Dermatotropic cellular immune responses induced by a novel smallpox vaccine

新型天花疫苗诱导的皮肤细胞免疫反应

• 批准号: 8260814
• 负责人: STEPHEN R WALSH
• 金额: $ 12.89万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260814
• 关键词: Adverse effects; Adverse event; Animal Model; Animals; Antigens; Atopic Dermatitis; Attenuated; Biometry; Bioterrorism; CCR5 gene; CCR9 gene; CD28 gene; CD8B1 gene; CXCR3 gene; Cells; Cellular Immunity; Cessation of life; Clinical Investigator; Clinical Trials; Clinical effectiveness; Communicable Diseases; Cutaneous; Data; Development; Development Plans; Diagnosis; Disease; Dose; Eczema; Eczema Vaccinatum; Encephalitis; Epidemiology; Flow Cytometry; Frequencies; GPR2 gene; Goals; Homing; Hospitals; Human; Immune response; Immunity; Immunocompromised Host; Immunology; Individual; Infection; Integrins; Interleukin-2; Interleukin-4; Intramuscular; Israel; Kinetics; Knowledge; Licensing; Life; Lung; Lymphocyte; Mammalian Cell; Medical center; Mentors; Methodology; Modified Vaccinia Virus Ankara; Nature; Occupational; Orthopoxvirus; Peripheral Blood Mononuclear Cell; Phase; Policy Making; Poxviridae; Public Health Schools; Randomized; Research; Research Personnel; Research Project Grants; Risk; Route; Safety; Secondary Immunization; Site; Skin; Smallpox; Smallpox Vaccine; Smallpox Viruses; Staining method; Stains; T-Lymphocyte; TNF gene; TNFRSF6 gene; TNFSF5 gene; Time; Training; Translating; Vaccinated; Vaccination; Vaccines; Vaccinia; Vaccinia virus; Vaccinium; Viral; Virulent; Virus; Virus Diseases; Virus Replication; Woman; animal data; attenuation; biodefense; career; career development; chemokine receptor; cytokine; design; experience; high risk; immunogenic; immunosuppressed; medical schools; novel; open label; patient oriented research; post-doctoral training; prevent; programs; public health relevance; research and development; research study; respiratory; response; skills; subcutaneous; trafficking; vaccine-induced immunity; vaccinology

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.

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。该候选人已完成传染病亚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，以实现既定的职业目标。本职业发展建议的总体目标是发展一个以患者为导向的研究项目，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，以及贝斯以色列女主教医疗中心、布里格姆妇女医院和哈佛医学院合作开展的指导研究项目。拟议的研究组成部分的目标是将尖端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。我们假设外皮接种和随后的野生型牛痘病毒（VACV）皮内复制导致痘病毒特异性T细胞的优先选择，这些T细胞表达亲皮肤淋巴细胞归巢分子，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，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），与常见的肌肉注射（IM）途径相比，对病毒特异性的皮肤性T细胞具有相似的优先选择。因此，本研究的具体目的是：1)研究MVA给药途径对促皮肤正痘病毒特异性T细胞的诱导作用；2)通过表皮划伤确定接种MVA的健康人体内正痘病毒特异性T细胞的动力学、大小和运输标记物表达；3)确定接种MVA的湿疹或特应性皮炎患者中正痘病毒特异性T细胞的动力学、大小和运输标记物表达。这些实验产生的数据将大大增加关于MVA与标准VACV疫苗接种引起的免疫反应的知识体系，从而为生物防御政策制定提供信息。通过完成全面的研究和职业发展计划，候选人将获得必要的技能，成为一名独立的疫苗学临床研究者。