Field trial and modeling of transmission blocking vaccine to prevent Lyme disease

摘要 美国疾病控制与预防中心的估计表明，每年有超过30万人被诊断为LD。 用生态学方法减少硬蜱中伯氏白僵菌的负担并传播给其他 寄主是人们非常希望使用的工具，而不是目前的“检查是否勾选”的方法。这很好 确定在脊椎动物宿主用伯氏杆菌OspA免疫后，它们会产生抗体 当一只喂食的扁虱摄取血粉时，它会杀死那只扁虱体内的伯格多尔费氏杆菌。它们被称为 传播阻断疫苗(TBV)。这些工具，包括TBV，还没有被证明可以减少 伯氏杆菌在临界中间偶发宿主中的暴露(S)。在北美，人类和 狗是伯氏杆菌的偶然宿主。我们和其他人已经证明了狗可以起到 人类接触受感染扁虱的替代物/替代物。猎犬是这次试验的有力模型。 因为它们既可以作为活跃的户外偶然宿主(如高危人群)的代理 而且是把扁虱带入家中栖息地的管道，增加了人类的暴露。目标是 这项工作的一项工作是证明以TBV为靶标的商业级水库可以改变伯氏杆菌。 在流行区(PA和MD)中，在与地理上不同的地区，探索者的感染流行率 第一次实地试验(纽约)。为了证明疏螺旋体传播的生态破坏，我们 建议：1)建立商业级储集层的靶向传输阻断效果 疫苗(TBV)在降低壁虱媒介中的伯氏杆菌感染率及其对临床的影响 一项为期五年的现场研究中偶然宿主(狗)的疾病使用贝叶斯分层统计 评估受感染生态系统的TBV治疗将如何改变人类伯氏杆菌暴露的模型。 这些拟议的研究作为TBV的现场试验示范，对公共卫生具有非常重要的意义 这扰乱了伯氏杆菌向偶然宿主的地方性传播循环。此外， 减少人类(偶发宿主)莱姆病的演示将通过随机 贝叶斯模型将为减少环境污染的新工具提供关键证据 莱姆病。这项工作的创新是作为一种有效的、易于分发的和 廉价的TBV可以降低伯氏杆菌在若虫和成虫以及B.burgdorferi中的流行率。 伯格多费氏吸虫从壁虱传播到偶发宿主。减少伯氏杆菌的传播至 由于TBV分布而产生的偶然宿主将被证明是一种范式转换策略，以减少 莱姆病在兽医和人类人群中的负担。建议的实验结果 这项研究将促进伯氏杆菌疫苗学的翻译知识，并将提供强有力的 有关TBV可能降低接触莱姆病的人类健康风险的证据 在美国各地。

Summary Estimates from the CDC indicate that over 300,000 people are diagnosed each year with LD. Ecological approaches to decrease B. burgdorferi burden in Ixodes ticks, and transmission to other hosts, are highly desired tools for use instead of the current `check for ticks' approach. It is well established that after a vertebrate host is immunized with B. burgdorferi' OspA they produce antibody that, upon bloodmeal ingestion by a feeding tick, kills B. burgdorferi within that tick. These are known as transmission-blocking vaccines (TBV). These tools, including TBV, have not been proven to decrease B. burgdorferi exposure in critical intermediate incidental host(s). In North America, both humans and dogs are incidental hosts of B. burgdorferi. We and others have demonstrated that dogs can serve as stand-in/proxies for human exposure to infected ticks. Hunting dogs are a robust model for this trial because they serve both as a proxy of an active outdoors incidental host (like people at high-risk of contracting LD) and are a conduit of ticks into domestic habitats, increasing human exposure. The goal of this work is to demonstrate that a commercial-grade reservoir targeted TBV alters B. burgdorferi infection prevalence in questing ticks, in endemic areas (PA and MD) geographically distinct from the first field trial (NY). To show proof-of-principle for an ecological disruption of Borrelia transmission, we propose to: 1) establish the efficacy of a commercial-grade reservoir targeted transmission blocking vaccine (TBV) in reducing prevalence of B. burgdorferi in the tick vector and how it affects clinical disease in incidental hosts (dogs) in a five-year field study 2) Use a Bayesian hierarchical statistical model to estimate how TBV treatment of infected ecosystems will alter human B. burgdorferi exposure. These proposed studies are highly significant to public health as a field trial demonstration of a TBV that disrupts the enzootic transmission cycle of B. burgdorferi to incidental hosts. Furthermore, demonstration of reduced human (incidental host) Lyme disease will be performed through a stochastic Bayesian model that will provide critical evidence for a new tool to decrease environmental exposure to Lyme disease. This work innovates as a demonstration of an efficacious, easily distributable and inexpensive TBV that reduces B. burgdorferi prevalence in nymphal and adult ticks, as well as B. burgdorferi transmission from ticks to incidental hosts. Reduction of transmission of B. burgdorferi to incidental hosts as a result of TBV distribution will prove to be a paradigm-shifting strategy to reduce the burden of Lyme disease in veterinary and human populations. Findings from experiments proposed in this study will advance translational knowledge of B. burgdorferi vaccinology and will provide strong evidence regarding the possibility of TBV reducing the human health risk of exposure to Lyme disease across the United States.