EAT UP YOUR VACCINES December 2000 GRAIN Hoping to turn around the debate on genetically modified food, the agbiotech industry is hyping up the second generation of transgenic crops. which bring promises of "functional foods"with tangible consumer benefits. Edible vaccines are being touted as an example of the benefits genetic engineering can bring to the South. Promised to be cheap, accessible and safe, and eliminating the need for the dreaded needle, edible vaccines sound like a dream come true. But the vaccine in a banana is still far from reality, and we will likely all be a lot better off without it anyway. 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 new Novartis/AstraZeneca agribusiness merger), 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-Hodgkins lymphoma vaccine. Planet Biology is conducting clinical trials on a monoclonal antibody produced in genetically modified 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 publics 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 (see Seedling, March 2000, p9), to convince a skeptical 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 has 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. Hoechsts 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." 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. Medicines Holy Grail Vaccination is one of the medical worlds 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 worlds children against six devastating diseases (diptheria, 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 2 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 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 World Health Organization. In determining the right dosage, the patients weight and age need to be considered, and the size and even ripeness of the banana would also have to be considered. 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. Which begs the question of 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, but it is generally recognised that the potato is unlikely to be a popular or practical vehicle. The potato can attribute its current popularity to the fact that it is easy to engineer. Bananas are being eyed up 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 (ie 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 at 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 dont grow very well when they are producing large amounts of foreign protein. The GM potatoes used in Cornells 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 option. 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, todays 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 WHO, to immunise a child it 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 dont 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 communitys 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). 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 2000. 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, the parameters considered in determining a products "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(see table on p 10), 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. 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 hosts 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 cells 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 University of Cornells Charles Arntzen, who first 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 ten 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 diptheria, 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." Select patents on edible vaccine technologies PATENT HOLDER CLAIM Ribozyme-Pharm Nucleic acid vaccine used to treat or prevent viral infections in plants, animals or bacteria Found. Advan. Mil. Med. (USA) Antibacterial vaccine expressed in plant cells, particularly useful against shigellosis University Loma Linda Gene constructs used to produce edible vaccines to treat autoimmune diseases, including diabetes and multiple sclerosis Rubicon-Lab Retrovirus expressed in animal or plant cells useful as virus and cancer vaccine Biosource (now Large Scale Biology) Plant viral vector with potential as anti-AIDS vaccine; recombinant proteins for use in vaccines to protect against parasitic infection, eg malaria Applied Phytologics Gene constructs for disease resistance, vaccine production in rice, barley, wheat, corn University of Texas Hepatitis B virus core antigen recombinant vaccine University of Yale Vaccine against invertebrates (insects, arachnids, helminths, etc) Biocem; Rhone-Merieux Rabies vaccine in transgenic plants Institute Pasteur Attenuated E Coli vaccine for use in gene therapy University of Texas A&M/Tulane University Transgenic plants containing E Coli enterotoxin B for edible vaccine application in animals USDA/Univ. Philadelphia Rabies vaccine expressed in tomato plant Cornell University Increasing foreign protein expression Scripps Research Institute Recombinant antigen production in lettuce, spinach, tobacco, kidney bean, or Chenopodium amaranticolor Prodigene Recombinant antigen production and transfer to plants cells using plasmid vector system; Transmissible Gastroenteritis Virus in tomato and potato; broad patent for edible vaccine technology in all plants Mycogen/Washington Univ. Series of broad patents covering plant-based edible vaccine tech. Agr. Genet/ Purdue Research Foundation Modified viruses used for vaccine production in plants, esp. against food and mouth disease, HIV and human rhino virus Source: Compiled by GRAIN from Derwent Technology Abstracts, October 2000 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 UNICEF and the WHO. In terms of the potential fof edible vaccines, the WHO is cautiously optimistic. According to the WHOs Uli Fruth, "WHO is very interested in technologies which (a) may render vaccines more affordable for use in developing countries, (b) which 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." WHO is not investing heavily in edible vaccine research, but has provided some seed-funding (Arntzens work on edible vaccines at Cornell) to help establish proof of principle. Fruth acknowledges that before endorsing such vaccines for human use, WHOs concerns related to quality assurance, efficacy and environmental impact will need to be addressed in a satisfactory fashion. But if the WHOs position on GM foods is anything to go by, its approach to safety issues is unlikely to 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 throw out 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 breath a big sigh of relief (at least for now), given the serious risks that edible vaccines pose. As Norways 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 infections 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. Main Sources: WH Langridge (2000), "Edible Vaccines," Scientific American, September 2000. 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), Sowing Diseases, New and Old, Third World Network Online, http://www.twnside.org.sg/title/heal-cn.htm M Hansen (1999), "Genetic Engineering is Not an Extension of Conventional Plant Breeding," Consumer Policy Institute, http://www.consumersunion.org/food/widecpi200.htm Glennerster and M Kremer (2000), "A World Bank Vaccine Commitment," Policy Brief #57, May 2000. World Health Organisation (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. WHO and UNICEF (1996), The State of the Worlds 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/ernaehr/art3.html A Pollack (2000), "Ventures Aim to Put Farms in Pharmaceutical Vanguard," The New York Times, May 14, 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 T Wilkins (1999), "Edible Vaccines Ill 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.