Development of mRNA-platform vaccines

mRNA平台疫苗的开发

• 批准号: 10541207
• 负责人: Fredrick Heath Damron
• 金额: $ 84.15万
• 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/10541207
• 关键词: 11 year old; Acellular Vaccines; Adjuvant; Adolescent; Adult; Antibodies; Antibody Formation; Antibody Response; Antibody-mediated protection; Antigen Targeting; Antigens; Avidity; Bacterial Vaccines; Belgium; Biological Assay; Bordetella; Bordetella pertussis; COVID-19 pandemic; Cells; Cellular Immunity; 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; Licensing; Life; Longevity; Manufacturer; 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 Disease; 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; 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; neutralizing antibody; novel; novel vaccines; pathogen; pertactin; pressure; protein expression; protein purification; response; screening; study population; symposium; technology platform; vaccine candidate; vaccine development; vaccine platform; vaccine strategy

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.

项目总结