New Scholar Award in Global Infectious Disease
Philip Ralph Dormitzer, M.D., Ph.D.
Children's Hospital, Boston

Structure-based Approach to Rotavirus Vaccine Design and Cell Entry

Rotavirus is the single most important cause of severe, dehydrating childhood gastroenteritis. Worldwide, rotavirus causes approximately 6% of all human deaths under the age of 5 years. A live, oral vaccine against rotavirus (RotaShield) was released in the United States in 1998, but was withdrawn due to a temporal association of immunization with intestinal intussusception. Therefore, a safe and effective vaccine against rotavirus is urgently needed. Detailed knowledge of the basis for antibody neutralization of rotavirus allows a rational approach to optimizing immunization strategies.

Our goal is the structure-based design of a subunit vaccine against rotavirus. Among major worldwide causes of childhood mortality, rotavirus gastroenteritis is particularly amenable to definitive public health intervention by a suitable vaccine. An effective vaccine that is designed using high-resolution structural data would provide a model for applying the powerful tools of structural biology to vaccine development. We will begin by completing a high-resolution structural model of the rotavirus outer capsid, the protein shell that mediates the initial interactions between rotavirus and the host cell. Using that model, we will dissect the mechanism of rotavirus entry into host cells by incorporating structure-based mutations into recoated infectious rotavirus particles. The molecular structures and rearrangements that emerge from this work will inform the design of engineered antigens that are inexpensively produced using widely available technology, require no cold chain for distribution and storage, and elicit a host immune response that protects against gastroenteritis caused by a wide range of rotavirus strains.

Contact Dr. Dormitzer.