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

 描述(申请人提供)：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。百日咳对其人类宿主高度专门化，并产生许多毒力因子，没有明确的保护相关性。尽管接种了广泛、积极的疫苗，百日咳在美国和其他工业化国家不仅持续存在，而且发病率正在上升。2012年，自1955年以来，美国报告的百日咳病例更多。百日咳学界、药剂界和监管部门的成员一致认为，需要一种更具免疫原性和更有效的百日咳疫苗，但如何实现这一点尚不清楚。因此，需要在百日咳发病机制和宿主保护机制的科学基础上取得进展。特别是，腺苷环化酶毒素(ACT)是未来疫苗的主要候选者，但很少有数据详细说明 ACT提供保护的机制或其作为多组分疫苗一部分生产和配制的适宜性。在这里，我们将对ACT在保护方面的作用进行首次系统评估。这项工作将结合体外生化和抗菌试验，以及使用可预测人类疫苗性能的小鼠感染模型进行被动和主动免疫实验。我们的目标是最终确定中和性和非中和性抗ACT抗体在疾病中的作用，并确定保护所需的免疫学机制和ACT表位。

 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.