Oral vaccines, which work exceptionally well to protect infants and children in the U.S., can fail to do so in developing countries. Case in point – the oral rotavirus vaccine has a strong track record in preventing the majority of cases of rotavirus-diarrhea hospitalizations and deaths in the U.S. In developing world settings, however, the vaccine has only worked half as well, leading to more than 450,000 children’s deaths annually due to rotavirus-related dehydration.  

Understanding and remedying this paradox is the goal and challenge of a new $2.2 million dollar 2.5-year research award from the Bill & Melinda Gates Foundation to University of Vermont Vaccine Testing Center (VTC) investigators. Led by Beth Kirkpatrick, M.D., professor of medicine and VTC director, co-investigators on the grant include Sean Diehl, Ph.D., E. Ross Colgate, M.P.H., Dorothy Dickson, M.Sc., and Benjamin Lee, M.D., a pediatric infectious disease specialist due to join the VTC, UVM College of Medicine Department of Pediatrics, and The UVM Children’s Hospital in August 2015.

The grant, titled “Improving Rotavirus Vaccination: Refining Correlates of Protection and Evaluating Durability,” builds on previous Gates Foundation-supported research performed by VTC team members between 2010 and 2014. The group’s initial work – the PROVIDE study – was a multi-institutional collaboration between the VTC, colleagues at the Bangladesh-based International Centre for Diarrheal Disease Research (ICDDR, B), and the University of Virginia. Investigators performed a large field-based efficacy study of the underperformance of oral polio and rotavirus vaccines in a group of infants in an urban slum of Dhaka.

“The PROVIDE study was an extensive analysis of possible biologic and immunologic factors that could contribute to oral vaccine failure, including malnutrition, socio-economic issues, and concurrent infectious diseases,” says Colgate, a VTC research analyst and UVM Clinical and Translational Science doctoral student. She lived in Dhaka for two years to establish and manage this initial work. The project team enrolled, vaccinated, and followed seven hundred children for two years, performing twice weekly home visits via thirty field workers and a dozen laboratory technicians and data managers in Bangladesh.

She and statistician Dickson, along with Marya Carmolli, a VTC senior research technician studying for a doctorate in epidemiology, are continuing their extensive analysis of PROVIDE data and will use these findings to educate the rotavirus vaccine investigations.

“This new award from the Gates Foundation builds upon the extensive database of clinical and microbiologic data from PROVIDE and adds in sophisticated immunologic techniques and advanced statistical modeling to better understand vaccine underperformance and predict durability,” says Kirkpatrick, who adds that laboratory tests will evaluate and assess improved readouts – called “correlates of protection” – to better determine whether the rotavirus vaccine is working in populations of children.

With support from this grant, Diehl, an immunologist and assistant professor of medicine, will lead research on immunological correlates of protection by leveraging his expertise in the development of immune memory and antibody function. “This award is a unique opportunity to gain a deeper understanding of the immune response to rotavirus, which will lead to new vaccination strategies to benefit the developing world,” he notes.

Another key investigator on the project will be soon-to-arrive pediatric infectious disease expert Lee, who in addition to contributing to the development of new correlates of protection in the laboratory, will also expand the hypothesis that common blood group antigens – which distinguish different blood types – contribute to decreased rotavirus vaccine efficacy.

“Understanding and improving rotavirus vaccines is critically important to the health of children through the world,” says Kirkpatrick. “We are particularly excited about this opportunity: it builds upon our interest and expertise in understanding the principles of correlates of protection in infants and children in developing countries and will help us better understand and improve their responses to vaccines.”