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; 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 百日咳是由bordetella bordetella budtussis引起的呼吸道疾病。两代 已开发和许可百日咳疫苗：全细胞百日咳（DTP）和细胞百日咳 （DTAP/TDAP）。百日咳被认为是过去的一种疾病，但最近重新出现了。数量 2012年的百日咳病例比（1976年）的最低年份为48倍，这也是50年的高度。 尽管百日咳的增加具有多个潜在原因，但流行病学研究清楚地表明 助推器后，DTAP和TDAP的免疫力持续时间都会迅速减弱，并退缩为非 - 人类的保护水平。全细胞疫苗的每剂含有数百种抗原，其中许多抗原 是免疫主导的。全细胞疫苗还会诱导T助手1和17（TH1/TH17）细胞免疫调查。 另一方面，细胞疫苗仅针对百日咳毒素的Th2介导的体液反应， 丝状血凝素，腹膜蛋白酶和纤维化。我们旨在开发一种诱导TH1的疫苗 反应并包括比细胞疫苗更多的抗原。 mRNA疫苗提供平台 对于靶向抗原/病原体，可以很容易地修改这种方法，并影响Th1反应。 mRNA疫苗 编码曾经表达的抗原会导致由TFH反应介导的免疫学。我们使用了mRNA 筛选B.百日咳抗原的平台，并确定了保护性多价配方（mRNA-DTP10; 8 鼠挑战模型中的百日咳抗原与白喉和tetanius抗原）。在这个项目中，我们将 进一步扩展我们的研究并研究了mRNA-Pertussis疫苗保护的相关性 带有寿命研究的鼠模型并检查了DTAP Prime / mRNA-Boost效应（SA1）。接下来，我们将使用 全身咳嗽的百日咳大鼠模型，以比较mRNA，全细胞和 细胞免疫可防止咳嗽（SA2）。我们将研究mRNA百日咳疫苗 使用百日咳的狒狒模型（SA3）进行免疫原性和挑战实验。最后，我们的目标是 为mRNA百日咳疫苗产生的表型抗体开发一套测定套件，并桥接每一个 百日咳模型将促进临床发展。通过这些研究，我们旨在表征 mRNA-Pertussis免疫力，并对该疫苗平台如何用于 克服采用多种病毒因素的“复杂或困难”病原体。我们期望获得的数据获取 在每个目标中，都会使对百日咳免疫力有更深入的了解，并照亮mRNA平台 对于细菌阴道。