyvalent AHSV vaccination strategy based on combinations of MVA-VP2 viruses each expressing a single VP2 antigen from a specific serotype. We showed that administration of 2 different recombinant MVA viruses, each expressing a single VP2 protein from AHSV serotype 4 or 9, denoted respectively as MVA-VP2(4) and MVA-VP2(9), induced virus neutralising antibodies against the homologous AHSV serotypes. Vaccination was more efficient when vaccines were administered simultaneously than when they were administered sequentially. A third and fourth dose of a different MVA expressing VP2 of AHSV serotype 5, given 4 months later to ponies previously vaccinated with MVA-VP2(4) and MVA-VP2(9), resulted in the induction of VNAb against serotypes 4, 5, 6, 8 and 9. The anamnestic antibody response against AHSV 9 and AHSV 4 following the MVA-VP2(5) boost suggests that it is possible some shared epitopes exist between different serotypes. In conclusion this study showed that it is feasible to develop a polyvalent AHSV vaccination regime based on the use of combinations of MVA-VP2 viruses.

Several laboratories worldwide have recently experienced problems related to serum cytotoxicity with the equine arteritis virus (EAV) neutralisation test (VN) when using Office International des Epizooties (OIE) reference laboratory prescribed rabbit kidney (RK-13) indicator cells. Cytotoxicity can be mistaken for viral cytopathic effect and has led to increasing difficulties in test interpretation, consequently causing disruption to both equine breeding and disease surveillance. Results from experimental and field-derived data suggest that this serum cytotoxicity is associated with use of a tissue-culture-derived equine herpesvirus vaccine, probably manifested through a vaccine-induced anti-cellular antibody response directed against RK-13 cells. Two alternative EAV VN methods were shown to significantly reduce the effects of cytotoxicity (from 73 to

Highlights • A recombinant modified Vaccinia Ankara virus expressing VP2 of African horse sickness virus serotype 9 was generated. • Four horses were vaccinated on days 0 and 20. Three unvaccinated controls were used. • Vaccinated and control horses were challenged intravenously with 107.4TCID50 of AHSV-9 on day 34 of the study. • At challenge, vaccinates had virus neutralising antibodies but were negative for antibodies to AHSV-VP7. • All vaccinates were completely protected against clinical signs of African horse sickness., African horse sickness virus (AHSV) is an arthropod-borne pathogen that infects all species of equidae and causes high mortality in horses. Previously, a recombinant modified vaccinia Ankara (MVA) virus expressing the protein VP2 of AHSV serotype 4 was shown to induce virus neutralising antibodies in horses and protected interferon alpha receptor gene knock-out mice (IFNAR −/−) against virulent AHSV challenge. This study builds on the previous work, examining the protective efficacy of MVA-VP2 vaccination in the natural host of AHSV infection. A study group of 4 horses was vaccinated twice with a recombinant MVA virus expressing the major capsid protein (VP2) of AHSV serotype 9. Vaccinated animals and a control group of unvaccinated horses were then challenged with a virulent strain of AHSV-9. The vaccinated animals were completely protected against clinical disease and also against viraemia as measured by standard end-point dilution assays. In contrast, all control horses presented viraemia after challenge and succumbed to the infection. These results demonstrate the potential of recombinant MVA viruses expressing the outer capsid VP2 of AHSV as a protective vaccine against AHSV infection in the field.