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Genetic engineering's new goal: food that includes a vaccine
By Tina Hesman
Of the Post-Dispatch
07/08/2001 07:11 PM

URBANA, Ill. — Schuyler Korban hopes that one day pediatricians will prescribe a bottle of apple juice to fend off serious childhood diseases.
The University of Illinois researcher and his colleagues are genetically engineering apples to produce a vaccine against a common and sometimes deadly virus, RSV. No vaccine exists yet, despite extensive research efforts to produce an injectable version. If successful, the medicinal apples could join other fruits and vegetables as the ultimate health foods — edible vaccines.

Scientists say that one day edible vaccines could stop the spread of many diseases, particularly in underdeveloped countries where traditional vaccination programs often fail because of a lack of resources. In countries where refrigeration is not readily available to preserve synthetic vaccines, mothers could vaccinate their children against cholera by feeding them banana chips. A glass of tomato juice might protect against the liver disease hepatitis.

And an apple may stave off the leading cause of childhood pneumonia, if Korban has his way.

A plant geneticist, Korban has been working to develop apple trees that can withstand plant diseases. It seemed like a natural extension of his research to make an apple that could protect people from human diseases, he said.

Discussions with a colleague quickly turned up the perfect candidate for an apple-based vaccine: the respiratory disease virus RSV (Respiratory Syncytial Virus). The disease strikes young children hard. Almost every child will be infected with the virus by the third birthday, said Dr. Pedro A. Piedra, a pediatrician at Baylor College of Medicine in Houston. Most experience severe cold-like symptoms. But about three out of every 100 children will be hospitalized because of an infection with the virus, Piedra said.

About 4,500 babies die every year in the United States from pneumonia and bronchiolitis caused by RSV, the Centers for Disease Control and Prevention says. Premature infants are particularly susceptible to the disease, Piedra said. He tracks the spread of the disease and is evaluating several vaccines against the virus, including Korban's.

Some medicines are available to treat RSV infections in infants, but the treatments are expensive and controversial. Korban estimates that it costs about $300 million for the drugs used to treat the 125,000 children who end up in the hospital with severe lung problems caused by the virus.

A vaccine to fight the virus could save $490 million to $1.15 billion in health care costs, according to a study by the National Academies of Science.




Choice of tomatoes speeds Korban's research


Korban's work may reveal why the injected vaccines failed and suggests that edible vaccines might be more effective in protecting against diseases that attack mucus-producing tissues, such as those in the nose, lungs, throat and digestive system.

The first step was determining whether the researchers could get a plant to produce certain proteins from the syncytial virus. The researchers needed to demonstrate that the virus proteins could survive the digestive juices in the stomach. Then, they would show that cells could latch onto the protein and signal the immune system to start building defenses against the virus. The scientists would then have to feed the vaccines to mice or other animals and test to see if the animals could make antibodies that would protect them from the virus.

Such studies take a long time, and that's where apples posed a bit of a problem for researchers who need quick results. It could take three to four years before an apple branch produces fruit. But Korban's group had a different apple they could turn to in a pinch — the love apple, also known as the tomato. It only takes two to three months for tomato plants to yield juicy clusters of vaccine-bearing tomatoes.

"The choice was obvious," said Korban. "We needed to go with something quickly."

So Korban and research associate Sergei Krasnyanski genetically engineered tomato plants to make virus proteins in their fruit. Once Krasnyanski identifies plants that carry the virus genes, he transfers the promising shoots from laboratory culture dishes to pots of soil in a nearby greenhouse on the Urbana campus.

Already the greenhouse is crowded with more than 50 genetically engineered tomato plants. Each plant bears several clusters of cherry tomatoes, some green, some just starting to ripen, and some a deep, ripe red.

Krasnyanski harvests the fruit and analyzes its vaccine content. He has discovered that riper fruits contain more vaccine and much of the protein seems to be concentrated in the seeds. That means that to get maximum and uniform doses, the tomatoes probably need to be crushed and made into juice, he said. Krasnyanski said he doesn't yet know if artificial ripening techniques will stimulate the tomato to make the vaccine protein or if storage will affect the proteins.

The researchers fed ripe tomatoes to mice. When the scientists examined blood and mucus membranes from the mice, they found that the vaccine caused the mice to make protective antibodies against the virus. More importantly, the immune cells in the mice's mucus-producing tissues responded to the virus proteins. The old injectable vaccines only activated immune cells in the bloodstream.

Both types of immune cells are important for completely fighting off respiratory virus infections, Korban said, but mucus membranes are the virus's first target. An effective vaccine must stimulate the mucus tissue's immune system.

Krasnyanski said he doesn't yet know if the tomato-delivered vaccine will keep people from getting sick with RSV. Mice don't get sick from the virus in the same way humans do. The researchers will repeat their experiment with white cotton rats, which experience the same symptoms as humans when infected with RSV, Krasnyanski said.

Babies prefer apple juice



Korban thinks apples are preferable to tomatoes as a vaccine source; tomatoes may be too acidic for babies, he said. With that in mind, his group is starting work to produce an RSV vaccine in apples. In three to four years they should have enough data from the tomato work to determine whether to apply for approval from the Food and Drug Administration to market the drug.

No edible vaccines are on the market now. There are two in clinical research trials elsewhere to determine the dose that will protect patients from disease: Tomato and potato-based vaccines against bacteria and viruses that cause diarrhea, and a tomato vaccine against the hepatitis B virus.

But it's just a matter of time before the technology is advanced enough to make plants viable vaccine factories, said Charles J. Arntzen, director of the Arizona Biomedical Institute at Arizona State University in Tempe. The real question is whether researchers will be able to raise enough money to shepherd their medicinal tomatoes, bananas and apples from the greenhouse to the pharmacy.

"It's really all about money," Arntzen said.

Drug companies don't have much financial incentive to develop cheap vaccines for use in poor countries, he said. He said he hopes a philanthropic group or large company will invest the $10 million to $25 million it might take to bring the vaccines his group has developed against diarrhea diseases to market.

A vaccine against RSV could cost much more — perhaps as much as $50 million to $100 million, Arntzen said. That's because there has never been a vaccine against the disease and any new drug will need extensive safety and efficacy testing, he said.

Many scientists are cautiously optimistic that edible vaccines might bring relief for RSV infections.

"The approach can have far-reaching benefits for society, but it's still early in its development," said Piedra, of Baylor.

Many more animal tests and clinical trials with people will be needed to show that the vaccine is safe and effective, he said. Researchers also need to work out the protective dosage and whether babies will need booster bottles of the vaccine.

And there are no guarantees that Korban's vaccine will fully protect babies from being infected by the virus. People can be infected many times with the natural virus. Over time some protection builds up — which is why healthy adults usually experience an RSV infection as just a bad cold instead of the pneumonia babies get — but no one is ever truly immune from the disease, Piedra said.

It is likely that an RSV vaccine would make the symptoms of the disease less severe, but not block infection entirely, he said. But even if the vaccine doesn't completely block infections, it may still have benefits.

"If you can prevent hospitalization, if you can prevent death," Piedra said, "you're going to do a lot of good."



Reporter Tina Hesman:
E-mail: thesman@post-dispatch.com
Phone: 314-340-8325



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