The Development of Norovirus Immunity in Early Childhood and Implications for Norovirus Vaccines

这项K24建议建立在十年来对儿童胃肠炎的临床和流行病学研究的基础上 尼加拉瓜由候选人西尔维娅·贝克尔-德雷普斯，医学博士，公共卫生硕士。作为贝克-德雷普斯博士的自然延伸 之前关于了解轮状病毒疫苗在资源受限环境下有效性降低的工作， 目前的提案扩展了Becker-Dreps博士的技能集，使她能够为开发有效的 儿童诺沃克病毒疫苗。这项建议还有目的地将受训人员纳入这项工作，并加强了Dr。 贝克尔-德雷普斯的指导技能，使她能够提供最高质量的指导尽可能。 候选人：贝克尔-德雷普斯博士是一名内科医生兼科学家，兼任家庭医学和流行病学专业。 她职业生涯的主要重点一直是推进病毒性胃肠炎的预防。她的团队已经 采用了多学科方法，将强有力的现场流行病学与最先进的实验室相结合 方法：研究方法。她的团队是第一个测量轮状病毒疫苗有效性和羊群保护的组织 社区水平，也表明母亲对轮状病毒的高水平免疫力之间存在关联 以及婴儿对疫苗的不良反应。现在轮状病毒疾病的负担正在减少，因为广泛的 轮状病毒疫苗的引入，诺沃克病毒被认为是胃肠炎的主要原因。计划中的职业 开发活动扩展了Becker-Dreps博士的技能集，使她能够更好地描述 诺沃克病毒免疫，并为儿童诺沃克病毒疫苗的设计和未来试验做出贡献。 研究计划：在儿童中开发有效的诺沃克病毒疫苗面临几个障碍。这些 包括在幼稚的婴儿中引发强大的初级免疫反应，以及引发持久的反应 对一系列诺沃克病毒株具有广泛的活性。更好地理解免疫的发展 预防自然诺沃克病毒感染将有助于揭示如何克服这些障碍。我们建议提供 通过利用现有的由R01资助的对尼加拉瓜400名儿童的出生队列研究，获得了这些信息。目标 本研究的主要目的是：1)描述诺如病毒胃肠炎的自然病程和发展。 出生后对诺如病毒感染的获得性免疫，包括阐明两者之间的抗原关系 不同的诺如病毒基因型别；2)表征接触前病史对后续感染的影响 3)调查母亲获得的诺沃克病毒免疫的潜在保护作用。 指导计划。贝克尔-德雷普斯博士在指导学员以病人为导向方面有着良好的记录 用于研究，并吸引在科学界代表性不足的群体的受训人员。目前，她的可用时间 导师的作用是有限的。在K24的支持下，她将重新致力于指导早期临床医生研究人员 因为他们努力成为独立的资金来源。她将利用北卡罗来纳大学的广泛资源来实现这一目标 Goal，包括NIH资助的中心和培训计划，以及北卡罗来纳大学的全球卫生和传染病研究所 疾病。

This K24 proposal builds upon a decade of clinical and epidemiologic research on childhood gastroenteritis in Nicaragua by the candidate, Sylvia Becker-Dreps, MD, MPH. As a natural extension of Dr. Becker-Dreps' previous work on understanding reduced rotavirus vaccine effectiveness in resource-constrained settings, the current proposal expands Dr. Becker-Dreps' skillsets to allow her to contribute to the development of an effective pediatric norovirus vaccine. This proposal also purposefully integrates trainees into this work, and enhances Dr. Becker-Dreps' mentoring skills, so that she can provide the highest quality mentoring possible. Candidate: Dr. Becker-Dreps is a physician-scientist dually appointed in Family Medicine and Epidemiology. The primary focus of her career has been to advance the prevention of viral gastroenteritis. Her group has employed a multidisciplinary approach that combines robust field epidemiology with state-of-the-art laboratory methods. Her group was the first to measure rotavirus vaccine effectiveness and herd protection at the community level, and also showed an association between high levels of maternal immunity against rotavirus and poor vaccine response in infants. Now that rotavirus disease burden is decreasing due to widespread rotavirus vaccine introduction, norovirus is recognized as a leading cause of gastroenteritis. The proposed career development activities expand Dr. Becker-Dreps' skillsets to allow her to better characterize the development of norovirus immunity and to contribute to the design and future trials of pediatric norovirus vaccines. Research Plan: The development of an effective norovirus vaccine in children faces several hurdles. These include eliciting a robust primary immune response in naïve infants, and eliciting a response that is long-lasting and broadly active against a range of norovirus strains. A better understanding of the development of immunity against natural norovirus infections would shed light on how to overcome these hurdles. We propose to provide this information by leveraging an existing R01-funded birth cohort study of 400 children in Nicaragua. The aims of this research are to: 1) Characterize the natural history of norovirus gastroenteritis and the development of adaptive immunity to norovirus infection after birth, including elucidation of antigenic relationships between different norovirus genotypes; 2) Characterize the effect of pre-exposure history on subsequent infections in early childhood; and 3) Investigate the potential protective effect of maternally-acquired norovirus immunity. Mentoring Plan. Dr. Becker-Dreps has an established track record in mentoring trainees in patient-oriented research, and for attracting trainees from groups underrepresented in science. Currently, her available time for mentorship is limited. With K24 support she will rededicate her efforts to mentoring early clinician investigators as they strive to become independently funded. She will leverage UNC's extensive resources to accomplish this goal, including NIH-funded centers and training programs, and UNC's Institute for Global Health and Infectious Diseases.