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.

项目摘要 百日咳是一种呼吸道疾病，由专性人类病原体百日咳博德特氏菌引起。两代 已经开发并获得许可的百日咳疫苗有：全细胞百日咳疫苗（DTP）和无细胞百日咳疫苗 (DTaP/Tdap）。百日咳被认为是过去的一种疾病，但最近又重新出现。的数量 2012年的百日咳病例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，但流行病学研究清楚地表明， DTaP和Tdap的免疫持续时间在加强免疫后每年都会迅速下降，并回归到非免疫状态。 人体的保护水平。每一剂全细胞疫苗含有数百种抗原，其中许多抗原 是免疫显性的。全细胞疫苗还诱导辅助性T细胞1和17（Th 1/Th 17）细胞免疫应答。 另一方面，无细胞疫苗仅将Th 2介导的体液应答集中于百日咳毒素， 丝状血凝素、perceptin和菌毛。我们的目标是开发一种诱导Th 1的疫苗 免疫应答，并且包括比无细胞疫苗更多数量的抗原。mRNA疫苗提供了一个平台 其可以容易地针对靶抗原/病原体进行修饰，并且它们诱导Th 1应答。mRNA疫苗 编码抗原，一旦表达，导致由Tfh应答介导的免疫。我们用mRNA 筛选B抗原的平台。百日咳，并确定了保护性多价制剂（mRNA-DTP 10; 8 百日咳抗原与白喉和破伤风抗原）。在这个项目中，我们将 进一步扩展我们的研究，并调查在儿童中的mRNA-pertussis疫苗保护的相关性。 小鼠模型进行寿命研究，并检查DTaP初免/mRNA加强效应（SA 1）。接下来，我们将利用 用全身体积描记法比较百日咳咳嗽大鼠模型的mRNA、全细胞和 无细胞免疫，用于预防咳嗽（SA 2）。我们将研究mRNA百日咳疫苗， 免疫原性和使用百日咳狒狒模型的攻击实验（SA 3）。最后，我们的目标是 开发一套检测由mRNA百日咳疫苗产生的表型抗体的方法， 百日咳模型，这将有助于临床开发。通过这些研究，我们的目标是 mRNA-百日咳免疫，并更清楚地了解这种疫苗平台如何用于 克服使用许多毒力因子的“复杂或困难的”病原体。我们希望获得的数据 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。