Controlled Infection Trial to Test Efficacy of Hookworm Vaccine with Different TLR Agonists

项目摘要/摘要 这份U01拨款提案将利用一种新的范式来早期评估疫苗的效力和 最佳疫苗配方的选择。我们将进行第二阶段临床试验，以评估 用受控钩虫攻击人体志愿者的钩虫疫苗研究 接种后感染(CHHI)。钩虫是最重要的寄生虫感染之一，有500多人 全球有100万人感染，其中大多数感染了美洲坏疽菌。钩虫感染的临床特征 是缺铁性贫血，是由肠道失血直接引起的这种寄生虫。谷胱甘肽-S- 美洲不动杆菌转移酶-1(Na-GST-1)是该肠道供血途径的一个组成部分 蠕虫，在动物研究中基于其保护作用而被选为临床开发。 在Alwater Gel®上配制的重组Na-GST-1被证明在健康人群中使用是安全的 在美国以及巴西和加蓬的钩虫流行区进行第一阶段试验的成年人。在建议的 第二阶段研究，健康钩虫幼稚成年志愿者将接种Na-GST-1/Alwater Gel® 然后用感染的美洲钩端螺旋体幼虫攻击它们，以确定接种疫苗对 钩虫感染的寄生虫学、血液学和免疫学参数。 传统上，研究疫苗的概念验证研究是在临床开发的后期进行的。 通常是在病原体流行地区的大型田间试验中。这些研究可能需要相当长的时间和 涉及大量参与者，具体取决于感染的发生率。本次U01的目标是 建议进行第二阶段临床试验，在此期间，这种新的钩虫疫苗的概念验证是 在临床开发早期和在一小部分志愿者身上进行了测试。此外，我们将利用状态- 综合评估体液和细胞免疫应答的ART免疫学技术 疫苗接种以及如何在CHHI模型中转化为保护。因此，拟议的临床试验将 还有助于优化最终疫苗配方的成分组合，特别是添加 新型Toll样受体免疫刺激剂，如GLA-AF和CpG。这项试验的结果将允许 关于进一步开发Na-GST-1钩虫疫苗及其最终版本的关键决定 在钩虫流行地区进行更大规模、成本更高的2期和3期试验之前，应先进行配方试验。

Project Summary/Abstract This U01 grant proposal will utilize a novel paradigm for the early assessment of vaccine efficacy and the selection of optimal vaccine formulation. We will conduct a Phase 2 clinical trial that enables the evaluation of an investigation hookworm vaccine by challenging human volunteers with a controlled human hookworm infection (CHHI) after vaccination. Hookworm is one of the most important parasitic infections, with over 500 million people infected worldwide, most with Necator americanus. The clinical hallmark of hookworm infection is iron deficiency anemia, resulting from intestinal blood loss directly caused by this parasite. Glutathione-S- Transferase-1 of N. americanus (Na-GST-1) is a component of the blood-feeding pathway of this intestinal helminth and was selected for clinical development based on its protective effect in animal studies. Recombinant Na-GST-1 formulated on Alhydrogel® has been shown to be safe when administered to healthy adults in Phase 1 trials in the USA and in hookworm endemic areas of Brazil and Gabon. In the proposed Phase 2 study, healthy hookworm‐naïve adult volunteers will be vaccinated with Na-GST-1/Alhydrogel® followed by challenging them with infective N. americanus larvae to determine the effect of vaccination on hookworm infection by parasitologic, hematologic, and immunologic parameters. Traditionally, proof-of-concept studies for investigational vaccines are conducted later in clinical development and usually in large field trials in pathogen endemic areas. These studies can take considerable time and involve large numbers of participants, depending on the incidence of the infection. The objective of this U01 proposal is to conduct a Phase 2 clinical trial in which proof-of-concept for this new vaccine for hookworm is tested early in clinical development and on a small number of volunteers. In addition, we will utilize state-of- the-art immunological technologies to comprehensively evaluate the humoral and cellular immune response to vaccination and how that translates into protection in the CHHI model. Hence, the proposed clinical trial will also serve to optimize the component combinations of the final vaccine formulation, especially the addition of novel Toll-Like Receptor immunostimulants such as GLA-AF and CpG. The results of this trial will permit critical decisions to be made on the further development of the Na-GST-1 hookworm vaccine and its final formulation, prior to conducting larger, more costly Phase 2 and 3 trials in hookworm endemic areas.