Development of mucosal vaccines to protect against pertussis

开发预防百日咳的粘膜疫苗

• 批准号: 10084257
• 负责人: Fredrick Heath Damron
• 金额: $ 59.22万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084257
• 关键词: Acellular Vaccines; Adenylate Cyclase; Adenylate Cyclase Toxin; Adjuvant; Adult; Aluminum; Antibodies; Antigen Presentation; Antigens; Bacterial Attachment Site; Binding; Bordetella parapertussis; Bordetella pertussis; Cells; Child; Clinical Trials; Complement; Data; Development; Diphtheria; Disease; Dose; Formulation; Generations; Glucans; Health; Hemagglutinin; Human; Immunity; Immunization; Immunize; Immunoglobulins; In Vitro; Incidence; Infant; Infection; Inflammatory Response; Intramuscular; Intramuscular Injections; Intranasal Administration; Letters; 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-induced immunity

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.

项目摘要 百日咳是一种革兰氏阴性病原体，是疾病咳嗽的主要原因 （百日咳）。全细胞百日咳疫苗（WPS：DTP；白喉，破伤风，百日咳）在 1940年代。然而，在1990年代，整个细胞疫苗的副作用不良，被替换为 细胞疫苗（APS：婴儿剂量DTAP和Booster dose-TDAP），其中包含三到五个毒力相关的 蛋白质（百日咳类毒素，丝状血凝素，胃激素和脂肪素）吸附到铝佐剂上。 自1990年代以来，在美国和世界的百日咳案件中一直在复兴，这增加了 需要新的，更有效的疫苗。 该提议旨在利用鼠和狒狒模型来建立鼻内增强疫苗 关于当前的细胞疫苗如何配制。我们已经证明了鼻内免疫 小鼠中的细胞疫苗可以预防百日咳挑战。提议的疫苗利用curdlan （线性β-1,3-葡聚糖）作为佐剂，并包括一种新的毒素抗原，该抗原将引导体液反应 这将中和腺苷酸环化酶毒素。 在这个项目中，我们将优化鼻内乳凝蛋白的辅助 /抗原组成 在临床前鼠模型中预防百日咳挑战（AIM 1），以防止百日咳挑战。曾经 已经建立了优化的股内疫苗，我们还将评估狒狒模型中的保护能力 百日咳。在AIM 2中，我们将与IP-AP免疫相比，表征股内介导的响应 老鼠。在第三个目的中，我们将研究cap内的提升，以此作为协同改善亚最佳IP-的一种机制。 AP疫苗接种。该项目完成时，我们希望已经制定了一类新的细胞百日咳 可以进一步开发用于临床试验的疫苗。方法论也可能建立 将适用于针对其他细菌病原体开发疫苗。