On May 20 last year, Health Minister Greg Hunt held a press conference at Monash University in Melbourne to announce a new tranche of research funding.
Dozens of similar press conferences are held every year as the government dispenses science dollars; they usually pass without remark.
Not this one. What happened next, in the chaotic early days of the pandemic, is strongly contested.
Professor Colin Pouton, a vaccine developer at Monash University, was at the press conference. He recalls talking to Hunt’s staff in the hope he could meet the minister.
Pouton believed he had a promising mRNA vaccine candidate for COVID-19.
With serious government investment, he thought it could be made into a home-grown jab. He wanted a chance to pitch the minister.
“We knew, maybe in April 2020, we actually had got as far as anyone else in this caper,” Pouton says. “ We were probably only a month behind [mRNA vaccine manufacturer] Moderna.”
But no meeting with the minister was ever forthcoming, although there were several discussions with advisers.
“We certainly tried to get in front of government. But it’s hard to do, hard for an academic scientist to talk directly to the ministers,” says Pouton.
That’s not how Hunt’s office remembers things. They claim Hunt did meet Pouton at the press conference and chatted about mRNA, but they said there was never a request for a formal meeting with the minister. There was also significant scepticism Pouton really did have a leading vaccine candidate.
“The Department and Office have reviewed all of the Minister’s diary, office accounts and departmental records. There is no record of having received a request from Colin Pouton or Monash to be briefed on this project.
“At no time did Colin Pouton seek a second meeting with Minister Hunt.”
What really happened? It’s not clear.
“I would have thought it was clear we wanted to meet but – formal request? – I don’t even know what that means. Maybe we should have persisted,” says Pouton.
But here’s the sting in the tail: Pouton didn’t know it at the time, but the vaccine he was working on used almost exactly the same design and technologies as vaccines being developed elsewhere, thanks to more than $1.5 billion in government funding, by Pfizer and Moderna.
About six months after that brief meeting at the press conference in Melbourne, scientists from the companies announced clinical trial results that shocked nearly everyone. MRNA had produced two extraordinarily powerful COVID-19 vaccines.
Pouton was on the right side of history, but just a few months too early.
“It’s just nuts,” says former colleague and mRNA Victoria Scientific Advisory Group member Professor Bill Charman. “Colin spoke with the Health Department, he couldn’t get through – but he shouldn’t feel as though he was in poor company, because the world’s biggest health company (Pfizer) couldn’t get through either.”
Pouton, who is described by colleagues as having the “disarming” manner – and accent – of a University of Cambridge English professor (he studied in London and Bath), merely calls it “frustrating”.
It would have been easy to retreat to the lab. Pouton chose a different path. A man who has spent a career avoiding the limelight became an activist.
In a few months those efforts will bear fruit, when the first doses of Australia’s first home-made mRNA vaccine roll off the production line.
Do it yourself
To make an mRNA vaccine for the Delta strain of COVID-19, draw up one millilitre of liquid mRNA, which should look like clear water in your syringe.
With a second syringe, draw from a dark glass jar half a millilitre of four fats: cholesterol and distearoylphosphatidylcholine, as well as special fats that can only be made in a lab.
Place your syringes into a squat, glass-fronted machine that costs about as much as a new BMW. The menu is a touch-screen; tap through to “recipes”, and then hit the one for a Delta vaccine. Now press the green button.
The fluids trickle into channels carved into a piece of black plastic the size of a credit card, which wind and come together. On a scale too small for the eye to make out, indentations in the channels act like river rapids, swirling the liquids together till they combine just so.
A dribble of clear fluid is ejected into a test tube. “That is, in every sense, a Delta vaccine,” says Dr Harry Al-Wassiti, a bioengineer in Professor Pouton’s lab. He warns against drinking it.
The doses made here are for the lab’s animal tests. In Boronia, in Melbourne’s East, a company called IDT has just taken delivery of a huge version of this machine, which it will use to make doses for a 150-person clinical trial, due to start in October.
An mRNA vaccine starts with a code, written in the four letters of the genetic alphabet, like auguuuguuuuucuuguuuu.
That’s the first 20 of about-300 genetic letters for the code for COVID-19’s spike protein.
Know the code, know your enemy.
Each of our cells contains a tiny factory, the ribosome, which together churn out the proteins that make up your body. Hair, skin, antibodies – nearly everything that makes you you is a protein, made for you by your ribosomes. MRNA provide the instructions to the factories. Need fingernails? Just feed in the code.
MRNA vaccines contain the code for a section of a virus. After injection, the ribosomes read the code, produce the virus section, and the immune system gets busy raising antibody armies.
At least that’s what everyone agreed was supposed to happen. But for decades it didn’t. After injection, the mRNA just kind of sat there. No one could get the delivery right.
Professor Damian Purcell, now head of the molecular virology laboratory at The Peter Doherty Institute, was building an mRNA vaccine in the early 2000s for HIV that used an electric shock to activate the mRNA.
“It worked,” he says. “But no one wants to get zapped.”
Unlike the biologists who dominate the study of mRNA, Pouton is a pharmacist who specialises in delivery. “He is one of the world experts in the use of lipids to enhance the delivery of pharmaceuticals,” says Charman.
Pouton had become focused on lipid nanoparticles, tiny balls of fat that can carry fragile molecules like RNA inside cells – where they actually do their work.
Much like RNA, lipid nanoparticles seemed for decades like a dead end. It took scientists until late last decade to find a way of making them non-toxic. With that advance in hand, they were suddenly the perfect delivery vehicle for RNA.
Pouton spotted that early; he had spent the last three years working on an mRNA-nanoparticle project. A trial version of his COVID-19 vaccine produced such extraordinary results when tested on mice at the Doherty Institute in August the Institute chose to partner with his team.
“I knew this was a big advancement, what he’d done, what he was making and the way he was delivering it,” says Purcell, who did those tests. “But he was really hand-to-mouth, struggling to move it along”.
Unfortunately for Pouton, Moderna and Pfizer had spotted the same potential in nanoparticles. And they had money – billions of dollars from Washington and Berlin. “We had the phenomenal sum of $2 million for all vaccine development,” says Purcell.
When Pfizer and Moderna published their clinical trials at the end of 2020, it was immediately clear they were going to make billions upon billions of dollars. Pouton had what he thought was a great vaccine, but almost no money – and even if he had funding, there was no one in Australia who could actually make his mRNA jab at scale.
“We thought if we just carry on with research, apply for grants, we’re not going to get anything done in a reasonable time frame,” says Pouton.
So he began reaching out to other scientists around Australia who had an interest in RNA. There weren’t many: originally just a group of six, meeting on Zoom every fortnight to plot and plan.
Associate Professor Archa Fox, one of the original members of a group they christened the Australia NZ RNA production consortium, says: “You do sometimes get with scientists a gatekeeper type attitude. He could have said, ’Look, I’m the only person in Australia developing mRNA vaccines. I have a strategic edge; I am going to use that to develop my own position. But he did not do that.”
Perhaps burnt by his experience, Pouton realised governments would never invest big money in a high-risk vaccine gamble, Fox thinks. They needed to show mRNA could be used for much more than COVID-19: gene therapies, blindness treatments, even new tools to attack cancer.
“Our job, we felt, was to convince them there was a future, and that it wouldn’t just be a one-trick pony,” she says.
And Pouton engaged with the media – not easy for a man colleagues say shies away from the limelight. In the six months from April through September 2021, his media profile jumped 252 per cent, compared with the previous six months, according to data from Streem.
It wasn’t hard to manufacture an mRNA vaccine for COVID-19, he told journalists in a front-page article. “It’s just a matter of the will to make it happen.”
There are some within government and industry who think he’s overselling it.
It can’t be that easy to make an mRNA vaccine, they say. There are only two companies in the whole world who have successfully done it.
“In simple terms, we know what all the steps are [to make a vaccine]. But it’s like saying you can go into a Michelin-star restaurant and make the dish,” Trent Munro, one of Australia’s most experienced biotech and biopharmaceutical experts at the University of Queensland, told The Age earlier this year (he declined to comment for this story).
And was Pouton really only “a month behind” Moderna in April? Moderna gave its first human doses in March; he hadn’t yet finished preclinical studies.
But any successful media campaign needs to build hype. Judged by results, Pouton’s campaign has been a triumph.
NSW and Victoria are in a multimillion-dollar arms race for mRNA manufacturing capacity; the federal government is courting Moderna and has pledged to spend millions on our own mRNA facility. In June 2021, Pouton finally got his big break – a grant from the Victorian government to fund a phase 1 clinical trial.
Without Pouton, all this probably doesn’t happen, says mRNA Victoria’s Charman.
“Government needs to have examples it can point to, to say, ‘This is not pie in the sky.’”
The obvious question to ask a scientist working on a COVID-19 vaccine in September 2021 is: why?
“We often ask the same thing ourselves. Is it really worth pursuing this?” says Pouton.
We have fantastic vaccines. To get approval, new vaccines have to be even better, a very high bar to hurdle.
Pouton’s vaccine is a gamble – a bet we’ll need a new type of vaccine to counter the antibody-evasive variants of COVID-19, like Delta, that continue to emerge.
Consider the twisting bundle of proteins that make up COVID-19’s spike. On the very tip of the spike is the receptor binding domain, a small molecular hook that needs to catch onto an ACE2 protein jutting off the side of a human cell.
The virus’ success is entirely dependent on that tiny hook catching. Build an antibody that gums it up, and you’re basically immune.
Unfortunately, your immune system doesn’t know that. It sees the entire spike, and builds antibodies for the whole thing. Some gum up the binding domain; most don’t, and many do nothing at all.
If the binding domain changes shape, your antibodies can’t stick to it.
Moderna and Pfizer are planning to update the shape of the spike for their boosters. Everyone’s hoping that works.
But there’s some chance it won’t, owing to a phenomenon immunologists call “original antigenic sin”.
This occurs when the immune system fails to spot the subtle differences between the spike protein in the original dose of vaccine and the new spike in the booster. It assumes they are the same – and doesn’t update its arsenal of antibodies.
Pouton’s solution: slice the tip off the spike. His vaccine contains only the receptor-binding domain from the Beta variant – the most vaccine-resistance of the variant cousins – of COVID-19’s spike.
“Rather than having the whole spike, we’re really targeting a region most of the neutralising antibodies develop against, keeping the immune response a bit more tight and focused on a region we think is the most important,” says Al-Wassiti.
Will it work? We’re months away from finding out. If it does, then comes the next step, striking a deal with a big pharma company to actually manufacture it.
“Obviously, in the end, we run out of big companies that would actually want to commercially develop this product,” says Pouton.
“For our vaccine to be developed commercially, it would definitely need a big pharma company to take it on. You just don’t know if that’s going to happen.”
Liam Mannix’s Examine newsletter explains and analyses science with a rigorous focus on the evidence. Sign up to get it each week.