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

项目概要/摘要 这项U 01拨款提案将利用一种新的范式来早期评估疫苗的有效性， 选择最佳疫苗配方。我们将进行一项2期临床试验， 通过用受控的人钩虫挑战人类志愿者来研究钩虫疫苗 接种疫苗后感染（CHHI）。钩虫是最重要的寄生虫感染之一， 全世界有1000万人感染，其中大多数是美洲钩虫。钩虫感染的临床特征 缺铁性贫血是由这种寄生虫直接引起的肠道失血引起的。谷胱甘肽-S- N. Na-GST-1是这条肠道的血液喂养途径的组成部分， 蠕虫，并根据其在动物研究中的保护作用选择用于临床开发。 在Alhydrogel®上配制的重组Na-GST-1已被证明是安全的， 在美国以及巴西和加蓬的钩虫流行区进行的1期试验中，拟议 II期研究，健康钩虫初治成人志愿者将接种Na-GST-1/Alhydrogel®疫苗 然后用感染性N.美洲象幼虫，以确定疫苗接种对 钩虫感染的寄生虫学、血液学和免疫学参数。 传统上，研究性疫苗的概念验证研究在临床开发后期进行 并且通常在病原体流行地区的大规模田间试验中。这些研究可能需要相当长的时间， 根据感染的发生率，涉及大量参与者。U 01的目的 一项建议是进行2期临床试验，在该试验中， 在临床开发的早期和少数志愿者身上进行了测试。此外，我们还将利用... 最先进的免疫学技术，以全面评估体液和细胞免疫反应， 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 还用于优化最终疫苗制剂的组分组合，特别是添加 新的Toll样受体免疫刺激剂如GLA-AF和CpG。这次审判的结果将允许 关于进一步开发Na-GST-1钩虫疫苗及其最终 在钩虫流行地区进行更大规模、更昂贵的第2和第3期试验之前，应先使用新制剂。

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.