syn·op·sis

Turning Over a New Leaf in Vaccine Production

Published by

Thomas Nucci

on

in

Vaccines are one of the most valuable innovations in modern medicine, saving an estimated four to five million lives every year (World Health Organization, 2019). Carter et al. (2021) estimate that vaccines could prevent 51 million deaths between 2021 and 2030. However, millions of people around the globe do not have access to vaccines (Figure 1). The solution to global inequality in vaccine distribution could come from an unexpected source: plants.

Figure 1. (a) World map with colours corresponding to World Health Organization (WHO) regions. The percentage of people fully vaccinated against COVID-19 in various lower-middle- and low-income countries (LMICs) is labelled (ranging from 2-55%). (b) Estimate of the deaths averted as a percentage of all deaths due to COVID-19 if the selected countries had the same per capita vaccination rate as the United States. This analysis found that over half of the deaths in LMICs could have been prevented if these countries had access to the same proportion of COVID-19 vaccines as the United States (Gozzi, et al., 2023).

Most vaccines are produced in eggs, animal cell cultures, or yeast (Streatfield and Howard, 2003; Gomez and Robinson, 2018). Compared to conventional vaccine production methods, plant-derived vaccines cost less, are easier to scale up, and are safer; since live pathogens are not used when producing vaccines in plants, there is no risk of a pathogen mutating (Stander, Mbewana and Meyers, 2022). Producing vaccines in plants is also an attractive option for lower-income countries, as plant-derived vaccines are stable in less complex and less expensive storage facilities than conventional vaccines.

Plant-derived vaccines are typically produced by inserting a gene that encodes the production of a target pathogen’s antigen into the plant genome (LeBlanc, Waterhouse and Bally, 2021). The newly inserted gene instructs the plant to produce a desired antigen protein. The protein is then extracted and purified to be used in a vaccine (Figure 2). Edible vaccines, in which a plant expresses a pathogen antigen in tissue that humans can ingest, are also an emerging area of research (Kurup and Thomas, 2020). Plants that produce edible vaccines could be harvested and directly consumed, bypassing the purification process. This would be even cheaper and faster to produce than typical plant-derived vaccines; however, no edible vaccine has been proven feasible.

Figure 2. Steps in creating a plant-derived vaccine. Step 1: a plasmid (DNA segment separate from a chromosome) is extracted from the bacteria Agrobacterium tumefaciens. A restriction enzyme cuts the transfer DNA (T-DNA) region of the plasmid. Step 2: foreign DNA, typically DNA encoding surface antigens of a pathogen, is cut by the same restriction enzyme. Step 3: the foreign DNA is inserted into the T-DNA section of the plasmid, where the endogenous DNA was removed. Step 4: the plasmid is reinserted into A. tumefaciens. Step 5: plant cells are infected with A. tumefaciens, which inserts the modified T-DNA into the chromosome of a host plant cell (this bacteria only infects plants, not humans). Step 6: Plant cells with the modified T-DNA inserted into their chromosomes are grown in culture. Step 7: the plant cells grown in culture mature into fully grown plants, where each cell expresses the gene inserted by A. tumefaciens and produces the surface antigens of a pathogen. The plant is then harvested, and the proteins produced by the T-DNA are purified, extracted, and used to make a vaccine (Girma, et al., 2019).

Ward et al. (2020) conducted the first large-scale study that investigated the efficacy of a plant-derived vaccine in humans. This study included 19,786 participants, half received an influenza vaccine produced in Nicotiana benthamiana (tobacco) plants, while the other half received a placebo. The vaccine was 35.1% effective at preventing influenza infections, showing vaccines manufactured in plants can be safe and efficacious on a large scale. The company that produced this vaccine was Medicago, a Canadian biotechnology company, that also produced a vaccine made in N. benthamiana that is 71% effective at preventing SARS-CoV-2 infections (Duong and Vogel, 2022). This vaccine targets the spike protein on SARS-CoV-2, which binds to the receptor angiotensin-converting enzyme 2, allowing the virus to enter human cells (Maharjan and Choe, 2021). An individual who receives this vaccine would produce antibodies that bind to the SARS-CoV-2 spike protein, neutralizing the ability of the virus to enter human cells. Medicago produced this vaccine less than a month after obtaining the genetic code of SARS-CoV-2, demonstrating the rapid speed at which plant-derived vaccines can be produced. This vaccine was approved by Health Canada, however, the WHO never approved the use of this vaccine since Medicago is partly owned by the tobacco company Philip Morris International. In response to the lack of WHO approval of its COVID-19 vaccine, Medicago was forced to shut down in 2023, after 26 years of operation and several breakthroughs in plant biotechnology (Benvenuto, et al., 2023).

Plant-derived vaccines hold great promise for providing safe, efficacious, and affordable immunizations to people around the world. As an emerging area of development, the regulatory approval process for plant-derived vaccines may be more complex than for traditional vaccines. However, producing vaccines in plants could be a significant step towards ending global vaccine inequality and combating the next global pandemic.

References

Benvenuto, E., Broer, I., D’Aoust, M.-A., Hitzeroth, I., Hundleby, P., Menassa, R., Oksman-Caldentey, K.-M., Peyret, H., Salgueiro, S., Saxena, P., Stander, J., Warzecha, H. and Ma, J., 2023. Plant molecular farming in the wake of the closure of Medicago Inc. Nature Biotechnology, 41(7), pp.893–894. https://doi.org/10.1038/s41587-023-01812-w.

Carter, A., Msemburi, W., Sim, S.Y., A. M. Gaythorpe, K., Lindstrand, A. and Hutubessy, R.C.W., 2021. Modeling the Impact of Vaccination for the Immunization Agenda 2030: Deaths Averted Due to Vaccination Against 14 Pathogens in 194 Countries from 2021-2030. https://doi.org/10.2139/ssrn.3830781.

Duong, D. and Vogel, L., 2022. Why is WHO pushing back on a Health Canada–approved Medicago SARS-CoV-2 vaccine? CMAJ : Canadian Medical Association Journal, 194(13), pp.E504–E505. https://doi.org/10.1503/cmaj.1095992.

Girma, B., Shegu, D., Muluneh, A. and Woldemariyam, F.T., 2019. Vaccine production in transgenic plants for animal and human diseases. [online] eScientific. Available at: https://escientificpublishers.com/vaccine-production-in-transgenic-plants-for-animal-and-human-diseases-AVAS-01-0006 [Accessed 17 March 2024].

Gomez, P.L. and Robinson, J.M., 2018. Vaccine manufacturing. Plotkin’s Vaccines, pp.51-60.e1. https://doi.org/10.1016/B978-0-323-35761-6.00005-5.

Gozzi, N., Chinazzi, M., Dean, N.E., Longini Jr, I.M., Halloran, M.E., Perra, N. and Vespignani, A., 2023. Estimating the impact of COVID-19 vaccine inequities: a modeling study. Nature Communications, 14(1), p.3272. https://doi.org/10.1038/s41467-023-39098-w.

Kurup, V.M. and Thomas, J., 2020. Edible vaccines: Promises and challenges. Molecular Biotechnology, 62(2), pp.79–90. https://doi.org/10.1007/s12033-019-00222-1.

LeBlanc, Z., Waterhouse, P. and Bally, J., 2021. Plant-based vaccines: The way ahead? Viruses, 13(1), p.5. https://doi.org/10.3390/v13010005.

Maharjan, P.M. and Choe, S., 2021. Plant-based COVID-19 vaccines: Current status, design, and development strategies of candidate vaccines. Vaccines, 9(9), p.992. https://doi.org/10.3390/vaccines9090992.

Stander, J., Mbewana, S. and Meyers, A.E., 2022. Plant-derived human vaccines: Recent developments. BioDrugs, 36(5), pp.573–589. https://doi.org/10.1007/s40259-022-00544-8.

Streatfield, S.J. and Howard, J.A., 2003. Plant-based vaccines. International Journal for Parasitology, 33(5), pp.479–493. https://doi.org/10.1016/S0020-7519(03)00052-3.

Ward, B.J., Makarkov, A., Séguin, A., Pillet, S., Trépanier, S., Dhaliwall, J., Libman, M.D., Vesikari, T. and Landry, N., 2020. Efficacy, immunogenicity, and safety of a plant-derived, quadrivalent, virus-like particle influenza vaccine in adults (18–64 years) and older adults (≥65 years): two multicentre, randomised phase 3 trials. The Lancet, [online] 396(10261), pp.1491–1503. https://doi.org/10.1016/S0140-6736(20)32014-6.

World Health Organization, 2019. Immunization. [online] Available at: https://www.who.int/news-room/facts-in-pictures/detail/immunization [Accessed 17 March 2024].

More posts