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When a novel coronavirus began infecting humans in late 2019, our immune systems were caught off-guard. The virus clogged lungs. It caused clotting and heart problems. It spread quickly and killed indiscriminately. Those who battled the virus and survived were left with lingering health issues, struggling for breath. The virus had evolved a near-perfect mechanism for invasion, and we could not contain it.
As the scale of the pandemic became clear, it was apparent there would only be one way out: We’d need a vaccine. The question rapidly morphed from “will they work?” to “how can we make them work as soon as possible?” Science moved rapidly, too.
Now, just 11 months after the coronavirus’s genetic sequence was revealed, two vaccine candidates hope the pandemic could come to an end sooner rather than later — and they use a breakthrough vaccine technology that could change how we battle illness and disease in the future.
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Biotech giant Pfizer and young upstart Moderna have announced preliminary results from large clinical trials demonstrating that their vaccines do prevent COVID-19 infections. Pfizer, and research collaborator BioNTech, have submitted their vaccine for emergency use authorization with the US Food and Drug Administration. Moderna is expected to follow suit in the coming weeks.
The accelerated development and testing are a spectacular and unprecedented achievement. Vaccines can take over a decade to create, but the two firms have built them in just 10 months. Their successes arise in part due to how they designed their new vaccines.
Both use synthetic messenger RNA, or mRNA, a molecule that tells cells how to build proteins. With it, you can trick cells into producing proteins usually found in SARS-CoV-2, the virus that causes COVID-19, and stimulate the immune system — without making patients sick — to provide protection against infection.
These are the first two vaccines to use this pioneering technology. If they are as effective as early data suggests, they could herald a new era in vaccine and therapeutic design. With significant refinement, mRNA vaccines could treat not just viral diseases like COVID-19, but inherited diseases, allergies or even cancer. “I think we’ll see some pretty incredible breakthroughs based on these technologies in the future,” says Larisa Labzin, an immunologist at the University of Queensland, Australia.
And if another pandemic catches our immune systems off-guard in the future, mRNA vaccines have the potential to put a stop to things faster than ever before.
Hijacking a factory
Cells are protein factories. Almost every cell in the body has a tiny compartment known as the nucleus, where the body’s instruction manual, DNA, is stored. DNA contains two strands, twisted into a double helix, composed of four bases. Stretches of DNA, containing a few bases or many thousands, form genes.
Genes are like chapters or sections in the manual. They contain the information necessary to build specific proteins. But reading the instructions requires a few steps. The DNA strands have to be unzipped so just one strand of bases is accessible. Once unzipped, an enzyme swoops in and builds the mirror image of that single strand in a process known as transcription.
This single strand is mRNA. Once the cell moves the mRNA to another machine in the factory, a ribosome, it’s able to construct a protein. Here’s where the new vaccines come in: You can skip the DNA unzipping and hand a cell the mRNA instructions directly, enabling it to make any protein you want.
With the coronavirus, scientists found the perfect protein to build: the spike.
Finding a target
For all the havoc it has wreaked, the coronavirus is not a complicated virus. Its greatest weapon is also its Achilles’ heel.
A single coronavirus particle is like the head of the medieval morning star; a tiny, spiked wrecking ball. Inside lies its entire genetic blueprint, from which it constructs protein spikes. The spikes, which jut out from SARS-CoV-2’s shell, allow it to force itself inside human cells and hijack the factories, inserting its genetic instructions to make more copies of itself.
As soon as the genetic blueprint for SARS-CoV-2 was known, in early January, scientists and researchers homed in on the spike protein. After the previous SARS pandemic in 2002-03, studies showed the protein would be a great target for vaccine development, because of its critical role in infection. SARS-CoV-2’s spike is very similar to the spike found in the SARS virus, with a couple of tiny genetic tweaks.
Early research showed that when immune cells identify the spike, some produce antibodies to neutralize the virus and others are recruited to kill any cells already infected. Importantly, some immune cells remember their interactions with the spike, allowing any subsequent infection to be fought off. The spike protein became a viable target for vaccines and development began in earnest.
There are several different ways to create a vaccine, but they all have the same goal. “We’re trying to trick the immune system into thinking that it’s seen the virus before,” says Labzin.
In the past, vaccines have utilized weakened versions of a virus or specific pieces of a virus to stimulate immunity. The human papillomavirus, or HPV, vaccine, for instance, contains pieces of four different HPV strains. Similarly, some COVID-19 vaccines in development are using inactivated virus or weakened versions of SARS-CoV-2. In these vaccines, the virus has been manipulated to stimulate the immune system — but it has been altered to ensure it does not make the patient sick.
Another high-profile vaccine candidate, developed by Oxford University and pharma company AstraZeneca, uses a different method again. “They basically get the virus and take out all the dangerous parts of it,” says Labzin. The chimpanzee virus becomes a courier, delivering DNA instructions to a human cell.
Pfizer’s and Moderna’s vaccines are completely different. They deliver synthetic mRNA to cells, and they’re the first vaccines ever built to fight infectious disease this way.
A plug-and-play vaccine
It’s no surprise mRNA vaccines zipped ahead in the race for a coronavirus vaccine.
Moderna has been tinkering with them for years. BioNTech, which partnered with Pfizer, has been trying to develop the tech for influenza. There was a lot of uncertainty as to how successful they could be. But the global pandemic provided an opportunity to really put the new vaccine strategy to the test.
Messenger RNA vaccines are platforms. To borrow a phrase from the tech world, mRNA vaccines work like plug-and-play devices. In each vaccine, mRNA instructions (software) are encapsulated inside a droplet of fat (hardware). In theory, you can plug any mRNA instructions you wish into the droplet and get the body to start making the protein of your choice.
In Pfizer’s and Moderna’s vaccines, the instructions code for the SARS-CoV-2 spike. Human cells recognize the spike, and the immune system responds as if infected by the real virus.
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Pfizer’s data suggests its mRNA vaccine is 95% effective. Moderna says its own vaccine is 94.5% effective. They can protect against mild and severe forms of COVID-19. But even though the initial data looks good, what exactly goes on inside the body is yet to be fully understood. “The mechanism by which specific mRNA vaccines activate the immune system is not yet fully known,” says Magdalena Plebanski, professor of immunology at RMIT University, Australia.
They’re also very quick and easy to produce. Where other types of vaccines take weeks of lab work, mRNA molecules can be assembled and placed in a vaccine within days.
However, it’s fragile and prone to destruction. As a result, mRNA vaccines require storage in ultra-low temperatures. Both Pfizer’s and Moderna’s vaccines must be kept at either -70 degrees Celsius or -20 degrees Celsius, respectively, and cannot be stored in a regular fridge for long periods of time. This threatens the supply chain and poses problems for production and storage.
Can we end all pandemics?
We’re yet to see how well these vaccines will hold up over the long term. The end of the current pandemic is still a ways off. The results that have been so positively received are preliminary and require extensive peer review. Even if they pass that process and the distribution and storage problems are ironed out, it will still be some time before COVID-19 is behind us.
Still, initial results show the two mRNA vaccines are safe and surprisingly effective. Analysis and follow-up over years will be required to understand how long the vaccinations last and how robust they are: Can they prevent disease altogether, giving us a chance to eradicate the disease? Or will they merely help slow the spread?
But the small successes do signify a leap forward for vaccine development. If mRNA vaccines can become truly plug-and-play and we can throw any instructions we like at them, we can begin to think about other diseases where they could be beneficial. We have found the keys to the protein factories — so what will we build?
One line of study is cancer research. Dozens of clinical trials are underway or completed, evaluating how mRNA might be used to combat different types of cancers. Some cancers express very specific proteins the body recognizes as foreign. By decoding the mRNA that produces these proteins, researchers can produce tailor-made vaccines against cancer — a lofty goal, but one that has demonstrated positive benefits in prostate cancer, lung cancer and bladder cancer.
That’s not to say Moderna or Pfizer and BioNTech can pivot their COVID-19 vaccine to cancer tomorrow and have a working prostate cancer fix. It’s here where the plug-and-play analogy breaks down a little. Even with certified hardware, each vaccine requires its own evaluation process.
“When you tweak an mRNA sequence or formulation in a vaccine, you are highly likely to need to go all the way back to square one,” says Plebanski. “Safety is the most important parameter for vaccines. That is why they take so long to be tested and deployed.”
If a new virus were to arise and cause a pandemic, the hardware built during today’s crisis will certainly help speed up vaccine development, but it won’t skip past the protocols that build safety into the process.
And it’s certain we will confront another pandemic. It’s certain our immune systems will be caught off-guard once again. The tried-and-true methods of social distancing, mask wearing and good hygiene will help keep the unknown disease at bay. But they may not be enough.
It’s too early to say if they will end all pandemics, but knowing that mRNA vaccines work in this one might give us a head start on the next.