Protective efficacy and neutralisation to select an optimal Zika virus vaccine

寨卡病毒(ZIKV)是一种由伊蚊传播的新出现的黄病毒，目前正在南美洲、中美洲和北美迅速传播。寨卡病毒是全世界的一个主要问题，原因是神经系统疾病，如法属波利尼西亚的格林-巴利综合征，以及2014至2015年间巴西寨卡病毒暴发期间小头畸形症的发病率同时增加了20倍。不幸的是，目前还没有预防感染的疫苗。我们最近开发了两个适合人类使用的新疫苗平台，基于复制缺陷的黑猩猩腺病毒载体ChAdOx和表达不同版本寨卡病毒结构抗原的改良疫苗Ankara。我们已经开始使用ELISAT和ELISPOT等细胞分析方法来评估我们的候选疫苗的免疫原性。在这里，我们建议将这些研究扩展到使用功能分析，如病毒中和和临床前模型感染，以选择在不久的将来进行临床试验的最佳候选疫苗。我们的建议旨在：(1)比较Jenner研究所生产的10种新型疫苗的保护效力，使用适合感染ZIKV的临床前模型在英国公共卫生实验室；(2)测量疫苗免疫血清中和ZIKV进入的能力，使用体外细胞培养来建立保护小鼠所需的定量中和抗体滴度；以及(3)识别墨西哥受感染志愿者样本中的抗体滴度，以确定在急性感染和疾病恢复期诱导的滴度，从而确定疫苗候选的生理相关性滴度。我们将把实验室数据与从寨卡病毒感染流行地区获得的现场数据结合起来，得到牛津NDM-墨西哥合作实验室基础设施的支持，这是一个致力于研究新发传染病的网络。这项研究结束时获得的信息将是为疫苗开发提供信息并确定最具免疫原性和保护性的适合临床试验的ZIKV候选疫苗的关键。该项目还将加强PHE(https://www.gov.uk/government/organisations/public-health-england)，牛津生物化学部(http://www.bioch.ox.ac.uk)，)牛津疫苗集团(http://www.ovg.ox.ac.uk)，牛津NDM-墨西哥新病原体网络(http://www.ndm.ox.ac.uk/mexico/home))和詹纳研究所(http://www.jenner.ac.uk/home))之间的新的协同联系，这将对英国快速应对新感染的能力起到无可估量的作用。

Zika virus (ZIKV) is an emerging Flavivirus transmitted by Aedes mosquitoes that is now rapidly spreading throughout South, Central and North America. ZIKV is a major concern worldwide due to the neurologic conditions, such as Guillain-Barré syndrome in French Polynesia, and a concurrent 20-fold increase in the incidence of microcephaly during the ZIKV outbreak in Brazil between 2014 and 2015. Unfortunately, no vaccine to prevent infection is currently available. We have recently developed two new vaccine platforms suitable for human use, based on replication-deficient chimpanzee adenoviral vectors ChAdOx and Modified Vaccinia Ankara expressing various versions of Zika structural antigens. We have started evaluating the immunogenicity of our vaccine candidates using ELISA and cellular assays, such as ELISPOT. Here, we propose to extend those studies to use functional assays such as neutralisation of viruses and infection of pre-clinical models to select the optimal vaccine candidate for a clinical trial in the near future. Our proposal aims are: (1) Compare the protective efficacy of 10 novel vaccines produced at the Jenner Institute, using pre-clinical models suitable for infection with ZIKV at the Public Health England laboratories; (2) Measure the ability of vaccine-immune sera to neutralise ZIKV entry using in vitro cell cultures to establish quantitative neutralising antibody titres required for protection in mice; and (3) Identify antibody titres in samples from infected volunteers in Mexico to define titres induced during acute infection and convalescent period of the disease, and thus define titers of physiological relevance for a vaccine candidate. We will combine laboratory data with field data obtained from areas with prevalence of ZIKV infection, supported by infrastructure of Oxford NDM-Mexico collaborative laboratories, a network dedicated to the study of emerging infectious diseases. The information obtained at the end of this study will be key to inform vaccine development and confirm the most immunogenic and protective ZIKV vaccine candidate that would be suitable for a clinical trial. This project will also strengthen new synergistic links between the PHE (https://www.gov.uk/government/organisations/public-health-england), Oxford Biochemistry Department (http://www.bioch.ox.ac.uk), Oxford Vaccine Group (http://www.ovg.ox.ac.uk), Oxford NDM-Mexico network for emerging pathogens (http://www.ndm.ox.ac.uk/mexico/home) and the Jenner Institute (http://www.jenner.ac.uk/home) that will be invaluable for the UK capability to respond rapidly to emerging infections.