Development of mRNA-platform vaccines

mRNA平台疫苗的开发

• 批准号: 10211558
• 负责人: Fredrick Heath Damron
• 金额: $ 82.63万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-21 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211558
• 关键词: 11 year old; Acellular Vaccines; Adjuvant; Adolescent; Adult; Antibodies; Antibody Formation; Antibody Response; Antigen Targeting; Antigens; Avidity; Bacterial Vaccines; Belgium; Biological Assay; Bordetella; Bordetella pertussis; COVID-19 pandemic; Cells; Cellular Immunity; Centers for Disease Control and Prevention (U.S.); Child; Clinical Trials; Collaborations; Complex; Coughing; Data; Development; Diphtheria; Diphtheria-Tetanus-acellular Pertussis Vaccines; Disease; Dose; Evaluation; Formulation; Generations; Goals; Health; Hemagglutinin; Human; Immune response; Immunity; Immunize; Immunologic Memory; Immunologics; Incidence; Infant; Inflammation; International; Intramuscular; Laboratories; Lead; Leukocytosis; Life; Longevity; Lung diseases; Manufacturer Name; Mediating; Membrane; Messenger RNA; Mission; Modeling; Molecular Conformation; Mus; Papio; Pertussis; Pertussis Toxin; Pertussis Vaccine; Phenotype; Population; Pre-Clinical Model; Production; Protein Subunits; Proteins; Public Health; RNA vaccine; Rattus; Research; Respiratory System; Respiratory Tract Infections; Respiratory physiology; Schedule; Scientist; Speed; Subunit Vaccines; Surrogate Endpoint; Technology; Tetanus; Toxin; United States National Institutes of Health; Vaccine Production; Vaccines; Virulence Factors; Whole Body Plethysmography; Whole Cell Vaccine; age group; antigen binding; base; booster vaccine; clinical development; clinical efficacy; clinical predictors; efficacy study; epidemiology study; experimental study; flexibility; human pathogen; immunogenicity; in vivo; interest; lipid nanoparticle; mouse model; nanoparticle delivery; neutralizing antibody; novel; novel vaccines; pathogen; pertactin; pressure; protein expression; protein purification; response; screening; study population; symposium; vaccine candidate; vaccine development

PROJECT SUMMARY Pertussis is a respiratory disease caused by the obligate human pathogen Bordetella pertussis. Two generations of pertussis vaccines have been developed and licensed: whole cell pertussis (DTP) and acellular pertussis (DTaP/Tdap). Pertussis was thought to be a disease of the past but has recently re-emerged. The number of cases of pertussis in 2012 was 48-fold over the lowest year on record (1976), which was also a 50-year high. While the increase of pertussis has multiple potential reasons, epidemiological studies clearly suggest that the duration of immunity of both DTaP and Tdap wanes quickly each year after a booster, and regresses to non- protective levels in humans. Each dose of whole cell vaccine contains hundreds of antigens, of which numerous are immunodominant. Whole cell vaccines also induce T helper 1 and 17 (Th1/Th17) cellular immune responses. On the other hand, acellular vaccines focus Th2-mediated humoral responses exclusively to pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae. We aim to develop a vaccine that would induce Th1 responses and include a greater number of antigens than acellular vaccines. mRNA vaccines provide a platform that can be easily modified for the targeted antigen/pathogen and they induce Th1 responses. mRNA vaccines encode the antigen, which once expressed, results in immunity mediated by Tfh responses. We used an mRNA platform to screen antigens of B. pertussis and identified a protective multivalent formulation (mRNA-DTP10; 8 pertussis antigens with diphtheria and tetanus antigens) in a murine challenge model. In this project, we will further extend our studies and investigate the correlates of protection of the mRNA-pertussis vaccine in the murine model with longevity studies and examine DTaP prime / mRNA-boost effects (SA1). Next, we will utilize the coughing rat model of pertussis with whole body plethysmography to compare mRNA, whole cell, and acellular immunity for protection against cough (SA2). We will study the mRNA pertussis vaccine in immunogenicity and challenge experiments using the baboon model of pertussis (SA3). Lastly, we will aim to develop a suite of assays to phenotype antibodies produced by mRNA pertussis vaccines and bridge each of the pertussis models, which will facilitate clinical development. Through these studies, we aim to characterize the mRNA-pertussis immunity and develop a clearer understanding of how this vaccine platform can be used to overcome “complex or difficult” pathogens that employ numerous virulence factors. We expect the data acquired in each aim will result in a deeper understanding of pertussis immunity as well as illuminate the mRNA platform for bacterial vaccines.

项目概要 百日咳是由两代人类专性病原体百日咳博德特氏菌引起的呼吸道疾病。 已开发并获得许可的百日咳疫苗：全细胞百日咳 (DTP) 和无细胞百日咳 (DTaP/Tdap) 百日咳曾被认为是一种过去的疾病，但最近又重新出现。 2012 年百日咳病例数是有记录以来最低年份（1976 年）的 48 倍，也是 50 年来的最高水平。 虽然百日咳的增加有多种潜在原因，但流行病学研究明确表明， DTaP 和 Tdap 的免疫持续时间在加强免疫后每年都会迅速减弱，并回归到非免疫状态。 每剂全细胞疫苗含有数百种抗原，其中有许多抗原。 全细胞疫苗还诱导 T 辅助细胞 1 和 17 (Th1/Th17) 细胞免疫反应。 另一方面，无细胞疫苗将 Th2 介导的体液反应专门针对百日咳毒素， 我们的目标是开发一种诱导 Th1 的疫苗。 反应并包含比非细胞疫苗更多的抗原，提供了一个平台。 可以针对目标抗原/病原体轻松进行修改，并诱导 Th1 mRNA 疫苗反应。 编码抗原，一旦表达，就会产生 Tfh 反应介导的免疫。 筛选百日咳博德特氏菌抗原的平台并鉴定了保护性多价制剂（mRNA-DTP10；8 百日咳抗原与白喉和破伤风抗原）在小鼠攻击模型中，我们将。 进一步扩展我们的研究并调查 mRNA 百日咳疫苗在 接下来，我们将利用小鼠模型进行长寿研究并检查 DTaP prime / mRNA 增强效应 (SA1)。 百日咳咳嗽大鼠模型，采用全身体积描记法比较 mRNA、全细胞和 用于预防咳嗽的非细胞免疫 (SA2) 我们将研究 mRNA 百日咳疫苗。 最后，我们的目标是使用百日咳狒狒模型（SA3）进行免疫原性和攻击实验。 开发一套测定 mRNA 百日咳疫苗产生的表型抗体的方法，并桥接每种抗体 百日咳模型，这将促进临床开发，我们的目标是表征。 mRNA-百日咳免疫，并更清楚地了解如何使用该疫苗平台 我们期望获得的数据能够克服使用多种毒力因子的“复杂或困难”病原体。 每个目标都将加深对百日咳免疫的了解并阐明 mRNA 平台 用于细菌疫苗。