Development of mucosal vaccines to protect against pertussis

开发预防百日咳的粘膜疫苗

基本信息

批准号：
10548222
负责人：
Fredrick Heath Damron
金额：
$ 58.56万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10548222
关键词：
Acellular Vaccines Adenylate Cyclase Adenylate Cyclase Toxin Adjuvant Adsorption Adult Aluminum Antibodies Antigen Presentation Antigens Bacterial Attachment Site Binding Bordetella parapertussis Bordetella pertussis Cells Child Clinical Trials Complement Data Development Diphtheria Disease Dose Generations Glucans Health Hemagglutinin Human Immunity Immunization Immunize Immunoglobulins In Vitro Incidence Infant Infection Inflammatory Response Intramuscular Intramuscular Injections Intranasal Administration Letters Licensing Life Mediating Methodology Mission Modeling Mucosal Immunity Mucous Membrane Mus Papio Pertussis Pertussis Toxin Pertussis Vaccine Phagocytes Phenotype Population Pre-Clinical Model Prevention Production Proteins Public Health Research Respiratory Tract Infections Respiratory distress Risk Role Secondary Immunization Site T memory cell Testing Tetanus Time Toxin Toxoids United States National Institutes of Health Vaccination Vaccines Virulence Whole Cell Vaccine adaptive immune response aluminum sulfate booster vaccine curdlan cytokine dectin 1 human pathogen improved mouse model mucosal vaccine nonhuman primate novel novel vaccines pathogen pathogenic bacteria pertactin pre-clinical prevent response side effect transmission process vaccine development vaccine formulation vaccine response vaccine-induced immunity

项目摘要

Project Summary Bordetella pertussis is a Gram-negative pathogen that is the primary cause of the disease whooping cough (pertussis). Whole cell pertussis vaccines (wPs: DTP; Diphtheria, Tetanus, Pertussis) were developed in the 1940s. In the 1990's, however, the whole cell vaccines, which had undesirable side effects, were replaced with acellular vaccines (aPs: infant dose-DTaP and booster dose-Tdap), containing three to five virulence-associated proteins (pertussis toxoid, filamentous hemagglutinin, pertactin, and fimbriae) adsorbed to aluminum adjuvant. Since the 1990s, there has been a resurgence in pertussis cases in the US and world which has augmented the need for new and more efficacious vaccines. This proposal seeks to utilize the murine and baboon models to develop an intranasal booster vaccine by building upon how the current acellular vaccines are formulated. We have demonstrated that intranasal immunization with acellular vaccine in mice can protect against B. pertussis challenge. The proposed vaccine utilizes curdlan (linear beta-1,3-glucan) as the adjuvant and includes a new toxoid antigen that will direct humoral responses that will neutralize the adenylate cyclase toxin. In this project, we will optimize the adjuvant / antigen composition of Intranasal curdlan acellular Pertussis vaccine (IN-caP) to protect against B. pertussis challenge in the pre-clinical murine model (aim 1). Once we have established the optimized IN-caP vaccine we will also evaluate the protective capacity in the baboon model of pertussis. In aim 2, we will characterize the IN-caP cell mediated responses in comparison to IP-aP immunized mice. In the third aim, we will examine IN-caP boost as a mechanism to synergistically improve sub-optimal IP- aP vaccination. At the completion of the project, we expect to have formulated a new class of acellular pertussis vaccine that can be further developed towards clinical trials. It is also likely that the methodologies established will be applicable to develop of vaccines against other bacterial pathogens.

项目概要百日咳博德特氏菌是一种革兰氏阴性病原体，是百日咳疾病的主要原因（百日咳）。全细胞百日咳疫苗（wP：DTP；白喉、破伤风、百日咳）是在 20 世纪 40 年代。然而，在 20 世纪 90 年代，具有不良副作用的全细胞疫苗被无细胞疫苗（APS：婴儿剂量-DTaP 和加强剂量-Tdap），含有 3 至 5 种毒力相关的疫苗蛋白质（百日咳类毒素、丝状血凝素、百日咳杆菌粘附素和菌毛）吸附到铝佐剂上。自 20 世纪 90 年代以来，美国和世界各地的百日咳病例再次出现，这加剧了需要新的、更有效的疫苗。该提案旨在利用小鼠和狒狒模型通过构建鼻内加强疫苗来开发目前的非细胞疫苗是如何配制的。我们已经证明鼻内免疫在小鼠体内使用无细胞疫苗可以预防百日咳博德特氏菌的攻击。拟议的疫苗利用凝胶多糖（线性 β-1,3-葡聚糖）作为佐剂，并包含一种新的类毒素抗原，可指导体液反应这将中和腺苷酸环化酶毒素。在这个项目中，我们将优化鼻内凝胶多糖无细胞百日咳的佐剂/抗原组成疫苗 (IN-cap) 可在临床前小鼠模型中预防百日咳博德特氏菌攻击（目标 1）。一旦我们已经建立了优化的 IN-cap 疫苗，我们还将评估狒狒模型中的保护能力百日咳。在目标 2 中，我们将与 IP-aP 免疫相比来表征 IN-caP 细胞介导的反应老鼠。在第三个目标中，我们将研究 IN-cap boost 作为一种协同改善次优 IP 的机制。 aP疫苗接种。该项目完成后，我们预计将配制出一类新的无细胞百日咳疫苗可以进一步开发用于临床试验的疫苗。所建立的方法也很可能将适用于开发针对其他细菌病原体的疫苗。