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This is now an archive page.- Recent Developments in edible and plant derived vaccines here. and our research into PMP vaccine trial status here


{ with special thanks to Charles J. Arntzen, the global expert on edible vaccines }

This link takes you to Time magazine's 2002 nomination of Dr Arntzen for his plant derived vaccine

Plant-derived Vaccines: A new approach to international public health
by Charles J. Arntzen and Richard T. Mahoney, The Arizona Biomedical Institute, Arizona State University, Tempe, AZ

Current situation for production of vaccines

Jenner inoculated children with pus from scabs of cows that were infected with cow pox. Pasteur initially vaccinated children against rabies using an attenuated, inactivated virus obtained from the spinal cord of rabbits. Other vaccines have been developed using organisms or cell lines including poxvirus, Chinese hamster ovary cells, other mammalian cells, adenovirus, vaccinia virus, baculovirus, insect cells, E. coli, and Salmonella.

With the advent of modern molecular biology techniques in the 1980s, new strategies were developed for the production of subunit vaccines. These are vaccines comprised of proteins derived from pathogenic viruses, bacteria or parasites; in general the proteins are produced not by the pathogens themselves, but by expression of the gene encoding the protein in a “surrogate organism.” For example, Valenzuela, Rutter and their collaborators decided to use yeast – an organism used in food and beverage production – to produce the Hepatitis B surface Antigen (HBsAg) which is now used in almost all commercial Hepatitis B vaccines. In the last decade we have learned that green plants also be used as the “surrogate production organism” to produce antigens of human pathogens (including HBsAg), and that these proteins can elicit priming and boosting immune response in humans when given orally. In addition, unlike almost all other cell lines used for production of vaccines, components of plant cells have always been an important part of the normal human diet. Plants, therefore, offer significant new opportunities for making safe and effective oral vaccines. The following discussion will address issues relating to the commercial development of plant-derived vaccines, and especially their usefulness in preventing infectious diseases in poor populations of developing countries.


Critical needs for Vaccine Development

The development and introduction of new vaccines for the poor in developing countries faces many challenges. The vaccines must address the need for lower costs, oral-activity, heat stability, and mucosal effectiveness, and they must include combination vaccines and those that protect against diseases that occur predominantly in developing countries.

Lower Costs: The costs of future human vaccines are projected to be considerably higher than current vaccine production costs. Several factors drive the projections

Regulatory hurdles in developed countries, particularly for construction of production facilities and for final quality control, have increased dramatically in recent years. Almost all new vaccines are first produced in these developed countries, requiring that the vaccine candidates be tested in the countries of origin according to their high regulatory standards. (Developing a candidate vaccine first in a developing country is a new strategy being pursued in a few cases.)

Largely because of the dramatically increased costs of meeting the regulatory hurdles, intellectual property rights have taken on crucial importance. Many new vaccines are produced with proprietary methodologies and patent holders vigorously prosecute their rights or conceal know-how because of its inherent intellectual property value.

In large multinational pharmaceutical companies, vaccines must compete for R&D resources against other products with high profit potential such as those against heart disease and cancer. Thus, when these vaccines enter the market they must generate comparable return on investment.

This combination of factors and the resulting higher costs of new vaccines have caused great concern about the potential availability of these vaccines to the poor. Traditionally, governments and international and national assistance agencies have had to pay only pennies per dose for vaccines. New vaccines, such as that against Haemophilus influenzae type b, cost $2 or more per dose or about 10- to 20-fold greater.

Oral Activity: Orally-active vaccines are sought because they obviate the need for injection equipment with the associated costs and risks of unsafe injection. The procurement, distribution, use and disposal of syringes and needles present continuing impediments to the delivery of vaccines. Of great concern is the high risk of unsafe injection caused by re-use, poor sterilization, and misuse. Oral activity is also important because it permits vaccines to be delivered by a wider range of service providers, and requires production and formulation regulations that may be less rigorous than those governing injected products.

Heat Stability: Heat stability is prized because it reduces the need for expensive cold-chain systems. Maintenance of the cold chain and extending its reach to remote areas are proving to be daunting challenges for ensuring continued high levels of coverage for existing and new vaccines.

Mucosal Effectiveness: Mucosal effectiveness is important because it is seen as the most powerful means to prevent diseases that are caused by infections at the mucosal membranes.

Combination Vaccines: Combinations are highly valued because they reduce the need for multiple injections or administrations. The early operation of the Global Fund for Children’s Vaccines through GAVI (the Global Alliance for Vaccines and Immunization) has shown that developing countries accord very high priority to combination vaccines.

Diseases Occurring Predominantly in Developing Countries: Most modern vaccine research relies extensively on collaboration with large pharmaceutical firms or biotechnology companies in developed countries. As a result, priority setting is invariably affected by the companies’ need to serve their markets and has led to a neglect of several important diseases that affect people in developing countries.

With the exception of combination vaccines, there has been little progress in addressing the challenges listed above. Cost of production continues to increase. Little research is underway to prepare orally active vaccines. GAVI has identified the use of sugar-glass technologies to improve heat stability of existing vaccines, but this technology can only increase the cost of the vaccine. Numerous combination vaccines are under development but they represent no savings and, in some cases, the cost of the combined vaccine is more than the sum or the cost of the separate vaccines. Although some research is being conducted on mucosal delivery of vaccines, most of the work is at an elementary level.

There is now the possibility of a new and novel approach – the production of vaccines using plants –, which the public sector can employ to address these challenges, particularly the need to develop vaccines for the poor in developing countries.

Research conducted over the last decade, including three human clinical trials, has validated the concept of using genetically-engineered plants to produce oral vaccines that induce immune responses when the plant samples are eaten. The new strategy for making vaccines uses a technology derived from agricultural research involving straightforward genetic modification, a technology that holds great promise for producing inexpensive vaccines for human beings.

Scientific background on plant-based vaccines:

Scientific advancements in plant-derived vaccines have occurred over the last decade; they include four major milestones.

· First, insertion of genes encoding antigenic proteins of human pathogens resulted in successful expression and assembly of multi-component structures within plant cells. These structures, which mimic the native immunogens, include "virus-like particles" (VLPs) for the hepatitis B surface antigen (HBsAg), Norwalk virus capsid protein (NV capsid), and oligomeric B subunit of the heat labile enterotoxin of E. coli (LT-B) either by itself or in association with the enzymatically active A subunit to form a holotoxin (LT). (Similar studies have also been completed for cholera toxin - CT.) Other than introduction of the genes encoding the antigens with an appropriate DNA vector modified to optimize gene expression, no further cellular engineering of the plant cells were required to obtain immunogens resembling the native pathogen proteins. Subsequent studies, which are continuing in other laboratories around the world, are verifying these findings for other antigenic proteins from human and animal pathogens.

· Second, oral immunogenicity of HBsAg, LT-B, and NV capsid was demonstrated by feeding plant material expressing these antigens directly to animals as feed. While two of these are from enteric pathogens, which might be anticipated to contain mucosally-active immunogens, hepatitis B is not an enteric pathogen and is usually not thought to invade the body via the gut. The emerging results portend success with different types of antigens through oral immunization, albeit with very significantly higher levels of immunogen than would be required for injection.

· Third, in Phase 1 human clinical trials, LT-B and NV capsid were found to stimulate both humoral and mucosal immune responses (as evidenced by serum and mucosal antibody responses) and HBsAg gave a strong boosting response in volunteers who had previously received the yeast-derived, injected commercial vaccine. Although the immune responses to NV capsid was modest in amplitude, it was achieved with unprocessed plant tissues (raw potato) with no adjuvants, buffers or additives; in all human clinical trials, the immunogens were active simply when the plant sample was eaten.

· Fourth, in unpublished studies, we have found that standard food industry freeze-drying technology can be used for multiple plant tissues (including tomato, potato and carrot) to yield heat-stable, antigen-containing powders. Freeze-dried tomato powder containing NV capsid and LT-B has been found to be immunogenic in pre-clinical trials, and studies of other antigens are underway. Different batch samples can be blended to give uniform doses of antigen and can be stored at room temperature without antigen loss.

A summary of the current status of plant-based vaccines was published on-line ( in TRENDS in Molecular Medicine, 2002, Volume 8: pages 324-329 (authors: Mason, H.S., Warzecha, H., Mor, T., Arntzen, C.J.; Title: Edible plant vaccines: applications for prophylactic and therapeutic molecular medicine). The next major milestone in development of plant-based vaccines will be animal and human clinical trials to show effectiveness of plant-derived vaccines in establishing protective immunity.

Potential to meet the Critical Needs; The Promise of Plant-Derived Vaccines

Low Cost:

· Production of vaccine antigens in plants is highly efficient. For example, enough hepatitis B antigen to vaccine all babies in the world each year could be grown on roughly 200 acres of land and all the HBV vaccine required annually for China could be produced on a 40-acre plot.

· Plant-produced antigens will have a lower “entry barrier” to production because they will not require capital-intensive pharmaceutical manufacturing facilities and the associated high staff expenses. In one example, enough antigen for one dose of hepatitis B vaccine can be produced in unprocessed plant material at a cost of $0.005.

· Plant-derived vaccines may also be cost efficient because development can proceed immediately in developing countries. One of the reasons that new vaccines are not introduced into developing countries soon after they first become available in developed countries is because of the high initial prescription cost. This initial cost is set in order to recoup the high cost of R&D and the expense of the production facility, market development, etc. Developed country producers can afford to offer “marginal cost of production” vaccines only after a large market is established for the vaccine. Since, with plant-derived vaccines, the need to recoup capital investments will be much lower, it will take considerably less time before the vaccine can be sold at a price close to the marginal cost of production. Additionally, the lower entry costs will allow manufacturers in the developing world to participate in new vaccine production.

Oral Activity: All the vaccines produced through plant biotechnology methodology are designed to be orally active, whereas most other new vaccines entering the market (produced in animal or yeast cell fermentation systems) must be injected. Injection results in additional costs and concerns about injection safety outlined above.

Heat Stable: Vaccines produced via plant biotechnology to yield dried plant extracts would not require a sophisticated cold chain. They should be stable at room temperature to the same extent any dried food powder is stable.

Mucosal Immunity: These vaccines stimulate the immune response at the mucosal level and thus would be especially effective against diseases – TB, pneumonia, flu, diarrheal diseases, STDs, HIV, et al. – that infect through the mucosal system.

Multi-antigen combined vaccines: Plant-derived vaccine technology would be applicable to the development of vaccines combining numerous antigens. For example, it could be possible to make a plant producing antigens to stimulate effective immune response to cholera, ETEC, and rotavirus. Alternatively, plant-derived vaccines could be blended prior to packaging for delivery.

Suitable for neglected or rare diseases: As this technology is proven, it will dramatically facilitate the development of vaccines against neglected or rare diseases such as cholera, dengue, hookworm, and rabies.

Another important aspect of the development of vaccines from plants is the opportunity it provides to initiate clinical testing in developing countries. The unfortunate intussusceptions occurrence which accompanied introduction of a new Rotavirus vaccine has led some to believe that it can be counterproductive to initiate in developed countries the clinical testing of vaccines of primary importance for developing countries. Regulatory standards may be formulated in the developed countries that are inappropriate for developing countries. Clinical trials may have to be designed to measure outcomes that are not of high priority in developing countries. As examples, PATH and GAVI have instituted programs for the development of new vaccines against rotavirus and S. pneumoniae with work originating in developing countries.

There has been a significant increase in sophistication about the production and distribution of plant-derived vaccines. In the early years of research, investigators proposed that antigen-bearing fruits or vegetables could be consumed directly. While “immunization-by-eating” is a fascinating prospect, detailed considerations have led to a more refined view of the use of plant-derived vaccines. Regulatory concerns will call for lot-to-lot consistency, uniformity of dosage, and purity, none of which are achievable through immunization-by-eating strategies.

An exciting vision is to use transgenic plants as very low cost, highly-efficient production systems, especially suitable for initial development and production in developing countries, of orally-active antigens that will be prepared for oral administration, controlled to meet appropriate regulatory requirements, and supplied as safe and effective vaccines.

At present, none of the major pharmaceutical companies has a development effort directed to plant-derived vaccines. The reasons relate to:

1] Doubts about the potential for significant return on investment

2] Uncertainties in the regulatory processes for licensure

3] Limited human clinical trial data that establish required dosages, timing of delivery, and evaluation of possible adverse immunological effects.

4] A lack, in pharmaceutical companies, of personnel with needed plant biology research and development expertise.

Therefore, this opportunity to develop vaccine produced using plants represents a classic example in which reliance on market forces to develop needed health products is failing. The public sector and the non-profit sector is needed to provide leadership and investment support to unlock the potential of plant-derived vaccines.

About the authors: Charles Arntzen was appointed to the Florence Ely Nelson Presidential Endowed Chair at Arizona State University in Tempe in 2000. He also serves as the Founding Director of the Arizona Biomedical Institute. Prior to joining ASU, Dr. Arntzen was the president and CEO of the Boyce Thompson Institute for Plant Research in Ithaca, New York. He has served on many national and international committees including service as Chairman of the National Institutes of Health’s Biotechnology Policy Board and as Chair of the Biobased Insdustrial Products Committee for the National Academy of Sciences. He was elected to the US National Academy of Sciences in 1983 and to the National Academy of India the following year. He currently serves as a member of President George W. Bush’s Council of Advisors on Science & Technology.

Richard Mahoney joined the faculty of Arizona State University in 2002, and with Dr. Arntzen is the co-founder of the proVacs (production of Vaccines using Applied Crop Science) Center. He has been an international pioneer in public sector management of intellectual property, and in policy issues related to the global introduction of vaccines. He formerly served as Vice President of PATH (the Program for Appropriate Technology in Health; Seattle, Washington), as chairman of the International Task Force on Hepatitis B Immunization, and as co-founder and Chief Development and Administrative Officer of IVI (the International Vaccine Institute; Seoul, Korea). He has spent the past 15 years focusing on vaccine production and supply issues, and has identified intellectual property as a crucial element in assuring vaccine supply to the developing world. Based upon this experience, he was the architect of recently created Center for Management of Intellectual Property in Health R&D (MIHR) program which is based in London, England.

Their mailing address is: Arizona Biomedical Institute, Arizona State University, PO Box 871601, Tempe, AZ 85287-1601

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