Vaccine-Induced Immunity against Influenza in Frailty

描述（由申请人提供）：Sean Leng，MD PhD，已经证明了巨大的希望和无与伦比的决心，成为临床/转化衰老研究的领导者。他在免疫学和分子病毒学、细胞因子研究和内科学方面接受过高级培训。在约翰霍普金斯大学获得老年医学和老年学的临床和研究奖学金后，他于2002年被聘为教师，并于2003年晋升为医学助理教授。他是NIA短期R21和约翰霍普金斯内部研究奖的获得者。Leng博士得到了老年医学和老年学系教授兼主任、老年医学和老年健康中心主任、老年病学家和流行病学家琳达·弗里德博士以及自身免疫疾病研究中心教授兼主任、免疫学家诺埃尔·罗斯博士的大力指导。他们将为他提供广泛的资源和刺激的跨学科环境，以启动他在转化衰老研究方面的独立学术生涯。 博士Leng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和对压力源（包括感染）的脆弱性增加，导致老年人严重的不良健康后果。根据Leng博士目前研究的初步结果，该项目提出了一项在社区居住的体弱和年龄匹配的非体弱老年人中进行流感免疫接种的试点研究。通过这种临床上成熟的体内免疫激发，我们将描述虚弱老年人的免疫失调，并在以下特定目标下将其含义转化为临床输入的背景：1）确定虚弱老年人是否具有通过病毒特异性抗体滴定剂测量的受损的体液免疫; 2）通过抗原特异性CD 4+和CD 8 + T细胞的数量来确定虚弱的老年人是否具有疫苗诱导的细胞介导的免疫（CMI）的损伤，IFN-γ和IL-2的细胞内产生以及细胞毒性T淋巴细胞（CTL）功能。Leng博士还将评估接种前特定T细胞表型（CD 8 + CD 28-T细胞）数量与疫苗诱导的CMI之间的关系; 3）描述接种疫苗的体弱老年人在接种后季节与非体弱对照组相比，流感感染及其并发症（肺炎、住院和死亡）的发生率是否增加。作为我们最初的转化努力，该项目将提高我们评估和加强免疫功能的能力，并最终预防相关的不良健康后果，包括流感感染及其并发症，为体弱的老年人。 博士Leng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，强大的导师制，精心设计的职业发展计划，支持性的环境和新颖的研究计划将为他提供发展成为一名非常成功的独立医生/老年医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.