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

不同 TLR 激动剂钩虫疫苗功效的对照感染试验

• 批准号: 10556618
• 负责人: Jeffrey Michael Bethony
• 金额: $ 48.09万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10556618
• 关键词: Activities of Daily Living; Adjuvant; Adult; Agonist; Alhydrogel; Animals; Antibodies; Antibody Affinity; Antibody Response; Antigens; Applications Grants; Area; Blood; Brazil; Child; Clinical; Clinical Trials; Combined Vaccines; Decision Making; Dendritic Cells; Detection; Development; Dissociation; Double-Blind Method; Evaluation; Flow Cytometry; Formulation; Gabon; Glutathione S-Transferase; Granzyme; Helminths; Hematology; Hemorrhage; Hookworm Infections; Hookworms; Human; Human Subject Research; Human Volunteers; Immune; Immune response; Immunity; Immunization; Immunologic Adjuvants; Immunologics; Incidence; Infection; Intestines; Investigation; Iron deficiency anemia; Label; Larva; Laws; Lipid A; Measures; Memory B-Lymphocyte; Microscopy; Modeling; Molecular Weight; NCAM1 gene; NK Cell Activation; Natural Immunity; Natural Killer Cells; Necator americanus; Outcome; Parasites; Parasitic infection; Participant; Pathway interactions; Peripheral Blood Mononuclear Cell; Persons; Phase II Clinical Trials; Phase II/III Trial; Population; Production; Property; Recombinant Proteins; Recombinants; Risk; Role; Safety; Sampling; Savings; Stains; Surface Plasmon Resonance; System; T-Lymphocyte; TLR4 gene; Technology; Testing; Time; Toll-like receptors; Translating; Vaccinated; Vaccination; Vaccines; aqueous; base; clinical development; cost; cytokine; efficacy study; efficacy testing; egg; enzyme linked immunospot assay; exposed human population; feeding; immunogenic; innovation; novel; novel vaccines; pathogen; phase 1 testing; phase 2 study; phase I trial; phase II trial; polyclonal antibody; protective effect; receptor; response; vaccination outcome; vaccine candidate; vaccine efficacy; vaccine formulation; vaccinology; volunteer

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.

项目摘要/摘要 该U01赠款提案将利用新颖的范式来早期评估疫苗效率和 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 通过受控人钩虫挑战人类志愿者的投资钩虫疫苗 疫苗接种后感染（CHHI）。钩虫是最重要的寄生虫感染之一，超过500 全球感染了百万人，大多数人都伴随着Americus。钩虫感染的临床标志 是铁缺乏贫血，是由于该寄生虫直接引起的肠失血而引起的。谷胱甘肽-S- 美国猪笼草（NA-GST-1）的转移酶-1是该肠道流血途径的一部分 Helminth并根据其在动物研究中的保护作用而被选为临床发育。 在Alhydrogel®上配制的重组Na-GST-1已被证明是安全的 在美国的第1阶段试验以及巴西和加蓬的钩虫内粒地区的成年人。在提议中 2阶段研究，健康的钩虫志愿者将接种NA-GST-1/Alhydrogel®接种 然后用感染性n.美属幼虫挑战他们，以确定疫苗接种对 寄生虫，血液学和免疫学参数感染钩虫感染。 传统上，研究疫苗的概念验证研究在临床开发中进行 通常在病原体内部分子区域的大型野外试验中。这些研究可能需要大量时间 取决于事件，涉及大量参与者。这个U01的目的 提案是进行2期临床试验，该试验的这种新的钩虫疫苗的概念概念证明为 在临床发展和少数志愿者中进行了测试。此外，我们将利用 ART免疫技术全面评估了对 疫苗接种以及如何转化为CHHI模型中的保护。因此，拟议的临床试验将 还可以优化最终疫苗配方的组合组合，尤其是添加 新型Toll样受体免疫刺激剂，例如GLA-AF和CPG。该试验的结果将允许 关于NA-GST-1钩虫疫苗的进一步开发及其最终的关键决定 公式在钩虫内分子区域进行较大，更昂贵的第2阶段和3期试验之前。