In a recent article by Defense One, it was reported that Medicago, a biopharmaceutical company headquartered in Quebec City and 40-percent owned by Philip Morris, had produced a COVID-19 vaccine 20 days after receiving the virus’ genetic sequence. While this is a timely and potentially exciting development, a bit of digging reveals a different story.
If their applied approach is equivalent to prior reports from this company, they will have produced a Virus-Like Particle (VLP) from a gene sequence of SARS-CoV-2 (virus causing the COVID-19 disease). Specifically, in all past efforts, the hemagglutinin (HA) DNA sequence of the virus of interest (e.g., seasonal influenza H1N1, avian influenza H5N1, and others) was cloned into a protein-expression plasmid. This construct is then bacterially transferred into hundreds of tobacco plants (leaves, specifically), and plants are incubated for 6 days to allow formation of the VLPs upon their hemagglutinin protein scaffolds. Twenty-five kilograms of tobacco leaves are then harvested and VLPs are purified from these leaves. The purified batch of VLPs would comprise what Medicago touts as their “vaccine”, and if parallel to past efforts, these VLPs in question are possibly composed of SARS-CoV-2 hemagglutinin esterase (HE) protein, which targets entry and virus spread through the mucosa: nevertheless, the specific coding sequence used was not identified.
The reported window of 20 days from acquiring virus genetic sequence to successful purification of VLPs is believable, though DNA acquisition, construct engineering, and bacterial and plant transformations must proceed perfectly. While past publications have shown Medicago is capable of producing hemagglutinin and their cognate VLPs in Nicotiana benthamiana, a close relative of tobacco—their first effort in 2008 did produce H1 and H5 proteins, with the latter used to produce VLPs and immunize mice. But no data have been presented regarding the successful production and purification of COVID-19 VLPs.
Medicago CEO Clark’s statement regarding producing 10 million doses a month is an estimate based on past protein production data and tests evaluating the antigenicity of those VLPs. If 20 micrograms of VLP/protein were sufficient for a single dose, then 10 million doses would require 200 grams of purified VLP. This could be achievable with their procedure. However, one of the major issues with this statement is that it demands the assumption that the produced COVID-19 VLPs would be sufficiently immunogenic, and there is no evidence to support this. Should COVID-19 VLPs not be sufficiently immunogenic, it could take months (or years) to optimize this antigen by engineering its fusion to other immune-targeting proteins and/or the testing of adjuvants that improve the human immune response. Hence, the likelihood of production of a successful vaccine within months—and broad regulatory approvals being granted by then—is slim-to-none.
An article from a different web outlet represents this development more accurately, in the sense that production of any scalable amount of COVID-19 VLPs would make this merely a vaccine candidate: “Production of the VLP is the first step in developing a vaccine for COVID-19 which will now undergo preclinical testing for safety and efficacy. Once this is completed, Medicago expects to discuss with the appropriate health agencies to initiate human trials of the vaccine by summer (July/August) 2020.”
While there are clearly merits and opportunities to the production of vaccine candidates in N. benthamiana, steep safety/regulatory requirements must be overcome by testing through extensive human clinical trials. While the COVID-19 pandemic is an obvious and critical opportunity to develop a vaccine, the seeming attempt to implement the crisis as leverage to accelerate safety and regulatory approvals of a system that has been in development for over a decade should raise concerns. Some messages conveyed in the Defense One article have basis in fact of Medicago’s capabilities—as evidenced by a few publications—but other statements are unfounded by data and hyperbolic, and unfortunately, will lead readers into a false sense of hope that Medicago’s approach will produce an efficacious COVID-19 vaccine. The reality is that they may have produced a candidate immunogen that will require extensive testing and approvals that are most likely impossible to obtain within months to validate as a vaccine. But one thing is for sure: prematurely hyping whatever they produced as a vaccine, doesn’t help anybody.