Plant-Based Vaccine Manufacturing for Influenza, Implications for Future Vaccines
Currently, the development of vaccines for influenza and other viruses typically relies on egg-based manufacturing. This approach, and the newer technique of vaccine production in cell cultures, carry the risk of mutations that may reduce the efficacy and immunogenicity of the vaccines. Additionally, there are ongoing needs for greater production speed and capacity to enable adequate epidemic and pandemic response.
An emerging body of research highlights plant-based vaccine manufacturing as a potential solution to some of these limitations. In a recent issue of the Lancet, investigators from the Research Institute of the McGill University Health Centre in Montreal, Quebec, and Medicago Inc., a Quebec-based biopharmaceutical company, described results of 2 randomized, observer-blinded phase 3 studies evaluating the efficacy of a recombinant quadrivalent virus-like particle (QVLP) influenza vaccine manufactured in Nicotiana benthamiana, a relative of the common tobacco plant.1 These studies represent the first large trials of any plant-derived human vaccine.
One trial tested the vaccine in adults aged 18-64 years (Clinicaltrials.gov Identifier: NCT03301051), while the other trial consisted of adults aged 65 years and older (Clinicaltrials.gov Identifier: NCT03739112) across North America, Asia, and Europe. Participants from both groups were required to be generally healthy at baseline. The studies were conducted during the 2017-2018 and 2018-2019 influenza seasons, respectively.
In the first trial, 5077 individuals were assigned to the QVLP vaccine group and 5083 were assigned to a placebo group. In the final per-protocol analysis, the groups consisted of 4814 and 4812 participants, respectively. The primary outcome was 70% absolute efficacy of the vaccine to prevent “laboratory-confirmed, respiratory illness caused by antigenically matched influenza strains,” which the study did not meet (35.1%; 95% CI, 17.9%-48.7%). Serious adverse events occurred in 1.1% of the QVLP group and 1.0% of the placebo group; 0.1% of each group experienced severe treatment-related or treatment-emergent adverse events.
In the second trial, 6396 participants were assigned to receive the QVLP vaccine and 6398 were assigned to receive a quadrivalent inactivated vaccine (QIV). The final per-protocol analysis included 5996 and 6026 participants, respectively. The primary outcome was the relative efficacy of the QVLP vaccine against laboratory-confirmed influenza-like illness caused by any strain of influenza, which was met with a relative efficacy of 8.8% (95% CI, -16.7% to 28.7%). Serious adverse events occurred in 4.1% of the QVLP group and 4.2% of the QIV group; 0.1% of each group experienced severe treatment-related or treatment-emergent adverse events.
These results indicate that while the “QVLP vaccine did not meet the success criterion for its primary endpoint in the 18-64 study, [the] vaccine can provide substantial protection against respiratory illness and influenza-like illness,” the authors concluded. Vaccine efficacy estimates are similar to other licensed vaccines on the market. The findings also indicate that the vaccine was well-tolerated, with a favorable safety profile in both studies.
In addition to the influenza vaccine evaluated in these trials, Medicago Inc. recently reported promising phase 1 results of a similar produced vaccine candidate for severe acute respiratory virus coronavirus 2 (SARS-CoV-2). To combat the coronavirus disease 2019 (COVID-19) pandemic, Medicago Inc. stated that their vaccine “induced robust neutralizing antibody and cellular immune responses” after 2 doses, as stated in a press release.2 “The Coronavirus-Like Particle COVID-19 vaccine candidate (CoVLP) is composed of recombinant spike (S) glycoprotein expressed as virus-like particles (VLPs).” The company is now conducting phase 2/3 trials of CoVLP using GlaxoSmithKline’s proprietary pandemic adjuvant and plans to submit results for regulatory review in 2021.3,4
To learn more about plant-derived vaccine manufacturing, we interviewed Ed Rybicki, PhD, professor and director of the Biopharming Research Unit in the Department of Molecular and Cell Biology at the University of Cape Town in South Africa. His team has been investigating these technologies for nearly 2 decades.
What does plant-based manufacturing of vaccines involve, and what are some of the benefits of this method?
Dr Rybicki: This is a big subject, but basically it involves using plants (usually N benthamiana) to produce the essential proteins needed in a subunit vaccine. This is done either by making the plants transgenic with a foreign gene inserted into the genome or – much more often lately – by using a bacterium called Agrobacterium tumefaciens to transfer recombinant DNA encoding gene(s) of interest into normal plants for transient expression.
The advantage of this technique is that one can go from having a gene sequence – for example, SARS-CoV-2 S protein – to having lots of protein in the time it takes to synthesize a gene, clone it into Agro, grow up a small volume of Agro, and use it to put the gene into a large number of plants (which could be kept as standby biomass, as they’re cheap to grow) to give you protein a week or so later. Medicago Inc. did this for SARS-2 S in 20 days or so.
Benefits include the most rapid scale-up time for any production method, very rapid preparation of cloned DNA to do it with, and far cheaper upstream costs compared to any of the stainless steel fermentation methods. So, this is a good pandemic response technology!
What is the significance of the current findings by Ward, et al?
Dr Rybicki: The findings suggest that a plant-made candidate 4-valent seasonal influenza vaccine is at least equivalent to conventional egg-made vaccine, and quite possibly better in terms of eliciting cellular responses because of its nature as virus-like particles instead of subunit proteins. There are no viable VLP-based flu vaccines available that are made in any other way. The clinical trial results established the Medicago flu vaccine candidate as a viable alternative to conventional offerings, and moreover, one that can be very quickly tailored to account for changes in circulating influenza virus strains, unlike egg production which involves a 6-month turnaround.
What are the potential implications of this technology for future vaccine manufacturing?
Dr Rybicki: The potential implications are that subunit vaccines, including for hepatitis B as well as papillomaviruses, which we have worked on here (HPV), may be more cheaply and conveniently produced in plants because proofs of concept already done. In addition, the flexible scaling of production volume may be a significant benefit in pandemic and epidemic response compared to conventional manufacturing methods. Plant-based vaccine manufacturing could possibly expand the range of candidate human and animal vaccines available and to enhance the rapid response capability.
Disclosure: Ed Rybicki, PhD declared affiliations with Medicago Inc.
1. Ward BJ, Makarkov A, Séguin A, et al. 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. Lancet. 2020;396(10261):1491-1503. doi:10.1016/S0140-6736(20)32014-6
2. Medicago. Press release: Medicago announces positive phase 1 results for its COVID-19 vaccine candidate. Published online November 10, 2020. Accessed online January 4, 2021.
3. Medicago. Press release: Medicago and GSK announce start of phase 2/3 clinical trials of adjuvanted COVID-19 vaccine candidate. Published online November 12, 2020. Accessed online January 4, 2021.
4. Medicago. Medicago’s development programs: COVID-19. Accessed online January 4, 2021.
Additional Suggested Reading
1. Rybicki EP. Plant molecular farming of virus-like nanoparticles as vaccines and reagents. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2020;12(2):e1587. doi:10.1002/wnan.1587
2. Rybicki E. Plant-made vaccines and reagents for SARS-CoV-2 in South Africa. ViroBlogy. Accessed online January 4, 2021.
3. Rosales-Mendoza S, Márquez-Escobar VA, González-Ortega O, Nieto-Gómez R, Arévalo-Villalobos JI. What does plant-based vaccine technology offer to the fight against COVID-19? Vaccines (Basel). 2020;8(2):183. doi:10.3390/vaccines8020183
4. Rockman S, Laurie KL, Parkes S, Wheatley A, Barr IG. New technologies for influenza vaccines. Microorganisms. 2020;8(11):1745. doi:10.3390/microorganisms8111745
5. Dhama K, Natesan S, Iqbal Yatoo M, et al. Plant-based vaccines and antibodies to combat COVID-19: current status and prospects. Hum Vaccin Immunother. 2020;16(12):2913-2920. doi:10.1080/21645515.2020.1842034
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