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2-Plants: Edible vaccines not ready for main course

-------------------------------- GENET-news -------------------------------

TITLE:  Edible vaccines not ready for main course
SOURCE: Nature Medicine 10: 881, by Peter Vermij
DATE:   Sep 2004 

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Edible vaccines not ready for main course
Plant-based vaccines face big scientific and regulatory hurdles

Edible vaccines produced in genetically modified crops promise cheap and
effective protection against infectious diseases in the developing world.
But vaccine manufacturers are reluctant to take a bite out of the projects.

Since 1992, when biologist Charles Arntzen proposed genetically modifying
bananas to serve as cheap vaccines against infectious diseases, research
on plant-based pharmaceuticals has grown rapidly. In July, the European
Union promised 12 million to European and South African scientists
developing vaccines or antibodies against HIV/AIDS, rabies and
tuberculosis. Work is further ahead in the US, where several acres of
crops, most of them still experimental, are planted each year.

Researchers have thus far produced more than 45 different antigens in a
wide range of plants. "In 10-15 years," says Hilary Koprowski, a veteran
vaccine researcher at Thomas Jefferson University, "plant-derived
vaccines will be fully appreciated."

At least in theory, plant-based vaccines would be safer than those
produced in animal tissues because the chances of unknown human pathogens
hitching a ride would be extremely small. Costs per dose would be low,
and scaling up would just mean planting a larger crop. During transport
and storage, vaccine-containing seeds or dried leaves would not need
refrigeration, a significant advantage in developing countries. Oral
vaccines especially, administered as juices or tablets to circumvent dose
variability, would pave the way for mass vaccinations in those countries.

But even Arntzen now says his original idea of distributing vaccine-
bearing fruit was naive, because regulatory agencies will not approve
vaccines with variable dosing.

Many in the field say that, at least in animals, plant-based oral
vaccines have been proven to be safe and effective. For instance, corn
loaded with proteins from a gastroenteritis virus is effective, at least
when used as a booster, in protecting pigs against the disease, says John
Howard, founder of the Texas-based firm ProdiGene.

In humans, several vaccines have passed safety trials. Arntzen's group at
Arizona State University tried vaccines produced in genetically modified
potatoes and corn against enterotoxic Escherichia coli and Norwalk virus.
Koprowski's group fed volunteers spinach containing a rabies booster
vaccine. Both groups have tested oral hepatitis B vaccines, either as
primary or booster vaccine, in lettuce, spinach and potatoes.

Although small phase 1 trials like these can't prove protection,
volunteers in the studies showed an "appropriate," though not always
strong, immune response, Arntzen says.

Arntzen is collaborating with companies in Egypt, South Africa and South
Korea, but outside developing nations, where there is an urgent need for
such vaccines, finding manufacturers willing to finance larger trials to
demonstrate efficacy has been a formidable challenge. "I've talked to all
of the [big companies]," says Koprowski, "and so far I regard it a waste
of time."

Vaccine manufacturers have little reason to replace existing production
lines, as most vaccines are economically unattractive. The medical
community is also focused on high-tech approaches, making farm-grown
vaccines a tough sell, Koprowski says. But smaller companies, led by
young people willing to take risks, could challenge the current thinking,
he says. "Then, others will follow."

Part of the hesitation stems from the fact that plant-based oral vaccines
constitute a new technology from both a regulatory and scientific
perspective, says renowned vaccinologist Stanley Plotkin, who now advises
Aventis Pasteur.

Before they can be approved, Plotkin says, plant-based vaccines will have
to consistently generate stronger immune responses, which would need to
be studied carefully for every crop. "If vaccines are intimately
presented together with food, the gut's immune system faces a conundrum,"
he notes. The gut is designed not to react to antigens in food, but must
produce a useful response against the vaccine. Instead of being
immunized, patients could even end up being 'tolerized,' meaning an
immune response against future invaders would be weakened, not intensified.

Researchers say they have not yet seen signs of such tolerance, but
Plotkin says experiments to convince regulators have yet to be designed.
"Immunologists will have to figure out how the gut can do this, and do it
right 99.9999% of the time," he says. Producing veterinary vaccines
first, followed by human booster vaccines, could be the sensible way
forward, he adds.

Convincing the general public that it is safe to grow vaccines in fields
poses a bigger challenge. Citing fears over supermarket shelves stocked
with vaccine-contaminated foods, consumer groups have called for a ban on
using food crops to produce pharmaceuticals. Some companies are avoiding
the issue by developing injectable plant-based vaccines, by using nonfood
crops or by not using genetically modified crops.

For instance, California-based Large Scale Biology uses genetically
engineered mosaic viruses to infect tobacco plants. A few weeks later,
says Larry Grill, the company's chief scientific officer, antibodies can
be purified from the harvested leaves. The company has produced patient-
specific antibodies against cancer cells just months after biopsies were

Once the scientific and regulatory hurdles are cleared, convincing
skeptics will be easier, researchers note. "If I could save millions of
lives in developing countries," says Arntzen, "I think I'd have a
pressure group that could stand up even against Greenpeace in Europe."


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