Kevin O'Donnell10.10.07
Vaccination is one of the medical world's greatest success stories. "Vaccines have accomplished near miracles in the fight against infectious disease."1 Between 1970 and the late 1990's, an international campaign to immunize 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. 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. Another two million die each year from other preventable diseases in a world where another 30 million have no access to immunization at all.2
Even though such campaigns have made incredible strides to rid the world of many insidious diseases, these obstacles still remain: expense, temperature sensitivity, cold storage availability, transportation, delivery by injection and supply.
Researchers throughout the world have actually turned to gardening to overcome these obstacles and believe they have found a solution. If all goes according to plan, edible, temperature-stable vaccines could help to reduce deaths from preventable diseases even in the most remote regions of the world to negligible numbers.
Farming is recognized as the cornerstone of modern human civilization. Now it has found itself entangled with cutting-edge medicine and at the center of a firestorm of controversy as genetically engineered plant research has evolved to producing, among other things, heat-stable vaccines for oral delivery.
The process is frequently referred to as pharming; the genetic engineering (GE) of plants to produce medicines, hormones and vaccines within modified leaves of fruits, vegetables, grains -- even tobacco. Their manufacturing cost is a fraction of most traditional methods. In the case of vaccines, the plants become miniature "bio-reactors" through genetic engineering, wherein a set of genes from human pathogens are introduced into plant cells. The intact plants "bio-manufacture" sub-unit vaccines consisting of the pathogen gene products. Feeding of the plant tissues to animals or humans results in an immune response to the subunit vaccine.3 The National Corn Growers Association estimated that at least 400 plant-based drugs were under development worldwide in 2004.
Professor Julian Ma, Center for Infection, St. George's Hospital, London, UK, is passionate about the benefits of pharming; he insists it could give hope to millions: "The advantages they offer simply cannot be equaled by any other system. They provide the most promising opportunity open to us to supply low-cost drugs and vaccines to the developing world." Other scientists around the world continue research on growing plants with genetic instructions to make antibodies, vaccines against diseases such as rabies, hepatitis B, HIV, non-Hodgkin's lymphoma, heart disease, and tooth decay.
Other researchers do not share Professor Ma's enthusiasm and there are certainly enough detractors, watchdog groups and environmentalists opposed to genetic modified plant propagation -- fearful of the risks to the world's food supply making this a very rough field to hoe. Add to it a generous portion of research expense and regulatory bureaucracy and the hope of edible vaccines seems like an insurmountable reality.
Expense
Traditional vaccines are expensive especially in light of recombinant vaccines, such as those being developed against AIDS and malaria. When such a vaccine against hepatitis B first came to market in the mid 1980's, the cost was roughly $150 a dose. Although the price has come down to only a fraction of its original cost, it is still unaffordable in most developing countries,4 and there is little incentive for large, profit-driven corporations to fund the R&D of vaccines for poor countries. Thus, competition for grants and private funding within academia is fierce, slowing the development of plant-derived vaccines.
Pharmed vaccines can be grown and harvested locally or regionally, some on marginal lands, leaving the more fertile soil for food crops, a distinct advantage for treating people in poorer countries. Pharmed plants exhibit good genetic stability, are cheaper to develop than traditional vaccines requiring little or no purification process, and are easy to scale up. Advocates say that just 250 acres of genetically engineered potato crop could produce enough hepatitis B vaccine to protect the entire population of southeast Asia from the disease for a year.5 Meanwhile, a research team at Arizona State University has modified the vaccine in tomatoes to produce vaccines against hepatitis B and Norwalk virus in guarded greenhouses and produced enough protein for 4,000 doses of vaccine from just 30 tomato plants.6
One of the key drivers to edible vaccines is to reduce costs, and the manufacturing price is only part of the overall spend. According to the World Health Organization (WHO), immunizing a child costs no more than $1 for the big six vaccines but $14 more for program costs such as laboratory expenses, transportation, cold chain, personnel and research. Advocates of GE vaccines insist edible vaccines can drastically reduce these costs.
Temperature Stability
A significant limitation affecting distribution of traditional vaccines is heat-sensitivity. Traditional vaccines must maintain refrigeration. The odds of interrupting cold-chain custody until the vaccine is administered at a patient level are high in remote regions of the world that not only lack refrigeration, but electricity. This has resulted in an enormous logistical challenge and comes at a significant financial cost. Temperature assurance often is not monitored and most compromised vaccines have reduced efficacy and potency. Many are rendered completely ineffective. Vaccine shipments suspected of temperature abuse are frequently discarded.
"It is estimated that worldwide, it costs $200 to $300 million each year to preserve vaccines at cold temperatures," according to Tomonori Nochi, Department of Microbiology and Immunology, Institute of Medical Science at the University of Tokyo, in his presentation, Rice-based Mucosal Vaccine as a Global Strategy for Cold-Chain and Needle-Free Vaccination, delivered at the Proceedings of the National Academy of Sciences, in March, 2007.
Some of the most promising and temperature stable mucosal vaccines against entropic diseases such as Norwalk virus, diarrhea and cholera, are being developed in rice. Dr. Nochi and his team are progressing with genetically engineered rice, citing that it can be stored at room temperature for a long time, which is very important for the development of the vaccine. He went on to say, "The vaccine against cholera expressed in rice remained stable and maintained immunology at room temperature for more than 18 months." Additionally, because they require no refrigeration, cold-chain management, or needles, "rice-based mucosal vaccines offer a highly practical and cost-effective strategy for orally vaccinating large populations against mucosal infections, including those that may result from an act of bioterrorism."
In terms of production and consumption, rice is by far the most important crop in developing countries. In some of the poorest Asian countries rice accounts for 80% of calories consumed.7
Needle-free Delivery
The WHO has called for new strategies to deliver vaccines to populations that existing programs have failed to reach either by lack of availability, expertise, or in some countries by social stigma and cultural ignorance.
Injectible vaccines are not only painful, but require skilled personnel to administer them, and needle availability is often a problem. Advocates for edible vaccines say technology is nearing the point where proper dosages prepared in capsules, tablets, powders or paste can be administered orally, eliminating the costs associated with needles, syringes and skilled personnel. It will also eliminate risk of secondary infection from the injection site, preventing pathogens from accidentally appearing in the vaccines, and eliminating the threat of pathogens spreading throughout a population.
Most traditional vaccines, with the exception of polio, must be injected. Oral polio vaccine, although no longer used in the U.S., is nearly 100% effective because even the weakened version of the virus in the vaccine survives long enough in the stomach to trigger the immune system.
It's no coincidence that polio has been virtually eradicated as a result of oral delivery. This same philosophy applies to edible vaccines. Although less efficient, antigens in plant-derived vaccines can survive in the stomach and reach the immune system because the tough outer wall of the plant cells protects the cells' contents from pepsin during digestion. When the plant walls break down in the intestines, the cells release their antigenic cargo and initiate the mucosal response. The systemic response continues as the antigens reach the blood, offering a one-two punch that injectible vaccines do not.
Transportation
Generally, vaccines are shipped to regional hubs around the world by air and are distributed through a varying network by any means available, due to geographical limitations and poor transportation infrastructures common in many emerging countries. Growing edible vaccines regionally is an attractive incentive to many, goes hand-in-hand with the challenges of cold-chain logistics, and drastically reduces the associated costs.
Here is where opponents to edible vaccines are most vocal. Genetic engineering of plants is a complicated and inherently risky business. Although there is a very clear distinction between the genetic mutation of plants (GM) for increased food yield and genetically engineered plants (GE) for pharmaceuticals, there are good arguments to be had on both sides of the issue. Cross-contamination is the biggest concern. When pharming began in earnest a decade ago, the isolation standards practiced were developed in the 1950's. But scientists are now armed with a battery of new technologies to stop cross-contamination of their plants, including growing sterile varieties, using fluorescent seed markers for identifying strays, and genetic tricks to stop foreign genes from appearing in pollen. Others think this is not enough and some want a ban on pharmaceutical plants grown outdoors due to unforeseen side effects. Everyone within the industry agrees however, that such plants should not be grown out of containment and their development should be closely monitored and regulated. These environmental and ecological risks make it questionable whether many countries should be expected to have the facilities, expertise and regulatory safeguards in place to grow the vaccines safely and successfully.
The FDA and USDA have jointly published draft guidance specifically addressing the use of bioengineered plants to produce pharmaceutical products. You can get more information at FDA's food biotechnology website.
Feeding the world to good health is brilliant on a sentimental level. However, genetically modified crops are increasingly controversial, especially in Europe. The lowest vaccine coverage in the world today is in sub-Saharan Africa, an area that depends on agricultural export to Europe. Fears of crop contamination with GM maize, for example, has led some governments to reject foreign food aid offers or demand that the food be milled, to eliminate seed use.
When such a drug does arrive, it will likely be in North America where opposition to GM technology is milder and transgenetic crops such as maize and cotton are already grown on a massive scale. The acceptance of GE vaccines and other medicines will eventually play out in the global court of public opinion. People opposed to GM crops for food would be much more likely to accept them as medicines because the benefits to society are more clearly defined and readily understood.
References
Langridge, W. H., "Edible Vaccines" Scientific American, September, 2000.
State of the World's Vaccines and Immunization, WHO and UNICEF 1996.
Arntzen, C. J., Ph.D., Arizona State University, meeting of the American Society of Plant Biologists, 24 July, 2004.
Eat Up Your Vaccines, The Seedling, Quarterly Newsletter of Genetic Resource Action International, December 2000.
Adam, D., Pharmaceutical Pharming, The Guardian, April 30, 2007.
Tenenbaum, D., The Why Files, University of Wisconsin -- Madison, Nov., 2002
International Food Information Council, Food Biotechnology -- Benefits for Developing Countries, "Food Insight" Jan/Feb 1999
Kevin O'Donnell is director and chief technical advisor to industry at Tegrant Corp., ThermoSafe Brands.
Even though such campaigns have made incredible strides to rid the world of many insidious diseases, these obstacles still remain: expense, temperature sensitivity, cold storage availability, transportation, delivery by injection and supply.
Researchers throughout the world have actually turned to gardening to overcome these obstacles and believe they have found a solution. If all goes according to plan, edible, temperature-stable vaccines could help to reduce deaths from preventable diseases even in the most remote regions of the world to negligible numbers.
Farming is recognized as the cornerstone of modern human civilization. Now it has found itself entangled with cutting-edge medicine and at the center of a firestorm of controversy as genetically engineered plant research has evolved to producing, among other things, heat-stable vaccines for oral delivery.
The process is frequently referred to as pharming; the genetic engineering (GE) of plants to produce medicines, hormones and vaccines within modified leaves of fruits, vegetables, grains -- even tobacco. Their manufacturing cost is a fraction of most traditional methods. In the case of vaccines, the plants become miniature "bio-reactors" through genetic engineering, wherein a set of genes from human pathogens are introduced into plant cells. The intact plants "bio-manufacture" sub-unit vaccines consisting of the pathogen gene products. Feeding of the plant tissues to animals or humans results in an immune response to the subunit vaccine.3 The National Corn Growers Association estimated that at least 400 plant-based drugs were under development worldwide in 2004.
Professor Julian Ma, Center for Infection, St. George's Hospital, London, UK, is passionate about the benefits of pharming; he insists it could give hope to millions: "The advantages they offer simply cannot be equaled by any other system. They provide the most promising opportunity open to us to supply low-cost drugs and vaccines to the developing world." Other scientists around the world continue research on growing plants with genetic instructions to make antibodies, vaccines against diseases such as rabies, hepatitis B, HIV, non-Hodgkin's lymphoma, heart disease, and tooth decay.
Other researchers do not share Professor Ma's enthusiasm and there are certainly enough detractors, watchdog groups and environmentalists opposed to genetic modified plant propagation -- fearful of the risks to the world's food supply making this a very rough field to hoe. Add to it a generous portion of research expense and regulatory bureaucracy and the hope of edible vaccines seems like an insurmountable reality.
Overcoming the Obstacles
Expense
Traditional vaccines are expensive especially in light of recombinant vaccines, such as those being developed against AIDS and malaria. When such a vaccine against hepatitis B first came to market in the mid 1980's, the cost was roughly $150 a dose. Although the price has come down to only a fraction of its original cost, it is still unaffordable in most developing countries,4 and there is little incentive for large, profit-driven corporations to fund the R&D of vaccines for poor countries. Thus, competition for grants and private funding within academia is fierce, slowing the development of plant-derived vaccines.
Pharmed vaccines can be grown and harvested locally or regionally, some on marginal lands, leaving the more fertile soil for food crops, a distinct advantage for treating people in poorer countries. Pharmed plants exhibit good genetic stability, are cheaper to develop than traditional vaccines requiring little or no purification process, and are easy to scale up. Advocates say that just 250 acres of genetically engineered potato crop could produce enough hepatitis B vaccine to protect the entire population of southeast Asia from the disease for a year.5 Meanwhile, a research team at Arizona State University has modified the vaccine in tomatoes to produce vaccines against hepatitis B and Norwalk virus in guarded greenhouses and produced enough protein for 4,000 doses of vaccine from just 30 tomato plants.6
One of the key drivers to edible vaccines is to reduce costs, and the manufacturing price is only part of the overall spend. According to the World Health Organization (WHO), immunizing a child costs no more than $1 for the big six vaccines but $14 more for program costs such as laboratory expenses, transportation, cold chain, personnel and research. Advocates of GE vaccines insist edible vaccines can drastically reduce these costs.
Temperature Stability
A significant limitation affecting distribution of traditional vaccines is heat-sensitivity. Traditional vaccines must maintain refrigeration. The odds of interrupting cold-chain custody until the vaccine is administered at a patient level are high in remote regions of the world that not only lack refrigeration, but electricity. This has resulted in an enormous logistical challenge and comes at a significant financial cost. Temperature assurance often is not monitored and most compromised vaccines have reduced efficacy and potency. Many are rendered completely ineffective. Vaccine shipments suspected of temperature abuse are frequently discarded.
"It is estimated that worldwide, it costs $200 to $300 million each year to preserve vaccines at cold temperatures," according to Tomonori Nochi, Department of Microbiology and Immunology, Institute of Medical Science at the University of Tokyo, in his presentation, Rice-based Mucosal Vaccine as a Global Strategy for Cold-Chain and Needle-Free Vaccination, delivered at the Proceedings of the National Academy of Sciences, in March, 2007.
Some of the most promising and temperature stable mucosal vaccines against entropic diseases such as Norwalk virus, diarrhea and cholera, are being developed in rice. Dr. Nochi and his team are progressing with genetically engineered rice, citing that it can be stored at room temperature for a long time, which is very important for the development of the vaccine. He went on to say, "The vaccine against cholera expressed in rice remained stable and maintained immunology at room temperature for more than 18 months." Additionally, because they require no refrigeration, cold-chain management, or needles, "rice-based mucosal vaccines offer a highly practical and cost-effective strategy for orally vaccinating large populations against mucosal infections, including those that may result from an act of bioterrorism."
In terms of production and consumption, rice is by far the most important crop in developing countries. In some of the poorest Asian countries rice accounts for 80% of calories consumed.7
Needle-free Delivery
The WHO has called for new strategies to deliver vaccines to populations that existing programs have failed to reach either by lack of availability, expertise, or in some countries by social stigma and cultural ignorance.
Injectible vaccines are not only painful, but require skilled personnel to administer them, and needle availability is often a problem. Advocates for edible vaccines say technology is nearing the point where proper dosages prepared in capsules, tablets, powders or paste can be administered orally, eliminating the costs associated with needles, syringes and skilled personnel. It will also eliminate risk of secondary infection from the injection site, preventing pathogens from accidentally appearing in the vaccines, and eliminating the threat of pathogens spreading throughout a population.
Most traditional vaccines, with the exception of polio, must be injected. Oral polio vaccine, although no longer used in the U.S., is nearly 100% effective because even the weakened version of the virus in the vaccine survives long enough in the stomach to trigger the immune system.
It's no coincidence that polio has been virtually eradicated as a result of oral delivery. This same philosophy applies to edible vaccines. Although less efficient, antigens in plant-derived vaccines can survive in the stomach and reach the immune system because the tough outer wall of the plant cells protects the cells' contents from pepsin during digestion. When the plant walls break down in the intestines, the cells release their antigenic cargo and initiate the mucosal response. The systemic response continues as the antigens reach the blood, offering a one-two punch that injectible vaccines do not.
Transportation
Generally, vaccines are shipped to regional hubs around the world by air and are distributed through a varying network by any means available, due to geographical limitations and poor transportation infrastructures common in many emerging countries. Growing edible vaccines regionally is an attractive incentive to many, goes hand-in-hand with the challenges of cold-chain logistics, and drastically reduces the associated costs.
Here is where opponents to edible vaccines are most vocal. Genetic engineering of plants is a complicated and inherently risky business. Although there is a very clear distinction between the genetic mutation of plants (GM) for increased food yield and genetically engineered plants (GE) for pharmaceuticals, there are good arguments to be had on both sides of the issue. Cross-contamination is the biggest concern. When pharming began in earnest a decade ago, the isolation standards practiced were developed in the 1950's. But scientists are now armed with a battery of new technologies to stop cross-contamination of their plants, including growing sterile varieties, using fluorescent seed markers for identifying strays, and genetic tricks to stop foreign genes from appearing in pollen. Others think this is not enough and some want a ban on pharmaceutical plants grown outdoors due to unforeseen side effects. Everyone within the industry agrees however, that such plants should not be grown out of containment and their development should be closely monitored and regulated. These environmental and ecological risks make it questionable whether many countries should be expected to have the facilities, expertise and regulatory safeguards in place to grow the vaccines safely and successfully.
The FDA and USDA have jointly published draft guidance specifically addressing the use of bioengineered plants to produce pharmaceutical products. You can get more information at FDA's food biotechnology website.
Hype or Hope?
Feeding the world to good health is brilliant on a sentimental level. However, genetically modified crops are increasingly controversial, especially in Europe. The lowest vaccine coverage in the world today is in sub-Saharan Africa, an area that depends on agricultural export to Europe. Fears of crop contamination with GM maize, for example, has led some governments to reject foreign food aid offers or demand that the food be milled, to eliminate seed use.
When such a drug does arrive, it will likely be in North America where opposition to GM technology is milder and transgenetic crops such as maize and cotton are already grown on a massive scale. The acceptance of GE vaccines and other medicines will eventually play out in the global court of public opinion. People opposed to GM crops for food would be much more likely to accept them as medicines because the benefits to society are more clearly defined and readily understood.
References