Clinical and translational evaluation of vector saliva based vaccination strategies for Zika and other important or emerging vector-borne diseases

尽管正在进行控制努力，但蚊媒疾病仍在世界范围内造成严重的发病率和死亡率。2015年，全球有2亿疟疾病例，造成近50万人死亡，其中大部分死亡病例发生在5岁以下儿童中。蚊子还传播虫媒病毒，包括登革热、黄热病、西尼罗河病毒、基孔肯雅热、裂谷热、日本脑炎和寨卡病毒。最近寨卡病毒在中南美洲以及加勒比海地区的爆发提醒人们，这些病毒传播的速度有多快，控制起来有多困难。 我们完成了一种新型通用蚊媒疾病疫苗的第一阶段研究，目前正在准备手稿。通过调节蚊子取食后的免疫系统，这种疫苗针对媒介唾液，并可能提供预防多种虫媒病毒和原虫疾病的方法。此外，疫苗可能导致蚊子在进食后寿命缩短，因此也减少了这些疾病的传播。该方案标志着针对蚊子唾液的疫苗首次在人类身上进行测试，也是美国国立卫生研究院临床中心首次在人类身上进行清洁的蚊子喂养。 作为我们与LMVR密切合作的延续，我们获得了NIH长凳到床边奖，并在过去一年完成了NIH临床中心的后续临床研究，以评估多次暴露于同一媒介对免疫反应的影响。这项研究包括对两种蚊子和沙蝇的评估，沙蝇是利什曼病的媒介。我们希望这项研究的最终数据有助于进一步了解针对媒介唾液的疫苗接种策略如何在地方病地区的个人中发挥作用。我们预计在明年完成分析。 在明年，我们将完成第三项临床试验，这是我们最初对AGS-v的研究的后续研究，使用的是更新版本的AGS-v Plus疫苗。根据CRADA协议，这项第一阶段研究将与LMVR和马里兰大学合作完成。我们已经启动了这项研究，预计在未来6-8个月内全面招生。这项研究应该继续我们在2018年启动的这一独特疫苗战略的临床开发。

Mosquito-borne diseases continue to cause significant morbidity and mortality worldwide despite on-going control efforts. In 2015, there were >200 million cases of malaria worldwide, causing nearly half a million deaths, with most of the deaths occurring among children under the age of 5 years. Mosquitoes also transmit arboviruses, including dengue, yellow fever, West Nile virus, chikungunya, Rift Valley fever, Japanese encephalitis, and Zika virus. The recent outbreak of Zika virus in Central and South America, as well as the Caribbean, serves as a reminder of how quickly these viruses can spread and how difficult they can be to control. We completed a Phase I study of a novel universal mosquito-borne disease vaccine and are now preparing a manuscript. Through modulation of the immune system after a mosquito feeding, this vaccine targets the vector saliva and may provide prophylaxis against multiple arboviral and protozoal diseases. In addition the vaccine potentially leads to a reduced mosquito lifespan after feeding therefore also reducing transmission of these diseases. This protocol marks the first time a vaccine targeting mosquito saliva has been tested in humans and the first time clean mosquito feedings on humans have been performed in the NIH Clinical Center. As a continuation of our close collaboration with LMVR we were awarded an NIH Bench To Bedside award and in the past year have completed enrollment of a follow up clinical study in the NIH Clinical Center to evaluate the effect on the immune response of multiple exposures to the same vector. This study included the evaluation of two species of mosquito as well as sandflies, the vector of leishmania. We expect the final data from this study to be instrumental in further understanding how vaccination strategies that target vector saliva may work in individuals from endemic disease areas. We expect to complete the analysis during the next year. During the next year we will complete a third clinical trial, a follow up study to our initial study of AGS-v with an updated version of the vaccine AGS-v Plus. This Phase Ib study will be completed in collaboration with LMVR and University of Maryland under a CRADA agreement. We have initiated the study and expect to fully enroll in the next 6-8 months. This study should continue the clinical development of this unique vaccine strategy we initiated in 2018.