Feenstra Femke, Maris-Veldhuis Mieke, Daus Franz J, Tacken Mirriam G J, Moormann Rob J M, van Gennip René G P, van Rijn Piet A
Central Veterinary Institute of Wageningen UR (CVI), Department of Virology, P.O. Box 65, 8200 AB, Lelystad, The Netherlands; Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Central Veterinary Institute of Wageningen UR (CVI), Department of Virology, P.O. Box 65, 8200 AB, Lelystad, The Netherlands.
Vaccine. 2014 Dec 12;32(52):7108-14. doi: 10.1016/j.vaccine.2014.10.033. Epub 2014 Oct 31.
Bluetongue virus (BTV) causes Bluetongue in ruminants and is transmitted by Culicoides biting midges. Vaccination is the most effective measure to control vector borne diseases; however, there are 26 known BTV serotypes showing little cross protection. The BTV serotype is mainly determined by genome segment 2 encoding the VP2 protein. Currently, inactivated and live-attenuated Bluetongue vaccines are available for a limited number of serotypes, but each of these have their specific disadvantages, including the inability to differentiate infected from vaccinated animals (DIVA). BTV non-structural proteins NS3 and NS3a are not essential for virus replication in vitro, but are important for cytopathogenic effect in mammalian cells and for virus release from insect cells in vitro. Recently, we have shown that virulent BTV8 without NS3/NS3a is non-virulent and viremia in sheep is strongly reduced, whereas local in vivo replication leads to seroconversion. Live-attenuated BTV6 without NS3/NS3a expression protected sheep against BTV challenge. Altogether, NS3/NS3a knockout BTV6 is a promising vaccine candidate and has been named Disabled Infectious Single Animal (DISA) vaccine. Here, we show serotype-specific protection in sheep by DISA vaccine in which only genome segment 2 of serotype 8 was exchanged. Similarly, DISA vaccines against other serotypes could be developed, by exchange of only segment 2, and could therefore safely be combined in multi-serotype cocktail vaccines with respect to reassortment between vaccine viruses. Additionally, NS3 antibody responses are raised after natural BTV infection and NS3-based ELISAs are therefore appropriate tools for DIVA testing accompanying the DISA vaccine. To enable DIVA, we developed an experimental NS3 ELISA. Indeed, vaccinated sheep remained negative for NS3 antibodies, whereas seroconversion for NS3 antibodies was associated with viremia after heterologous BTV challenge.
蓝舌病病毒（BTV）可导致反刍动物患蓝舌病，并通过库蠓叮咬传播。疫苗接种是控制媒介传播疾病的最有效措施；然而，已知有26种BTV血清型，它们之间几乎没有交叉保护作用。BTV血清型主要由编码VP2蛋白的基因组片段2决定。目前，灭活和减毒活蓝舌病疫苗仅适用于少数血清型，但每种疫苗都有其特定的缺点，包括无法区分感染动物和接种疫苗的动物（DIVA）。BTV非结构蛋白NS3和NS3a在体外对病毒复制不是必需的，但对哺乳动物细胞中的细胞病变效应以及体外从昆虫细胞中释放病毒很重要。最近，我们发现缺失NS3/NS3a的强毒BTV8无毒，绵羊的病毒血症显著降低，而局部体内复制会导致血清转化。缺失NS3/NS3a表达的减毒活BTV6可保护绵羊免受BTV攻击。总之，缺失NS3/NS3a的BTV6是一种有前景的疫苗候选物，已被命名为失活感染单动物（DISA）疫苗。在这里，我们展示了仅交换血清型8的基因组片段2的DISA疫苗在绵羊中具有血清型特异性保护作用。同样，通过仅交换片段2，可以开发针对其他血清型的DISA疫苗，因此就疫苗病毒之间的重配而言，可以安全地将其组合成多血清型混合疫苗。此外，自然感染BTV后会产生NS3抗体反应，因此基于NS3的ELISA是伴随DISA疫苗进行DIVA检测的合适工具。为了实现DIVA，我们开发了一种实验性NS3 ELISA。事实上，接种疫苗的绵羊NS3抗体仍为阴性，而异源BTV攻击后，NS3抗体的血清转化与病毒血症相关。
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