Clinical and translational evaluation of vaccination strategies for Zika, Chikungunya, Dengue, Leishmania, Malaria, 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。 2020年，我们发表了一项新型通用蚊媒疾病疫苗AGS-V的第一阶段研究，该疫苗在蚊子觅食后调节免疫系统。这种疫苗以媒介唾液为靶标，可预防多种虫媒病毒和原虫疾病。正如我们在《柳叶刀》上发表的文章中所描述的那样，该疫苗被发现是安全的和免疫原性的。这份出版物标志着针对蚊子唾液的疫苗首次在人类身上进行了测试，并且首次在NIH临床中心进行了清洁的蚊子喂养。我们认为，这项研究是开发这类疫苗的基线，并为进行这类试验打开了大门。 作为我们与LMVR密切合作的继续，我们获得了NIH长凳到床边奖，并于2018年在NIH临床中心完成了一项后续临床研究，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。在过去的3年里，我们进行了详细的实验室分析，但由于与COVID相关的延误，我们没有完成工作。我们预期在明年年初准备好公布结果，因为工作已经恢复，应该很快就会完成。 我们完成了第三项临床试验的分析，这是我们对AGS-v的初始研究的后续研究，AGS-v Plus是疫苗的更新版。根据CRADA协议，这项第一阶段研究是与LMVR和马里兰大学合作完成的。这项研究现在已经发表，为这一独特的疫苗策略的进一步重要临床开发铺平了道路，我们在2018年启动了这一策略的研究。 我们继续与约书亚·拉西纳和LMVR小组密切合作，开始开发利什曼挑战模型。该模型将在利什曼病新型疫苗的开发中发挥关键作用。我们希望在未来一年与他们密切合作，以获得全额资金，并开发一种安全、道德和可复制的人体模型，该模型将在这些重要疫苗的开发中提供重要的见解和好处。

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. In 2020 we published a Phase I study of a novel universal mosquito-borne disease vaccine, AGS-V, that modulates the immune system after a mosquito feeding. This vaccine targets the vector saliva and may provide prophylaxis against multiple arboviral and protozoal diseases. The vaccine was found to be safe and immunogenic as described in our publication in Lancet. This publication 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. This study we believe serves as a baseline for this type of vaccine to be developed and opens the door for these types of trials to be done. As a continuation of our close collaboration with LMVR we were awarded an NIH Bench To Bedside award and in 2018 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. During this past 3 years detailed laboratory analysis was performed, but due to COVID related delays we did not complete the work. We expect to have the results ready to publish early in this next year as work has resumed and should be completed soon. We completed analysis of a third clinical trial, a follow up study to our initial study of AGS-v an updated version of the vaccine, AGS-v Plus. This Phase Ib study completed in collaboration with LMVR and University of Maryland under a CRADA agreement. The study is has now been published pacing the way for further important clinical development of this unique vaccine strategy that we initiated studies with in 2018. We continue to work closely With Joshua Lascina and the LMVR group to begin the development of a leishmania challenge model. This model will play a key role int he development of novel leishmania vaccines. We expect to work closely with them in the coming year to gain full funding and to develop a safe, ethical, and reproducible human model that will provide significant insights and benefit in the development of these important vaccines.