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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.

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Outbreaks of bluetongue disease have occurred in Spain six times and have been caused by the following serotypes of bluetongue virus (BTV), in chronological order: BTV10, BTV2, BTV4, BTV1 and BTV8. Serotypes BTV1, BTV2 and BTV4 may have entered the country in Culicoides transported by wind; BTV8 via infected animal movements; and BTV10 across the Portuguese border. The evolution of each serotype has been different: BTV1, BTV4 and BTV10 spread throughout mainland Spain; BTV2 did not spread from the Balearic Islands to the Iberian Peninsula; and BTV8 has proven very poor at spreading throughout mainland Spain. The significant economic impact of the disease has led authorities to adopt control and eradication measures, which have evolved as new diagnostic tools and vaccines have become available. This review describes BTV infection in Spain, and it focuses on the clinical disease produced by each serotype, the Culicoides species which were present at what time, the origin of the virus and the control measures adopted. In the field, it has proven necessary to vaccinate livestock against each new BTV serotype as it arrived. Therefore, future eradication strategies should focus on developing polyvalent vaccines and vaccines that allow the differentiation of infected and vaccinated animals. As of 1 January 2013, the Iberian Peninsula is considered a restricted area for BTV1, and a small zone in southern Spain is a restricted area for BTV4, which includes the little BTV8 restricted area. Serotypes BTV1 and BTV4 were detected in sentinel animals in January and November and in March 2012, respectively. The last BTV8 positive animal was detected in November 2010, which implies that in the coming months, Spain may be declared free of BTV8.