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 百日咳杆菌是一种革兰氏阴性病原体，是百日咳的主要病因。 (百日咳)。全细胞百日咳疫苗(WPS：DTP；白喉、破伤风、百日咳)是在 20世纪40年代。然而，在20世纪90年代的S，副作用不佳的全细胞疫苗被替换为 无细胞疫苗(APS：婴儿剂量-DTaP和加强剂量-Tdap)，包含三到五种与毒力相关的疫苗 蛋白质(百日咳类毒素、丝状血凝素、Pertactin和菌毛)吸附在铝佐剂上。 自20世纪90年代以来，百日咳病例在美国和世界各地死灰复燃，扩大了 需要新的更有效的疫苗。 这项提议寻求利用小鼠和狒狒模型来开发鼻腔增强疫苗，方法是建立 根据目前的脱细胞疫苗是如何配制的。我们已经证明了鼻腔免疫 用无细胞疫苗在小鼠体内可以预防百日咳杆菌的攻击。建议的疫苗使用可德兰。 (线性β-1，3-葡聚糖)作为佐剂，并包括一种新的类毒素抗原，它将指导体液反应 这将中和腺苷环化酶毒素。 在这个项目中，我们将优化鼻用柯德兰无细胞百日咳的佐剂/抗原组成。 疫苗(IN-CAP)用于预防临床前小鼠模型中百日咳杆菌的挑战(目标1)。一旦我们 已经建立了优化的帽内疫苗，我们还将评估在恒河猴模型中的保护能力 百日咳。在目标2中，我们将与IP-AP免疫比较，描述IN-CAP细胞介导的反应的特征 老鼠。在第三个目标中，我们将研究In-Cap Boost作为协同改善次优IP的机制- 美联社疫苗接种。在该项目完成后，我们预计将形成一种新的无细胞百日咳药物。 可以进一步开发用于临床试验的疫苗。也有可能建立的方法学 将适用于针对其他细菌病原体的疫苗的开发。