Dermatotropic cellular immune responses induced by a novel smallpox vaccine

描述(申请人提供)：此申请的目的是促进候选人发展成为一名独立的临床研究人员。应聘者已完成传染病专业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，以实现所述的职业目标。这项职业发展提案的总体目标是开发一个以患者为导向的研究计划，调查疫苗引发的宿主对生物恐怖主义相关病毒感染的免疫，同时成为一名成功的独立临床医生和研究人员。拟议的职业发展计划包括通过哈佛公共卫生学院提供高级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有指导的研究项目。拟议研究部分的目标是将尖端免疫学方法转化为评估实验性疫苗诱导的对正痘病毒免疫的临床试验的设计和实施。我们假设，野生型痘苗病毒(VACV)的皮肤接种和随后的皮内复制导致优先选择表达皮肤嗜性淋巴细胞归巢分子的痘病毒特异性T细胞，包括皮肤淋巴细胞相关抗原(CLA)和特异性趋化因子受体，如CCR4和CCR10。我们进一步假设，与普通肌肉注射(IM)途径相反，通过ID、皮下(SC)和皮下(SC)途径改良安卡拉牛痘(MVA)的实验性天花疫苗接种对病毒特异性亲皮肤T细胞具有类似的优先选择。因此，这项研究的具体目的是：1)调查MVA给药途径对亲皮性正痘病毒特异性T细胞诱导的影响；2)通过皮肤划痕测定健康受试者接种MVA后正痘病毒特异性T细胞的动力学、大小和运输标记的表达；以及3)确定湿疹或特应性皮炎患者接种MVA后正痘病毒特异性T细胞的动力学、大小和运输标记的表达。这些实验产生的数据将大大增加关于MVA与标准VACV疫苗相比所引起的免疫反应的知识，从而为生物防御政策的制定提供信息。在完成全面的研究和职业发展计划后，候选人将获得成为疫苗学独立临床调查员所需的技能。 公共卫生相关性：目前可用的天花疫苗有大量严重的副作用，由于不良事件的高风险，不能在许多人身上使用。这项提案将调查一种新的天花疫苗在湿疹或特应性皮炎患者中使用是否安全，并确定新的天花疫苗诱导的免疫反应是否类似于传统天花疫苗诱导的免疫反应。

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. Public Health Relevance: Currently available smallpox vaccines have a large number of serious side effects and cannot be used in many people due to the high risk of adverse events. This proposal will investigate whether a new smallpox vaccine is safe to use in people with eczema or atopic dermatitis and determine whether the immune responses induced by the new smallpox vaccine are similar to immune responses induced by traditional smallpox vaccines.