Covid-19 focused the world’s scientists and politicians like never before. The breakthroughs made to manage it could now lead to vaccines against HIV and even cancer. By Rick Morton.
Part two: How Covid-19 began an ‘mRNA revolution’
For more than four decades, scientists have tried and failed to develop a vaccine for HIV, the notoriously tricky human immunodeficiency virus that can cause AIDS and has killed tens of millions of people around the world since the 1980s.
Although treatments have evolved and a daily preventive pill arrived almost a decade ago, a vaccine remains the single greatest hope for eradicating the virus, especially in developing countries.
Then, suddenly, researchers at the United States National Institutes of Health (NIH) revealed exciting new results earlier this month from vaccine trials in monkeys and mice. The team behind the new science is led by National Institute of Allergy and Infectious Diseases director Anthony Fauci, who famously spearheaded the US’s Covid-19 response in a tense and tenuous position under then president Donald Trump.
The vaccine platform that has underpinned this new approach is one NIH scientists developed in concert with Moderna to fight Covid-19, and which was separately pioneered by Katalin Karikó at German company BioNTech.
“This experimental mRNA vaccine combines several features that may overcome shortcomings of other experimental HIV vaccines and thus represents a promising approach,” said Fauci, who is a co-author of the Nature Medicine paper.
Like the Covid-19 vaccines from Moderna and Pfizer-BioNTech, this experimental shot carries mRNA instructions that direct the production of proteins. In this case, the targets are two key HIV proteins, Env and Gag.
Once ordered, these proteins are then assembled by muscle cells in vaccinated animals to form “virus-like particles”, or VLPs, which are adorned with multiple copies of Env proteins that closely match those in the real-world virus but with none of the infectious risk.
“We are now refining our vaccine protocol to improve the quality and quantity of the VLPs produced,” study lead Paolo Lusso said.
“This may further increase vaccine efficacy and thus lower the number of prime and boost inoculations needed to produce a robust immune response. If confirmed safe and effective, we plan to conduct a phase one trial of this vaccine platform in healthy adult volunteers.”
University of Sydney biomedical scientist Dr Darren Saunders, who has spent his career studying cell properties of cancer, tells The Saturday Paper that we are now at the beginning of an mRNA revolution, accelerated by the coronavirus pandemic.
“Scientifically, that’s been bubbling away for a really long time. And I think Covid was kind of the perfect situation to bring it into the mainstream, if you like, and to show, really, what its potential is,” he says.
“And at the same time, gain wider acceptance for its sort of power and ability. And one of the great advantages it’s got going for it is that it is, you know, synthetic: we can sort of dial in what we need and punch out this genetic sequence, which is different to the way we’ve tried to do that in the past.
“So that’s really powerful because it means it’s really flexible. You can sort of adapt it to anything.”
In the past few months alone, the two companies at the centre of the mRNA revolution have made a series of announcements that show the breadth of potential new applications of the platform.
On November 19, BioNTech revealed it had received a fast-track designation from the US Food and Drug Administration (FDA) for its investigational cancer immunotherapy product that uses a set combination of mRNA encoded tumour-associated antigens “for the potential treatment of advanced melanoma”.
The drug, BNT111, is currently in phase two clinical trials with patients recruited from Australia, the US, Britain, Spain, Germany, Italy and Poland.
“With the Fast Track status and support by the FDA, we aim to expedite the further development of the BNT111 program to provide a new therapeutic option for patients with life-threatening, hard-to-treat melanoma,” BioNTech co-founder and chief medical officer Özlem Türeci said in a statement.
The so-called “FixVac” platform, wholly owned by the German company, also has candidate drugs for prostate cancer, ovarian cancer and HPV16+ head and neck cancer in either phase one or two clinical trials. It also is in preclinical investigation of a product that targets non-small-cell lung cancer, which accounts for about 80 to 85 per cent of all lung cancers.
Beyond the FixVac program, BioNTech has a series of other mRNA candidate products designed to treat solid tumours. A team from the firm presented early phase one/two trial results at a conference in November, which showed the drug had a “manageable” safety profile with no serious adverse events and, in three patients, resulted in tumour shrinkages of between 18 and 27 per cent.
A month earlier, the German company announced the first human had been dosed in a trial of its mRNA-based “individualised immunotherapy” for colorectal cancer.
Over at Moderna, the updates have been similarly fast-paced. The US company, co-founded by Drew Weissman, who worked with Katalin Karikó on a crucial mRNA safety breakthrough study in 2005, never had a drug receive approval before its Covid-19 vaccine hit the market. In a slew of market updates, Moderna has now shown positive results from trials to boost “reparative and disease-modifying” options for patients with chronic heart failure and in its phase one mRNA influenza vaccine.
It has also dosed first patients in phase two/three trials for a respiratory syncytial virus vaccine on the same platform that used mRNA to instruct cells in the production of immune-boosting properties. The same has been achieved for Moderna’s phase three trial of a cytomegalovirus vaccine and phase one/two trial of a therapeutic for people with methylmalonic acidemia, an inherited condition that prevents the human body from processing certain types of fats and proteins, causing death via stroke, toxin build-up, organ failure and a host of other pathologies.
Moderna has been working with the NIH on its HIV vaccine candidate (BioNTech also has one in the pipeline) and has products at various stages of clinical and preclinical trials designed to combat autoimmune disorders, the Zika and Nipah virus, and a tailored cancer vaccine.
“That’s the huge thing at the moment,” Saunders says of a “personalised” cancer vaccine. “So again, there’s a few different ways of doing that, but one of the ways they do it is they basically train your immune system to recognise your particular cancer. But at the moment doing that is very expensive, very, very time-consuming and requires really big, specialised labs full of people.
“And so I imagine they’re looking at ways of doing that, that are much more flexible, and much, much more amenable to being rolled out to more people.”
When Moderna and Pfizer-BioNTech brought their wildly successful Covid-19 vaccines to market in late 2020, there were very few places in the world that could actually manufacture mRNA products at scale.
The nascent technology has now been proved billions of times over with the promise of more developments to come.
On Tuesday, Prime Minister Scott Morrison, along with the acting Victorian premier, James Merlino, and Health Minister Greg Hunt, announced an in-principle agreement with Moderna to establish a “sovereign vaccine manufacturing” capability for the mRNA platform in Victoria from 2024.
“The mRNA vaccines have proven to be, I’d argue, the biggest scientific discovery over the course of this pandemic,” Morrison told reporters at the Peter Doherty Institute in Melbourne.
“And that means that they are a big part, a massive part, of the future of vaccines, not just here in this country, but all around the world.
“And so we set about the task of ensuring that we have the manufacturing capability to do that. First of all, to keep Australians safe and to protect their health not just against Covid but against the many other communicable diseases.
“And with Moderna, we have a partner that ensures that their IP, their knowledge, their advances and medical science can be brought here and be part of an ecosystem here that will see Australia also be a leader in this area.”
Merlino agreed. “As far as announcements go, this is a big one. This is a huge announcement and it’s incredibly exciting for Victoria,” he said at the press conference on Tuesday.
“And when you think about mRNA, this is a huge announcement because this is the first time in the southern hemisphere that we will have mRNA manufacturing, based in this nation ... And it’s not just in regards to vaccine developments, whether it’s variants of coronavirus right now, pandemics of the future, but beyond, beyond that: treatment of cancer, treatment of rare diseases. This is a massive game changer. And to have that manufacturing capacity, the research capacity right here in Melbourne, Victoria, Australia is a great thing.
“This will create jobs. One thousand jobs, 500 in construction, 500 ongoing. But beyond that, it saves lives, whether it’s dealing with a pandemic, treatment of cancer, treatment of rare diseases. This is a major, major announcement.”
The plan is welcome news in the Australian scientific community, but it is bittersweet. In October, the Coalition said it would not renew a contract with CSL – also in Victoria – for the production of 51 million doses of the Oxford University AstraZeneca vaccine. When the company finishes its manufacture of these in the first half of next year, there will be at least an 18-month gap in which Australia produces no Covid-19 vaccine for its own citizens or those in developing nations.
The pandemic is not over. Vaccinations are crucial and, as cases surge again in New South Wales at present with a mix of Delta and the new variant Omicron, the booster program locally has taken on even more significance.
For Dr Saunders, a flagship facility manufacturing one of the newest technologies in the world – the possibilities of which are only now being conceived – will produce a “halo effect … for the entire research ecosystem”.
He says, “Having high-tech research and development and manufacturing going on acts as a kind of a catalyst for other things to develop alongside. It’s really fertiliser for that ecosystem.”
The co-inventor of the platform upon which the medical revolution is being staged, Katalin Karikó, was asked what advancements in science would now be possible thanks to mRNA. Ever the scientist, she deals only in what is reasonable.
“You know, I couldn’t get money for my own company because I am a scientist and I always say, ‘Oh, we can’t do everything.’ RNA won’t go through tissues layer, it won’t go through mucous.
“But if you have to reach, to make inside the cell a specific protein, you have to reach somehow that cell. And that is where the future is coming.
“How you wrap up the RNA and put something there … you can just inject and it is much cheaper then. And now that money is pouring in … actually, even before the pandemic there were companies in Japan, Korea, China and they are doing different projects.”
A malaria vaccine is being developed and tested. Dozens upon dozens of other products are being designed. All of these rest on the decades of work that turned into the extraordinary progress of a single year.
If this pandemic happened 20 years ago, Karikó said, it wouldn’t have been enough just to have a genetic sequence of the coronavirus upon which to build a vaccine. There have been two decades of scientific achievements and improvements in a host of technologies between the year 2000 and now that have provided the springboard for mRNA.
This is something Darren Saunders thinks has been an underappreciated revelation of the pandemic: a deeper, broader public understanding of the way science is done, the realisation that any one breakthrough cannot be decoupled from past brilliance. Each step is necessary.
“You know, it’s not all just breakthrough. It’s kind of like, two steps forward, one step back, and I think people have got a little bit of a better understanding of that now.
“We have sort of been watching it play out in real time, rather than just hearing about the thing when it’s all done and dusted. I think it also gives people a better appreciation of the fact that you can’t just suddenly reach into your bag of tricks and magically produce something.
“Even these amazing new mRNA vaccines, they’ve been in development for decades, right? And you’ve got to have that sort of work going on so that when a new challenge arises, you can draw on the stuff that you’ve been doing.”
Establishing a manufacturing operation for this new marvel of science is a major coup, but whether this more intricate public awareness translates to broader policy backing remains to be seen.
To reframe Saunders’ point: what future scientific breakthrough will rely on advances that have not yet been made because the research needed now is not happening, is not funded or is currently stalled?
There have been few, if any, good news stories arising from the pandemic. The astonishing, global scientific response is one of them.
The test now is whether governments will continue to fund and co-ordinate science, to accept failure as a key element of every breakthrough. Will they support the next Katalin Karikó, and the one after that, whose work is specialised and esoteric, who labours without significant results for decades, until one day her sturdy belief in the science of her work changes the world overnight?
Read part one of this series: The true story of the Covid-19 vaccines
This article was first published in the print edition of The Saturday Paper on December 18, 2021 as "Part two: How Covid-19 began an ‘mRNA revolution’".
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