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 The use of plants to produce life-saving pharmaceuticals captured
global attention when it was revealed that the Ebola drug ZMapp is
produced in the leaves of tobacco plants.
Even as Ebola cases multiply in West Africa, a far greater market
for plant-based biopharmaceuticals will likely be influenza vaccines
used to fight pandemics, industry experts said. Making vaccines from
plants may turn out to be faster and cheaper than current methods
which use chicken eggs to grow the virus needed to make the
vaccines.
Leading producers such as GlaxoSmithKline Plc and Sanofi SA need six
months to produce flu vaccine once scientists identify the dominant
virus expected to circulate during flu season. Vaccine production
from tobacco plants by Quebec City-based Medicago or Bryan,
Texas-based Caliber Biotherapeutics could do it in weeks.
"Seven to 10 years from now, plants might be the dominant
vaccine-production system," said Brett Giroir, an M.D. and CEO of
Texas A&M Health Science Center in Bryan. Texas A&M has one of three
U.S. facilities tasked by the government with being ready to produce
and deliver 50 million doses of flu vaccine in just 12 weeks. It is
working with Caliber toward that goal.
If the upstarts succeed, they will make little difference to the
tobacco industry, which regards even a $3 billion market as
marginal. But they could threaten the pharma giants that dominate
flu vaccine production - or be gobbled up by them.
Medicago is now testing its flu vaccine in elderly people, who are
most at risk, and plans to launch a large human trial in 2016. "We
hope to hit the market in 2019," said Jean-Luc Martre, director of
government affairs.
Tobacco plants could be enlisted in the fight against flu even
sooner if a pandemic hit. The 50 million doses that labs like Texas
A&M's pledged they'd be able to produce in a few months can't be
manufactured in today's egg-based systems.
"If there is a need for it that requires plant-based production,
we'd turn to Caliber," said Giroir, referring to an accelerated
vaccine-production schedule to counter a flu pandemic.
WAITING FOR CHICKEN EGGS
Each year, manufacturers including Sanofi, Novartis, the Medimmune
unit of AstraZeneca and GSK make about 155 million doses of flu
vaccine for the U.S. market alone, growing the virus in chicken
eggs. Usually the doses, which protect against strains that experts
predicted the previous February, are ready in time and in sufficient
quantity.
But if the strain that appears during flu season was not the one
experts forecast, the vaccines might not work. The appearance of
H1N1 swine flu in 2009-2010 took experts by surprise, and the flu
was already on its second wave before a vaccine was ready; an
estimated 61 million people in the U.S. got swine flu and 12,500
died.
Failures such as that led the U.S. government to award $400 million
in start-up funding to three Centers for Innovation in Advanced
Development and Manufacturing (CIADMs) to boost biodefense and
preparedness for pandemic flu.
"There's no way you can produce 50 million doses in 12 weeks" with
current production technology, said Giroir. "But plant-based
production could."
While one chicken egg can produce one or two doses of flu vaccine,
one tobacco plant can produce 50 at a fraction of the cost.
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The Defense Advanced Research Projects Agency (DARPA), an arm of the
Defense Department that funds cutting-edge research, is impressed
enough with the potential of tobacco-plant production systems to
have awarded multi-million-dollar grants to both Medicago and
Caliber, and so far the support has paid off.
In a 2012 DARPA challenge, Medicago, jointly owned by Philip Morris
International and Mitsubishi Tanabe Pharma Corp, produced 10 million
doses of H1N1 flu vaccine in just a month in tobacco plants inside
its sprawling North Carolina greenhouses. In animal tests, the
experimental vaccine successfully triggered the production of
protective antibodies against H1N1.
HURDLES AHEAD
All the company had to go on was part of the virus's genetic
sequence. But while in egg-based production whole flu viruses are
injected into the eggs, where they replicate and form the basis for
the vaccine, all that's really needed to trigger immunity are the
proteins that stud the virus's coat.
Those proteins, called hemagglutinins, are what the immune system
attacks. They can be produced by splicing the hemagglutinin gene
into almost any kind of cell; Medicago uses harmless bacteria to
carry the hemagglutinin genes into the tobacco plant leaves.
Technicians at the greenhouses in North Carolina then soak
36-day-old Nicotiana benthamiana plants (cousins of those used for
cigarettes) upside down in a liquid containing the Trojan Horse
bacteria, explained chief scientist Marc-Andre D'Aoust. Through a
process called vacuum infiltration, air is drawn out of the leaves
and they suck up the bacteria.
After growing in special chambers for a week, the leaf cells are
churning out hemagglutinins. Extracted, purified, and combined with
other bits of the virus, they form the basis for a vaccine.
To succeed, the companies will have to persuade the U.S. Food and
Drug Administration not only that the vaccine is safe and effective,
as clinical trials are designed to show, but also that the
hemagglutinin or other proteins can be extracted from the leaves
cleanly and that the largely-untested manufacturing process yields a
uniform, reliable product.
Major vaccine makers are cautious about the new technology. “We tend
to avoid publicly speculating on what future technologies we might
embrace,” said Robert Perry, a Glaxo spokesman said.
"Today, all of our flu-vaccine production is in (chicken) eggs,"
said Rene Labutat, vice-president of manufacturing for Sanofi. "But
we are looking at the recombinant approach, including in mammalian
cells, algae, fungi and plants."
(Reporting by Sharon Begley; Editing by Michele Gershberg and John
Pickering)
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