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Seeds of a New Medicine
Genes, plants, and edible vaccines
By Sharon Guynup

Featured Article.

A long line of mothers and children makes its way around the periphery of a dusty village square. At the head of the line, a nurse practitioner distributes a serving of pureed banana to each eager child. But this is not a picture of a nutrition program; nor is it an ordinary snack. The bananas have been genetically modified to protect against Hepatitis B, measles, and the dysentery-causing Norwalk virus. For Charles Arntzen, of the Boyce Thompson Institute for Plant Research at Cornell University, this is the dream that has driven a decade's research: the quest to design "a simple oral vaccine that was active in a plant as you ate it."

Although his dream may still be a few years away, recent human clinical trials, which use his modified potatoes to deliver a Norwalk virus vaccine, have brought it one step closer to reality, according to a study published in the July issue of the Journal of Infectious Diseases. And elsewhere, in labs and greenhouses from New York to Australia, researchers are racing to refine what may be the next wave in public health—edible vaccines that make immunization as easy as eating your fruits and vegetables.

Why edible vaccines? The World Health Organization (WHO) has called for new strategies to deliver vaccines. WHO estimates that 10 million children die in developing countries each year from infectious diseases that could be prevented with vaccines. Existing vaccines are expensive and require a semi-skilled person to give the injection—with needles that are hard to come by in developing countries. Reused needles can transmit viruses such as Hepatitis B and C and HIV. Injectable vaccines also require refrigeration. "In some countries, you never know when the electricity is going to go off," says Arntzen.

Plant-based edible vaccines are safer, cheaper, and could be grown—or freeze-dried and shipped—anywhere. And vaccines delivered in food trigger a two-way immune response. "Many people think of immunity as something in the blood," explains Carol Tacket, of the University of Maryland School of Medicine (UMSM). This is the systemic response created by injected vaccines. But oral vaccines also initiate mucosal immunity, which fights infections in places where germs first attack the body: in the mucous membranes of the nose, mouth, lungs, gut, and genitals.

View image of "Incredible edible vaccines" (469KB Adobe Acrobat .pdf file)

Arntzen and John Clements, of Tulane University Medical School, launched an immunological battle against gut-invading bugs in 1991 using "bio-pharmed" tobacco to target a form of Escherichia coli (E-coli), a diarrhea-causing bacterium that kills approximately three million infants each year. The tobacco was genetically modified to only manufacture the antigen, a component protein expressed by a bacterium or the surface of a virus—unlike older vaccines that used the whole infectious organism. Antigens trip the immune system's red alert signals, launching the body's disease-fighting regiments.

To build these pharmaceutical factories, researchers take cells from plants and coax them to multiply like bacteria cultures. Then they insert the desired gene, and "plant" the cells in a growing medium, where they sprout new plants—and hopefully the antigen gene is expressed in the fruit or vegetable.

Then, Arntzen and his team worked with Yasmin Thanavala, of Roswell Park Cancer Institute in Buffalo, NY, coaxing tobacco to produce a vaccine against a virus—Hepatitis B. "The question was: If plants made the antigen, would an animal's immune system recognize it?" says Thanavala. The answer: yes, it worked in mice.

Charles J. Arntzen, Ph.D.

Scientists began altering potatoes two years later because "mice like raw potatoes and the turnaround time from seed to potato is relatively short," says Arntzen. "Raw" is the key. Many plants could carry antigens, but the final vaccine must be produced in fruits or vegetables that can be processed and eaten raw. Cooking breaks down the proteins that provoke the needed immune response.

And although raw potatoes may not make the most delectable snack, volunteers have willingly eaten diced transgenic potatoes in clinical trials. The world's first human trials of edible plant vaccines were conducted in 1997 at UMSM's Center for Vaccine Development, testing anti-E-coli potatoes. Out of 20 participants, 19 produced appropriate antibodies—with no adverse reactions.

Last year, another group of volunteers ate potatoes engineered to fight the Norwalk virus. "All showed some immune response, though some were stronger than others," says Tacket, who worked on both trials. "This is proof that plant-based edible vaccines work."

And last summer, Thanavala began human trials with potatoes engineered to carry a vaccine for Hepatitis B, a killer virus, which is also a major cause of liver cancer. At Loma Linda University, California, William Langridge and his research team successfully vaccinated mice with a cholera vaccine. Human papilloma virus genes are being inserted into tobacco plants by scientists at North Carolina State and Georgetown University in an attempt to fight cervical cancer. And in Melbourne, Australia, Ian Dry of CSIRO Plant Industry and Steven Wesselingh of Alfred Hospital's Infectious Diseases Unit have successfully constructed a measles-fighting tobacco plant. They have begun pilot studies to assess the feasibility of oral plant-based vaccines for malaria and HIV.

Yasmin Thanavala, a researcher in Roswell Park Cancer Institute's Department of Immunology, helped develop a genetically altered potato.

Scientists at the Boyce Thompson Institute have produced powdered tomatoes that carry Norwalk virus DNA. Once they get FDA approval, they will begin Phase I clinical trials. If the tomatoes elicit an immune response in Phase II, they will need to adjust the level of antibody production. In Phase III, they will feed volunteers the tomato vaccine and then the virus itself to see if they produce an immune response.

The team is also working with bananas. Arntzen believes that it may be the ideal vaccine vector: Bananas are tasty fruits that grow in tropical countries, are eaten raw—and are a favorite of children. "The important thing is to make it fit with any culture so these diseases can be eradicated."

Before the vaccines reach the market, researchers must hurdle a number of obstacles. So far, plants have produced the desired proteins in relatively small amounts. Assuring a consistent dose may present another problem. But the scientists believe that within three years, they will have the technical capacity to produce the first of these vaccines—Hepatitis B and Norwalk. "Now this needs to be embraced by the pharmaceutical industry," says Thanavala. Scientists hope that they may ultimately combine several vaccines into one tasty treat that would be dispensed by specially trained health workers.

What is Charles Arntzen's ultimate dream? "In my lifetime, I'd like to participate in the eradication of Hepatitis B," a dream he shares with Thanavala. "My goal is to produce technology—in terms of seed—that can be adopted anywhere. Even countries with virtually no manufacturing capabilities know how to grow food. It would be great to get this to the level of herbal medicine so even the local shaman can administer vaccines."

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Tacket, C.O., Mason, H.S., Losonsky, G., Estes, M.K., Levine, M.M. & Arntzen, C.J. Human immune responses to a novel Norwalk virus vaccine delivered in transgenic potatoes. J Infect Dis 182, 302-305 (July 2000).
Tacket, C.O., Mason, H.S., Losonsky, G., Clements, J.D., Levine, M.M. & Arntzen, C.J. Immunogenicity in humans of a recombinant bacterial antigen delivered in a transgenic potato. Nat Med 4, 607-609 (May 1998).

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