Vaccine Problems Stall Promise Of Atlanta Doctors' Rotavirus Breakthrough

BETHESDA, Md. — More than 30 years after two Atlanta physicians glimpsed the first evidence that a germ called rotavirus was killing hundreds of thousands of children, efforts to create a vaccine have encountered repeated frustrations.

A study in early 1980s by Drs. Roger Glass and Barbara Stoll, a husband-and-wife team from Atlanta, led to the realization that the virus is the single largest cause of infant death from diarrhea in the world.

Epidemiologists estimate that each year rotavirus, so named because it resembles a tiny pinwheel, kills more than 600,000 infants. Most of them die in remote villages, overcrowded hospitals and urban slums in the undeveloped world. Fewer than 70 deaths are reported among American babies annually, although the disease causes 70,000 hospitalizations.

Finding a vaccine hit another bump Tuesday when the Food and Drug Administration announced it had received 28 reports of a dangerous twisting of the small intestine among children who received a newly licensed vaccine. The agency has not suspended use of the vaccine, but it ordered the manufacturer, Merck and Co. Inc., to change the drug's label to include a warning of the possibility of the disorder, known as intussusception.

The number of reported cases appears to be lower than the number expected to occur among American children who never receive rotavirus vaccine, the agency said. However, intussusception caused a previous rotavirus vaccine to be withdrawn from the market eight years ago.

The FDA said it hoped the label change would encourage further reports, a strategy sometimes referred to as "shaking the tree," and lead to a better idea of whether the currently reported incidents are being caused by the vaccine or amount to normal "background" occurrences.

Glass and Stoll were working at the International Center for Diarrheal Disease Research in Bangladesh in the early 1980s when they discovered the importance of rotavirus.

Stoll is now chair of the department of pediatrics of Emory University School of Medicine. Glass was an official at the Centers for Disease Control and Prevention until last year, when he was appointed director of the Fogarty International Center of the National Institutes of Health.

When they went to work at the Bangladesh center in 1979 they knew that diarrhea was the largest cause of infant death in the world, Glass said in an interview. They believed the cause was likely cholera, E. coli, salmonella, or some combination of those and other well-known diarrhea-causing pathogens.

But to get a definitive answer, Stoll set up a screening program in which a stool specimen was taken from every 25th child to come through the center's hospital in Dhaka.

Examination of the specimens soon made it apparent that the major cause of the illnesses was not one of the traditional diseases, but rotavirus. This was the first indication that rotavirus was the chief culprit in the deaths of hundreds of thousands of children.

"We knew very little about this virus," Glass said. In fact, rotavirus was unknown to anyone before 1973, when an Australian microbiologist first isolated it.

Since then, diarrhea experts have come to know it as a wildly contagious germ that can cause severe dehydration in a few hours, and death if not treated. Glass noted that as few as 10 individual particles of virus inside a microscopic drop of water that lands on a baby's thumb can multiply to billions within 24 hours.

Nearly every human being has the disease during infancy or early childhood, he said, and then is equipped with protective antibodies for years to come. While there is evidence of outbreaks among elderly persons, whose immunity has declined, bouts during adulthood are usually mild, if unpleasant.

But when a small child has his or her first rotavirus infection, the impact can be devastating.

Marty Porter, a Cumming, Ga., registered nurse, recalled the scary time seven years ago when her 2-year-old daughter Jessica came down with nausea and diarrhea.

"I'd call the pediatrician and he'd tell me to get an over-the-counter medicine to stop her from throwing up," she said, "but she was so sick she couldn't keep the medication down."

She said she took Jessica to the emergency room twice, "and the second time, I said I wouldn't leave until they put her on an IV, because she had been sick for five days and she was lethargic."

Unable to eat, Jessica had lost four pounds. When the solution to rehydrate her started dripping into her veins, it appeared that her cells had lost so much protein that they could not contain the water.

"She started puffing up," Mrs. Porter said, "but after a couple of days, she was all right."

After Glass and Stoll returned to Atlanta from Bangladesh, he plunged into the effort to get a vaccine developed for rotavirus. Early versions were not effective at stimulating immunity, and when an effective version was developed, it was withdrawn because of the same intussusception effect.

Last year, two drug companies, Merck and GlaxoSmithKline, received FDA licenses for two different versions of a vaccine for the disease. The GlaxoSmithKline vaccine, Rotarix, uses a weakened form of the human virus to stimulate immunity. The Merck version, named RotaTeq, is based on a genetically modified bovine rotavirus.

RotaTeq is the vaccine for which FDA ordered a label change. Because of the earlier problem with intussusception, FDA required both manufacturers to test the vaccines among more than 70,000 youngsters before it would issue a license.

When reports of the clinical trials were published in the New England Journal of Medicine last year, indicating immunity levels of 85 to 95 percent, the development was compared to vaccines against killer diseases like polio, smallpox and measles.

Authors of the reports were given "paper of the year" awards from the Lancet, a British medical journal.

The journal said judges had considered papers reporting breakthroughs in the understanding of diseases like cancer, HIV-AIDS and age-related macular degeneration.

"In the end, the overwhelming winners were the trials of the two rotavirus vaccines," editors of the Lancet said.