Phase Ib trial of a simple, multivalent vaccine to prevent Zika and Chikungunya

该项目的目的是完成一种新的双价疫苗的Ib阶段试验，以诱导对寨卡病毒和基孔肯雅病的同时免疫，从而简化未来两种疾病在同一地区共同传播的国家的疫苗接种活动，以及需要对两种疾病进行预防的国家。由于格林-巴雷综合征等神经系统疾病，寨卡病毒感染是全世界的一个主要问题，2014至2015年间巴西和墨西哥寨卡病毒暴发期间小头畸形症的发病率同时增加了20倍，墨西哥已确认由寨卡病毒引起的小头畸形症。伊蚊在同一地理区域传播基孔肯雅病毒(CHIKV)、寨卡病毒和登革热。CHIKV在大约三分之一的感染者中会产生症状性疾病，在许多情况下会导致所有年龄段的人出现长期后遗症。持续性关节炎会导致几年的残疾，导致贫困，因为年轻人无法进行工作所需的体力活动。由于需要给患者服用消炎药以提供短期缓解，家庭和政府的成本增加了。目前还没有疫苗被批准用于预防寨卡病毒或寨卡病毒感染。寨卡病毒和基孔肯雅病毒突然出现在同一地理区域，使已经受到登革热挑战的卫生系统不堪重负，从而增加了在疫情爆发期间未能向其人口提供治疗和预防措施的情况，同时由于寨卡病毒和基孔肯雅病的长期后遗症超过6年，这两种疾病的治疗都面临着新的挑战。由于社会经济条件差、气候变化和移民等促成因素，这些疾病正在从流行病性质向地方性疾病过渡。一项重大突破将是为各国政府提供同时抗击这些高度流行的虫媒病毒疾病的工具，而能够同时预防寨卡病毒和基孔肯雅病的多价疫苗将是理想的预防性解决方案。这项建议有五个主要目标：1.生产一大批GMP ChAdOx1-寨卡病毒(向Innovate UK提交的平行提案可以支持一大批ChAdOx1-Chikungenya疫苗的GMP)2.二价疫苗在墨西哥韦拉克鲁斯市的Ib期试验，那里两种疾病都很流行。评估寨卡病毒和奇孔肯雅病毒在韦拉克鲁斯和米却肯州寨卡病毒和奇孔肯雅病毒流行地区的发病率的研究，为墨西哥未来的IIb期疗效试验提供信息。在墨西哥韦拉克鲁斯发展进行临床试验的能力。寨卡病毒疫苗的生殖毒理学研究，以支持其在孕妇中的使用。这将包括对小鼠胚胎-胎儿、产前和产后发育的研究。这项提议与官方发展援助完全一致，重点是开发适合于低收入和中等收入国家使用的疫苗，例如墨西哥，该国最近分别于2015年和2016年爆发了基孔肯雅热和寨卡病毒，而且虫媒病毒疾病正在加剧贫困。

The aim of this project is to complete a Phase Ib trial of a new bivalent vaccine to induce simultaneous immunity against Zika and Chikungunya, simplifying future vaccination campaigns for countries where both diseases co-circulate in the same regions, and where protection against both diseases is needed. Infection by ZIKV is a major concern worldwide due to the neurologic conditions, such as Guillain-Barré syndrome and a concurrent 20-fold increase in the incidence of microcephaly during the ZIKV outbreak in Brazil between 2014 and 2015 and in Mexico, where microcephaly caused by ZIKV has been confirmed. Aedes mosquitoes transmit Chikungunya virus (CHIKV), ZIKV and Dengue in the same geographical regions. CHIKV produces symptomatic disease in approximately ¾ of infected people, leading in many cases to long-term sequelae in people of all ages. Persistent arthritis cause disability for several years, contributing to poverty as young adults are unable to perform their physical activities required for work. Costs for families and governments are augmented due to the need to administer anti-inflammatory drugs to provide a short-term relief in patients. No vaccine is yet licensed for the prevention of CHIKV or ZIKV infections.The sudden presence of Zika and Chikungunya in the same geographical regions have overwhelmed health systems that were already challenged by Dengue, thus increasing the failure to provide treatment and preventive measures to their populations during the outbreak, while posing new challenges for treatment of both Zika and Chikungunya due to the long-term sequelae of more than 6 years for these diseases. These diseases are transitioning from an epidemic nature towards endemic diseases due to enabling drivers such as poor socioeconomic conditions, climate change and migration. A major breakthrough will be to provide governments with tools to simultaneously fight these highly prevalent arbovirus diseases and a multivalent vaccine able to protect against both Zika and Chikungunya would be an ideal preventive solution. This proposal has five major aims:1. Production of a large GMP batch of ChAdOx1-Zika (A parallel proposal submitted to Innovate UK could support alarge GMP batch of a ChAdOx1-Chikungunya vaccine).2. A Phase Ib trial of the bivalent vaccine in Mexico, in the city of Veracruz, where both diseases are prevalent.3. A study to assess incidence of Zika and Chikungunya in the ZIKV and CHIKV-endemic regions of Veracruz andMichoacan, to inform future Phase IIb efficacy trials in Mexico.4. Capacity development in Veracruz, Mexico to perform clinical trials.5. Reproduction toxicology for the Zika vaccine to support their use in pregnant women. This will consist of an embryo-foetal, pre- and post-natal development studies in the mouse.This proposal is fully aligned with the Officiald Development Assistance (ODA) and focuses on the development of vaccines that are appropriate for use in low- and middle- income countries, such as Mexico where recent outbreaks of Chikungunya and Zika have taken place in 2015 and 2016, respectively, and where arboviral diseases are contributing to poverty.