Gates grant injects new life into vaccine program

By Poul Olson

The Bill & Melinda Gates Foundation has awarded a three-year, $885,000 subcontract grant to the lab of Harriet Robinson in support of her ongoing research to develop a DNA-based vaccine for measles.

The grant is the first substantial funding for Robinson’s measles vaccine program, which is being conducted in collaboration with Diane Griffin of Johns Hopkins University and Paul Rota of the Centers for Disease Control and Prevention.

The Gates funding comes on the heels of a World Health Organization campaign, launched this spring, to halve the number of measles deaths by the year 2005. A highly contagious virus spread through respiratory droplets, measles accounts for some 900,000 of the estimated 1.6 million annual deaths worldwide due to childhood vaccine-preventable diseases.

Despite widespread inoculation programs, measles remains endemic in many developing counties. The vaccine usually is administered to children at 15 months of age. If given before that time, the temporary immunity conferred to the child by maternal antibody blocks the vaccine’s ability to raise protective immunity in the child. Unfortunately, children in many developing countries either receive the vaccine too early or not at all.

“The presence of maternal antibody is one of the biggest problems for childhood vaccination programs not just against measles,” said Robinson, chief of microbiology and immunology at Yerkes. “The immaturity of the neonatal immune system also makes it challenging to develop effective vaccines for infants.”

The WHO believes that at last 90 percent of children must be vaccinated to reduce measles deaths in developing countries. To that end, it views as crucial the development of a vaccine that can work in the presence of maternal antibody.

Following the DNA model that has shown promise in the development of an AIDS vaccine, Robinson has been testing a measles vaccine developed from the genes for the hemagglutinin and fusion proteins—two surface components of the measles virus. The vaccine regimen consists of an initial shot to prime the immune system followed by a booster.

In its current form, Robinson’s DNA vaccine has not raised antibody in the presence of the maternal antibody. Robinson suspects that this phenomenon may result from the interface between the measles antigen and how the immune system recognizes that antigen in the presence of antibody.

“If we can manipulate the measles antigen so that they will raise antibody in the presence of maternal antibody, it will be a tremendous boon for the development of vaccines for the first year of life,” Robinson said.

Robinson plans to focus on refining the vaccine to further improve antibody response and reduce the dosing regiment to one injection.

Rhesus monkeys are the only animal model available for studying measles. The pathogenesis of the virus is remarkably similar in both macaques and people. Because of its virulence and potential threat to the larger colony, all monkeys enrolled in the measles vaccine program are vaccinated at Yerkes and the transferred to JHU, where they are challenged with the virus. At Johns Hopkins, Griffin also is conducting a parallel study on the pathogenesis of the virus.

Measles vaccines based on both killed and live virus have existed since the early 1960s. Typically given as part of the MMR regimen that includes vaccines for mumps and rubella, the vaccine has successfully reduced incidence of the disease in the United States to less than 500 cases per year.

Although healthy children typically survive the infection, the mortality rate for those in developing regions of the world, especially in sub-Saharan Africa, can be as high as 25 percent because of malnutrition. The disease also produces many complications. Among African children, it is a leading cause of blindness and mental retardation.

With the most recent grant to Robinson, the Gates Foundation is now funding more than $1.6 million in vaccine research at Yerkes, including nearly $790,000 for malaria vaccine development.