Covifenz is a vaccine indicated for the active immunization of persons aged 18–64 years to prevent COVID-19 infection caused by the SARS-CoV-2 coronavirus.
Covifenz, which is a recombinant adjuvant vaccine made from coronavirus virus-like particles (CoVLP), is the first of its kind because it is produced by plant cells.
Covifenz, developed by Canada’s Medicago, was approved by Health Canada in late February 2022.
- At the end of March 2022, the World Health Organization (WHO) refused to approve Covifens because one of Medicago’s majority shareholders is tobacco giant Philip Morris International. The main medical regulator of the planet takes a tough stance on tobacco smoking and tobacco industry. On the one hand, this is the right decision, because such approval would benefit Philip Morris, which, by continuing to diversify its sources of income, would improve its reputation at the expense of its contribution to public health. On the other hand, if the WHO had certified the vaccine, the Canadian government, which has invested $173 million in Medicago, could have sent a batch of Covifens to COVAX, a worldwide initiative aimed at ensuring equitable access to tests, therapies and vaccines against COVID-19 in low- and middle-income countries.
The vaccine is administered intramuscularly in a course of two doses, 21 days apart.
The vaccine is stored at 2 to 8 °C, which implies that it is logistically managed using the available cold chain.
Previously, it was thought that the vaccine could be called by other brand names, such as Adcovax, Covixta, or Covimic.
For Canada, which has been batching all Covifenz-related preclinical and clinical data for early regulatory approval since late April 2021, Medicago has promised to prioritize delivery of up to 76 million doses of the finished vaccine.
Medicago’s current production capacity is sufficient to produce up to 80 million doses of Covifenz per year. Once the Quebec production site is completed, which is expected by 2024, volumes will rise to 1 billion doses.
Covifenz: Production Features
The vaccine product developed by Medicago is self-assembled virus-like particles (VLPs) containing trimers of recombinant modified S protein of SARS-CoV-2 and encapsulated in a lipid shell. VLPs present coronavirus antigens to the human immune system, which organizes a protective and sustained response. VLPs mimic the structure of the virus but are not infectious or capable of replication.
Adjuvant System 03 (AS03) by GlaxoSmithKline was chosen as the immunological adjuvant: It was successfully used in the Arepanrix and Pandemrix influenza vaccines used during the A/H1N1 swine flu pandemic. Adjuvant AS03, which enhances immune response and helps reduce antigen dose, consists of alpha-tocopherol (vitamin E), squalene, and polysorbate 80.
The bioreactor for VLPs production is the plant Nicotiana benthamiana (colloquially known as “benth” or “benthi”), a close relative of tobacco and Nicotiana species growing in Australia. A feature of the production strain N. benthamiana is its extremely weakened immune system, a result of natural genetic changes over hundreds of thousands of years. The extremophile plant has lost its defense mechanisms against pathogens, as all of its energy has been directed toward rapid germination and flowering to ensure survival in the extreme habitat of central Australia, even after little rainfall. Thanks to a loss-of-function mutation in the Rdr1 gene encoding RNA-dependent RNA polymerase 1, N. benthamiana is highly susceptible to virus infection.
In the proprietary molecular pharming technology Proficia, the genetic sequence of the viral antigen is inserted into the transport DNA of the binary bacterial vector Agrobacterium tumefaciens, which transfers the antigen into the cells of N. benthamiana leaves. For this purpose, plants are immersed in a liquid containing A. tumefaciens and then air is sucked out between N. benthamiana cells using a vacuum so that they absorb this liquid in an accelerated manner, like a sponge. At the end of the “bacterial bath,” the plants are moved to the greenhouse for six to eight days, where they rapidly produce and accumulate large quantities of virus-like particles, which are subsequently extracted from the leaves of the mature plants and purified to produce the final vaccine product.
Covifenz: Efficacy and Safety
The NCT04636697 phase 3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial evaluated the efficacy and safety of Covifenz vaccine developed by Medicago among more than 24,000 adult volunteers.
The overall Medicago’s vaccine efficacy rate was 71,0% (95% CI: 58.7 to 80.0).
Covifenz provided protection against the development of moderate, moderate-to-severe, and severe COVID-19 at 76.5% (95% CI: 50.5 to 90.0), 78.1% (95% CI: 53.9 to 90.5), and 100% (95% CI: −204.4 to NA), respectively.
The vaccine efficacy was 70.9% (95% CI: 57.7 to 80.4) и 76.8% (95% CI: 21.5 to 94.8) in healthy adults younger than 65 years of age and in those with coexisting illnesses.
The corresponding rate for people with baseline seronegative status indicating no previous exposure to COVID-19 was 75.6% (95% CI: 64.2 to 83.7).
The protective efficacy of Covifenz against the development of COVID-19 of any severity caused by the Delta variant of SARS-CoV-2 was demonstrated to be 75.3% (95% CI: 52.8 to 87.9). Against the Gamma variant, 88.6% (95% CI: 74.6 to 95.6).
The study reported a small number of severe COVID-19 cases developing after vaccination, and only in the placebo group. No cases of COVID-19 infection caused by variant Alpha, Lambda, or Mu were noted in the vaccinated group; there were 12 in the placebo group. The Omicron variant was not yet circulating at the time of the study.
Covifenz vaccine was characterized by acceptable tolerability: Severe local adverse events in response to its second dose were registered in 2.1% of the subjects. In general, Reactogenicity was mild-to-moderate and transient, with symptoms lasting one to three days. The most common systemic adverse events included headache, myalgia, fatigue, feeling of general discomfort.
Up-to-date scientific information about the new Omicron variant of SARS-CoV-2/COVID-19.
With many variants of SARS-CoV-2 now circulating, developing vaccines have a harder time demonstrating their own efficacy than first-wave vaccines. So protection of 71% against all variants looks good.
Again, a 75% efficacy against the Delta variant, previously dominated the entire world, is quite acceptable.
- By the way, the actual effectiveness against the Delta variant of coronavirus of such vaccines as Comirnaty, Spikevax and Vaxzevria/Covishield, developed by Pfizer/Biontech, Moderna, and AstraZeneca, respectively, are approximately 39–93%, 76–87%, and 60–67%. For the Johnson & Johnson vaccine, this figure is 78%.
It is encouraging that no cases of severe COVID-19 or hospitalization were reported in the vaccine group, while three and two were reported in the placebo group, respectively.
Medicago’s key problem is its limited production capacity. This is understandable: No one knew that the vaccine would be acceptably effective, so the plan was not to build a large production facility in advance.
The role of Medicago’s vaccine in the fight against the COVID-19 pandemic is still unclear, but its success is a remarkable milestone for the company itself in terms of the validation of vaccine technology built around plants.
As demand for booster vaccines (third and subsequent shots) grows in advanced economies, Medicago intends to test its vaccine in this application.
In 2013, Japan’s Mitsubishi Tanabe Pharma acquired 60% of Medicago, later increased to 79%, with the remaining 21% owned by tobacco giant Philip Morris International.
Mitsubishi Tanabe believes that Medicago’s vaccine, codenamed MT-2766, will take its rightful place in the anti-COVID-19 armamentarium, as global demand for vaccines will remain decently high for a long time to come. There is great uncertainty about the emergence of new variants of the coronavirus, which could prove highly infectious and very deadly. The advantage of Covifenz is that its production (including repurposing for new variants of SARS-CoV-2) is relatively cheap and done in a short time, and storage and transportation do not require deep freezing.
- Airfinity estimates that the cost of a single dose of Medicago’s vaccine will not exceed $10.
Mitsubishi Tanabe hopes to apply to the Japanese regulator for approval of MT-2766 in March 2022, a phase 1/2 clinical trial NCT05065619 has been organized for this purpose.
It should be understood that a newcomer like Medicago will have a hard time convincing the public, which apparently tends to have more confidence in vaccines of well-known brands. Medicago still has a lot of work to do to stabilize the production process for the mass release of the vaccine product.
Covifenz. Prescribing information. Canada. [PDF]
Efficacy and safety of a recombinant plant-based adjuvanted Covid-19 vaccine. N Engl J Med. 2022 Jun 2;386(22):2084-2096. [source]