Here at Berkshire, we’re always excited to learn about the latest developments emerging from the nation’s cleanrooms indeed from contamination-controlled environments across the globe. And as we come across innovative and timely research, we’re committed to keeping you up to speed too. Even when the research involves a material, process, or concept that might – at least on first glance – seem unlikely. In the past, we’ve thrown the spotlight, for instance, on perilous pickles and mycotoxic molds, and whoever would have thought that the new popularity of a prehistoric protein would be so intriguing? And today’s analysis on the work coming out of cleanrooms is no different. So grab a cup of coffee or maybe brew up some tea and settle in for the ride.
Let’s ease into today’s subject with a little free association: what do you think of when we say the word ‘tobacco’? Take a couple of seconds but don’t overthink it. The chances are that you said ‘cigarettes,’ ‘addiction,’ ‘smoke,’ ‘lung cancer’, or similar. In short, the immediate responses we have to the idea of tobacco tend towards the negative. The days when we absorbed the notion of tobacco use as a marker of good taste (remember the ads claiming that most doctors smoke Camels? or the association of Marlboro with rugged masculinity?) are long gone because – hopefully – when we know better, we do better.
But, as with the beans from your morning cup of joe or the leaves steeping in that mug of tea you’re enjoying while reading this, tobacco is actually – at base – a natural product. Despite our association of it with carcinogenic properties, tobacco is just a plant and, if research emerging from Canada and here at home is a measure, it might even be about to redeem its reputation by emerging as a life-saving plant. That is quite a volte face, so let’s dig deeper to uncover what’s inspiring us to this view.
Traditionally used in the Americas as a social, ceremonial, and medicinal plant, ‘tobacco’ is actually an umbrella term for more than 70 species of the genus Nicotiana, family Solanaceae.
And long-time readers of Cleanroom News and Food Contact Surfaces will no doubt spot that this puts tobacco plants in the same family – the nightshades – as eggplants, tomatoes, and peppers, produce we associate more with healthy salads than with cancer-causing addiction. But did you know that all members of the Solanaceae family contain nicotine to some degree? However, it is not tobacco’s addictive compounds that have piqued our interest, but rather its use in engineering what could be the holy grail of the bio-medical field: a vaccine for COVID-19.
According to an article published this month in Massive Science, a media outlet delivering up-to-the-minute research and expertise in multiple fields of science, there are currently ‘close to two hundred coronavirus vaccine candidates in development, 42 of which have entered clinical trials.’(1) But among this bevy of potential vaccines, one stands out as different: it is produced in a plant. Headquartered in Quebec City, Canada, with research facilities also in North Carolina, Medicago is ‘a pioneer of plant-based transient expression and manufacturing, [… and is] ready to disrupt the traditional approach to vaccines and therapeutics.’(2) Indeed, it could could well be in the position of establishing itself as the leading player in the newly emerging plant-based biotechnology field. With its purpose built ‘2300m2 cGMP pilot production facility […] used to prepare material for clinical studies and […] 1300m2 greenhouse that meets strict confinement standards’ the company is focused on the development of plant-based vaccine technology that could not only be leveraged for use in oncology but also for the production of vaccines.(3)
Vaccines from plants?
Let’s take a closer look. As we already know, vaccines work by introducing an antigen which triggers an autoimmune response, thereby creating antibodies to enabling the body to recognize the disease. It sounds simple enough and the actual process for engineering vaccines is also relatively straight-forward. According to data from the Centers for Disease Control and Prevention (CDC), the majority of traditional vaccines are engineered either from the live pathogen which is grown most commonly chicken embryo or fertilized egg cells, or from recombinant proteins which are engineered in bioreactors or in yeast. Once grown, the resulting antigens are released from their growth medium and purified via ultrafiltration and/or separation through chromatography. In the penultimate stage of engineering, an adjuvant is added to enhance the intended subject’s immune response, and stabilizers and contamination control substances such as formaldehyde may also be incorporated. The final mixture is packaged into sterile vials or syringes and safety sealed prior to distribution.
Where Medicago’s approach differs is, as said, in the use of plants as a substitute for animal cells in the role of bioreactors.
What’s more, according to the company, the process actually results in the development of a Virus-like Particle, or VLP, which is ‘a non-infectious particle that mimics the target virus, without the use of any live viruses.’(4) Non-infectious and devoid of live viruses? This certainly seems to be a technology worth exploring but how does it work? Medicago uses Nicotiana benthamiana, a relative of the tobacco plant, as a host for viral genetic material. Interestingly, N. benthamiana is actually an edible member of the genus, although it is not used commercially for food. While we can’t even guess at its flavor, the fact that the plant is edible means it lends itself to use in the formulation of edible vaccines – that is, vaccines which do not rely on delivery via injection or oral intake. According to researcher David P. Clark, inoculation via plant ingestion could be especially useful in countries which lack the necessary infrastructure for the safe distribution of vaccines requiring careful handling and storage.(5) Where a reliable source of electricity for refrigeration is lacking, for instance, plant material expressing antigen proteins can be transported and stored in the same ways as non-medicinal vegetables. Moreover, they also offer a more cost-effective way of achieving wide-scale immunization.
Medicago’s plant-based platform allows for greatly increased flexibility in the production process to pivot with new data. For example, the use of plant hosts increases researchers’ ability to adapt to newly emerging information on annual influenza strains: shorter development times mean that even when initial projections on viral profiles are incorrect, the process can be redirected with minimal delay in production. Why? Again, the Massive Science article offers an explanation: ‘Normally, vaccines take years to progress through development pipelines before they are approved for use. Many of the vaccines we use today were created more than 50 years ago using old technology. It is only in the past 20 years that scientists have begun working to harness the power of plants in order to produce vaccines and other pharmaceutical products – like enzyme replacement therapies, antibodies, proteins, and biosimilar drugs – to treat a variety of diseases.’(6)
So if vaccines take such a long time to develop, why the buzz about Medicago’s VLPs? The answer is simple: while many nations were still grappling with even accepting the reality of COVID-19, Medicago was already working on engineering the VLP. In a press release dated March 12, 2020, the company announced that it had ‘successfully produced a Virus-Like Particle (VLP) of the coronavirus just 20 days after obtaining the SARS-CoV-2 (virus causing the COVID-19 disease) gene.’(7)
And if the 20 day turnaround of source genetic material to final VLP seems unlikely, it’s worth examining Medicago’s past performance. In 2009 the biopharma engineered a vaccine candidate against H1N1 in just 19 days; in 2012 it took just one month to manufacture 10 million doses of an influenza vaccine for the Defense Advanced Research Projects Agency (DARPA); and in 2015 it worked with Biomedical Advanced Research and Development Authority (BARDA) to roll out an anti-Ebola drug in record time. Suffice to say, the company has form. At this stage, the latest projections we have suggest that a possible COVID-19 vaccine is still in Phase 1 clinical trials, although the company expects to move into Phase 2/3 trials this month.
Of course, Canadian Medicago is not the only player in town. On this side of the 45th parallel, Kentucky BioProcessing, Inc. (KBP) is also using tobacco plants to develop specific proteins for use in vaccines and other applications. Operating since 2006, the company moved from the use of traditional greenhouses to a state-of-the-art climate controlled, multi-level indoor growing facility that enables the production of as many as 3 million tobacco plants in a five-week cycle. According to the company’s literature, the tobacco plants have been successfully transformed into ‘“biomanufacturing plants” that have the ideal proportion of leaves and stems for the process-development and protein-production work we do. The plants effectively become manufacturing centers that produce the protein that we extract and purify for pharmaceutical and commercial applications.’(8)
And the rationale for choosing N. benthamiana for generating recombinant proteins remains the same: ‘Using plants to create complex products means the process can be done faster and less expensively compared to traditional methods that involve animals, yeast, bacteria, cold storage requirements and other means. It also results in higher accuracy and confidence in the composition of the final product. This speed and efficacy could be critical for saving lives vulnerable to existing and future health issues.’(9)
But in the flurry to perfect a vaccine, let’s not lose sight of one important fact: although in the time of the pandemic this goal is critical and indeed laudable, it is not wholly altruistic. Whichever biopharma is first across the finish line in bringing a vaccine to an increasingly desperate global population is in a powerful – and immensely profitable – position. And where this opportunity for dominance and potential revenue exists, so too does the temptation to cut corners. And when shortcuts are taken, contamination issues can arise.
Of course, the extant vaccine system is problematic for a section of the population, with those opposed to vaccines on principle sounding more stridently their concerns. According to an article published this month in British journal The Lancet, a report issued by the Centre for Countering Digital Hate (CCDH) ‘noted that 31 million people follow anti-vaccine groups on Facebook, with 17 million people subscribing to similar accounts on YouTube. […] A survey commissioned by the CCDH and released alongside their report found that around one in six British people were unlikely to agree to being vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and a similar proportion had yet to make up their mind.’(10)
And although the means of information distribution are different, this type of concern is not. According to Healthline, a reluctance to vaccinate dates back to the introduction of inoculations themselves: ‘Refusing vaccines started back in the early 1800s when the smallpox vaccine started being used in large numbers. The idea of injecting someone with a part of a cowpox blister to protect them from smallpox faced a lot of criticism. The criticism was based on sanitary, religious, and political objections. Some clergy believed that the vaccine went against their religion.(11) Contemporary hesitations seem centered on a wariness of the biopharmaceutical industry, political partisanship, and a generalized mistrust of science.
That aside, the modern history of vaccine is nonetheless peppered with problematic incidents, in the CDC’s archives dating as far back as 1955. In the ‘Cutter Incident’ of that year batches of live polio virus slipped past safety testing, causing over 250 cases of disease-induced paralysis and becoming the ‘defining moment in the history of vaccine manufacturing and government oversight of vaccines, [and leading] to the creation of a better system of regulating vaccines.’(12)
Despite the ‘better system,’ however, problems continued to arise.
In years following the Cutter Incident, an estimated 10% – 30% of polio vaccines – in both their inactivated (IPV) and oral (OPV) forms – were found to be contaminated with simian virus 40 (SV40) which was traced back to the use of monkey kidney cells. In 2007, a voluntary recall was issued for 1.2 million doses of Haemophilus influenzae type b (Hib) vaccines which were potentially contamination with Bacillus cereus (B. cereus). This bacterium is more commonly food-borne and exposure to it can result in gastro-intestinal discomforts such as diarrhea and vomiting, and moreover ‘reports of respiratory infections similar to respiratory anthrax have been attributed to B. cereus strains harboring B. anthracis toxin genes.’(13) Additional contamination issues and potential links of vaccines with conditions such as multiple sclerosis (MS), Guillain-Barré Syndrome (GBS), the bowel condition Intussusception, and narcolepsy have also been investigated. And between 1976 and 2013 the CDC recorded problems with vaccines against hepatitis B, swine flu (Menactra vaccine), rotavirus gastroenteritis (RotaShield vaccine), the monovalent 2009 H1N1 influenza (Pandemrix vaccine), and a human papillomavirus (HPV) vaccine (Gardasil), among others.
In short, the history of inoculation is not without its complaints.
That being said, on a global scale the benefits of the level of immunity offered through vaccination statistically outweigh the problems and present the strongest line of defense against life-crippling or fatal disease.
As we know better, we do better, and the science of safety systems with its manufacturing, production, distribution, and handling protocols has certainly advanced even since the last reported controversy. So perhaps we need to look at how the public relations arms of biopharma can keep pace with with technological developments emerging from their cleanrooms. After all, whether it is sourced from traditional processes or from the new plant-based platform, a vaccine is only effective if it is accepted by a majority of the population. It’s no doubt a question to which we will return as the story continues to unfold.
In 2006, the Book of Longing was published by singer-songwriter and poet Leonard Cohen. It was his first compilation of poetry to emerge in almost two decades and included the work, ‘The Cigarette Issue’:
‘But what is exactly the same
is the promise, the beauty
and the salvation
the little Parthenon
of an opened pack of cigarettes’
While Cohen was reflecting specifically on his own relationship with smoking tobacco, the new potential promise of the plant is compelling.
In times of coronavirus, it is interesting to see whether Nicotiana benthamiana might be key to a vaccine and, moreover, whether the plant may become an icon of beauty, a beacon of our salvation. This is pure speculation, of course. But if companies like Kentucky BioProcessing, Medicago, and others maintain their pace of development – while operating squarely within safety guidelines – this otherwise maligned plant may be offered a shot at rehabilitation, a shifting of its reputation from social outcast to propitious protector. Only time will tell.
Tobacco as key to vaccine development?
Do you have confidence that this approach might work? Or would you prefer to see additional emphasis on more traditional research? We’d love to know your thoughts!