Phase 1 Trial of Na-APR-1 and Na-GST-1 Hookworm Vaccines in Brazilian Adults

Na-APR-1 和 Na-GST-1 钩虫疫苗在巴西成人中的一期试验

• 批准号: 9107814
• 负责人: David Joseph Diemert
• 金额: $ 77.36万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-08 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107814
• 关键词: Activities of Daily Living; Adjuvant; Adult; Adverse event; Affinity; Agonist; Alhydrogel; Antibodies; Antibody Affinity; Antibody Formation; Antibody Response; Antigens; Applications Grants; Area; Autoimmunity; B-Lymphocytes; Biological Assay; Biological Markers; Biological Response Modifier Therapy; Blood; Brazil; Clinical; Clinical Trials; Decision Making; Development; Dissociation; Dose; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Frequencies; Future; Health; Hookworms; Human; Human Subject Research; Humoral Immunities; Hypersensitivity; IgG1; IgG3; IgG4; Immune response; Immunization; Immunoglobulin G; Immunologic Adjuvants; Immunologics; Individual; Laws; Licensure; Life; Life Cycle Stages; Lipid A; Maintenance; Measures; Memory B-Lymphocyte; Methods; Molecular Weight; Necator americanus; Parasites; Phase I Clinical Trials; Phase II/III Trial; Population; Production; Property; Protein Subunits; Recombinant Proteins; Recombinant Vaccines; Recombinants; Regimen; Resources; Risk; Role; Safety; Site; Staging; Subunit Vaccines; Surface Plasmon Resonance; Surrogate Markers; System; TLR4 gene; Techniques; Technology; Testing; Time; Vaccinated; Vaccine Antigen; Vaccines; Viral; Virus; Work; antibody-dependent cell cytotoxicity; atopy; attenuation; base; biodefense; disability-adjusted life years; enzyme linked immunospot assay; feeding; immunogenicity; immunoreactivity; innovation; neglected tropical diseases; neutralizing antibody; novel; novel vaccines; pathogen; response; vaccination schedule; vaccine development

 DESCRIPTION (provided by applicant): This U01 grant proposal will utilize a new paradigm for early assessment of new vaccine antigen combinations. It will utilize several state-of-the-art immunological technologies to determine the impact of co-administering the novel Na-GST-1 and Na-APR-1 (M74) hookworm vaccines on the immune response to each antigen in a Phase 1 clinical trial conducted in healthy adults living in a hookworm-endemic area of Brazil. The aim is to induce the highest specific neutralizing antibody response to each component of a future co-formulated product, preferably with an IgG1 and IgG3 subclass response with induction of antibodies of high affinity and a significant B-cell memory response. If co-administration does not result in increased safety risk and does not negatively impact the humoral immune response to either of the two antigens, work will proceed to develop a bi-component, coformulated vaccine that will be used in future clinical trials in hookworm-endemic sites. In addition, the proposed clinical trial will serve to optimize the component combinations that will go into the bi-component product early in clinical development, especially the addition of the immunostimulant GLA-AF, thus economizing on time, resources, and the number of subjects required in clinical trials. The result will enable earlier decision-making regarding the optimal components of a new vaccine, in turn accelerating the time to licensure and delivery to the populations in need living in hookworm endemic areas. In most cases, immune responses to vaccines are evaluated by standard technologies such as the indirect enzyme-linked immunosorbent assay (ELISA), virus neutralization, or radiometric antibody-dependent cell-mediated cytotoxicity assay. This is despite the fact that over the last decade several major advances in antibody profiling and B cell techniques have been made in related areas such allergy and atopy, autoimmunity, biotherapeutics, and biodefense. These include the ImmunoCAP method to quantify induced antibody levels, Surface Plasmon Resonance to investigate antibody affinity, and ELISPOT to quantify vaccine-induced specific memory B cells. The objective of this U01 proposal is to apply these advances early in the clinical development of a new vaccine for hookworm, one of the most prevalent and important of the Neglected Tropical Diseases, at a point when they can be used to predict the effect of combining antigens into a single vaccine product before a co-formulated vaccine is developed and tested in larger, more costly Phase 2 and 3 trials.

 描述（由申请人提供）：这项 U01 拨款提案将利用一种新的范例来早期评估新的疫苗抗原组合，它将利用几种最先进的免疫学技术来确定共同施用新型 Na- 的影响。在巴西钩虫流行区的健康成年人中进行的一期临床试验中，GST-1 和 Na-APR-1 (M74) 钩虫疫苗对每种抗原的免疫反应，旨在诱导最高的免疫反应。如果共同给药不会导致安全风险增加，则对未来联合配制产品的每种成分产生特异性中和抗体反应，优选具有 IgG1 和 IgG3 亚类反应，并诱导高亲和力的抗体和显着的 B 细胞记忆反应。并且不会对两种抗原的体液免疫反应产生负面影响，因此将继续开发一种双组分复合疫苗，该疫苗将用于未来钩虫流行地区的临床试验。此外，拟议的临床试验还将进行。服务优化临床开发早期双组分产品的成分组合，特别是添加免疫刺激剂 GLA-AF，从而节省临床试验所需的时间、资源和受试者数量。尽早就新疫苗的最佳成分做出决策，从而加快向钩虫流行地区有需要的人群提供许可和交付的时间。在大多数情况下，通过间接技术等标准技术评估疫苗的免疫反应。尽管在过去的十年中，抗体分析和 B 细胞技术在相关领域取得了一些重大进展，但仍存在一些问题。过敏和特应性、自身免疫、生物治疗和生物防御，其中包括量化诱导抗体水平的ImmunoCAP方法、研究抗体亲和力的表面等离子共振以及量化的ELISPOT。 U01 提案的目的是在钩虫新疫苗的临床开发早期应用这些进展，钩虫是最流行和最重要的被忽视的热带疾病之一。在开发联合配制疫苗并在更大规模、更昂贵的 2 期和 3 期试验中进行测试之前，可用于预测将抗原组合到单一疫苗产品中的效果。