Cast your mind back to 2020, if you can bear it. As the year progressed, so did the impact of covid-19. We were warned that wearing face coverings, disinfecting everything we touched, and keeping away from other people were some of the only ways we could protect ourselves from the potentially fatal disease.
Thankfully, a more effective form of protection was in the works. Scientists were developing all-new vaccines at rapid speed. The virus behind covid-19 was sequenced in January, and clinical trials of vaccines using messenger RNA started in March. By the end of the year, the US Food and Drug Administration issued emergency-use authorization for these vaccines, and vaccination efforts took off.
As things stand today, over 670 million doses of the vaccines have been delivered to people in the US.
This is an astonishingly fast turnaround for any new drug. But it follows years of research on the core technology. Scientists and companies have been working on mRNA-based treatments and vaccines for decades. The first experimental treatments were tested in rodents back in the 1990s, for diseases including diabetes and cancer.
These vaccines don’t rely on injecting part of a virus into a person. Instead, they deliver genetic code that our bodies can use to make the relevant piece of viral protein ourselves. The entire process is much quicker and simpler than using bits of virus. It sidesteps the need to grow viruses in a lab and purify the proteins they make, for example. And while the first approved mRNA vaccines are for covid-19, similar vaccines are being explored for a whole host of other diseases. Malaria, HIV, tuberculosis, and Zika are just some of the potential targets.
mRNA vaccines might also be used in cancer treatments tailored to individual people. Here, the idea is to trigger a specific response by the immune system—one that is designed to attack tumor cells in the body.
Moderna, the biotech company behind one of the two approved mRNA vaccines for covid-19, is developing mRNA vaccines for RSV (respiratory syncytial virus), HIV, Zika, Epstein-Barr virus, and more. BioNTech, which partnered with Pfizer on the other approved mRNA-based covid-19 vaccine, is exploring vaccines for tuberculosis, malaria, HIV, shingles, and flu. Both companies are working on treatments for cancer. And many other companies and academic labs are getting in on the action.
Self-made vaccines
Messenger RNA itself is a strand of genetic code that can be read by your DNA and used to make proteins. The lab-made mRNA used in vaccines can code for a specific protein—one that we’d like to train our immune systems to recognize. In the case of covid-19 vaccines, the code is for the spike protein found on the outer shell of the Sars-CoV-2 virus, which causes the disease. The mRNA itself is packaged up in lipid nanoparticles—tiny little envelopes that help it survive the journey into your body.
The vaccines are cheap, quick, and easy to make, says Katalin Karikó, an adjunct professor at the University of Pennsylvania who has pioneered research into the use of mRNA for vaccines. They are also very efficient. “You put [the mRNA] in cells, and half an hour later, they are already producing the protein,” she says.
The idea is that once your immune system has been exposed to such a protein, it is better placed to mount a strong response should it ever encounter the virus itself. In the case of covid-19, this is thought to be largely due to the production of antibodies—proteins that protect us against infections. Trained-up immune cells play an important role, too.
In theory, we could make mRNA for pretty much any protein—and potentially target any infectious disease. It’s an exciting time for mRNA vaccine technology, and vaccines for plenty of infectious diseases are currently making their way through clinical trials.
Universal protection
It’s tricky to predict exactly which mRNA vaccines might be the next to make it into health clinics. But hopes are high for a flu vaccine. Potentially, a universal vaccine could protect against multiple strains of flu, while protecting against the coronavirus at the same time.
The current flu vaccine works by introducing a protein from the virus to your immune system, which should mount a response and learn how to defeat the virus. But it takes months to grow the virus in eggs to make this protein. The production process has to start in February in order to have a vaccine ready for October, says Anna Blakney, who studies RNA at the University of British Columbia in Vancouver, Canada. Every year, scientists in the Northern Hemisphere guess which strain of flu is likely to take off there by looking at what has happened in the Southern Hemisphere.
These guesses aren’t always spot on, and the flu virus can mutate over time, even while it is in the eggs. As a result, “it’s a notoriously underperforming vaccine,” says Blakney. The flu vaccine used in the US in 2019-2020 was 39% effective, but the one used in the 2004-2005 flu season was only 10% effective, according to estimates from the US Centers for Disease Control and Prevention.
mRNA vaccines, on the other hand, are relatively quick to make. “You could imagine having a one-month turnaround for an RNA vaccine,” says Blakney. By September, scientists should have a much better idea of which flu strain is likely to take off in October and be better placed to target it.
There’s another potential benefit. Scientists can make mRNA vaccines that encode for more than one viral protein—which could allow us to create vaccines that protect against multiple strains of flu. Norbert Pardi at the University of Pennsylvania and his colleagues are working on a universal flu vaccine—one that Pardi believes would protect against every type of flu that can make humans sick. His team recently showed that the vaccine could protect mice and ferrets from 20 flu subtypes. Other labs are working on mRNA vaccines that protect against all coronaviruses.
If we can include the code for several proteins, there’s the possibility to protect against multiple diseases in one shot. Moderna’s vaccine for covid, flu, and RSV is already in clinical trials, for example. In the future, we could go even further—just one or two shots could, in theory, protect you from 20 different viruses, says Karikó.
Cancer vaccines
Before anyone had started developing mRNA vaccines for the coronavirus that causes covid-19, researchers were trying to find ways to use mRNA to treat cancer. Here the approach is slightly different—the mRNA would be working as a “vaccine therapeutic.”
In the same way that we can train our immune systems to recognize viral proteins, we could also train them to recognize proteins on cancer cells. In theory, this approach could be totally personalized—scientists could study the cells of a specific person’s tumor and create a custom-made treatment that would help that individual’s own immune system defeat the cancer. “It’s a fantastic application of RNA,” says Blakney. “I think there’s huge potential there.”
Cancer vaccines have been trickier to make, partly because there’s often no clear protein target. We can make mRNA for a protein on the outer shell of a virus, such as the spike protein on the virus that causes covid-19. But when our own cells form tumors, there’s often no such obvious target, says Karikó.
Cancer cells probably require a different kind of immune response from that required to protect against a coronavirus, adds Pardi: “We will need to come up with slightly different mRNA vaccines.” Several clinical trials are underway, but “the breakthrough hasn’t happened yet,” he adds.
The next pandemic
Despite their huge promise, mRNA vaccines are unlikely to prevent or treat every disease out there, at least as the technology stands today. For a start, some of these vaccines need to be stored in low-temperature freezers, says Karin Loré, an immunologist at the Karolinska Institute in Stockholm, Sweden. That just isn’t an option in some parts of the world.
And some diseases pose more of a challenge than others. To protect against an infectious disease, the mRNA in a vaccine will need to code for a relevant protein—a key signal that will give the immune system something to recognize and defend against. For some viruses, like covid-19, finding such a protein is quite straightforward.
But it’s not so easy for others. It might be harder to find good targets for vaccines that protect us against bacterial infections, for example, says Blakney. HIV has also been difficult. “They’ve never found that form of the protein that induces an immune response that works really well for HIV,” says Blakney.
“I don’t want to give the impression that mRNA vaccines will be the solution for everything,” says Loré. Blakney agrees. “We’ve seen the effects that these vaccines can [have], and it’s really exciting,” she says. “But I don’t think that, overnight, all vaccines are going to become RNA vaccines.”
Still, there’s plenty to look forward to. In 2023, we can expect an updated covid-19 vaccine. And researchers are hopeful we’ll see more mRNA vaccines enter clinics in the near future. “I really hope that in the next couple of years, we will have other approved mRNA vaccines against infectious disease,” says Pardi.
He is planning ahead for the next global disease outbreak, which may well involve a flu virus. We don’t know when the next pandemic will hit, “but we have to be ready for it,” he says. “It’s crystal clear that if you start vaccine development in the middle of a pandemic, it’s already too late.”
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