Several other antigens have been expressed through different methodologies to
the purpose of manufacturing (nonedible) candidate vaccines intended for clinical
(Tables 3 and 4) and veterinary use (Table 5). Plant-made antigens targeting various
pathogens have been shown to be effective in animal models (Table 3). Many of
these candidates have reached phases I–II human clinical trials (Table 4). Safety of
these vaccines was demonstrated; nevertheless, at present, there are no plant-made
vaccine antigens approved for clinical use.
Despite this, plant-based expression platforms demonstrated to be able to tackle
important sanitary problems even in emergency contexts. As already explained,
in emergency, the transient methods assure the shortest leading times to the final
products. That’s why the major examples of plant-made vaccines in clinical trial are
from transient approaches (Table 4). As an example, influenza virus, a very complex
pathogen with 16 different hemagglutinin (HA) subtypes and characterized by
occurrence of antigenic shift abolishing cross-protective immunity of the host even
against strains of the same subtype, has the potential to be pandemic as happened in
2009 for the H1N1-type influenza virus. To control its diffusion by vaccination, fast
production of a new HA antigen was needed. Medicago Inc. was able to develop a
technology obtaining the accumulation of HA virus-like particles (virus-like particles, VLPs) in the apoplast of N. benthamiana cells by transient expression (D'Aoust
et al. 2010; US patent application number 20130183341). Phase I (5, 10 or 20 μg of
H5-VLP subcutaneously injected twice with alum adjuvant) and II (20, 30 or 45 μg
of H5-VLP) clinical trial of the VLP composed of HA protein of H5N1 influenza
virus (A/Indonesia/5/05) has showed, respectively, the induction of hemagglutinin
inhibition titres at all tested doses and cross-protective CD4+ T-cell responses,
indicating strong induction of long-term cell-mediated immunity by plant-made
H5-VLP after 6 months of vaccination (Landry et al. 2012). No detectable IgE
responses (and, therefore, allergy or hypersensitivity) against plant-specific mannose
residues were found, one of the main issues that are often risen against the production of protein-based pharmaceuticals in plant-based systems (Ward et al. 2014).
Medicago Inc. performed also a phase I clinical trial with 5, 13 or 28 μg of H1N1
influenza (A/California/7/09) VLPs that demonstrated safety and induced immune
response to the virus, including cell-mediated immunity (Landry et al. 2010).
Other plant-based influenza vaccines (HA from A/California/04/2009 H1N1
(HAC1) and A/Indonesia/05/05 H5N1 (HAI-05); Fraunhofer CMB USA) based on
transient expression have successfully completed phase I clinical trial (Shoji et al.
2011, 2015).
Plant-based platforms have been identified also as promising approaches to
tackle chikungunya virus, the emerging pathogen initially found in East Africa and
currently spread in many regions of the world. No licensed vaccines are available,
and thus the need for advancing in this research field is great. Beside the preclinical
stage candidates in trial, also the implementation in parallel of low-cost production
platforms will be determinant as chikungunya is mainly affecting developing
countries where access to vaccines is limited due to the high cost of conventional
formulations. Based on the previous experiences on influenza and other viral
pathogens, plant-made VLPs seem the most efficacious approach to render immunogenic formulations also in this case (Salazar-González et al. 2015).
Engineering Plants for the Future: Farming with Value-Added Harvest
77
the purpose of manufacturing (nonedible) candidate vaccines intended for clinical
(Tables 3 and 4) and veterinary use (Table 5). Plant-made antigens targeting various
pathogens have been shown to be effective in animal models (Table 3). Many of
these candidates have reached phases I–II human clinical trials (Table 4). Safety of
these vaccines was demonstrated; nevertheless, at present, there are no plant-made
vaccine antigens approved for clinical use.
Despite this, plant-based expression platforms demonstrated to be able to tackle
important sanitary problems even in emergency contexts. As already explained,
in emergency, the transient methods assure the shortest leading times to the final
products. That’s why the major examples of plant-made vaccines in clinical trial are
from transient approaches (Table 4). As an example, influenza virus, a very complex
pathogen with 16 different hemagglutinin (HA) subtypes and characterized by
occurrence of antigenic shift abolishing cross-protective immunity of the host even
against strains of the same subtype, has the potential to be pandemic as happened in
2009 for the H1N1-type influenza virus. To control its diffusion by vaccination, fast
production of a new HA antigen was needed. Medicago Inc. was able to develop a
technology obtaining the accumulation of HA virus-like particles (virus-like particles, VLPs) in the apoplast of N. benthamiana cells by transient expression (D'Aoust
et al. 2010; US patent application number 20130183341). Phase I (5, 10 or 20 μg of
H5-VLP subcutaneously injected twice with alum adjuvant) and II (20, 30 or 45 μg
of H5-VLP) clinical trial of the VLP composed of HA protein of H5N1 influenza
virus (A/Indonesia/5/05) has showed, respectively, the induction of hemagglutinin
inhibition titres at all tested doses and cross-protective CD4+ T-cell responses,
indicating strong induction of long-term cell-mediated immunity by plant-made
H5-VLP after 6 months of vaccination (Landry et al. 2012). No detectable IgE
responses (and, therefore, allergy or hypersensitivity) against plant-specific mannose
residues were found, one of the main issues that are often risen against the production of protein-based pharmaceuticals in plant-based systems (Ward et al. 2014).
Medicago Inc. performed also a phase I clinical trial with 5, 13 or 28 μg of H1N1
influenza (A/California/7/09) VLPs that demonstrated safety and induced immune
response to the virus, including cell-mediated immunity (Landry et al. 2010).
Other plant-based influenza vaccines (HA from A/California/04/2009 H1N1
(HAC1) and A/Indonesia/05/05 H5N1 (HAI-05); Fraunhofer CMB USA) based on
transient expression have successfully completed phase I clinical trial (Shoji et al.
2011, 2015).
Plant-based platforms have been identified also as promising approaches to
tackle chikungunya virus, the emerging pathogen initially found in East Africa and
currently spread in many regions of the world. No licensed vaccines are available,
and thus the need for advancing in this research field is great. Beside the preclinical
stage candidates in trial, also the implementation in parallel of low-cost production
platforms will be determinant as chikungunya is mainly affecting developing
countries where access to vaccines is limited due to the high cost of conventional
formulations. Based on the previous experiences on influenza and other viral
pathogens, plant-made VLPs seem the most efficacious approach to render immunogenic formulations also in this case (Salazar-González et al. 2015).
Engineering Plants for the Future: Farming with Value-Added Harvest
77