For months, experts have been calling for mRNA to be manufactured onshore. It’s not too late to kick-start the process, if the will is there.
Last September, German biotech company BioNTech bought a production site from Swiss drugs giant Novartis to manufacture the mRNA COVID-19 vaccine it was developing with US pharma company Pfizer.
In less than six months, the drugmaker began manufacturing en masse the mRNA vaccine that has now been injected into millions of people across the world. Their plan was to produce 250 million doses in the first half of the year. The ultimate aim is to turn out one billion doses annually, about 40% of BioNTech/Pfizer’s total output. It’s a significant achievement, and one that Australia has so far deemed impossible. But how impossible is this?
“[Germany] didn’t start from scratch,” says Professor Thomas Preiss, a molecular biologist at the Australian National University and an mRNA expert.
The BioNTech site is located in Preiss’s home town, Marburg, about 100 km north of Frankfurt. Set up in 1904, it is part of a life science park with a highly established infrastructure. Since 2015, the site has been used to make biologics, cell and gene therapies.
BioNTech acquired a functioning facility that was making products related to mRNA; with it came more than 300 skilled employees from Novartis. “They didn’t build a new facility on a green field, and had all the know-how to make their own product,” says Preiss.
“With an appropriate sense of urgency and the resources behind it, something similar could be done here,” he says.
Because mRNA vaccines are a new technology, Australia does not yet have a manufacturing plant to produce them. The German effort could be somewhat replicated in Australia, experts agree, but things might take longer down under.
mRNA vaccines are much simpler to make than other vaccines. Traditional vaccines, such as the common influenza vaccines, require the isolation of the virus that is then cultivated in eggs (literally hens’ eggs), purified and finally deactivated. The process requires handling large amounts of live virus, which represents a substantial risk in cases such as SARS-CoV2. The virus deactivation process also presents risks and challenges. Protein-base vaccines such as the AstraZeneca COVID-19 vaccine solve those problems, but proteins are hard to handle in a lab setting and require large volumes of cells to be produced.
This new breed of mRNA vaccines have no need to grow cells in large volumes. Instead, it’s a synthetic process.
Once scientists identify the code to make the antigen protein – which in the case of SARS-CoV2 is the spike protein – they insert the sequence corresponding to the mRNA into a small DNA molecule that can replicate itself and acts as a template to make RNA. After it’s synthesised, the mRNA is purified and encapsulated into a lipid nanoparticle.
The nano-particles are then mixed with an aqueous buffer at physiological – human-friendly – pH. The vaccine is ready to be portioned into vials and dispatched.
What would it take to set up such a process in Australia?
Firstly, the government must reach a licensing agreement with one of the mRNA COVID-19 vaccine developers, such as Pfizer or Moderna, and stump up the money to buy equipment and train local manufacturers.
A licensing agreement would see an mRNA vaccine developer sharing its patent and know-how – given that certain conditions and payments are met – with another company or government, which would then be allowed to make that product. This is what happened between AstraZeneca and CSL, which is commissioned to produce 50 million AstraZeneca doses at its Parkville plant in Victoria.
As to costs, the Australian RNA Production Consortium President, Associate Professor Archa Fox from the University of Western Australia, has said that establishing a production facility would cost around $100 million. The government has been reported to be talking to multiple potential mRNA vaccine manufacturers and has stated there’s a possibility of more than one manufacturing operation being established. Following the Budget, in May, Health Department Secretary Brendan Murphy said that he hoped manufacturing would begin in 2022.
Assuming that licensing and a manufacturing facility are sorted, the maker would still need to arrange a supply chain, obtain regulatory approval, and recruit qualified staff.
Preiss says several companies in Australia can manufacture mRNA vaccines by repurposing their facilities. One such company is BioCina, an international biotech enterprise that bought Pfizer’s biologics manufacturing plant at Thebarton, in South Australia, last August.
“We can manufacture mRNA with the equipment and expertise we already have in house,” says BioCina CEO Ian Wisenberg.
He says the 4600m2 plant has more than 35 years of experience with microbial fermentation – a process required for RNA manufacturing. “It is the most advanced facility of its kind in Australia and the only one approved by the TGA and US FDA.”
Wisenberg says the plant could mass-produce mRNA vaccines within 12 months, with Commonwealth approval and financial support. CSL has also engaged recently with the Australian Government to discuss how it can make mRNA vaccines onshore. The biotech giant, which is currently making 50 million doses of the AstraZeneca vaccine at its Parkville plant in Victoria, is applying the new mRNA technology to other products, such as flu vaccines.
“CSL is probably the only company able to do that kind of exercise at the moment,” says Professor Colin Pouton, a pharmaceutical biologist at Monash University. He points out that the bottleneck might be commercial opportunities rather than a lack of expertise.
“How much risk are they willing to take in spending their own money to get set up and then not really knowing what the future holds for manufacturing?” Pouton asks. “How much help are they going to get from the government?”
In April, the Victorian Government released a $50 million investment to set up a facility to develop and manufacture mRNA vaccines in Australia. Monash University’s experts are working with the Victorian Government, the University of Melbourne and the Doherty Institute to establish and scale mRNA vaccine manufacturing. According to Pouton, that amount will be enough to get clinical trials started and perhaps set up a facility that can produce enough vaccine to run them. But to set up a facility able to make vaccines for our population, many tens of millions more will be needed.
Monash researchers, led by Pouton, started working on mRNA vaccines for COVID-19 as soon as the pandemic began. By April last year, they had the first candidates. But while their US counterparts at Pfizer and Moderna were being showered with billions of dollars by their government, the Monash group had insufficient funding to begin animal testing.
“We didn’t really have any funding until almost the end of 2020,” Pouton says. “mRNA vaccines were a completely unfamiliar technology. We were pretty confident that mRNA would work, but it was such an unknown that it wasn’t really possible to get money from the government at that time.”
Monash researchers have developed an mRNA vaccine that only encodes the tip of the spike rather than the whole spike protein, as the currently used vaccines do. They hope to elicit an even stronger immune response by focusing solely on the portion of the spike that is responsible for cell binding. Thanks to the Victorian Government funding, the team is planning to begin phase one clinical trials in October, after obtaining promising results from animal studies.
“The vaccine is performing very well, and we are now getting into the manufacturing,” says Pouton. “But at the moment, there’s nowhere in Australia where you can go to have an mRNA vaccine made.”
As a result, the mRNA will need to be manufactured overseas and shipped to Melbourne, where it can be encapsulated into lipid nanoparticles and portioned into vials. Pouton hopes that part of the Victorian Government funding will help local biotech companies upskill to be able to have the capability to produce the vaccine on Australian soil – at least on a small scale – within six to 12 months.
“How long it takes to set up an mRNA plant depends on the scale of investments,” says Preiss.
Any effort will come too late to solve the current shortage of mRNA vaccines, which are now the preferred choice for most Australians after the recent recommended changes for the AstraZeneca vaccine, prompted by concerns over rare blood clot risks.
But experts agree that it’s never too late to build capacity for the mRNA technology. The benefits of developing an mRNA industry in the country go beyond the current shortage of vaccines, they say.
We will likely need COVID-19 booster shots in the years to come to enhance our immunity or to fight emerging variants. Several companies worldwide, including Pfizer and Moderna, are already running clinical trials to test vaccines against a range of viruses, as well as cancer vaccines and immunotherapies.
“There will be many other uses of this technology,” says Preiss. “Australia can play a leading role, harnessing the academic research that we have in this space and developing a local industry that will have a global market.”
Dr Manuela Callari is a Sydney-based freelance science writer who specialises in health and medical stories.