Defining the role of cross-protective antibodies in protection against emerging viruses at the species and sub-species level

RNA病毒，如副粘病毒和冠状病毒，不断进化以响应外部刺激，如抗体选择压力。这种进化是由这些病毒的病毒RNA聚合酶的高错误率辅助的。易出错复制、快速复制和大规模流行病/大流行也有助于基因组中许多同义核苷酸变化和非同义蛋白质变化的普遍积累，对表型的影响是中性的。区分与表型相关的氨基酸变化和非功能性的氨基酸变化是至关重要的，特别是在识别可能导致新宿主感染的突变以及设计和应用疫苗方面。在本项目中，我们将研究两组重要病毒（β -冠状病毒和亨尼帕病毒）的病毒糖蛋白（vGP）变异如何影响已建立和/或实验性疫苗对它们的中和作用。以正在进行的SARS-CoV-2大流行为重点，我们将调查现有疫苗是否能够对新出现/已建立的变体提供强大的免疫力。在更广泛的范围内，我们将研究基于henipvirus的疫苗提供的免疫广度，以及对这些疫苗的中和抗体反应是否能够中和同一属内的不同物种。在这些结果的基础上，我们将描述所涉及的表位，以定义支撑这种中和的分子机制，建立对种内和种间保护的详细理解。这些数据将为疫苗设计提供信息，以保护牲畜免受未来已知或未知的亨尼帕病毒暴发的影响，并防止进一步传播给人类。BBSRC优先领域：这项研究将解决BBSRC优先领域的动物健康、合作研究和公共政策研究。作为基因型到表型英国（gp -UK）联盟的一部分，我们将研究SARS-CoV-2变体和相关β -冠状病毒感染哺乳动物宿主的能力，这些宿主可能作为SARS-CoV-2在人类和动物群体中持续传播的宿主。我们还将与gp - uk和英国公共卫生部（PHE）合作，评估SARS-CoV-2疫苗对新出现或已建立变体的有效性，目的是为公共卫生战略提供信息。此外，已经证明亨尼帕病毒可以跨越物种屏障，在自然和实验中引起人类和动物的病理。特别是尼帕病毒，已被世界卫生组织确定为需要研究和开发的优先人畜共患病原体。因此，我们建议开发一种交叉保护疫苗，以防止未来对农业、牲畜和公共卫生构成重大威胁的亨尼帕病毒（已知或未知）的爆发和持续传播。

RNA viruses, such as paramyxoviruses and coronaviruses, continually evolve in response to external stimuli such as antibody selection pressure. This evolution is aided by the high error rates of the viral RNA polymerases of these viruses. Error prone replication, rapid replication and large epidemics/pandemics also contribute to the general accumulation of many synonymous nucleotide changes in the genome and non-synonymous protein changes with neutral effects on phenotype. Discriminating between phenotypically relevant amino acid changes and those that are non-functional is vital, especially in identifying mutations that could confer infection in new hosts, and for the design and application of vaccines. Within this project we will examine how variation in the viral glycoproteins (vGP) of two important groups of viruses, beta-coronaviruses and Henipaviruses affects their neutralisation by established and/or experimental vaccines. Focusing on the ongoing SARS-CoV-2 pandemic we will investigate whether existing vaccines can provide robust immunity to emerging/established variants. On a broader scale, we will examine the breadth of immunity offered by Henipavirus-based vaccines and whether neutralising antibody responses to these vaccines are capable of neutralising different species within the same genera. Building on these results we will characterise the epitopes involved to define the molecular mechanisms underpinning this neutralisation, building a detailed understanding of intra-species and inter-species protection. These data will inform vaccine design to protect livestock from future known or unknown Henipavirus outbreaks and to prevent onward transmission to humans. BBSRC priority areas: This research will address the BBSRC priority areas of animal health, collaborative research and research that informs public policy. As part of the Genotype to Phenotype UK (G2P-UK) Consortium, we will investigate the ability of SARS-CoV-2 variants and related beta-coronaviruses to infect mammalian hosts that could act as reservoirs for sustained SARS-CoV-2 transmission in human and animal populations. We will also assess the effectiveness of SARS-CoV-2 vaccines against emerging or established variants in collaboration with G2P-UK and Public Health England (PHE), with the aim of informing public health strategies. In addition, Henipaviruses have been shown to cross the species barrier and cause pathology in humans and animals, both naturally and experimentally. In particular, Nipah virus, has been identified by the World Health Organisation as a priority zoonotic pathogen that requires research and development. We therefore propose to develop a cross-protective vaccine that could prevent future outbreaks and sustained transmission of Henipaviruses (known or unknown) that pose a major threat to agriculture, livestock and public health.