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黄病毒，目前正在南美洲、中美洲和北美洲迅速传播。由于神经系统疾病，ZIKV是全球范围内的主要问题，例如法属波利尼西亚的格林-巴利综合征，以及2014年至2015年巴西ZIKV爆发期间小头畸形的发病率增加了20倍。不幸的是，目前还没有预防感染的疫苗。我们最近开发了两种适合人类使用的新疫苗平台，基于复制缺陷型黑猩猩腺病毒载体ChAdOx和表达各种形式的寨卡结构抗原的改良牛痘安卡拉。我们已经开始使用ELISA和细胞测定法（如ELISPOT）评估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性测定，如病毒中和和临床前模型感染，以选择最佳的候选疫苗用于不久的将来的临床试验。我们的提案目标是：（1）在英国公共卫生实验室使用适合ZIKV感染的临床前模型，比较詹纳研究所生产的10种新型疫苗的保护效力;（2）使用体外细胞培养物测量疫苗免疫血清中和ZIKV进入的能力，以建立小鼠中保护所需的定量中和抗体滴度;和（3）鉴定来自墨西哥受感染志愿者的样品中的抗体滴度，以确定在疾病的急性感染和恢复期期间诱导的滴度，从而确定与候选疫苗生理相关的滴度。我们将联合收割机实验室数据与从ZIKV感染流行地区获得的现场数据相结合，并得到牛津NDM-Mexico合作实验室基础设施的支持，该实验室是一个致力于研究新发传染病的网络。在本研究结束时获得的信息将是告知疫苗开发并确认适合于临床试验的最具免疫原性和保护性的ZIKV疫苗候选物的关键。该项目还将加强公共卫生和环境部（https：//www.gov.uk/government/organisations/public-health-england）、牛津生物化学部（http：//www.example.com）、牛津疫苗集团（http：//www.example.com）、牛津NDM-墨西哥新兴病原体网络（http：//www.ndm.ox.ac.uk/mexico/home）和詹纳研究所（http：//www.jenner.ac.uk/home）之间新的协同联系，这对联合王国迅速应对新兴感染的能力将是非常宝贵的。www.ovg.ox.ac.uk www.bioch.ox.ac.uk

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.