Systematic evaluation of B. pertussis ACT’s role as a protective antigen

百日咳博德特氏菌 ACT 作为保护性抗原的作用的系统评估

• 批准号: 9056231
• 负责人: Eric T Harvill
• 金额: $ 39.06万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9056231
• 关键词: Acellular Vaccines; Active Immunization; Address; Adenylate Cyclase; Adenylate Cyclase Toxin; Adjuvant; Anti-Bacterial Agents; Antibodies; Antibody Response; Antigens; Bacterial Adhesins; Binding; Biochemical; Biological Assay; Bordetella; Bordetella pertussis; Calmodulin; Cell membrane; Cells; Chimera organism; Clinical; Communities; Complement; Cyclic AMP; Data; Developed Countries; Diphtheria-Tetanus-acellular Pertussis Vaccines; Disease; Engineering; Epitopes; Escherichia coli; Evaluation; Fc Receptor; Formulation; Future; Genomics; Goals; Human; ITGAM gene; IgG1; Immune response; Immunization; In Vitro; Incidence; Individual; Infant; Infection; Intoxication; Leukocytes; Licensing; Mediating; Monoclonal Antibodies; Morbidity - disease rate; Morphologic artifacts; Mus; Passive Immunization; Pathogenesis; Performance; Pertussis; Pertussis Toxin; Pertussis Vaccine; Pharmacologic Substance; Point Mutation; Protein Engineering; Proteins; Proteolysis; Reporting; Role; Surface; Tertiary Protein Structure; Testing; Toxin; Transgenic Mice; Vaccination; Vaccines; Variant; Virulence Factors; Work; Yeasts; bactericide; base; design; immunogenic; immunogenicity; improved; in vivo; infant death; killings; member; mortality; mouse model; neutralizing monoclonal antibodies; polyclonal antibody; programs; public health relevance; receptor; research study; respiratory

 DESCRIPTION (provided by applicant): Before the introduction of modern vaccination programs, whooping cough, caused by the bacteria Bordetella pertussis, was the primary infectious cause of infant death. B. pertussis is highly specialized to its human host and produces a number of virulence factors, with no clear correlate of protection. Despite wide-spread, aggressive vaccination, pertussis not only persists but is increasing in incidence in the US and other industrialized countries. In 2012, more pertussis cases were reported in the US since 1955. Academic, pharmaceutical and regulatory members of the pertussis community agree on the need for a more immunogenic and efficacious pertussis vaccine, but how to achieve this is not clear. Therefore, advances in the scientific basis of pertussis pathogenesis and host protective mechanisms are needed. In particular, the adenylate cyclase toxin (ACT) is the leading candidate for inclusion in future vaccines, yet there is very little data detailing the mechanisms by which ACT confers protection or its appropriateness for manufacturing and formulation as a part of a multi-component vaccine. Here, we will perform the first systematic evaluation of ACT's role in protection. This work will involve a combination of in vitro biochemical and anti-bacterial assays as well as passive and active immunization experiments using a murine model of infection which is predictive of vaccine performance in humans. We aim to conclusively define the role of neutralizing and non-neutralizing anti-ACT antibodies in disease as well as to identify the immunological mechanisms and ACT epitopes necessary for protection.

 描述（由申请方提供）：在引入现代疫苗接种计划之前，由百日咳杆菌引起的百日咳是婴儿死亡的主要感染原因。B。百日咳对人类宿主具有高度特化性，并产生许多毒力因子，但没有明确的保护相关性。尽管广泛传播，积极的疫苗接种，百日咳不仅持续存在，而且在美国和其他工业化国家的发病率正在增加。自1955年以来，2012年美国报告了更多的百日咳病例。百日咳学界的学术、制药和监管成员一致认为需要一种免疫原性更强、更有效的百日咳疫苗，但如何实现这一目标尚不清楚。因此，需要在百日咳发病机制和宿主保护机制的科学基础方面取得进展。特别地，腺苷酸环化酶毒素（ACT）是包含在未来疫苗中的主要候选物，但是很少有数据详细描述其在疫苗中的作用。 ACT提供保护的机制或其作为多组分疫苗的一部分的生产和配制的适当性。在这里，我们将对ACT在保护方面的作用进行首次系统评估。这项工作将涉及体外生物化学和抗菌试验以及被动和主动免疫实验的组合，使用鼠感染模型预测疫苗在人体中的性能。我们的目标是最终确定中和和非中和抗ACT抗体在疾病中的作用，以及确定保护所需的免疫机制和ACT表位。