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[SANET-MG] plant based vacciines and therapeutic antibodies



July 18, 2004

Prof. Joe Cummins

“Plant based pharmaceuticals: vaccines and therapeutic antibodies”

Plant based vaccines and therapeutic antibodies are an emerging area of
commercial development, for example , the European Union (EU) recently
announced a major program to produce plant based vaccines and
therapeutic antibodies (1).The risks of plant based edible vaccines were
exposed two years ago (2). Vaccines are produced using antigen proteins
from disease organisms such as viruses or bacteria, such antigens have
active sites consisting of a short chain of amino acids or amino acid
chains modified with carbohydrates called epitopes. The epitopes of the
antigen trigger production of antibodies following injection into the
blood stream or ingestion with food. The plant based vaccines are mainly
produced from synthetic genes whose DNA code words have been altered for
maximum activity in a crop plant (3). Along with the plant based
vaccines antibodies used to treat disease are also being produced in
plants, such antibodies are being developed to treat both animal and
plant diseases, such antibodies are effective but plagued by the
powerful immune response that they may elicit in animals following
repeated exposure to the antibody.

Plant based vaccines are mainly geared towards mucosal immunization
following oral intake. Oral vaccines can be effective but such vaccines
may elicit oral tolerance if there is repetitive exposure. Oral
tolerance is the animal’s defense against antigens in food , after
repeated exposure to an oral antigen the mucosal immune system ceases to
view the antigen as toxin but views it as food. The animal then becomes
easy prey for the pathogen(4). The promoters of plant based vaccines
seldom mention the problem of oral tolerance arising when the genes for
the vaccine pollute the food supply Journals publishing scientific
studies on plant based vaccines seldom mention oral tolerance and the
government regulators have been very lax in approving field test
releases that may contaminate food crops . The problem has, however,
been mentioned in at least one review of plant based vaccines(5). Oral
tolerance has been used to treat autoimmune disease such as diabetes,
plants producing an antigen eliciting the autoimmune response in
diabetes have created to be fed to diabetics to protect against the
autoimmune response in diabetes (6). Oral tolerance is the main threat
from pollution of the food supply with vaccine genes, therapeutic
antibodies threaten a direct immune response. These two impacts are
seldom discussed by promoters of plant genetic modification and science
journals seem negligent in failing to discuss the problem in
publications on plant based vaccines and therapeutic antibodies. As well
the use of synthetic antigen genes has ramifications regarding
recombination and stability of the genes in crop plants and these
ramifications have not yet been explored, but should be explored prior
to commercial production of the modified crops.

Edible plant based vaccines have been reviewed extensively. The vaccines
have been produced using synthetic nuclear genes, synthetic chloroplast
genes or plant viruses modified with synthetic genes. The nuclear gene
insertions frequently failed to produce sufficient protein to evoke an
oral immune response while chloroplast genes tended to provide adequate
protein levels (the chloroplast allowed insertion of multiple gene
copies with less problem of gene silencing than nuclear gene
insertions). The chloroplast transformations produced antigen up to 25%
of total soluble protein while nuclear inserts generally produced less
than 1% total soluble protein, endosperm localization of nuclear gene
products allowed up to 10% antigen in maize kernels (7). Numerous plant
viruses modified with vaccine antigens have been released in field
tests. Such viruses can produce up to 10% total soluble protein in the
infected plant but most frequently produce about 1% total soluble
protein as vaccine (8). Little consideration was given to containment of
the modified plant viruses which can be spread by sucking insects, plant
wounding or by blowing plant debris. Furthermore, a recent study shows
that plant viruses may be spread by wind, either in water droplets from
the plant surface or by abrasive contact between plant leaves (9). In
general, field test releases of crop plants modified for vaccine
production have been undertaken with little regard for the consequences
of food crop pollution with the vaccine genes.

The appendix provides a list of 30 human and animal diseases for which
plant based vaccines have been created, the list is representative of
the extensive production and testing of plant based vaccines. It is
worth mentioning that about half of the transgenic crops on the list
were produced using plant viruses including tobacco mosaic virus, cow
pea mosaic virus, alfalfa mosaic virus, potato virus X, plum pox poty
virus and tomato bushy stunt virus. The virus constructions are
productive but pose special long term risks associated with release of
the virus to the environment and predicable virus recombination to
produce novel diseases. Little effort seems given to monitoring such
hazardous experiments.

Numerous plant based therapeutic antibodies have been created and
released in field tests. Antibodies have been produced for treating
human ,animals and plant diseases. The plant based antibodies are made
from synthetic antibody genes and they are also greatly influenced by
the pattern of glycosylation (sugar modification of protein) produced in
the plant (10). Further examples of plant based monoclonal antibodies
include monoclonal antibodies isolated from mice that conferred
resistance to a herbicide when synthetic copies of a gene whose product
inactivated the herbicide were in introduced into a crop plant (11).,
Kholer and Milstein discovered a method for preparing monoclonal
antibodies in 1975 (12). That discovery has been an exceptional
contribution to development of clinical analytical technology and to
therapy but that application has not reached full expectation as a
“magic bullet” for treating disease because the antibodies provoked a
strong immune response if applied repeatedly.

In the reviews mentioned previously numerous plant based vaccines were
described (7,8) the following discussion will focus cancer vaccines and
vaccines for human immunodeficiency virus (HIV). A vaccine against a
colorectal cancer was produced in tobacco plants (13). A vaccine for
treatment of non-Hodgkins lymphoma was produced in tobacco plants (14).
A vaccine against the papilloma virus oncogene product causing human
cervical cancer was produced using a potato virus-X vector (15). These
cancer vaccines are an important effort to control cancer while careless
environmental release of the vaccines in crop plants could greatly
increase susceptibility to specific cancers.

The Gag gene from Simian Immunodeficiency virus (SIV) a surrogate for
HIV was used to transform potato(16). In that experiment the native SIV
gene was used to transform the potato rather than a plant enhanced
synthetic copy. Failure to alter the genetic code to the form most
active in plants may explain the relatively low production of Gag
protein. The coat protein of alfalfa mosaic virus was modified to
express antigenic peptides for rabies virus and HIV . Antibodies against
rabies and HIV were expressed in mice immunized with the antigenic
peptides (17). Simian-human immunodeficiency virus (SHIV) tat gene was
fused cholera toxin subunit gene and the combination was used to
transform potato and the fusion protein was found to suitable for
mucosal immunization (18) In the publications above the environmental
consequences of polluting spread of the virus genes was not discussed.

A number of technical enhancements have been attempted to enhance the
vaccine antigen production in plants. Codon usage enhancement is
illustrated in the production of vaccine antigens in crop plants as
discussed previously (3). Various combinations of promoters and
enhancers were studied in expression of a gene from rabbit hemorrhagic
virus in potato(19). The potato patatin promoter proved more effective
than the CaMV or the ubiquitin promoter. Ricin B a lectin sub-unit of
ricin has been proposed as a delivery adjuvant for mucosal vaccines
(20). At least as far as the published information is concerned plant
based vaccines and antibodies are far from ready for major commercial
production. Production of plant based vaccines in primary food crops
such as maize and rice is unwise on environmental grounds but a recent
publication indicates that maize, at least, is still promoted by crop
plant vaccine promoters (21).

In conclusion, there has been extensive creation and field test releases
of plant based vaccines and therapeutic antibodies. For, the most part
little care has been given to the environmental consequences of field
releases of the modified crops. Even major accidental exposures of the
public do not seem to have dampened the increased pace of creation and
testing, The consequences of such heedless testing may be disastrous but
production is likely lead to a monumental poisoning of the primary food
supply. It is not too late to impose a sound approach to commercializing
plant based vaccines and antibodies , however, most of the development
is secretive and unknown to the pubic rendering reforms difficult to apply.

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