Principal Investigator: Sarah Caddy

DESCRIPTION (provided by applicant): 

Rotavirus (RV) is a leading cause of severe gastroenteritis in children under the age of 5. Low to middle income countries (LMIC) suffer disproportionate RV disease burden, partly due to reduced efficacy of vaccines for children in these regions. This is likely multifactorial, but higher levels of maternal antibodies have been correlated with poorer vaccine responses. The role of maternal antibodies in the prevention of RV disease and RV vaccine interference remains understudied, generating a gap in knowledge of how to improve the vaccine efficacy. This gap is widened by the current inability to study human rotaviruses in small animal models due to species-specificity of RV.

Our goal is to use both host-targeted and virus-targeted approaches to study human RV pathogenicity in a mouse model, enabling study of maternal antibody interference of RV vaccines. For host factors, we will evaluate the role of the infant microbiome and intestinal mucin layer on viral pathogenicity. This will involve use of antibiotics and transgenic mice to control the host intestinal environment. To study viral factors that limit cross-species infections, we will use RV reverse genetics to produce chimeric viruses that will induce immunity to human RV epitopes in mice. We will also study RV in breeding mice, to allow us to analyze how neonatal immunity is affected by maternal antibodies delivered therapeutically and induced naturally. Understanding the mechanisms that underlie lower vaccine efficacy in LMIC via mouse models will provide a foundation to develop improved therapeutics and vaccines in future work.