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Through an innovative feat of plant biotechnology and vaccine design,
researchers in the Biodesign Institute at Arizona State University have
successfully turned tobacco plants into vaccine production factories to
combat the deadliest form of plague, January 2006.

The vaccine elicits a protective immune response in guinea pigs. The
results are considered to be a milestone in the future development of a new
vaccine for human use.

Plague, caused by a rod-shaped bacterium called Yersinia pestis, no longer
invokes the "black death" feared throughout history, having been widely
tamed since the advent of antibiotics. But a new concern has emerged in
recent years with respect to bioterrorism.

"There have been discovered some resistant strains to antibiotics and that
poses a concern, especially if plague would be used as a bioweapon," said
Luca Santi, a research assistant professor at the institute and lead author
of the study published in the early online edition of the journal
Proceedings of the National Academy of Sciences. "A new vaccine approach
would be the best way to prevent infection."

In addition to manmade threats, the Centers for Disease Control estimates
1,000 to 3,000 outbreaks still occur in the world every year as a result of
people coming into close contact with rodents infected with fleas that
harbor the bacteria.

Particularly worrisome to human health is the pneumonic form of the disease,
which can spread by an airborne route after infecting the lungs. It is
considered universally fatal if not detected and treated after symptoms
arise one to six days after the initial exposure.

Current vaccines against plague are severely limited from widespread
adoption by having problems with high adverse reaction rates and side
effects.

The research team included Santi, Hugh Mason and Charles Arntzen, all
members of the institute's Center for Infectious Disease and Vaccinology.
They worked out a new plant-based system to rapidly and stably produce high
levels of proteins, called antigens, which conferred immunity against the
plague.

"This current work represents a new direction in our research because we've
come to the realization that plants also have the potential for the
production of antigens that can be purified and delivered by typical
intramuscular or subcutaneous injections -- the way most vaccines are
normally given," said Mason, an associate professor in the School of Life
Sciences. "This new system produces really high levels of antigens in
relatively short periods of time."

The researchers modified tobacco plants to make high levels of the plague
antigens F1, V and a combination of the two, a so-called F1-V fusion
antigen. All are known to be important for the plague bacteria to produce
its toxic effects.

The antigens were purified from the plants and injected into guinea pigs.
Testing using an aerosolized form of plague was performed by Chad Roy and
Robert Webb at the U.S. Army Medical Research Institute of Infectious
Disease at Fort Detrick, Maryland. This project was also the first
comparison study designed to test more than one kind of antigen during the
same challenge.

"The idea with any recombinant subunit vaccine is that you can pick and
choose selective antigens that can confer protection and limit the potential
for adverse reaction," said Mason.

More than half the vaccinated animals survived the challenge with all forms
of the antigen, and guinea pigs vaccinated with V antigen alone had the
highest survival rates.

"This study provided validation of our plant expression system, that it can
produce the bacterial antigens in a native form that will allow for an
appropriate immune response against a bacterial pathogen." Mason.

Critical to the success of the study was a collaboration set up with Anatoli
Giritch, Victor Klimyuk and Yuri Gleba, who originally developed the plant
expression system at Icon Genetics, located in Halle, Germany.

The group's results are the first to use Icon's viral expression system that
adapts the tobacco mosaic virus (TMV) to produce a plant-based vaccine
against plague. TMV, a common scourge of the plant world, causes widespread
plant disease and can damage and mottle the leaves, flowers and fruits of
whole crops. In the system, TMV is simply injected into the leaves of the
tobacco plants.

Like most crops, producing vaccines in tobacco plants primarily revolved
around issues of speed, low cost and high yield. "The major advantage of the
vaccine is the rapidity of the system," said Santi. "In a matter of 10 days,
we can go from infecting the plants to harvesting the plants. From there, we
purify the antigens in an additional one to two weeks to create the
vaccine."

The approach also eliminates the typical year-long lag time necessary to
establish and characterize genetically modified, or transgenic plants.

The beauty of system is its potential versatility that can be adapted to
fight against other pathogens as well. The research team's next step is to
refine their methods to achieve a large-scale commercial production of the
vaccine.

The Biodesign Institute at Arizona State University addresses challenges to
human health by integrating research in biology, chemistry, physics,
medicine, agriculture, environmental science, electronics, engineering and
computing. This bold approach ensures discoveries are rapidly converted into
applications and adopted by the private sector. For information, visit
www.biodesign.org

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