Realising the potential of a safe and protective universal vaccine for African horse sickness disease
Lead Research Organisation:
London School of Hygiene & Tropical Medicine
Department Name: Department of Pathogen Molecular Biology
Abstract
African horse sickness is a devastating viral disease of horses with a ~90% mortality rate. AHSV and Bluetongue Virus, BTV, that affects livestock, are closely related and spread by the same Culicoides vectors, prevalent in UK & Europe. Currently available vaccines against AHSV are neither safe nor effective and a safe vaccine that protects against all AHSV serotypes is desirable. Enabled by BBSRC funding we have designed novel vaccine candidates for all nine AHSV serotypes which are strictly replication-deficient in normal cells or animal hosts and demonstrated their suitability in ponies. To investigate their potential for commercialisation, we will investigate the duration of protection in ponies; develop a unique universal vaccine for all serotypes; define the immune response and those that are responsible for cross-protection; and develop a DIVA vaccine strain. Our data will support a broadly protective vaccine with easy production and good shelf life for protection against AHSV
People |
ORCID iD |
| Polly Roy (Principal Investigator) |
Publications
| Description | 9 ECRA AHSV vaccines have been generated representing all 9 serotype. 6 horses were inoculated with 2 cocktails which together contained all 9 serotypes of ECRA AHSV, to determine the safety and efficacy of these cocktails as a potential vaccine. Horses were monitored for the development of clinical signs, and serum samples were collected regularly. No animal developed clinical symptoms of AHSV although some did develop mild clinical signs consistent with the induction of an immune response. All positive animals showed evidence of seroconversion, and demonstrated the production of neutralising antibodies against all 9 serotypes of AHSV. These data demonstrate that a cocktail of 9 ECRA AHSV viruses is a safe and viable vaccination strategy against AHSV. |
| Exploitation Route | The safety and efficacy of the vaccine has now been tested and the vaccine has proven to be highly successful. We are now hoping to commercialise this vaccine through appropriate collaborations and industrial partners to make it available to commercially. |
| Sectors | Agriculture, Food and Drink,Leisure Activities, including Sports, Recreation and Tourism |
| Description | 9 ECRA AHSV viruses is a safe and viable vaccination strategy against AHSV. |
| First Year Of Impact | 2019 |
| Sector | Agriculture, Food and Drink,Leisure Activities, including Sports, Recreation and Tourism |
| Impact Types | Economic |
| Description | The RNA interactome necessary and sufficient for Orbivirus genome packaging |
| Amount | £743,074 (GBP) |
| Funding ID | BB/V008846/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 04/2021 |
| End | 03/2024 |
| Description | The dynamics of cell entry and genome replication in a model complex virus |
| Amount | £1,793,281 (GBP) |
| Funding ID | 221749/Z/20/Z |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 06/2021 |
| End | 05/2026 |
| Title | AHSV1 VP6-expressing cell line |
| Description | Cell line expressing AHSV1 VP6 for vaccine development. |
| Type Of Material | Cell line |
| Provided To Others? | No |
| Impact | Complementary cell line for vaccine development. |
| Title | Complementing cell line for AHSV |
| Description | Complementing cell line constitutively expressing AHSV VP6 protein for the development of disable replication viruses and vaccine generation. |
| Type Of Material | Cell line |
| Provided To Others? | No |
| Impact | This cell line can be used for recovery of replication deficient viruses, candidates for vaccine development |
| Title | ECRA AHSV 9 Serotype Cocktail Trial |
| Description | 6 horses were inoculated with 2 cocktails that together contained all 9 serotypes of ECRA AHSV, to determine the safety and efficacy of these cocktails as a potential vaccine. Horses were monitored for the development of clinical signs, and serum samples were collected regularly. |
| Type Of Material | Physiological assessment or outcome measure |
| Year Produced | 2020 |
| Provided To Others? | No |
| Impact | No animal developed clinical symptoms of AHSV although some did develop mild clinical signs consistent with the induction of an immune response. All positive animals showed evidence of seroconversion, and demonstrated the production of neutralising antibodies against all 9 serotypes of AHSV. These data demonstrate that a cocktail of 9 ECRA AHSV viruses is a safe and viable vaccination strategy against AHSV. |
| Title | ECRA AHSV Vaccine Strains (Serotypes 1- 9) |
| Description | 9 ECRA AHSV vaccines have been generated representing all 9 serotype. These carry 11 premature stop codons within segment 9, which expresses VP6 (an essential structural protein) and NS4 (a minor, non-essential, non-structural protein). Viruses carrying these stop codons cannot express a functional VP6 and so are incapable of replication. Propagation of these viruses is therefore achieved by replication in a complementary BSR cell line stably expressing a functional VP6. To generate DISC AHSV viruses of all 9 serotypes we substituted the outer capsid proteins of the DISC viruses with those for other serotypes, Segment 2 (VP2) and Segment 6 (VP5). Several serotypes required additional substitutions to replicate efficiently; however, ECRA viruses were successfully generated for all 9 serotype. |
| Type Of Material | Biological samples |
| Year Produced | 2019 |
| Provided To Others? | No |
| Impact | Testing virus vaccine strains is essential to support them for commercial development. These have been used in an assessment to determine their ability to elicit a neutralising antibody response. |
| Title | Evaluation of vaccine efficacy |
| Description | Replication-deficient vaccine strains were tested in animals as monovalent or in multivalent combinations and the protection analysed by Elisa and serum neutralisation assays. |
| Type Of Material | Technology assay or reagent |
| Provided To Others? | No |
| Impact | Testing these virus vaccine strains is essential to support them for commercial development |
| Description | Natural host - vaccine testing in horses |
| Organisation | French Agency for Food, Environmental and Occupational Health & Safety (ANSES) |
| Country | France |
| Sector | Public |
| PI Contribution | Development and testing of AHSV vaccine candidates. Optimization of vaccine preparation and storage. |
| Collaborator Contribution | Testing of AHSV vaccine candidates on ponies |
| Impact | African horse sickness virus is one of the most devastating diseases of horses. Since AHSV is closely related to bluetongue virus that recently emerged in Northern Europe and also both are transmitted by the same culicoides vector, AHSV could be expected to emerge outside of its usual geographic boundaries in Africa. The live virus vaccines that are currently used can lead to sufficient viremia for uptake and spreading by insect vectors, reversion to virulence and reassortments. Thus, it is essential to develop highly efficacious vaccines for all AHSV serotypes and such vaccines must be completely safe in horses, generating no viremia. To this end, we generated replication-deficient AHSV variants and assessed their protective efficacy in ponies. Vaccinated animals were completely protected against virulent virus challenge demonstrating the suitability of these deficient viruses as vaccines in animals. |
| Start Year | 2016 |
| Title | Designing attenuated AHSV vaccines (2016) |
| Description | African horse sickness virus (AHSV) is an orbivirus, a member of the Reoviridae family. Nine different serotypes have been described so far. AHSV is vectored by Culicoides spp. to equids, causing diseases with a high mortality rate and dissemination potential thus engendering considerable economic impacts. For development of a safe attenuated vaccine, we previously established a highly efficient reverse genetics (RG) system to generate replication-deficient virus strains for all nine serotypes and demonstrated the vaccine potential of these strains in type I interferon receptor (IFNAR)-knockout mice (1). Here, we evaluated the protective efficacies of these replication-deficient viruses in AHSV natural hosts, e.g. ponies. One monoserotype (def-AHSV4) vaccine and one multivalent cocktail (def-AHSV1/4/6/8) vaccine were tested and ponies were challenged with a virulent AHSV4. All vaccinated ponies were completely protected from virulent homologous virus challenge and did not develop AHSV clinical symptoms. Furthermore, the cocktail def-AHSV vaccinated ponies produced neutralizing antibodies against all serotypes present in the cocktail, and a foal born during the trial was healthy and had no viremia. These results validate the suitability of these deficient strains as a new generation of vaccines for AHSV. IMPORTANCE African horse sickness virus is one of the most devastating diseases of horses. Since AHSV is closely related to bluetongue virus that recently emerged in Northern Europe and also both are transmitted by the same culicoides vector, AHSV could be expected to emerge outside of its usual geographic boundaries in Africa. The live virus vaccines that are currently used can lead to sufficient viremia for uptake and spreading by insect vectors, reversion to virulence and reassortments. Thus, it is essential to develop highly efficacious vaccines for all AHSV serotypes and such vaccines must be completely safe in horses, generating no viremia. To this end, we generated replication-deficient AHSV variants and assessed their protective efficacy in ponies. Vaccinated animals were completely protected against virulent virus challenge demonstrating the suitability of these deficient viruses as vaccines in animals. |
| IP Reference | |
| Protection | Patent application published |
| Year Protection Granted | 2016 |
| Licensed | No |
| Impact | African horse sickness virus (AHSV), an orbivirus in the Reoviridae family with nine different serotypes, causes devastating disease in equids. The virion particle is composed of seven proteins organized in three concentric layers, an outer layer made of VP2 and VP5, a middle layer made of VP7, and inner layer made of VP3 that encloses a replicase complex of VP1, VP4, and VP6 and a genome of 10 double-stranded RNA segments. In this study, we sought to develop highly efficacious candidate vaccines against all AHSV serotypes, taking into account not only immunogenic and safety properties but also virus productivity and stability parameters, which are essential criteria for vaccine candidates. To achieve this goal, we first established a highly efficient reverse genetics (RG) system for AHSV serotype 1 (AHSV1) and, subsequently, a VP6-defective AHSV1 strain in combination with in trans complementation of VP6. This was then used to generate defective particles of all nine serotypes, which required the exchange of two to five RNA segments to achieve equivalent titers of particles. All reassortant-defective viruses could be amplified and propagated to high titers in cells complemented with VP6 but were totally incompetent in any other cells. Furthermore, these replication-incompetent AHSV particles were demonstrated to be highly protective against homologous virulent virus challenges in type I interferon receptor (IFNAR)-knockout mice. Thus, these defective viruses have the potential to be used for the development of safe and stable vaccine candidates. The RG system also provides a powerful tool for the study of the role of individual AHSV proteins in virus assembly, morphogenesis, and pathogenesis. IMPORTANCE: African horse sickness virus is transmitted by biting midges and causes African horse sickness in equids, with mortality reaching up to 95% in naive horses. Therefore, the development of efficient vaccines is extremely important due to major economic losses in the equine industry. Through the establishment of a highly efficient RG system, replication-deficient viruses of all nine AHSV serotypes were generated. These defective viruses achieved high titers in a cell line complemented with VP6 but failed to propagate in wild-type mammalian or insect cells. Importantly, these candidate vaccine strains showed strong protective efficacy against AHSV infection in an IFNAR(-/-) mouse model. |
| Description | Microbiology Society Conference, 2019, UK |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Professional Practitioners |
| Results and Impact | Talk about the article: Mapping the pH sensors critical for host cell entry by a complex noneveloped virus. Weining Wu, Cristina C. Celma, Adeline Kerviel, Polly Roy |
| Year(s) Of Engagement Activity | 2019 |