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[SANET-MG] corn with vaccine for travelers diarrhea



May 14, 2004

Prof. Joe Cummins

“Open field testing of maize modified with a gene for traveler’s
diarrhea antigen”

Production of biopharmaceutical drugs in crop plants is a growing area
of focus in the biotechnology industry and an area of grave concern to
the public who fear contamination of the food supply with drugs
resulting from accidental release of modified food crops. The
biopharmaceutical drugs being produced in crops include vaccines,
monoclonal antibodies, anticoagulants, immune modulators, growth
hormones, enzymes and pathogen control proteins such as lysozyme and
lactoferrin. None of the biopharmaceutical drugs under test has been
finally approved for commercial production but a loophole in regulations
has allowed marketing of the products produced in field test plots.
Production of oral vaccines in crop plants poses special problems
related the creation of oral tolerance in humans and animals consuming
food or feed polluted by genes from the test plot. Oral tolerance
renders the exposed individuals unable to produce antibodies to a pathogen.

Ken Wang of Iowa State University has applied to undertake field tests
of maize modified with a gene for a traveler’s diarrhea antigen (vaccine
or vaccine adduct) in Logan County Colorado ( a rural county bordering
the state of Nebraska not far from Denver). The test plot is about one
quarter acre in size with a buffer of 50 feet on each side. The plot is
set to be isolated by a distance of one mile from commercial corn
production(1), however, no considerations seems to have been given to
sweet corn or feed corn production in home garden plots. Some
consideration was given volunteer corn on the plot in following seasons
but no consideration was given volunteer plants produced from animal or
mechanical transport from the test site .

The gene introduced into the test maize plants is a synthetic alteration
of the Escherichia coli bacterial toxin causing travelers diarrhea. The
bacterial toxin LT has two regions LT-A that causes the disease and LT-B
a site that binds to a gut cell receptor. The LT-B portion of the toxin
provoked antibody production for the entire toxin and that portion of
the toxin gene was introduced into the maize plants. The synthetic gene
was altered in codon selection to optimize production in maize
(bacterial genes prefer codons that are not well utilized in plants).
The synthetic genes lack genetic homology with the bacterial genes from
which they originated and do not readily transform soil bacteria. The
modified maize also included the maize zein gene promoter (active in
grain endosperm) and the soybean storage protein transcription
terminator. The maize was also modified with the BAR gene
(phosphinothricin acetyl transferase) conferring tolerance to the
herbicide glufosinate, the BAR gene was activated by ubiquitin promoter
and the Agrobacterium nopaline transcription terminator. The BAR gene
was active in all the maize cells while the LTB-B gene was active only
in corn seed . As much as 3.7% of the maize seed protein was antigen(1).
Interestingly, any sweet or seed corn pollinated by transgenic pollen
would produce LT-B antigen in the season that the pollination took place.

Mice fed LT-B maize seed or maize spiked with bacterial LT-B produced
immunity to the bacterial infection , indeed, the maize LT-B proved more
effective than the bacterial antigen. The maize LT-B fed mice did not
develop oral tolerance (2).Mice fed LT-B containing potato did not
develop immunity unless the animals were primed with an injection of raw
potato juice (3). The potatoes had much lower levels of PT-B antigen
than did the corn grain.

The problem of oral tolerance in edible biopharmaceutical crops has been
acknowledged by regulatory agencies (4). In the case of LT-B antigen,
can it be presumed that absence of oral tolerance in mice provides
evidence that human will also be free of oral tolerance? The answer is
clearly, no way! The proof of human response can only be safely
determined by human ingestion of the corn.

In conclusion, it is unwise to produce transgenic biopharmaceutical
products in major food crops. In the Colorado tests , the question of
oral tolerance in humans is crucial to allowing the corn to be released
to the environment even in field test releases. There is no apparent
reason why the human studies cannot be conducted using greenhouse grown
maize. The proposed field test release seems to be blissfully unaware of
home garden grown maize food and feed and rather loose in the monitoring
area. The field test releases should not be allowed until the question
of human oral tolerance in answered, furthermore, recombination of the
synthetic LT-B gene with soil bacteria or fungi appeared to be totally
ignored and that prospect should be addressed. In the long run it would
be better to produce vaccines and pharmaceuticals in plants that are not
major food and feed sources.

References

1. Wang,K. “Application for permit under 7CFR340 US Department of
Agriculture”5 May 2004 pp1-29

2. Chikwamba, R., Cunnick, J., Hathaway, D., McMurray, J., Kirk, D.,
Mason, H., Wang, K..(2002) A functional antigen in a practical crop:
Corn derived LT-B protects mice against Escherichia coli heat labile
enterotoxin (LT) and the cholera toxin (CT). Transgenic Research,
11:479-493.

3. Lauterslager,T,Florack,D, van der Wal,T,Molthoff,J,Langeveld ,J,
Bosch,D, Boersma,W. and Hilgers,L “Oral immunisation of naive and primed
animals with transgenic potato tubers expressing LT-B” 2001 Vaccine 19 ,
2749–55

4. Bonetta,L. “Edible vaccines: not quite ready fro prime time” 2002
Nature Med. 8,94

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