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

这项K24建议建立在对儿童胃肠炎进行的十年临床和流行病学研究的基础上， 尼加拉瓜的候选人，西尔维亚贝克尔-德雷普斯，医学博士，公共卫生硕士。作为贝克-德雷普斯博士 先前关于了解在资源有限的环境中轮状病毒疫苗有效性降低的工作， 目前的建议扩展了贝克尔-德雷普斯博士的技能，使她能够为开发一种有效的 小儿诺如病毒疫苗这项建议也有目的地将受训人员纳入这项工作，并提高博士。 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可能。 候选人：贝克-德雷普斯博士是家庭医学和流行病学双重任命的医生和科学家。 她职业生涯的主要重点是促进病毒性胃肠炎的预防。她的团队 采用多学科方法，将强大的现场流行病学与最先进的实验室相结合 方法.她的小组是第一个在2010年测量轮状病毒疫苗有效性和牛群保护的小组。 社区水平，也显示了高水平的母亲对轮状病毒的免疫力之间的关联 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， 诺如病毒是引起肠胃炎的主要原因。提议的职业 开发活动扩展了Becker-Dreps博士的技能，使她能够更好地描述 诺如病毒免疫，并有助于儿童诺如病毒疫苗的设计和未来的试验。 研究计划：在儿童中开发有效的诺如病毒疫苗面临着几个障碍。这些 包括在初生婴儿中引发强有力的初级免疫应答，并引发持久的应答 并且对一系列诺如病毒株具有广泛的活性。更好地了解免疫力的发展 对抗天然诺如病毒感染的研究将为如何克服这些障碍提供线索。我们建议一 利用现有的R 01资助的尼加拉瓜400名儿童的出生队列研究，目标 本研究的主要目的是：1）描述诺如病毒胃肠炎的自然史和 出生后对诺如病毒感染的适应性免疫，包括阐明 不同的诺如病毒基因型; 2）表征暴露前病史对随后感染的影响， 3）研究母体获得性诺如病毒免疫的潜在保护作用。 指导计划。Becker-Dreps博士在指导学员以患者为导向方面有着良好的记录 研究，并吸引来自科学代表性不足的群体的受训人员。目前，她的可用时间为 指导是有限的。在K24的支持下，她将重新致力于指导早期临床研究人员 因为他们努力独立筹资。她将利用英特尔的广泛资源来实现这一目标 目标，包括NIH资助的中心和培训计划，以及美国国家卫生研究院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.