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

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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.