Every child on earth acquires a highly infectious pathogen, therotavirus, in his or her intestines.
This wagon-wheel-shaped, double-stranded RNA virus causes severeinfantile diarrhea. It kills some 870,000 of its small victims annuallyIn Third World countries. In the U.S., rotavirus sends 75,000 kids tothe hospital every year, at an estimated drain on the economyexceeding one billion dollars.
Rotavirus infects animal as well as human babies; calves in particularcome down with the dehydrating diarrhea.
Virologists laid this slaughter of innocents at the door of rotavirus aquarter-century ago, and immunologists have been striving ever sinceto develop effective vaccines to arm the very young with immunity.
Some evidence suggests that newborns inherit temporary resistancefrom their mothers. "That's not absolutely proven," said molecularvirologist Mary Estes, "but there certainly is a transfer of antibody.As a baby gets older, it develops immunity to the virus itself."
The most severe illness, she told BioWorld Today, "occurs betweensix months and two years of age, suggesting that as antibody wanes,that's when kids really get susceptible to the disease."
Estes is the senior author of a paper in today's Science titled "Age-dependent diarrhea induced by a rotaviral nonstructuralglycoprotein." She and her co-workers at Baylor College ofMedicine, in Houston, discovered this immunogenic molecule "byaccident, an example of serendipity," she revealed.
"It's a glycoprotein that is normally important during the replicationcycle of the virus, in the assembly of viral particles inside targetintestinal cells," Estes explained. "We made an antibody in order toget more information about this assembly process, and to do so hadsynthesized a peptide analogue of the native viral protein.
"When we injected that synthetic peptide into mice," she said, "withno rotavirus anywhere near, they got diarrhea."
The team then ran experiments to show that the full-length naturalprotein _ far removed from the virus _ can also cause diarrhea,"and that we can block the severity of virus-induced disease bygiving antibodies to it.
"One of the words for that kind of pathogenic protein," Estesobserved, "is `enterotoxin.' Many of the bacteria that we know about,like cholera and toxigenic Escherichia coli, make enterotoxins. That'snever been described before in a virus."
Clinical Trials After Verification In Humans
If she can show that the preliminary data in Science, reporting thattheir antibodies protect mice from rotavirus diarrhea, "also works inhumans, that might be used in treatment."
She foresees such clinical trials in the next couple of years andsuggests two ways of doing such studies:
* "Take children as soon as they come into the hospital, or kids inday-care centers, where there are outbreaks of the disease all thetime. Treat them with orally administered antibodies _ somethinglike the Salk polio vaccine _ and see if they get well faster, or have amilder disease.
* "Do a prospective study. We know that these infections occur everyfall, like influenza; you can predict almost when they're going tostart. So set up a study feeding antibody to still-healthy children, andsee if you can prevent infection."
Estes vouchsafed that "some companies are discussing commercialapplications with our tech transfer people. That's all I can say at thispoint."
Now and then, a maverick adult, usually elderly or immuno-compromised, comes down with rotavirus infantile diarrhea. Howcome?
"We now think," Estes surmised, "based on our work, that a receptorfor the enterotoxin protein is present in younger mice and children, asopposed to older people. If this idea is correct, the receptor'sreappearance in some susceptible adults could explain their gettingsick. And it may be that there are other factors there that we don'tunderstand at this point."
Back to back with the Baylor article in today's Science is a secondreport titled: "Protective effect of rotavirus VP6-specific IgAmonoclonal antibodies that lack neutralizing activity." Its seniorauthor is Stanford University virologist and gastroenterologist HarryGreenberg.
"We decided to approach the problem of designing vaccines againstthe rotavirus by isolating a specific type of secretary antibody calledthe immunoglobulin A (IgA) antibody," Greenberg told BioWorldToday. "We selected IgA because it is most likely to confer immunityafter rotavirus infection."
The antibody targeted an internal viral protein, VP6, Greenberg said,"which represents 50 percent of the virion's structural mass." Hecompared VP6 to the wheel-shaped virus's spokes.
Greenberg and his colleagues injected a little over a millionhybridoma cells that express IgA under the skin covering thebackbones of mice, where they grew. His animals were either naive_ uninfected _ or chronically infected with non-lethal disease.
"Cells lining mucosal surfaces, as in the intestine," Greenberg said,"have a special mechanism to take IgA molecules from the serumside of the cell, move them through the cell and secrete them into thelumen of the gut. The antibody to VP6 appears to be having anantiviral effect while moving through the cell during transcytosis,rather than extracellularly.
"The take-home message from our study was that antibodies to aprotein that had previously not seemed to be involved in immunity,VP6, were highly effective in both preventing infection, or ineliminating it from a chronically infected animal.
VP6 Protein Already In Phase III _ By Proxy
"This protein, VP6, appears to be an additional target for protectiveimmunity in rotavirus," said Greenberg, who is also a medicalinvestigator at the Veterans Administration hospital in Palo Alto,Calif., near Stanford.
"What this study in Science says," he concluded, "is that VP6represents another target for vaccination. They are already in well-advanced Phase III trials of a live-virus vaccine, from work done byAlbert Kapikian at the National Institute of Allergy and InfectiousDiseases. When you get that vaccine, you are making antibodies toVP6 as well as to other viral proteins. So our study may help explainwhy the currently-being-examined live-virus vaccine is as effective asit is." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.