Clinical and translational evaluation of vector saliva based 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，但蚊子传播的疾病继续在全世界造成严重的发病率和死亡率。 2015年，全球有超过2亿例疟疾病例，造成近50万人死亡，其中大部分死亡发生在5岁以下的儿童中。 蚊子也传播虫媒病毒，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。 最近在中美洲和南美洲以及加勒比地区爆发的寨卡病毒提醒人们，这些病毒传播的速度有多快，控制起来有多困难。 在过去的一年里，我们发表了一项关于一种新型通用蚊媒疾病疫苗AGS-V的I期研究，该疫苗在蚊子喂食后调节免疫系统。 该疫苗以载体唾液为靶点，可预防多种虫媒病毒和原生动物疾病。 如我们在《柳叶刀》上发表的文章所述，发现该疫苗是安全的和免疫原性的。 该出版物标志着首次在人类中测试了针对蚊子唾液的疫苗，并且首次在NIH临床中心对人类进行了清洁的蚊子喂养。 我们认为这项研究可以作为开发这种疫苗的基线，并为这些类型的试验打开大门。 作为我们与LMVR密切合作的延续，我们被授予NIH Bench To Bedside奖，并于2018年在NIH临床中心完成了一项后续临床研究的招募，以评估多次暴露于同一载体对免疫反应的影响。 这项研究包括两种蚊子以及白蛉，利什曼原虫的载体的评价。 我们希望这项研究的最终数据有助于进一步了解靶向载体唾液的疫苗接种策略如何在地方病地区的个体中发挥作用。 在过去的一年里，我们进行了详细的实验室分析，我们预计将在明年初公布结果。 在过去的一年里，我们完成了第三次临床试验，这是我们对AGS-v疫苗的初步研究的后续研究，AGS-v疫苗的更新版本。 根据CRADA协议，这项Ib期研究与LMVR和马里兰州大学合作，于今年完成了入组。 我们目前正在完成研究的后续访问，并计划在2021年准备好数据以供发表。 这项研究延续了我们在2018年启动的这项独特疫苗策略的重要临床开发。 此外，我们还继续与洛克菲勒大学的王泰雅（Taia Wang）合作，她现在已经搬到了斯坦福大学。 在这项合作中，我们继续研究蚊媒疾病免疫力和抗体结构和功能的各个方面，以便更好地了解保护的相关性。 通过提供在我们的试验中收集的临床样本，这种合作能够产生有趣的数据，这些数据可能有助于进一步开发新型疫苗和疫苗策略。

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. This past year 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 year detailed laboratory analysis was performed and we expect to have the results ready to publish early in this next year. During this past year we completed 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 enrollment this year in collaboration with LMVR and University of Maryland under a CRADA agreement. We are completing the follow up visits for the study now and plan to have the data ready for publication during 2021. This study continues the important clinical development of this unique vaccine strategy we initiated studies with in 2018. In addition, we have continued to collaborate with Taia Wang at Rockefeller University who has now moved to Stanford University. In this collaboration we continue to investigate aspects of mosquito borne disease immunity and antibody structure and function in order to better understand correlates of protection. By providing clinical samples collected in our trials this collaboration is able to generate interesting data that may help in the further development of novel vaccines and vaccine strategies.