Dermatotropic cellular immune responses induced by a novel smallpox vaccine

描述（由申请人提供）：本申请的目的是促进候选人发展成为独立的临床研究者。候选人已完成传染病专科培训和基础免疫学博士后培训，并正在寻求进一步的导师指导培训，以实现既定的职业目标。该职业发展计划的总体目标是开发一个以患者为导向的研究计划，调查疫苗引起的宿主对生物恐怖主义相关病毒感染的免疫力，同时成为一名成功的独立临床研究人员。拟议的职业发展计划包括通过哈佛公共卫生学院提供先进的流行病学和生物统计学培训的教学培训，以及贝丝以色列女执事医疗中心、布里格姆妇女医院和哈佛医学院合作开展的一个指导性研究项目。拟议的研究部分的目标是将尖端的免疫学方法转化为临床试验的设计和实施，以评估实验性疫苗诱导的对正痘病毒的免疫力。我们假设，表皮接种和随后的皮内（ID）复制的野生型牛痘病毒（VACV）导致优先选择痘病毒特异性T细胞表达皮肤嗜性淋巴细胞归巢分子，包括皮肤淋巴细胞相关抗原（CLA）和特定的趋化因子受体，如CCR 4和CCR 10。我们进一步假设，通过ID、皮下（SC）和表皮途径接种实验性天花疫苗修饰的安卡拉牛痘（MVA），与常见的肌内（IM）途径相比，对病毒特异性亲皮肤性T细胞具有相似的优先选择性。因此，本研究的具体目的是：1）研究MVA的给药途径对向皮性正痘病毒特异性T细胞诱导的影响; 2）确定通过表皮划痕接种MVA的健康受试者中正痘病毒特异性T细胞的动力学、大小和运输标志物表达;和3）测定接种MVA的湿疹或特应性皮炎受试者中正痘病毒特异性T细胞的动力学、大小和运输标志物表达。与标准VACV疫苗接种相比，这些实验产生的数据将显著增加关于MVA引起的免疫应答的知识体系，从而为生物防御决策提供信息。通过全面的研究和职业发展计划的完成，候选人将获得必要的技能，成为一个独立的疫苗临床研究者。

DESCRIPTION (provided by applicant): The purpose of this application is to facilitate the development of the candidate into an independent clinical investigator. The candidate has completed infectious diseases subspecialty training and post-doctoral training in basic immunology and is seeking further mentor-guided training to attain the stated career goals. The overarching goal of this career development proposal is to develop a patient-oriented research program investigating vaccine-elicited host immunity to bioterrorism-associated viral infections, while becoming a successful independent clinician-researcher. The proposed career development plan consists of didactic training that will provide advanced epidemiology and biostatistics training through the Harvard School of Public Health and a mentored research project to be conducted as a collaborative effort between Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, and Harvard Medical School. The goal of the proposed research component is to translate cutting-edge immunology methodology into the design and implementation of clinical trials evaluating experimental vaccine-induced immunity to orthopoxviruses. We hypothesize that the epicutaneous inoculation and subsequent intradermal (ID) replication of wild-type vaccinia virus (VACV) leads to preferential selection of poxvirus-specific T cells which express skin-tropic lymphocyte homing molecules, including the cutaneous lymphocyte-associated antigen (CLA) and specific chemokine receptors such as CCR4 and CCR10. We further hypothesize that vaccination with the experimental smallpox vaccine modified vaccinia Ankara (MVA) by the ID, subcutaneous (SC), and epicutaneous routes has a similar preferential selection for viral-specific dermatotropic T cells as opposed to the common intramuscular (IM) route. The Specific Aims of the research are therefore to: 1) Investigate the effect that route of administration of MVA has on the induction of dermatotropic orthopoxvirus-specific T cells; 2) Determine the kinetics, magnitude, and trafficking marker expression of orthopoxvirus-specific T cells in healthy subjects vaccinated with MVA via epicutaneous scarification; and 3) Determine the kinetics, magnitude, and trafficking marker expression of orthopoxvirus-specific T cells in subjects with eczema or atopic dermatitis vaccinated with MVA. The data generated by these experiments will add significantly to the body of knowledge regarding immune responses elicited by MVA compared with standard VACV vaccination and thus inform biodefense policy-making. By the completion of the comprehensive research and career development plan, the candidate will have obtained the requisite skills to become an independent clinical investigator in vaccinology.