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Plant-Derived Human Vaccines; An Overview



Atousa Aliahmadi, Nasim Rahmani and Mohammad Abdollahi
 
ABSTRACT

Biotechnology has offered important and efficient means for improving human life and health. However in spite of incredible development of biotechnological procedures, there are problems in point of economical view, especially in the case of products which are needed in huge amounts and relate to human health, such as vaccines. Application of biotechnology in such way that eliminates or reduces time-consuming and expensive processes, regarding production and subsequent quality control steps, can help better vaccination programs for large population, especially in the developing countries. The aim of this study was to summarize all data about human plant-based vaccine development including candidate antigens, transgenic plants and corresponding immunological responses in animal models or human using complete literature bibliography. The conclusion is that viral vaccines have been studied more than bacterial ones. Crude extracts of transformed plant materials as well as purified recombinant antigens expressed in plants have been found to induce immunological response in some investigations. Most of animal studies have been done with great success. Although few studies have been performed in humans but most of them have lead to hopeful results. Presently none of the commercially available products are produced in plants while most of biotechnology products which are comprised of proteins and possibly DNA-based vaccines are good potential candidates for plant-based production. Continuing investigations on plant-based vaccines is very crucial.

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  How to cite this article:

Atousa Aliahmadi, Nasim Rahmani and Mohammad Abdollahi , 2006. Plant-Derived Human Vaccines; An Overview. International Journal of Pharmacology, 2: 268-279.

DOI: 10.3923/ijp.2006.268.279

URL: https://scialert.net/abstract/?doi=ijp.2006.268.279

INTRODUCTION

Vaccines are administered to humans and animals for induction of their immune response against viruses, bacteria and other types of pathogenic organisms as well as some autoimmune diseases (Carter and Langridge, 2002; Ma and Jevnikar, 1999).

However, manufacturing of vaccines is time-consuming and expensive process yet regardless of being provided from whole microorganism (live, killed or attenuated) or structural subunits like toxins (Streatfield et al., 2002). Parenteral route is the most common vaccine administration.

Many healthy hazardous infective agents (enteric, respiratory and sexually transmitted pathogens) use mucosal epithelium for attachment and penetrating inside the body. Mucosal immunization against infectious disease and for treatment of some autoimmune diseases (e.g., rheumatoid arthritis, inflammatory bowel diseases, Bechet’s disease and lupus erythematosus) has recently attracted much interest (Rezaie et al., 2005; Hadjbabaie et al., 2005; Rigano and Walmsley, 2005). Orally administrated vaccines are effective means for induction of mucosal immunization using IgA response and subsequent mucosal immunologic memory. There are also evidences for arising of humoral (Marquet-Blouin et al., 2003) and cellular immunological reactions via B and T lymphocytes (CD8+ cytotoxic cells and CD4+ helper cells), as well as natural killer (NK) cells (Rigano and Walmsley, 2005; Walmsley and Arntzen, 2003; Holmgren et al., 2003). There are some reports about mucosal adjutants and these necessary components of such vaccines have been developed especially based on native or detoxified bacterial toxins (Holmgren et al., 2003; Lycke, 1997; Pizzia et al., 2001), derivatives or CpG motif-containing DNA (McCluskie et al., 2000).

Oral vaccines have some advantages such as better uptake and higher efficacy (Streatfield et al., 2002). However, of all the vaccines being produced today, only a few are being produced for oral administration (polio, cholera, typhoid and tuberculosis).

Anyway, there are many candidate pathogens which could be subjected for mucosal vaccine development; these include vaccines for intestinal pathogens (e.g., Helicobacter pylori, hepatitis virus and entero-toxigenic E. coli), respiratory pathogens (rhinovirus, influenza and tuberculosis) and genito-urinary sexually transmitted diseases (e.g., HSV, HIV). This list of microbial and viral pathogens is become increasingly larger considering pathogens that are common between animals and humans.

Subunit vaccines and role of biotechnology: Subunit vaccines are purified antigens that have been made especially based on specific proteins of infectious agents by biotechnological tools and administrated parenterally or orally and can induce systemic as well as mucosal immunization (Nemchinov et al., 2000; Lauterslager et al., 2001; Rigano et al., 2006).

Application of recombinant DNA technology has increased both safety and efficacy of biopharmaceuticals but not the cost of industrial production of some products such as subunit vaccines, considering expensive materials and procedures (e.g., purification steps).

According to the report published by the Pharmaceutical Research and Manufactures of America (PhRMA; Washington, DC), vaccines are the largest category of products amongst different biopharmaceutical products which reached clinical trial phase annually, followed by monoclonal antibody-based products (PhRMA, 2002).

The choice of an expression system for the production of recombinant proteins depends on many parameters, regarding technical and economical aspects. As mentioned above, addition of any extraordinary process for purification, refolding, posttranslational modification, long-term storage, scaling up, maintenance of biological activity of the protein, as well as quality control procedures in the production of therapeutic proteins increase the cost of successful and commercial production of a recombinant protein (Macrides, 1996; Datar et al., 1993).

PLANT-BASED PRODUCTS

Amongst living organisms employed for production of recombinant proteins; either with clinical use or not, plant systems have recently attracted much interest as a means for production of purified recombinant proteins especially in exactly or partially folded structure and also as edible products in which express and deliver subunit vaccines.

Molecular farming has been applied for two decades for production of wide range of recombinant proteins. The most important future of plant-based expression systems have been reviewed elsewhere (Streatfield et al., 2002; Faye et al., 2005; Goldstein and Thomas, 2004) and recent advances in genetic engineering have provided the efficient tools for transformation of plants by foreign genes and expression of variety of biofarmaceutics in such a level appropriate for commercial purpose (Rigano and Walmsley, 2005; Schillberg et al., 2005). The first generation of recombinant proteins produced in transgenic plants is now reaching commercial status (Fischer et al., 2004). Research now underway for production of other therapeutic agents including monoclonal antibodies (Verch et al., 1998), antimicrobial agents (Chong et al., 2000), hormones (Barta et al., 1996), blood components (Sijmons et al., 1996) and various interferons (De Zoeten et al., 1989). It should not be forgotten that presently none of the commercially available products are produced in plants while most of biotechnology products which are comprised of proteins and possibly DNA-based vaccines are good potential candidates for plant-based production (Goldstein and Thomas, 2004).

The first clinical trial of an edible plant vaccine which expressed in potatoes was done in 1997 with permission of US Food and Drug Administration (Tacket et al., 1998). In spite of numerous studies that currently underway in field of edible plant vaccines, the majority remain in the phase I/II of clinical trials and a few have been tested on human volunteers (Thanavala et al., 2005; Tacket et al., 2000, 2004; Yusibov et al., 2002; Kapusta et al., 2001). The most important future of clinical trial phases and commercialization of plant vaccines have been reviewed by Kirk and Webb (2005).

The main objective of the present paper is to summarize all investigations about plant vaccines production against human pathogens including bacteria and viruses.

Plants: The variety of plant species have been used for the production of recombinant proteins like alfalfa (Due Santos et al., 2005), potato (Arakawa et al., 1997), tobacco (Ghosh et al., 2002), maize (Chikwamba et al., 2002), arabidopsis (Rigano et al., 2006), corn (Streatfield et al., 2002), tomato (Walmsley et al., 2003), carrot (Bouche et al., 2003), lettuce (Kapusta et al., 2001), cowpea (Durrani et al., 1998), spinach (Karasev et al., 2005) and even unicellular algae such as Chlamydomonas SPP (Sun et al., 2003; Goldschmidt-Clermont, 1991). Fruits (apple, banana, grape, melon, kiwi, peanut), barley, canola, cauliflower, cranberry, cucumber, pea, pepper, raspberry, rice, service berry, soybean, squash, strawberry, sugar beet, sugarcane, sunflower and sweet potato have also been used (Richter and Kipp, 1999). Some of mentioned plants have advantages in regard of easy cultivation and high volume yield, especially in the case of production of proposed plant vaccines for domestic animals. However many human vaccines that should be administered to infants, have to be consumed uncooked for prevention of protein denaturation and must have no toxic materials if applied as edible and unprocessed vaccines (direct ingestion of plant materials). In the case of transformation of tobacco, the expressed protein must be extracted and purified (Koya et al., 2005; Watson et al., 2004; Aziz et al., 2002). Low nicotinic tobacco has been used in some studies (Pogrebnyak et al., 2005). Tobacco has been used in many studies according to ease of transformation and extensive genomic sequence knowledge (Sala et al., 2003). Various parts of plants (leaves, seeds, fruits, root hairs, chloroplasts) can also be used as vehicles for the biomedical products.

Systems: Plant transformation is achieved by two main tools including stable plant transformation (stable integration of desired genes into the plant genome, either nuclear DNA or chloroplast DNA) and transient transformation of plants through infection of plants by modified plant viruses which have a desired gene.

Stable plant transformation: Agrobacterium tumefacience is most frequently studied plant parasite which is used for integration of the gene of interest to nuclear genome. However integration occurs at random chromosomal sites by this mean. Chloroplast can be transformed in stable system. Chloroplast genome is a circular DNA which is present in multiple copies (up to 10000 copies) in plant cells and can accept large and multiple coding sequences as well as nuclear DNA. Furthermore, site-specific integration of genes to chloroplast DNA, the presence of great knowledge about its nucleotide sequence (which ensures proper integration of foreign genes using well known flanking sequences) and the ability of chloroplast for production of correct folded eukaryotic proteins are important futures of stable transformation of plants via integration of genes to chloroplast (Daniell et al., 2002). Beside the higher production of recombinant protein than nuclear system, production and accumulation of the foreign protein in the chloroplast does not significantly affect photosynthetic efficiency (Sala et al., 2003). However, the main limitation for application of chloroplast-based transformation system is that chloroplast DNA transformation still requires optimization in many plant species (Kuroda and Maliga, 2001) expect of tobacco (Koya et al., 2005).

Transient plant transformation: Transient expression systems are used for expression of foreign genes which are not integrated to genomic DNA and cannot pass over the generations. Virus-based systems are frequently used approach and the viral genome is designed in such a way to express the interested gene within coat glycoprotein without any interfering with self assembly properties of virions. Plant viruses having plus-sense, single-stranded RNA as genome have been applied for this purpose (Zhang et al., 2000; Yusibov et al., 1997) with shorter time for cloning of the foreign gene in the viral genome as compared with time required to transform the plant cells, the ease at which antigen production can be scaled up and the wide host range of plant viruses that allow the use of multiple plant species as biofactories (Koprowki and Yusibov, 2001).

BENEFITS OF PLANT-BASED VACCINES

The most important futures of plant-based system for production of vaccine can be listed as follow:

Inexpensive large scale production; cost will be reduced 100-1000 times as compared with that of traditional vaccines (Sala et al., 2003).
Easy storage (heat stability and prevention of contamination by microorganisms except those are produced in tomato and tobacco which should be kept at 4°C and frozen, respectively (Stoger et al., 2002).
Easy processing (use as raw food or dry powder, or partially or completely purified materials) (Sala et al., 2003).
Convenient, easy and safe administration (in oral route) and applicable as parentral (Bouche et al., 2003) or nasal (Tregoning et al., 2005) products when be purified.
Good result in the case of systemic and mucosal immunity induction (Lauterslager et al., 2001; Rigano, 2006).
Localization of expressed protein in desired cellular compartment (e.g., chloroplast) (Koya et al., 2005; Daniell et al., 2001; Tregoning et al., 2003).
A proposed application against bio-terrorism or biological weapons (Sala et al., 2003).
A proposed application for large scale vaccination of domestic animals.

Besides important future of plant-based system for vaccine production listed above two other opportunities can be achieved using such systems:

Formulation of multicomponent vaccines: Another important future of plant-derived vaccine technology is 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, enterotoxigenic E. coli (ETEC) and rotavirus. In the mentioned study, a cDNA which contains cholera toxin (CT) B and A2 subunit coding sequence and rotavirus enterotoxin and enterotoxigenic E. coli fimbrial antigen genes was expressed in potato. Orally immunized mice showed detectable levels of serum and intestinal antibodies against 3 pathogens as well as significant increase in CD4+ lymphocyte numbers in their spleens (YU and Langridge, 2001). In another study, an edible vaccine for hepatitis B and HIV have been designed (Schelkunov et al., 2004).

Easier multiple boosting: Immunization against some infectious agents such as malaria causative agents, hepatitis viruses, HIV and measles virus need a broad immune response that is achieved via multiple boosting of available vaccines (e.g., hepatitis B). However simultaneous administration of DNA vaccines and plant materials expressed measles proteins could arise immune response in mice (Webster et al., 2002). Similar strategy could be achieved to overcome the mentioned problem which could also decrease the risk of blood born agent transmission. The immunization strategy for a plant-derived measles virus (MV) vaccine was optimized and resulted in a significant increase in MV-neutralizing antibodies. An enhanced immune response to a prime-boost vaccination strategy combining a DNA vaccine with orally delivered plant-derived vaccines was demonstrated (Webster et al., 2002).

PLANT-BASED VACCINES INVESTIGATIONS

Production of bacterial and viral plant vaccines have been studied in some investigations. Here almost all of such experiments have been shown in Table 1 and 2. Only vaccines with future application in human have been considered in the present study.

Table 1: Plant-based vaccine investigations for human bacterial pathogens and corresponding immunological responses
*This is the first report of transgenic chloroplasts manufacturing a plant-derived vaccine. ** This is the first report of an orally delivered, subunit, tuberculosis vaccine priming an antigen-specific, Th1 response

Table 2: Plant-based vaccine investigations for human viral pathogens and corresponding immunological responses

CONCLUSIONS

Viral vaccines have been studied more than bacterial ones. Crude extracts of transformed plant materials as well as purified recombinant antigens expressed in plants have been found to induce immunological response in some investigations. Most of animal studies have been done with great success and although few studies have been performed in humans, but most of them have lead to hopeful results. The continuing investigations in plant-based vaccines seems very essential.

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