Covid abnormal: why is Australia so far behind on making its own mRNA vaccines?

F rom September – more than nine months after it was approved for emergency use in the United States – the first doses of the Moderna Covid-19 vaccine will arrive on Australian shores. The second mRNA (messenger ribonucleic acid) vaccine against the coronavirus is a welcome boon amid a period of rolling lockdowns and record case numbers.

But Australia’s notoriously sluggish vaccine rollout has been marred by the failure of a locally developed vaccine candidate, as well as changes to age-group recommendations for the AstraZeneca vaccine as a result of its link to rare but blood clots.

But above all, insufficient supplies of mRNA vaccines – primarily the vaccine jointly produced by Pfizer and the German firm BioNTech – have undoubtedly slowed the pace. What’s stopping Australia from manufacturing its own doses?

Small biotech sector

Dr Archa Fox, an RNA (ribonucleic acid) expert at the University of Western Australia, says mRNA technology was initially tested for cancer treatments.

“About 10 years ago, companies like Moderna, BioNTech and CureVac started up, basically trying to take this research idea of making RNA, modifying it [and] delivering it into cells to give some therapeutic benefit,” she says.

“What they found in the early clinical trials was that there was this strong immune response.

“They actually figured out that perhaps they could use that immune response for vaccines.”

Back in 2018, mRNA vaccines were heralded as “a new era in vaccinology” for their “high potency, capacity for rapid development and potential for low-cost manufacture and safe administration”.

Though the two mRNA Covid vaccines were brought to market quickly, the technology has been in development for years, Fox says.

“There really was only Moderna and BioNTech. They were not large companies and they had not yet been able to bring a drug to market.”

In some respects, it is unsurprising that there has been no local production of mRNA Covid vaccines to date.

“Given that our biotech sector is fairly small to start with, there was no commercial appetite to jump into something that was as yet unproven at that point,” Fox says.

Prof Trent Munro of the University of Queensland says the relative lack of biotechnology infrastructure in Australia, compared with countries such as the US, Singapore and South Korea, is also a factor. “Complex pharmaceutical manufacturing infrastructure – we’re very limited here, outside of CSL and a few small facilities.”

Slow off the mark

In only May, the federal government announced an approach to market, calling on bids from biotech firms interested in manufacturing mRNA vaccines onshore. The government received proposals last month from a number of local players, including frontrunner CSL Limited, which is currently Australia’s only onshore vaccine manufacturer.

The Australian biotech company has been producing local doses of the AstraZeneca vaccine, which is an adenovirus-based vaccine. Before a University of Queensland vaccine trial was halted – the candidate vaccine resulted in false-positive test results for HIV – CSL had also been contracted by the commonwealth to supply 51 million doses of that vaccine.

Lorna Meldrum, the vice-president of pandemic readiness at Seqirus, CSL’s vaccine division, says the firm already has an mRNA research program, with human clinical trials for influenza vaccines to commence next year.

“We’re actively exploring mRNA manufacturing options for the company,” she says.

Vaccine manufacturing capacity “can’t be set up overnight”, she says. “It takes time and investment.”

Complex technology

Each of the cells in our bodies contain genetic material in the form of DNA, with its familiar form as a double-stranded helix.

RNA is similar but is single-stranded instead: viruses use it as their genetic code, while in many organisms including humans it is made by enzymes that unzip the double helix of DNA and take a copy of one of the strands.

There are different types of RNA. One particular kind, messenger RNA – mRNA, for short – has a crucial role as the blueprint for making proteins, and is naturally present in all of our cells.

mRNA Covid vaccines contain a synthetic mRNA sequence – a blueprint – that tells cells in our body to produce the Covid-19 virus’s spike protein. The presence of that spike protein – which during a real Covid infection is used by the virus to infects our cells – then triggers an immune response.

The blueprint can easily be varied to encode for other proteins – which means it isn’t just limited to treating Covid.

Simply put, the Covid mRNA vaccines are made in a three-step process: as a first step, bacteria grow DNA strands in small molecules known as plasmids, which are then purified and converted to mRNA by enzymes. The final step is to coat the mRNA in a layer of lipid – a class of substances to which fats belong.

The final step in the process is the most challenging, says Prof Robert Booy of the University of Sydney. “It’s incredibly important because mRNA is rapidly broken down unless it’s protected and encapsulated.”

Max Rossetto, head of business development at Luina Bio, agrees. Luina Bio is a Brisbane-based pharmaceutical manufacturer, among the firms which have submitted a domestic manufacturing proposal to the federal government.

“In mRNA vaccines the trick is not so much making the mRNA as making the lipid capsule around it,” Rossetto says. “Finding this technology is what made Pfizer and Moderna so successful.”

Dr Wayne Finlayson, the chief executive of Servatus, a Sunshine Coast drug developer and manufacturer which has also submitted a government bid, says to his knowledge only two companies in the world currently produce the lipid nanoparticle capsules.

“Even Moderna and Pfizer outsource that,” he says. “We would have to develop that technology in Australia if no one was going to give it to us.”

IP licensing

In the government’s approach to market, it called for mRNA manufacturing proposals that would be fully operational at a population scale in a timeframe between 12 months and three years.

Booy says several factors may result in manufacturing holdups, including supply chain issues for raw materials and vaccine licensing issues. (In a statement, Pfizer says its Covid vaccine “involves the use of more than 280 materials from 86 suppliers in 19 different countries”.)

Finlayson believes the fastest path to full-scale manufacturing would be to license the Covid vaccines off Pfizer and Moderna. “If we had the money, and we were directed to do it, we could do it in probably 18 months.”

Munro has a similar estimate, but is less optimistic: “Even if we were to get Pfizer or Moderna to come and partner with someone, my view is it’s an 18-month to two-year timeframe under the best of circumstances.”

In May, BioNTech announced it would set up a regional vaccine manufacturing facility in Singapore. In the same month, it signed a licensing deal with Chinese firm Fosun Pharma to allow for domestic production of 1bn doses of its Covid vaccine.

It is unlikely they will set up in Australia in the near future. In a statement to Guardian Australia, Pfizer says it “is focused on global manufacturing in our Europe and US manufacturing hubs for pandemic supply of our Covid-19 vaccine to Australia”.

“Once the pandemic supply phase is over and we enter a phase of regular supplies, Pfizer will evaluate all additional available manufacturing opportunities.”

The Australian science minister, Christian Porter, said last week the chances of either Pfizer or Moderna licensing their IP to a local manufacturer were “remote”, and that discussions were continuing with Moderna – which Guardian Australia has contacted for comment – about the firm setting up its own manufacturing facility domestically.

Fox says: “If we had to go down the route of developing our own mRNA vaccine …then it’s looking more like that three-year time-frame.” The process would be lengthier because of the need for clinical trials. Trials of one locally produced mRNA vaccine, developed by Monash University, are set to begin later this year.

‘Critical’ investment

Finlayson says mRNA vaccines are “a game changer” because they can be rapidly updated, including for Covid variants. “All you have to do is know the sequence of the virus and within six weeks you can essentially get ready to start manufacturing.”

Australia is a global exporter of flu vaccines, and could eventually also become an exporter of Covid vaccines, Booy says.

But given the long timeframe until a locally manufactured mRNA Covid vaccine, is the investment in RNA technology even worth it?

Prof John Shine, the president of the Australian Academy of Science, wrote this week that onshore RNA capability “is critical not only for vaccine development but also to address problems such as assessing new biosecurity threats and supporting climate change adaptation in agriculture”.

Fox says: “It’s possible, as with annual flu shots, that we will just have to get annual Covid-19 shots for a long time. I suppose you could argue: well, let the Modernas and Pfizer-BioNTechs elsewhere in the world produce them and then ship them to us.

“I think there is still an argument, even for Covid [vaccines], to set up here.”

Wider uses of mRNA vaccines will likely include individualised cancer treatments, and treatments for autoimmune diseases and non-viral pathogens such as malaria.

“This is really a disruptive technology that is going to change all sorts of medical products.”