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Which coronavirus vaccine will win the race? The clues are in the vial

Story Lab By Annika Blau, Ben Spraggon, Joshua Byrd and Catherine Hanrahan
Inside the coronavirus vaccine
Photo ABC News: Ben Spraggon

The old-school, the slow and the silver bullet: three options for a vaccine to free the world.

Dr Ross Jennens has devoted his career to saving lives — and now he's on the coronavirus frontline.

But not in the way you might expect.

Dr Jennens has put his hand up, or rather his arm, and become one of the first people in the world to receive a vaccine that could protect him from coronavirus.

If it works, he'll be able to treat his cancer patients at Epworth Hospital without worrying that he poses a risk to the very lives he's trying to save.

But you don't need to work in a hospital to be hanging out for a coronavirus vaccine. Without one, Australia could remain a hermit kingdom at the end of the Earth, cut off from the global community.

The world is in limbo and it's unclear which, if any, of the more than 100 vaccine candidates might reach the finish line first.

Broadly speaking, there are three classes of vaccine and each has its own promises and drawbacks.

  • The old-school approach that can carry some risk.
  • The new-school approach that's worked well before but still takes time we don't have.
  • A silver bullet that's cheap, could be produced quickly and could take us closer to a cure for cancer — but it's never been used in humans before.

All three approaches have this in common: scientists are racing to solve the biggest problem in the world by tackling a microscopic one first.

How you become a virus factory

A virus is simply "a piece of bad news wrapped up in protein", as the biologists Jean and Peter Medawar put it.

The coronavirus is no different. The "bad news" is its genetic code.

The "protein" is actually 29 proteins, each with a different job.

Unlike bacteria, viruses aren't really alive. Much like a vampire, they need to latch onto living things to survive.

A virus can't reproduce on its own — first, it has to hijack the cells of a healthy person like you.

See, your cells are like little factories, constantly building proteins.

The coronavirus hijacks your factories and gets them to build baby coronaviruses instead — genius, right?

This is how that hijacking goes down.

See those spikes? They're the coronavirus's super-power.

As we said, every protein in the virus has a job. The spike protein's job is very important — it unlocks the door to the factory.

The spike is like a key and the lock is a protein on the surface of your cells called ACE2.

The spikey key unlocks the cell, and then the virus can slip inside and start wreaking havoc.

Part of what makes this coronavirus so contagious is how sticky the spike is. It's around 10-20 times as sticky as the spike on the original SARS virus. As The Conversation put it, if that was like glue, then this is superglue.

Now that the virus has hijacked your cell it turns it into a virus-making factory, using your cell's machinery.

The new baby viruses float out of the infected cell and make their way throughout the body to enslave more of your healthy cells.

Thousands and thousands more.

So where does a vaccine come into this? Well, the vaccine is like a dress rehearsal and this next bit is the performance it's training your body for.

As the viruses are wreaking havoc, your immune system kicks into gear. This is a "B cell".

B cells make antibodies…

...which are shields that block the virus's spikes from unlocking other healthy cells.

Once the shields have blocked the virus, it's gobbled up by a white blood cell called a "macrophage", which is Greek for "big eater".

The macrophage is sort of like Pac-Man, munching away debris.

Meanwhile, "T cells" also kick into action.

They're like your foot soldiers, which slaughter infected cells to shut down the virus production lines.

B cells (the shields) and T cells (the foot soldiers) are the key to taking this deadly virus down — and preventing it from coming back.

After they've destroyed the virus, some will stick around, patrolling your body for months or years to come. They remember what your enemy looks like, and are ready to take it down again.

What a vaccine does is get these "memory" cells ready for you, ahead of time.

The most important thing in a war is to "know your enemy". No matter what type of vaccine you have, they're all attempting to offer the immune system a preview of the virus, without any of the destructive power of the real coronavirus.

So which paper tiger is most likely to beat COVID-19?

Option 1: The whole virus

The old-school approach that carries a bit of risk

Traditionally, vaccines have offered the body a preview of a virus by injecting a copy of the whole virus that's either massively weaker ("live attenuated vaccine") or killed ("inactivated" vaccine).

Let's call these approaches 'Coronavirus Lite' — like light beer, it's still alcohol, but a little bit of it won't mess you up.

Just two of the 14 coronavirus vaccine candidates in human trials use these old-school approaches, because they hold some drawbacks.

A live attenuated (weakened) vaccine has the potential to go rogue inside the body and "revert" to full strength. This is extremely rare. But it's what has caused vaccine-derived outbreaks of polio that are spreading uncontrolled across West Africa right now.

What's more, live attenuated vaccines often aren't given to people with highly compromised immune systems as they may not be able to fight even a very weak copy of the virus. These are, of course, the very same people most at risk from coronavirus.

Inactivated vaccines are much safer because the virus is completely dead. A good example is your annual flu shot, which all starts with a vast sea of chicken eggs.

Yes… chicken eggs.

The flu virus is grown inside eggs because it can't reproduce unless it's in an environment where it can take over cells. And it turns out a simple egg provides the perfect, contained environment for that to happen.

But growing a virus inside thousands upon thousands of chicken eggs is an expensive process that takes months. And as you can imagine, a giant warehouse full of deadly virus isn't an OHS dream.

So why would we use this old-school technology?

Well, because the immune system is spotting a whole virus, it takes it very seriously.

The live but weakened vaccines can produce a super strong immune response that for some pathogens can last a lifetime without the need for booster shots — they're usually the ones you get as a child, like the measles, mumps and rubella shot.

Plus, researchers are starting to question whether live vaccines could actually be boosting your immune system across the board, like a kind of wonder-shot that supercharges your ability to fight bugs.

And this is the theory behind what went into Dr Jennens' arm, one of the first vaccines to be trialled for coronavirus, here in our own backyard.

Over the years, health workers noticed that children in developing countries who received the BCG tuberculosis vaccine died less than other kids — and not just from TB.

Research has since confirmed that the vaccine protects against a number of diseases, and so 4,000 Australian health workers like Dr Jennens have put their hands up to test whether this coronavirus is one of them.

"I was happy to play a small part in this worldwide effort", says Dr Jennens of joining the international "BRACE" trial.

"If it's effective, I would feel safer going to work and caring for my patients."

Being almost a century old, the safety of the BCG vaccine is long established, which could save a lot of time in testing. But there's no guarantee it will offer enough protection, if any, against the coronavirus.

Enter, the new-school approach.

Option 2: A bit of the virus

The new-school approach — that takes a while to get right

What if, instead of previewing the whole virus, we could just show the immune system a bit of the virus — enough for it to recognise the real invader when it arrives?

It's a bit like when you see a police sketch of a criminal on the run. It's not a full likeness, but you get a sense of who you're looking out for.

Scientists nowadays are creating a preview using a fragment of the virus (a "sub-unit") — whether that's a lone protein or an empty shell with no bad genes inside.

Because it's just a bit of the virus, not the full thing, it can't go rogue. "There is very little risk of safety issues arising," says virologist Dr Lisa Sedger from UTS.

For this kind of vaccine, you want to give the body a preview of part of the virus that triggers the immune response in the body (an "antigen"). With the coronavirus, the spike protein is a good option.

Scientists grow this protein by inserting its DNA into the DNA of a microbe like yeast, a process called "recombination". Yeast is able to grow the virus proteins very quickly and on an industrial scale.

The isolated protein is then injected into the body with an "adjuvant" — a chemical that sends a danger signal to get the immune system to notice the intruder.

In a successful vaccine, the body will mount a strong immune response, releasing antibodies that neutralise the spike, and memory cells that patrol your body going forward.

It's not so much the spike protein itself but its pairing with the adjuvant that RMIT vaccine expert Dr Kylie Quinn says is "pretty cool".

Adjuvants are quite literally the industry's "dirty little secret".

They came about when researchers noticed that early vaccines from slightly contaminated test tubes were more effective.

(A little dirt never hurt anyone, right?)

They've come a long way since dirt in a test tube and they offer the best shot at the immune response you want.

"Adjuvants control the type of immune response a vaccine induces," says Dr Quinn.

"You have to find the right immune response that will kill the virus without causing damage to other cells."

There's another option for getting the immune system's attention. Nothing gets it jumping like an invader, so what if we could use another virus as a sort of Trojan Horse to get inside the body?

This new approach, which worked for Ebola, takes a harmless virus (the "vector") and genetically engineers it to build coronavirus proteins once it gets inside a cell.


It's two viruses spliced together — like taking a tiger and lion and making a liger.

Because it's a whole virus rather than just a fragment, it provokes a strong immune response, but because the carrier virus is harmless to humans, it doesn't cause disease.

These vaccines that preview part of the virus are where most experts are laying their bets. "It's tried and tested", says Dr Quinn. It's what you get with your Hep B, HPV and whooping cough shots, plus it's worked for coronaviruses in animal models in the past.

So should you start mapping out your international travel plans now?

Not quite.

We don't know if any of these vaccines in trials will find the Goldilocks sweet spot of an immune response that's "just right".

Plus, growing the virus proteins in a substance like yeast and then separating it back out again is very difficult. The protein loves to fall apart, change shape or become contaminated with yeast proteins.

It takes months, as does finding the right "dirt" for the test tube.

We could use a faster solution.

Option 3: Just the virus's genetic code

A silver bullet — that's never been used in humans before

As we saw, previewing just a bit of the virus is safer than injecting the whole virus. But what if we took another step back — what if we just injected the virus's genetic code?

Why would we do this? Well, as we've discussed, most vaccines need to be grown in giant vats, which is expensive and time-consuming.

But what if we told you that with a different approach, there are already 7 billion potential vats around the planet right now?

Remember how we told you your cells are like miniature factories, constantly building proteins?

Well, what if instead of growing vaccines in giant vats, we used the protein-making factories that are your very own cells?

That's exactly what a new class of vaccines, called genetic vaccines, attempts to do. Yes, this approach might just mean asking you to step up and become a human vat.

These vaccines inject the genetic blueprint for the spike protein, which directs your cells to build it inside of you.

It's a bit like turning your body into a 3D printer and printing little bits of the coronavirus inside you.

It starts with the spaghetti-looking thing inside the virus — the "bad news" inside the protein.

That's RNA — the virus equivalent of DNA.

The gene-spaghetti is injected into the body inside a bubble of fat that protects it like bubble-wrap.

Then, your cell's builders use that blueprint to assemble the coronavirus proteins.

You're programming your body, just like a computer.

And the spike proteins you've printed should get your B and T cells racing.

Because your own cells are effectively growing the vaccine, production should be relatively cheap and we can design vaccines and get them into trials far more quickly.

Just 63 days after the coronavirus's genetic sequence was made public, a small US firm called Moderna leapt to human trials with a potential RNA vaccine, at a point when most Pharma giants would still be drafting their plan of attack.

If they manage to get an RNA vaccine working in humans, it'll be a giant leap for medicine.

By turning our bodies into 3D printers, we could print all sorts of things we need, from specific antibodies for new viruses to special cells that destroy tumours. There's even hope of preventing allergies with genetic vaccines.

"We could use messenger RNA for cancer vaccines or to deliver drugs or to create specific proteins that modulate the function of cells," says Dr Quinn.

"And because we're in such an urgent time, it can advance the field really quickly which is incredibly exciting."

Genetic vaccines could revolutionise how we fight infectious disease, making future pandemics more manageable — but first, they must work.

RNA is fragile, so fragile that a breath of air or a speck of saliva could destroy it. DNA vaccines, which work in a similar way, are more stable, but can struggle to stimulate a strong immune response.

But the fact RNA vaccines have never succeeded in humans didn't stop the US Government throwing almost half a billion dollars at Moderna, more than it gave to any of the companies who've actually delivered vaccines to market before.

The much-hyped company has seen its share capital soar.

"They're now rolling in money, whether they'll be successful or not," says Monash University bioethicist Professor Paul Komesaroff.

"It seems like a good thing that people are seeking new products, but that doesn't mean the capital will necessarily go to the right places."

Will we even get a vaccine?

Years later, we still don't have a vaccine for SARS, MERS or any other coronavirus — although nobody has splashed cash on those like they are now.

Part of the reason it's so difficult to make a vaccine is because coronaviruses cluster in our noses and throats, which the immune system thinks of more like an external surface of our bodies.

"It's a bit like trying to get a vaccine to kill a virus on the surface of your skin", Professor Ian Frazer, who developed the HPV vaccine, says.

And even if you can reach those cells, it can actually make inflammation worse — what's called "immune enhancement".

"With other coronaviruses in animals we've had trouble," says infectious diseases expert Professor Peter Collignon from ANU. "SARS infection was enhanced by some vaccines candidates and the same thing may have happened with a few candidates for RSV."

Truly the opposite of what you want from a vaccine.

Adding to the difficulty, this coronavirus doesn't infect mice, forcing us to test on ferrets and monkeys instead.

As we saw with the baboons that ran wild in Newtown in February, housing hordes of monkeys is complicated, so you simply can't run as many tests at once.

Fortunately, scientists genetically modified mice to allow them to be infected during the original SARS pandemic.

A savvy mouse wheeler and dealer froze the sperm of the spliced mice, which has become a hot commodity in 2020.

But it's quite literally become a rat race to get the mice to research teams in time.

While there seems to be a new team taking a vaccine to trial every week, only a third of vaccine candidates are successful for infectious diseases.

There's a reason the time "from lab to jab" is also called "the valley of death".

Scientists are trying to condense a decade-long process to 18 months and there's no guarantee that will work.

What's more likely is that the first round will produce some "almost there" vaccines that offer partial immunity, according to Dr Quinn.

"The flu vaccine offers 60-70 per cent protection. But those people who are infected are producing less virus and transmitting to fewer people and disease severity is reduced. So it still reduces the burden on the healthcare system."

But as Dr Collignon says, "You're not able to control the disease with partial protection — you'd need to keep doing the additional measures on top."

From lab to jab

We might think that finding a vaccine that's safe and effective is the challenge. But that's just the beginning.

The real bottleneck, says Dr Quinn, will be "building the infrastructure" for billions of doses.

Almost daily, companies are announcing supply deals for their yet to be proven vaccines, like Johnson and Johnson's "commitment to supply one billion doses" of the vaccine it does not yet have.

Bill Gates has put his hand up to lose "a few billion dollars" building factories for the seven most promising vaccine candidates, estimating that about five of them will go unused. "It's worth it", he said.

It's an expensive gamble that could crash and burn — or revive the global economy.

But who gets those early doses? There's a risk that vaccine distribution could end up like the fight for ventilators, masks and gloves, somewhat like toilet-paper-gate on the global stage.

The vaccine candidates that first reached human trials emerged from the US, whose foreign policy slogan is "America First", and Chinese state-run firms.

In what may be an early sign of what's to come, President Trump blocked a shipment of medical equipment from reaching Germany in March, which the German government called "modern piracy", before attempting to take over the promising German vaccine firm CureVac.

Meanwhile, China has been showering struggling countries with coronavirus aid, which has been described as "mask diplomacy".

If a vaccine were to become a "get out of jail free" card for China, how might that play out in distribution?

Governments are still haunted by the swine flu vaccine, which wealthy countries including Australia essentially hoarded.

Dr Komesaroff hopes we can avoid repeating the HIV crisis, where life-saving drugs were funnelled to "those in New York who could afford it" while in some African countries, the life expectancy halved.

"With HIV, it was easy for wealthy countries to remain comfortable, but if COVID-19 becomes widely disseminated in Africa and Asia, including Indonesia, which is of particular relevance for Australia, there will be risks to the rest of the world."

The best shot we'll get

Mention "the coronavirus vaccine" and you'll be swiftly reprimanded by Dr Collignon — "it's not 'when' the coronavirus vaccine, it's a big 'if'."

But the experts agree the scientific community has never worked like this before.

"The way we do science has completely changed," says Dr Quinn. "The way we normally distribute information is through publication which can take years. Now, the pre-print services mean there's no delay."

Then there's the millions being poured into experimental fields like genetic vaccines that could be applied far beyond infectious disease.

Perhaps in five years, Dr Jennens won't be putting his arm forward to receive a coronavirus vaccine, but administering a cancer vaccine.

"When you have something like this that galvanises the scientific community, you can jump start some pretty incredible new fields", says Dr Quinn.

In a worst-case scenario, we fail to develop a coronavirus vaccine, as we have with SARS and MERS. But the knowledge we gain along the way could change our health in ways we can't even yet imagine.

As Professor Adrian Hill from the Oxford University team put it, "Vaccines are good for pandemics, and pandemics are good for vaccines."

This is part of a series from the ABC News Story Lab on how we solve the coronavirus crisis. Our next piece looks at the treatments that could give our bodies the best shot at survival.

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