Eat up your vaccines

Edible vaccines are being touted by the agbiotech industry as an example of
the benefits genetic engineering can bring to the South. Claims that they
will be cheap, accessible and safe, and eliminate the need for the dreaded
needle, sound like a dream come true. But the vaccine in a banana is still
far from reality, and we will all likely be a lot better off without
itanyway.

Genetic Resources Action International (GRAIN)

_____

NOT only have the first generation of genetically modified (GM) crops been
disappointing in terms of their agronomic and economic returns, they have
been a spectacular failure in terms of generating public support for GM
foods. In many countries, the spread of GM crops has largely come to a
standstill. As a result, the agbiotech industry has changed direction and is
hoping to win the public over with its new collection of designer crops.

Unlike the first generation, which supposedly delivered benefits for the
producer, the second-generation crops will - we are promised - be designed
with the consumer in mind.

The second generation is focusing on what are known as 'functional foods'.
Broadly defined, these are products with a claimed consumer benefit, such as
taste, nutritional value, or as a drug delivery system. Functional foods,
such as chocolate bars with ginseng, are already widely available in Europe
and the US. To date, the extra 'function' has been added during processing,
rather than as a result of genetic manipulation, but this is set to change
shortly. All the major agbiotech giants - such as Syngenta (the agribusiness
company formed in November 2000 from the merger of Novartis Agribusiness and
Zeneca Agrochemicals) , Monsanto and Aventis - are investing heavily in
functional foods. Their agenda is clear. Daniel Vasella, chairman and CEO of
Novartis, echoes the hopes of the whole industry in his belief that
'tangible consumer benefits could turn the debate on genetically modified
food.'

Some of the more ambitious functional foods in the pipeline are those with
pharmaceutical applications. A growing number of companies are starting to
engineer plants to produce therapeutic proteins to be used as drugs and
vaccines. Up to now, mammalian and microbial cell cultures have been used as
'bioreactors' to produce these therapeutic proteins, which generate more
than US$18 billion in combined sales per year, a figure projected to
increase by 20-30% this decade.

The attraction of plant-based systems is that they exhibit good genetic
stability, and are cheaper to develop and easier to scale up for commercial
production. The US-based company Epicyte Pharmaceutical has a number of
'plantibodies' (proprietary technologies for producing antibodies in plants)
in clinical development. CropTech corporation is genetically modifying
tobacco to produce therapeutic proteins and Large-Scale Biology is working
on a non-Hodgkin' s lymphoma vaccine. Planet Biology is conducting clinical
trials on a monoclonal antibody produced in GM plants that prevents the oral
bacterial infection that contributes to tooth decay.

Edible vaccines

Of all the work on functional foods, research into edible vaccines has
captured the public's imagination the most. 'One day children may get
immunised by munching on foods instead of enduring shots,' suggests
Scientific American magazine. 'More important, food vaccines might save
millions who now die for lack of access to traditional inoculants.'

Edible vaccines are the latest, greatest hope of the floundering biotech
industry, along with Vitamin A or 'golden' rice, to convince a sceptical
public that genetic engineering will help the hungry and sick in the South
as well as the North. Foods under study as edible vaccines include bananas,
potatoes, tomatoes, lettuce, rice, wheat, soybeans and corn. The media have
delighted in conjuring up images of African families venturing no further
than their garden to pluck a vaccine-laden banana from their homegrown tree
to protect them from the major killer diseases of the day. Hoechst's
in-house magazine, Future, says that 'We may some day think that getting a
shot against hepatitis is a rather primitive, old-fashioned way to
administer a vaccine.'

The advantages, says Scientific American, 'would be enormous. The plants
could be grown locally, and cheaply, using the standard growing methods of a
given region. Because many good plants can be regenerated readily, the crops
could potentially be produced indefinitely without the growers having to
purchase more seeds or plants year after year. Homegrown vaccines would also
avoid the logistical and economic problems posed by having to transport
traditional preparations over long distances, keeping them cold en route and
at their destination. And, being edible, the vaccines would require no
syringes - which, aside from costing something, can lead to infections if
they become contaminated. '

Medicine's Holy Grail

Vaccination is one of the medical world's greatest success stories.

'Vaccines have accomplished near miracles in the fight against infectious
disease,' proclaims Scientific American. Between 1970 and the late 1990s, an
international campaign to immunise all the world's children against six
devastating diseases (diphtheria, whooping cough, polio, measles, tetanus
and tuberculosis) increased the number of infants vaccinated from 5% to
about 80%, and reduced the annual death toll from those infections by
roughly three million. But, vaccine proponents argue, the 20% of infants
still missed by the six vaccines account for about two million unnecessary
deaths each year, especially in the most remote and impoverished parts of
the globe. Regions harbouring infections that have faded from other areas
are like bombs ready to explode, and international travel and trade increase
the mobility of infectious diseases. 'Until everyone has routine access to
vaccines, no one will be entirely safe,' warns Scientific American.

The World Health Organisation (WHO) has called for new strategies to deliver
vaccines to reach the populations that existing programmes have failed to
reach. Existing vaccines are expensive, need refrigeration and require a
skilled person to give the injection - with needles that are hard to come by
in some places. Hence the appeal of edible vaccines. But just how realistic
or desirable is the dream of the backyard vaccine banana?

Backyard bounty

Appealing as it is, reality will probably fall short of the backyard banana
tree. 'Our main worry with this technology is the dosage,' says Bernard
Ivanoff, global coordinator for vaccines at the WHO. In determining the
right dosage, the patients' weight and age need to be considered, as would
the size and even ripeness of the banana. Charles Arntzen, one of the
pioneers of edible vaccines, acknowledges the challenge of assessing how
much an infant, in particular, ingests. 'A baby may eat a bite and not want
any more, may spit up half of it, or eat it all and throw it up later,' he
concedes.

Researchers are now recognising that edible vaccines would be unlikely to
make the role of the vaccine provider redundant, and that attempting to
concentrate the vaccine into a teaspoon of baby food would be more practical
than administering a whole banana. This, then, begs the question: why bother
to engineer it into a banana in the first place?

Big task for a banana

Because heat denatures (inactivates) vaccines, the food material being
engineered to produce the vaccine will have to be eaten raw. Many current
studies focus on engineering vaccines into potatoes - the potato can
attribute its current popularity to the fact that it is easy to engineer -
but it is generally recognised that the potato is unlikely to be a popular
or practical vehicle.

Bananas are being eyed as the vehicle of choice, particularly for Third
World applications, because of their worldwide popularity, abundance and
baby-friendliness. But bananas have their own problems. They contain very
little protein, so they are unlikely to produce large amounts of recombinant
proteins (i.e., vaccines). Banana trees also take a few years to mature and
the fruit spoils fairly rapidly after ripening, making transportation and
storage difficult. Researchers at Cornell University in the US have so far
been unsuccessful in their attempts to engineer a vaccine into a banana
plant. Even if they can be tweaked to produce viable amounts of vaccine, it
is well known that plants don't grow very well when they are producing large
amounts of foreign protein. The GM potatoes used in Cornell's human trials
were small - about the size of a thumb.

Transportation

One of the big draws for edible vaccines is the potential to drastically
reduce or eliminate transport costs. But the impracticality of the backyard
banana means that the elimination of transport costs is not a realistic
scenario. Some researchers imagine vaccines being produced in national or
regional greenhouses, which would be an improvement on flying the vaccines
in from overseas, but this could probably better be achieved by establishing
a conventional vaccine plant in-country. The environmental and ecological
risks posed by edible vaccines (see below) also make it questionable whether
many countries in the South should be expected to have the facilities and
expertise available to grow the vaccines safely and successfully.

Needle-free shots

Another much-hyped advantage ignores the fact that if they could be given
orally, today's vaccines already would be. Few vaccines are absorbed well
from the gut because they are too big to cross the gut wall easily and/or
are broken down by the gut enzymes. Edible vaccines would be subject to the
same limitations as any other oral drugs.

Cheap, cheap, cheap?

One of the key goals of the edible-vaccine pioneers is to reduce
immunisation costs. The theory goes that edible vaccines would be far
cheaper than current injectable vaccines since they would not have to
undergo the expensive purification and refrigeration of traditional
vaccines, and shipping costs would be much reduced. As we have seen,
shipping costs may not necessarily be significantly reduced, and edible
vaccines may still require refrigeration. Even if edible vaccines are
cheaper, it is not clear that this will lead to increased vaccination
coverage, since the cost of the vaccine is a small part of the whole
package. According to the WHO, to immunise a child costs no more than $1 for
the big six vaccines, but $14 for programme costs (laboratories, transport,
cold chain, personnel and research). For the newer, more expensive vaccines,
such as hepatitis B and AIDS, the cost of the vaccine plays a more
significant role, but the nature of the vehicle (banana or syringe) will
still only represent a small part of the total cost.

Will they work?

Research into edible vaccines is still at a very early stage and they have a
long way to go in proving their efficacy. Getting plants to express adequate
amounts of the vaccine is proving challenging enough, let alone translating
that into an appropriate immunological response in people. Producing stable
and reliable amounts of vaccines in plants is complicated by the fact that
tomatoes and bananas don't come in standard sizes. There may also be
side-effects due to the interaction between the vaccine and the vehicle. In
many countries in the South, stringent quality control standards for
standard drugs are quite a luxury, let alone dealing with the added
complications posed by edible vaccines. People could ingest too much of the
vaccine, which could be toxic, or too little, which could lead to disease
outbreaks among populations believed to be immune.

Oral vaccines are also more difficult to formulate than injectables - for
example, the oral polio vaccine is more convenient but less effective than
the injectable one. The vaccines are likely to need cofactors (adjuvants)
such as cholera toxin to enhance their uptake and increase their
effectiveness. In addition, new vaccines have to be tested worldwide, since
their effectiveness is not uniform in different contexts. When the
tuberculosis vaccine (BCG) was tested in the UK, it proved to be effective.

But it did not work in India, probably because tuberculosis is linked to
nutritional status.

Environmental and health risks

Over the last two decades, there has been a dramatic increase in outbreaks
of new and re-emerging infectious diseases. One of the factors implicated in
this phenomenon is the transfer of genes across unrelated species of animals
and plants. This 'horizontal gene transfer' has been pinpointed as being
responsible for the new bacterial strains involved in the cholera outbreak
in India in 1992 and the Streptococcus epidemic in the UK in 1993.

Antibiotics and traditional vaccines already contribute to horizontal gene
transfer. Recombinant vaccines, like those that would be used in edible
vaccines, would exacerbate such transfer. This is a serious concern for the
release of any genetically manipulated organism, but particularly worrisome
in the case of vaccines, because of their disease-causing potential.

The ecological and environmental risks of edible vaccines seem to have
received little attention, despite the fact that they present major hazards
(see box). Containing these risks, assuming they are taken seriously, would
certainly eliminate the possibility of the backyard banana, and greenhouse
facilities would need to be rigidly controlled. The risks associated with
edible vaccines are particularly worrisome given the medical community's
blind faith in vaccination in general and its seeming unwillingness to take
seriously evidence that has been accumulating related to vaccine safety
(such as the rise of autoimmune diseases).

Regulators are trying to figure out how to deal with plants engineered to
produce drugs. Some safeguards are already in place. In the US, all field
tests of drug-producing plants require government permits, while some field
tests of other modified crops require only notification of the relevant
government body. For no particular sound scientific reason, the required
distance by which the drug-bearing plants must be isolated from other plants
to prevent cross-pollination has been set at double the usual distance. But,
as with releases of all genetically modified organisms (GMOs), the
parameters considered in determining a product's 'safety' are extremely
limited, and do not inspire confidence in dealing with the many and varied
risks associated with edible vaccines.

Vaccine movers and shakers

Much research on edible vaccines is being undertaken in the public sector at
present (see box). The industry is eager to hype up the benefits of edible
vaccines to win over support for genetic engineering, but this seems to be
more of a public relations exercise than real commitment. As indicated by
the roster of patent applications on edible vaccines ( table not included),
most industry research is being undertaken by small technology companies,
rather than the big vaccine producers. A few large companies, like Mycogen
(Dow Agrosciences) , are looking into edible vaccines, but are more
interested in the livestock market than human application.

Cornell University's of Cornell's Charles Arntzen, who pioneered the idea of
edible vaccines, says he has had little success in selling the idea of
edible vaccines to the big vaccine producers. He sees two main reasons for
this. Firstly, his main focus has been on vaccines for the South, such as
diarrhoeal vaccines, which are not seen as a good investment by the
companies. Secondly, they 'have the market sewn up with traditional
injections'. Arntzen believes that a small vaccine start-up will have to
lead the way in proving the viability of the technology, and that the big
companies will follow.

Historically, profit margins in vaccine markets have been low as compared to
pharmaceutical markets primarily due to the non-proprietary nature of common
vaccines. In the 1970s and 1980s, innovation was slowed by the paucity of
resources and competition in this area, primarily due to concerns of
liability and commercial viability. In the US, legislation in the last 10
years that removed liability from companies except in relation to
manufacturing defects has encouraged re-entry into the market. Vaccine
companies are reaping bigger profits again. The world vaccine market was
estimated to be $3.6 billion in 1999 and is growing at 12% annually.

The market is highly concentrated, with three pharmaceutical giants
(SmithKline Beecham, Aventis [which has swallowed up both Merck and Pasteur
Connaught Merieux] and Wyeth Lederle) accounting for more than 75% of sales.

The advent of recombinant vaccines, which are being developed against
malaria, AIDS and hepatitis B, means that vaccines are no longer necessarily
cheap. When it first came on the market in the US, the hepatitis B vaccine
cost $150 a shot. Although the price has now come down to $1, it is still
well out of the range of affordability in developing countries. Some
researchers point to these new recombinant vaccines as possible candidates
for edible vaccines: the injectable vaccines against diphtheria, tetanus,
pertussis, and so on are so cheap now that there would be little incentive
to develop edible vaccines for them. But it is just these technologies that
the corporations would be hugging tightly to their chests for as long as
their patents will allow.

Vaccine companies are only interested in developing vaccines that will sell
in the North. As HIV vaccine developer Stanley Plotkin of Aventis Pasteur
explains, 'The keystone of the [global vaccination] system is that the
research costs are recouped in North America and Europe, and the vaccines
are sold in the developing world at much, much lower margins.' Hence, very
little research is undertaken on diseases that have no market in the North.

According to the World Bank, funds for global public and non-profit malaria
research in 1993 totalled about $84 million, with only a small part of that
devoted to vaccine research. The amount of private sector spending is
'generally considered to be even smaller.' Because of this, the World Bank
is looking into setting up a $1 billion fund to help countries purchase
vaccines. Such a fund could 'ensure that there would be a market for
malaria, tuberculosis or AIDS vaccines if they were developed, and thus
would create incentives for vaccine research.'

How effective the establishment of such a fund would be in stimulating
research in the industry remains to be seen, but it would no doubt be
welcomed by the agencies involved in vaccination programmes in the South,
such as the United Nations Children's Fund (UNICEF) and the WHO.

In terms of the potential of edible vaccines, the WHO is cautiously
optimistic.

According to the WHO's Uli Fruth, the 'WHO is very interested in
technologies which (a) may render vaccines more affordable for use in
developing countries, (b) may allow future vaccine production in developing
countries and (c) can be delivered needle-free. All three conditions appear
to be fulfilled in this case.' The WHO is not investing heavily in
edible-vaccine research, but has provided some seed-funding (Arntzen's work
on edible vaccines at Cornell) to help establish proof of principle. Fruth
acknowledges that before endorsing such vaccines for human use, the WHO's
concerns related to quality assurance, efficacy and environmental impact
will need to be addressed in a satisfactory fashion. But if the WHO's
position on GM foods is anything to go by, its approach to safety issues is
unlikely to be very wide-reaching or reassuring. A joint WHO/FAO
consultation on the safety of GM foods recently concluded that the
pre-marketing safety assessment [of GM foods] already gives assurance that
the food is as safe as its conventional counterparts. '

Just a pipe dream?

Despite their willingness to present edible vaccines as an example of the
benefits of GM foods, the pharmaceutical and agbiotech industries seem to be
merely tinkering with the idea at the moment, and are not investing heavily
in research. A few small biotech companies and university departments are
pioneering the way. It is possible that in time they may convince the
corporate giants to let go of their established technology and invest in
edible vaccines, but this seems unlikely given the complexity of the
challenge of creating a safe, convenient and affordable product. People all
over the world can breathe a big sigh of relief (at least for now), given
the serious risks that edible vaccines pose. As Norway's biosafety expert
Terje Traavik has pointed out, 'there is a most striking lack of holistic
and ecological thinking with regard to vaccine risks. This seems to be
symptomatic of the real lack of touch between research in medicine and
molecular biology on one hand, and potential ecological and environmental
effects of these activities on the other.'

The potential for harm that edible vaccines pose highlights the need for
thorough and wide-reaching risk assessments for GMO releases.

Current frameworks for regulation are woefully inadequate. In addition,
researchers and policy makers need to examine closely the whole field of
infectious diseases. There are other ways of preventing the spread of
infectious diseases (such as breaking transmission chains) and these must be
given greater attention instead of focusing solely on the technofix solution
of vaccination. This does not necessarily mean abandoning vaccination
altogether, but developing a more holistic approach to the management of
infectious diseases.

Genetic Resources Action International (GRAIN) <www.grain.org
<http://www.grain. org%20<http: /www.grain. org> <http://www.grain. org>> is
an international non-governmental organisation promoting the sustainable
management and use of agricultural biodiversity based on people's control
over genetic resources and local knowledge, with a special emphasis on
developing countries. The above article first appeared in GRAIN' quarterly
newsletter, Seedling (December 2000).

Main Sources

*WH Langridge (2000), 'Edible Vaccines' Scientific American, September 2000.

*T Traavik (1999), 'Environmental Effects of Genetically Engineered

Vaccines,'hird World Network Online,
<http://www.twnside. org.sg/title/ vaccine.htm>

*Mae-Wan Ho et al (1999), 'Sowing Diseases, New and Old', Third World
Network Online, <http://www.twnside. org.sg/title/ heal-cn.htm>

*M Hansen (1999), 'Gnetic Engineering is Not an Extension of Conventional
Plant Breeding,'Consumer Policy Institute,
<http://www.consumer sunion.org/ food/widecpi200. htm>

*R Glennerster and M Kremer (2000), 'A World Bank Vaccine Commitment'
Brookings Policy Brief #57, May 2000.

*'Safety Aspects of Genetically Modified Foods of Plant Origin', Report of a
Joint FAO/WHO Expert Consultation on Foods Derived from Biotechnology, WHO,
Geneva 2000. WHO and UNICEF (1996), The State of the World's Vaccines and
Immunisation, <http://www.unicef. org/newsline/ vpressr.htm>

*V Griffith (2000) 'Fighting Disease with Edible Vaccines,' Future (Hoechst
in-house
magazine),http://www.archive. hoechst.com/ english-3er/ publikationen/ future/er
naehr/art3.htm

*A Pollack (2000), 'Ventures Aim to Put Farms in Pharmaceutical Vanguard,'
New York Times, 14 May 2000.

*J Toonen (1996), 'Seeds of a New Medicine,' Biotechnology and Development
Monitor No.27, pp 12-14,
<http://www.gene. ch/www/pscw. uva.nl/monitor/ 2707.htm>

. Wilkins (1999), 'Edible Vaccines I'll Take Mine With a Grain of
Salt,' Biotech Times Vol.5, No.2.

*Personal communication with Charles Arntzen, Arizona State University; Uli
Fruth, Vaccines and Biologicals, WHO; and Ted McKinney, Mycogen.

Box stories

Who is doing what with edible vaccines?

. The first human clinical trial of an edible vaccine took place in
1997, when volunteers ate raw potatoes genetically engineered against
diarrhoea-causing E coli. Ten of the 11 volunteers who received the vaccine
had fourfold rises in serum antibodies.

. Researchers from the Boyce Thompson Institute (BTI) at Cornell
University conducted another clinical trial of an edible vaccine in 1999.
Potatoes containing the Norwalk virus (which causes vomiting and diarrhoea)
fed to volunteers elicited an immune response in 19 out of 20 subjects. BTI
researchers are attempting to engineer vaccines into bananas and have
produced powdered tomatoes that carry Norwalk virus DNA. BTI scientists have
also been awarded a Rockefeller Foundation grant - $58,000 for three years -
to collaborate with Mexican researchers at the Mexican health agency,
CINESTAV.

. Prodigene and Stauffer Seeds (a spin-off of Staffer Chemical,
formerly a division of Novartis) have conducted clinical trials on pigs
using an edible vaccine for transmissible gastroenteritis virus (TGEV)
expressed in corn, and are developing a Hepatitis B vaccine for humans.

. The US' Large Scale Biology Corporation is developing a
patient-specific non-Hodgkin' s lymphoma vaccine in plants. Current methods
for making the custom vaccine require up to a year to produce vaccine for
patient use; LSB thinks its production process could reduce that time to 6-8
weeks.

. Under license from Mycogen, the UK's Axis Genetics was developing
an oral hepatitis B booster vaccine in edible plants, and had plans for
Norwalk virus and diarrhoea. Axis went out of business in 2000, saying that
protests over bioengineered food had scared off investors. Myocgen continues
to work on edible vaccines for animals.

. Under license from Groupe Limagrain, Meristem Therapeutics has
developed industrial processes for the large-scale production of recombinant
therapeutic proteins in plants. Plants including tobacco, corn, potato and
rape seed are being used as bioreactors for the production of enzymes,
antibodies, and vaccines.

. The Scripps Research Institute is working on an edible HIV vaccine.

Initial success has been reported in splicing amino acids from HIV into the
cowpea mosaic virus (CPMV). When inoculated with CPMV, cowpea plants
reproduce HIV.

. Scientists in Poland working with the US' Thomas Jefferson
University have tested a hepatitis B vaccine contained in lettuce on human
subjects.

. In Melbourne, Australia, CSIRO has grown a measles-fighting tobacco
plant and has begun pilot studies with oral plant-based vaccines for malaria
and HIV.

Genes going wild

Genetic engineering is inherently hazardous because it depends on developing
gene transfer vectors (carriers) specifically designed to cross wide species
barriers. It promotes the transfer of genes horizontally across species,
instead of vertically within species by inheritance. It is also increasingly
designed to overcome the species' defence mechanisms which degrade or
inactivate foreign genes. It is still a very crude science, with genes being
inserted at random points in the host's genetic material (genome), rather
than being carefully pinpointed as happens in traditional breeding. For
these and other reasons, genetic engineering destabilises the genomes of its
plant and animal hosts, and the effects ricochet through the neighbouring
ecosystem. There is growing evidence that by facilitating horizontal gene
transfer and recombination, genetic engineering may be contributing to the
emergence and re-emergence of infectious, drug-resistant diseases.

Edible vaccines (even subunit vaccines) will always entail the ingestion of
recombinant viral genetic material, and hence pose considerable risks to the
environment and health. Edible subunit vaccines are likely to be less
dangerous than those that may be produced using genetically modified viruses
and viruses used as vectors (carriers) for the vaccine. But they still
involve the insertion of foreign genes into the plants and the implications
thereof. Genetically tweaking the pathogen to reduce its potency is even
more risky. It has been demonstrated that minor genetic changes in, or
differences between, viruses can result in dramatic changes in host spectrum
and disease-causing potentials. According to Terje Traavik of the Norwegian
Institute of Gene Ecology, 'For all these vaccines, important questions
concerning effects on species other than the targeted one are left
unanswered so far.' There are also considerable risks related to the
possibility of a genetically engineered vaccine virus engaging in
recombinations with naturally-occurring relatives. New viruses resulting
from such events 'may have totally unpredictable characteristics with regard
to host preferences and disease-causing potential,' says Traavik.

Naked DNA vaccines, which comprise the genes of the pathogen without the
virus 'shell,' are perhaps the most risky. These short pieces of DNA are
readily taken up by cells of all species, and may become integrated into the
cell's genetic material. Unlike chemical pollutants which dilute out and
degrade over time, these small DNA fragments can be taken up by cells and
multiply and mutate indefinitely. They are known to have significant and
harmful biological effects, including cancers in mammals. Upon release or
escape to the wrong place at the wrong time, horizontal gene transfer with
unpredictable biological and ecological effects is a very serious, and as
yet unregulated, hazard.

Sources: T Traavik (1999), 'Environmental Effects of Genetically Engineered
Vaccines,' Third World Network Online,

<http://www.twnside. org.sg/title/ vaccine.htm>; Mae-Wan Ho et al (1999),

'Unregulated Hazards of Naked and Free Nucleic Acids', ISIS report for the
Third World Network. <http://www.i- sis.org/naked. shtml>

How vaccines work

Vaccines work by priming the immune system to swiftly destroy specific
disease-causing agents before they can multiply enough to cause symptoms. To
date, this priming has been achieved by presenting the immune system with
whole viruses or bacteria that have been killed or 'attenuated' (made too
weak to proliferate much). The immune system responds to this vaccine as if
it were under attack by a fully potent antagonist and mobilises its forces
to destroy the foreign body. Memory cells are then left behind on alert,
ready to unleash whole armies of defenders if the real pathogen ever finds
its way into the body.

Classic vaccines pose a small risk in that the killed or attenuated
microorganism can sometimes spring back to life, causing the disease they
were meant to prevent. For this reason, 'subunit' vaccines (which contain no
genes, just proteins derived from them) are now favoured, since they reduce
this risk. They are, however, often not as effective as live vaccines.

Subunit vaccines are also expensive, because they are produced in cultures
of bacteria or animal cells and have to be purified and refrigerated.

Many researchers hope that they will be able to develop edible vaccines
which are similar to subunit preparations, containing only the genes coding
for certain antigens, not the whole virus or bacterium. One of the main
hurdles to be overcome here is that the antigens could be degraded in the
stomach before having time to act. (Typical subunit vaccines have to be
delivered by injection precisely because of this). Researchers working on an
edible hepatitis B vaccine suggest that oral doses may need to be 10-100
times higher than the injectable dose to elicit a comparable immune
response.

Source: WH Langridge (2000), 'Edible Vaccines', Scientific American,
September

Edible vaccines

Professor Joe Cummins points out the risks of edible vaccines now under
development in a variety of common food plants.

IN the early 1980s, the World Health Organisation called for oral vaccines
that do not need refrigeration and are inexpensive to produce.

Such vaccines, it was believed, would eradicate most infectious diseases
worldwide.

During the past 10 years, crop genetic modification has been investigated as
a means of making edible vaccines that could be produced locally without
refrigeration. Food vaccines have been developed using bananas, potatoes and
tomatoes, as well as lettuce, rice, wheat, soybeans and corn. Corn and
alfalfa have been developed to provide vaccines for farm animals. For the
most part, the vaccines are developed using selected proteins from the virus
or bacterium being protected against. In some instances, plant viruses such
as alfalfa mosaic virus or tobacco mosaic virus are modified to produce
antigens (proteins eliciting immune reaction) of mammalian virus or
bacterial disease. The modified plant viruses rapidly produce high levels of
antigens for oral immunisation against mammalian viruses or bacterial
pathogens [1]. Many edible vaccines are poised for release and clinical
trial, even though numerous important questions remain unsolved.

One complication with oral vaccines is 'oral tolerance'. When antigens are
taken up in food repeatedly, the production of antibody in the immune
response may be suppressed. In autoimmune diseases such as arthritis,
diabetes and multiple sclerosis, antigens are produced in tissues which are
attacked by the body's own immune response. When quantities of the target
antigen, such as collagen in arthritis, are eaten, the autoimmune disease is
suppressed, and many patients experience relief. Indeed, antigens for
autoimmune disease are being introduced into crop plants to treat the
symptoms of autoimmune disease. For the same reason, however, oral vaccines
in food may lead to undesirable suppression of immunity to the disease
normally protected by the vaccine [1,2].

Food crops containing vaccines may readily contaminate crops that are used
as food. This point has been made previously [3]. For example, it is assumed
that potatoes do not spread by pollination or by over-wintering tubers.

Actually, both modes of transfer are known. Genes for the vaccines may also
spread horizontally by sucking insects and by transfer to soil microbes. The
genes and proteins may be released during plant wounding or breakdown of
roots and rootlets and pollute surface and ground water. The vaccines may
provoke allergic responses if humans or other mammals or birds are
repeatedly exposed to the allergen.

In addition, many instances of recombination between viral transgenes and
viruses have already been reported (reviewed in [4]). Have these plants been
assessed for their ability to generate recombinant viruses? When genes of
viruses infecting human beings are incorporated into plants, are we not
increasing the potential for generating new recombinant viruses that may
cross from plants to human beings?

The crops modified to produce edible vaccines should be scrupulously
maintained for that purpose alone. Recently corn modified as an edible
vaccine for a swine virus was promoted by the company inventing it. It was
promised that the genetically modified (GM) corn would be grown under
'rigorously controlled conditions, and used only for the expressed purpose
of vaccine production' [5]. Such a commitment is essential but such promises
should be viewed in the light of StarLink corn that was approved only for
animal consumption but appeared in foods for human consumption.

GM crops as edible vaccines should be restricted to plant tissue culture or
to contained plant growth chambers or high-security greenhouses. During
epidemics such as the foot-and-mouth disease outbreak, there is likely to be
pressure to widely grow GM alfalfa modified with foot-and-mouth virus
structural proteins [6]. However, widespread and prolonged exposure to the
virus antigens is likely to defeat the purpose of the vaccine. There is also
the risk of creating new strains of foot-and-mouth virus as well as viruses
that cross between plant and animal kingdoms [3].

In conclusion, edible vaccines made up of GM crops modified with genes from
disease organisms are inexpensive to produce and do not need refrigeration.

However, careless releases of GM vaccine crops to the environment and
general food supply are likely to produce undesirable side-effects such as
greater disease impact or allergy to the food. Edible vaccines in GM crops
should be strictly confined to laboratory tissue culture, growth chambers or
greenhouses.

1. Landridge,W. (2000). 'Edible Vaccines'. Scientific American online,
September.

2. Weiner, H. (1997). 'Oral tolerance for treatment of autoimmune
diseases'. Ann Rev Med 48,341-51.

3. Ho, M. W. and Steinbrecher, R. (1998). 'Fatal Flaws in Food Safety
Assessment'. Environmental & Nutritional Interactions 2, 51-84

4. Ho, M. W., Ryan, A. and Cummins, J. (2000). 'Hazards of transgenic
plants with the cauliflower mosaic viral promoter'. Microbial Ecology I in
Health and Disease 12, 6-11.

5. 'Edible Vaccine Success'. In Brief, Nature Biotechnology 18,367,2000.

6. Wigdorovitz, A., Carrillo, C., Dus Santos, M., Trono, K., Peralta, A.,
Gomez, M., Rios, R., Franzone, P., Sadir, A., Escribano, J. and Borca,M.
(1999). 'Induction of a protective antibody response to foot and mouth
disease virus in mice following oral or parenteral immunisation with alfalfa
transgenic plants expressing the viral structural protein VP1'. Virology
255,347-53.