Development of a vaccination strategy for the control of malignant catarrhal fever

该提案旨在进一步发展和完善我们最近在控制恶性卡他热（MCF）的免疫策略方面取得的突破，方法是通过改进佐剂（与病毒抗原一起给予的化合物，有助于指导对传染性病原体的免疫反应类型，并改善其强度和持续时间——这对一种好的疫苗都很重要）和在坦桑尼亚进行实地试验，测试潜在的疫苗问题。恶性卡他热（MCF）是牛、鹿、野牛和猪的一种致命疾病，由一组病毒（疱疹病毒）引起，包括羊疱疹病毒-2和羊疱疹病毒-1。这些病毒有效地感染它们的天然宿主（OvHV-2感染绵羊，AlHV-1感染角马），不引起明显的疾病，但在疾病易感动物中，MCF通常是致命的，因此对动物福利和生产产生深远影响。该病毒通过气溶胶或接触传播，大多数羔羊或角马幼崽在出生后不久就被感染，然后能够感染易感的牛。目前还没有针对MCF的疫苗，但我们最近开发了一种在实验研究中效果良好的潜在疫苗。AlHV-1 MCF对撒哈拉以南非洲牧民社区的影响是深远的，具有社会、经济和福利影响。在坦桑尼亚和肯尼亚进行的两项MCF研究发现，研究地区的发病率分别为6%和10%。牛的高死亡率意味着MCF被认为是角马接触地区最重要的疾病风险。坦桑尼亚的实地试验对于确定AlHV-1 MCF疫苗的效力至关重要，并将为必要时进一步改进疫苗提供信息。重要的是确定保护受感染牛的免疫反应的不同组成部分的贡献。虽然病毒中和抗体与保护之间存在很强的相关性，但我们需要确定细胞介导免疫（CMI）包括细胞毒性T细胞活性（CTL）是否参与保护。此外，我们需要鉴定能刺激牛保护性免疫反应的病毒成分抗原。这将允许开发针对羊疱疹病毒-2 （OvHV-2，一种与AlHV-1高度遗传相关的病毒）MCF的疫苗，这不仅是非洲的一个问题，而且是世界范围内的一个问题，因为自然携带动物和疾病易感动物混合在一起。这种双重方法很重要，因为AlHV-1和OvHV-2 MCF疫苗比单独使用任何一种疫苗更有可能被商业化。这项研究将使用确定的新一代佐剂化合物来改进目前的AlHV-1 MCF疫苗，并在坦桑尼亚进行实地试验。只需很少的额外努力，我们就可以识别出AlHV-1的保护性病毒成分抗原，并使用等效的OvHV-2抗原来尝试针对OvHV-2 MCF的疫苗。这增加了MCF疫苗商业化的机会。这项工作的预期主要成果将是实施一项疫苗疾病控制战略，以便在本项目结束后的5年内对MCF造成的动物死亡率产生影响，并改善牧民和农民的生活质量。

This proposal aims to further develop and refine our recent breakthrough of an immunisation strategy for the control of malignant catarrhal fever (MCF) by increasing the magnitude and duration of immunity through improved adjuvancy (compounds given along with virus antigens that help direct the type of immune response to an infectious agent and improve its magnitude and duration - all important for a good vaccine) and testing the potential vaccine in field trials in Tanzania where MCF is a problem. Malignant catarrhal fever (MCF) is a fatal disease of cattle, deer, bison and pigs, caused by a group of viruses (herpesviruses) including ovine herpesvirus-2 and alcelaphine herpesvirus-1. These viruses infect their natural hosts efficiently (sheep for OvHV-2 and wildebeest for AlHV-1), causing no apparent disease, but in the disease-susceptible animals, MCF is usually fatal and consequently has a profound affect on animal welfare and production. The virus is transmitted by aerosol or by contact and most lambs or wildebeest calves are infected shortly after birth and are capable of then infecting susceptible cattle. There is no vaccine currently available for MCF, but we have recently developed a potential vaccine that works well in experimental studies. The effect of AlHV-1 MCF on pastoralist communities in sub-Saharan Africa is profound, with social, economic and welfare impact. In two studies of MCF in Tanzania and Kenya, incidence in studied areas was found to be 6% and 10% respectively. The high rate of cattle death meant that MCF was rated as the most important disease risk in areas with wildebeest contact. Field trials in Tanzania are essential to determine the efficacy of the alcelaphine herpesvirus-1 (AlHV-1) MCF vaccine and will inform further refinement of the vaccine as necessary. It is important to determine the contribution of the different components of an immune response that will protect affected cattle. Although there is a strong correlation between virus-neutralising antibody and protection, we need to determine whether cell-mediated immunity (CMI) including cytotoxic T cell activity (CTL) is involved or not in protection. Furthermore, we need to identify virus component antigens that stimulate protective immune responses in cattle. This will allow vaccine development for ovine herpesvirus-2 (OvHV-2, a highly genetically-related virus to AlHV-1) MCF, which is a problem not only in Africa but worldwide where natural carrier animals and disease-susceptible animals mix. This dual approach is important as there is more likely to be a commercial uptake of an AlHV-1 and OvHV-2 MCF vaccine than either one singly. This study will use defined new generation adjuvant compounds to improve the current AlHV-1 MCF vaccine and test this in field trials in Tanzania. For very little extra effort, we can identify the protective virus component antigens of AlHV-1 and use the equivalent OvHV-2 ones to attempt a vaccine to OvHV-2 MCF. This increases the chances of commercial uptake of an MCF vaccine. The expected principal outcome of this work wil be implementation of a vaccine disease control strategy to have an impact on animal mortality due to MCF and improvement of quality of life of pastoralists and farmers within 5 years of the conclusion of this project.