The University of Vermont (UVM) College of Medicine and University of Virginia (UVa) School of Medicine are conducting a study to determine why vaccines that work so well on children in the developed world don’t work as well on children in poorer countries.

Oral vaccines for paralytic polio and life-threatening rotavirus have been a miracle of modern medicine for millions of children around the globe; yet these same vaccines aren’t always protecting thousands of children in poor and less developed countries – and scientists don’t know why. One key to solving this challenge lies in understanding what’s different in the biological makeup of children whose bodies reject the protection they so desperately need from these diseases. Thanks to a $14.7 million grant from the Bill & Melinda Gates Foundation, scientists at UVM and UVa now have the opportunity to investigate why oral vaccines fail in the very children who need them the most.

The PROVIDE (Performance of Rotavirus and Oral Polio Vaccines In DEveloping countries) study is co-led by William A. Petri Jr., M.D., Wade Hampton Frost professor of medicine at the UVa School of Medicine, and Beth Kirkpatrick, M.D., associate professor of medicine at the UVM College of Medicine. They are working with an international team of investigators to understand the spectrum of biologic reasons for failure of the oral vaccines for polio and rotavirus.

“The average child who contracts paralytic polio in India has received more than the four recommended doses of the oral polio vaccine,” explains Petri, citing a 2007 study published in Lancet. “Similarly, the new and life-saving vaccine against rotavirus is only half as effective in Bangladesh as it is in the United States.”

Nearly 1000 infants will be enrolled in this study in the first month of life: 700 children at the International Centre for Diarrheal Disease Research, Bangladesh (ICDDR, B) in Dhaka and 300 children at the National Institute of Cholera and Enteric Diseases (NICED) in Kolkata, India.

“These populations of children do respond to injected vaccines, so determining why – from an immunobiological perspective – oral vaccines do not work is critical,” says Kirkpatrick.

Researchers will be investigating their hypothesis that chronic intestinal inflammation and damage from these infections leads to a selective defect in a child’s response to oral vaccines. To test this theory, the UVa-UVM research team will determine if children who fail oral vaccination have more episodes of diarrhea, or are more malnourished, than children with a normal vaccine response. They also will measure the role of the intestinal bacterial flora or microbiome, and the impact of intestinal damage on the nature of the immune response to vaccination (antibody or cell mediated responses). Tests will be conducted in collaboration with the laboratories of Jeffrey Gordon, M.D., of Washington University in St. Louis, Mo., and Mark Davis, Ph.D., of Stanford University in Calif.

Results from this study could lead to targeted interventions to prevent oral vaccine failure, such as the use of injected vaccines to boost oral vaccination and the prevention or treatment of intestinal barrier disruption.

Expert international collaborators – including Rashidul Haque, Ph.D., and Firdausi Qadri, Ph.D., of ICDDRB, and Drs. Cecil Czerkinsky, Ph.D., and Dipika Sur, M.D., of NICED – will be integrally involved in the field for these studies.

The UVM team has two roles in the study: managing logistics and operations and the development of lab assays to help measure whether or not children in the study have an immune response to vaccination. In addition to Kirkpatrick, UVM research team members include Ross Colgate, study manager; Marya Carmolli, lab coordinator, Iori Ueki, research scientist; and Mary Claire Walsh, clinical coordinator. Program and database management analyses will be directed by Josyf Mychaleckyj, D.Phil., along with Uma Nayak, Ph.D., and Cynthia Snider, M.D., at UVa.

(This article has been adapted from a news release written by Peter Jump, University of Virginia.)