Characterization of Protection Afforded by a Bivalent Virus-Like Particle Vaccine against Bluetongue Virus Serotypes 1 and 4 in Sheep

Abstract

BackgroundBluetongue virus (BTV) is an economically important, arthropod borne, emerging pathogen in Europe, causing disease mainly in sheep and cattle. Routine vaccination for bluetongue would require the ability to distinguish between vaccinated and infected individuals (DIVA). Current vaccines are effective but are not DIVA. Virus-like particles (VLPs) are highly immunogenic structural mimics of virus particles, that only contain a subset of the proteins present in a natural infection. VLPs therefore offer the potential for the development of DIVA compatible bluetongue vaccines.Methodology/Principal FindingsMerino sheep were vaccinated with either monovalent BTV-1 VLPs or a bivalent mixture of BTV-1 VLPs and BTV-4 VLPs, and challenged with virulent BTV-1 or BTV-4. Animals were monitored for clinical signs, antibody responses, and viral RNA. 19/20 animals vaccinated with BTV-1 VLPs either alone or in combination with BTV-4 VLPs developed neutralizing antibodies to BTV-1, and group specific antibodies to BTV VP7. The one animal that showed no detectable neutralizing antibodies, or group specific antibodies, had detectable viral RNA following challenge but did not display any clinical signs on challenge with virulent BTV-1. In contrast, all control animals' demonstrated classical clinical signs for bluetongue on challenge with the same virus. Six animals were vaccinated with bivalent vaccine and challenged with virulent BTV-4, two of these animals had detectable viral levels of viral RNA, and one of these showed clinical signs consistent with BTV infection and died.ConclusionsThere is good evidence that BTV-1 VLPs delivered as monovalent or bivalent immunogen protect from bluetongue disease on challenge with virulent BTV-1. However, it is possible that there is some interference in protective response for BTV-4 in the bivalent BTV-1 and BTV-4 VLP vaccine. This raises the question of whether all combinations of bivalent BTV vaccines are possible, or if immunodominance of particular serotypes could interfere with vaccine efficacy.

Rapid Generation of Replication-Deficient Monovalent and Multivalent Vaccines for Bluetongue Virus: Protection against Virulent Virus Challenge in Cattle and Sheep

“…These results demonstrate that the multivalent cocktail vaccine afforded complete protection in sheep against each virulent serotype and that there was no evidence of interference between the serotypes present in the cocktail. These results are very similar to those of previous vaccine efficacy studies performed in sheep with cocktails of virus-like particles (VLPs) (2 or multiple serotypes), where VLPs of multiple BTV serotypes were shown to be completely protective against homologous virulent virus challenges with no interference between serotypes (34)(35)(36). These results are also consistent with the commercially available live attenuated and inactivated virus vaccines, where limited interference was observed in the cocktail BTV vaccines.…”

Current and next-generation bluetongue vaccines: Requirements, strategies, and prospects for different field situations

“…Booster vaccination with this cocktail vaccine protected against homologous challenge to all five serotypes after 4 and 14 months post-vaccination and partially against some heterologous serotypes . When testing a cocktail of VLPs of serotypes 1 and 4; however, some interference in protective response for serotype 4 was measured (Perez de Diego et al, 2011). Large animal experiments to test the efficacy of VLPs have been undertaken with 50-200 sheep per trial.…”

The MultiBac Baculovirus/Insect Cell Expression Vector System for Producing Complex Protein Biologics

“…In the three decades since these hallmark contributions, baculovirus expression has become a widely adopted technology for academic and industrial applications, in research and development as well as manufacturing, and a wide range of proteins have been made by baculovirus expression vector systems (BEVS) [2,[4][5][6][7]. Multicomponent virus like particles (VLPs) resembling complex virus shells, have been produced successfully with BEVS, including VLPs from bluetongue, rotavirus and others [8][9][10][11]. More recently, the first baculovirus produced proteins have been approved in the therapy or prevention of human disease, including vaccines against influenza …”