Vaccine-Induced Immunity against Influenza in Frailty

描述(由申请人提供)：肖恩·冷，医学博士，已经展示了成为临床/转化性衰老研究的领导者的巨大希望和无与伦比的决心。他曾接受过免疫学和分子病毒学、细胞因子研究和内科的高级培训。在约翰霍普金斯大学获得老年医学和老年学临床和研究奖学金后，他于2002年被聘为该校教员，并于2003年被提升为医学助理教授。他是NIA的短期R21奖学金的获得者，并获得了约翰霍普金斯大学的内部研究奖。冷博士得到了老年病学家和流行病学家Linda Fry博士(老年医学和老年病学部教授兼主任和老龄化与健康中心主任)和免疫学家Noel Rose博士(自身免疫病研究中心主任)的大力指导。他们将为他提供广泛的资源和激励的跨学科环境，以启动他在翻译老龄化研究方面的独立学术生涯。 冷博士的研究兴趣是虚弱，这是一种常见的老年综合征，其特征是多个生理系统的失调，以及对包括感染在内的压力因素的易感性增加，这些压力因素会导致老年人严重的不良健康后果。根据冷博士目前研究的初步结果，该项目建议在社区居住的体弱和年龄匹配的非体弱老年人中进行一项试点流感免疫研究。有了这一临床上公认的体内免疫挑战，我们将描述虚弱老年人的免疫失调特征，并将其在以下特定目标下的临床应用应用：1)确定虚弱老年人是否存在通过病毒特异性抗体效价测定的体液免疫受损；2)确定虚弱老年人是否存在疫苗诱导的细胞免疫(CMI)受损，通过抗原特异的CD4+和CD8+T细胞数量、细胞内干扰素-γ和IL-2的产生以及细胞毒性T淋巴细胞(CTL)功能来衡量。冷博士还将评估接种前特定T细胞表型CD8+CD28-T细胞的数量与疫苗诱导的CMI的关系；3)描述接种疫苗后体弱老年人与非体弱对照组相比，流感感染率及其并发症(肺炎、住院和死亡)是否增加。作为我们最初的翻译工作，该项目将提高我们评估和加强免疫功能的能力，并最终防止相关的不良健康后果，包括流感感染及其破坏性并发症，对虚弱的老年人来说。 冷博士在临床老年医学和基础免疫学/分子病毒学和细胞因子研究方面的双重培训、强大的指导、精心设计的职业发展计划、支持性环境和新颖的研究计划将使他获得发展成为一名非常成功、独立的内科医生/老年病科学家所需的经验和工具。

DESCRIPTION (provided by applicant): Sean Leng, MD PhD, has demonstrated great promise, and unsurpassed determination, to become a leader in clinical / translational aging research. He has had advanced training in Immunology and Molecular Virology, Cytokine Research, and Internal Medicine. After a clinical and research fellowship in Geriatric Medicine and Gerontology at Johns Hopkins, he was recruited to its faculty as an Instructor in 2002 and was promoted to Assistant Professor of Medicine in 2003. He is a recipient of a short-term R21 from NIA and an internal research award at Johns Hopkins. Dr. Leng has strong mentorship from geriatrician and epidemiologist Dr. Linda Fried, Professor and Director of the Division of Geriatric Medicine and Gerontology and Center on Aging and Health, and from immunologist Dr. Noel Rose, Professor and Director of Center for Autoimmune Disease Research. They will provide him with extensive resources and a stimulating interdisciplinary environment to launch his independent academic career in translational aging research. Dr. Leng's research interest is in frailty, a common geriatric syndrome characterized by dysregulations in multiple physiologic systems and increased vulnerability to stressors, including infections, that result in severe adverse health outcomes in older adults. Based on the preliminary findings from Dr. Leng's current research, this project proposes a pilot influenza immunization study in community-dwelling frail and age-matched non-frail older adults. With this clinically well-established in vivo immune challenge, we will characterize immune dysregulation of frail older adults and translate its implications in the context of clinical import under the following specific aims: 1) Determine whether frail older adults have impaired humoral immunity measured by viral-specific antibody tilers; 2) Determine whether frail older adults have impairment in vaccine-induced cell-mediated immunity (CMI) measured by number of antigen-specific CD4+ and CD8+ T cells, intracellular production of IFN-y and IL-2, and cytotoxic T lymphocyte (CTL) function. Dr. Leng will also evaluate the relationship of pre-vaccination number of specific T cell phenotype, CD8+CD28-T cells, with vaccine-induced CMI; 3) To delineate whether vaccinated frail older adults have increased rate of influenza infection and its complications (pneumonia, hospitalization, and death), compared to non-frail controls, during the post-vaccination season. As our initial translational effort, this project will improve our ability to evaluate and strengthen immune function, and ultimately prevent related adverse health outcomes, including influenza infection and its devastative complications, for frail older adults. Dr. Leng's dual training in clinical geriatric medicine and basic immunology/molecular virology and cytokine research, strong mentorship, carefully designed career development program, supportive environment, and novel research plan will give him the experience and tools that he needs to develop into a highly successful, independent physician/geriatrician-scientist.