The race for a vaccine is on. Earlier this month, the U.S. government agreed to pay $4 billion to six pharmaceutical companies, including $1.6 billion to drug developer Novavax, in return for the promise of delivering 100 million doses of a new vaccine against the novel coronavirus by early 2021. This timetable is breathtakingly fast, as new vaccine development typically requires several years, but it demonstrates the urgency with which scientists around the world are trying to slow down COVID-19.
The sprint for a vaccine could bring a new technique to the fore: using messenger RNA (mRNA). If successful, the treatment would be the first-ever commercially available mRNA vaccine. In May, the pharmaceutical company Moderna released preliminary data showing that its mRNA vaccine safely offered some degree of immunity against COVID-19. A partnership between Pfizer and bioNTech also showed positive results in June. These results were based on tests in small groups of people, but they show the potential of this approach.
What is an mRNA vaccine?
Inside the human body, messenger RNA supplies the information that DNA uses to make proteins, which regulate our cells and tissues. Viruses use RNA for a much more devilish purpose. They lack the cellular machinery to replicate themselves, so they invade healthy cells and propagate within them, sometimes causing sickness or death. For example, the mRNA in the novel coronavirus behind COVID-19 enables a “spike protein” that pierces cells throughout the body. This is particularly damaging whenever the virus invades the lungs, making the simple act of breathing difficult.
An mRNA vaccine contains a synthetic version of the RNA that a virus uses to form proteins. The vaccine doesn’t contain enough genetic information to produce viral proteins; just enough to trick the immune system into thinking a virus is present so that it will spring into action to make antibodies, which are proteins specifically designed to fight a virus.
Traditional vaccines, such as for flu or measles, activate the immune system by injecting people with small amounts of a virus. Vaccines may include weaker “attenuated” forms of the virus, or a virus that scientists have killed but whose viral proteins can still stimulate immunity. Drew Weissman, an immunologist at the University of Pennsylvania and an expert about mRNA vaccines, says that in some very rare cases the virus is not dead despite best efforts to kill it, or the attenuated dose is so strong it makes some sick. The mRNA vaccines eliminate that concern because they do not contain any virus.
"You can never make an infectious virus with mRNA," he says.
Another weakness of traditional vaccines, he says, is that they can take a long time to develop. To make a vaccine, scientists typically grow a weakened form of the virus in chicken eggs and test which parts of the virus successfully elicit antibodies. This can take four to six months in the case of the annual flu vaccine, even though scientists already know how to make these vaccines and which flu strains are likely to predominate any given year. With a brand-new virus, the vaccine-making process can stretch into years or even decades. Large-scale testing of a new vaccine, while necessary to assure safety, also takes time.
"Let's say you want to make a killed virus,” Weissman says. “First you have to figure out how to grow it, and how to grow it at large scale. Then you have to figure out to kill it, but not change it so it no longer makes an immune response that protects the host. Then after you do that, you have to show that, in fact, the virus is dead.”
With a pandemic going on, speed is of the essence, and so vaccine researchers are trying to accelerate that timetable. "The advantage of RNA is that it takes you literally days to make a new vaccine," Weissman says.
Once researchers determine the mRNA that results in the virus in question producing its proteins, scientists can make synthetic RNA that becomes the basis of a new vaccine. In an ideal scenario, scientists would use specially selected enzymes to stimulate the production of this synthetic mRNA, and then wrap the mRNA in protective wrapping to prevent it from degrading.
So where are our mRNA vaccines?
The possibility of mRNA vaccines has existed since 1990 when researchers first injected mRNA into mice and elicited antibody production. In these early years, mRNA delivery was dangerous; mice sometimes died due to excessive inflammation after receiving the RNA. These unfortunate mice had activated what is known as the innate immune response, an indiscriminate strategy that mammals use to resist anything that might be harmful. This was a serious hurdle, as researchers could not make a useable mRNA vaccine without figuring out how to suppress this response, Weissman says.
The story began to change in the mid-2000s when Weissman and his colleague Katalin Karikó discovered how to reduce or eliminate the risk of inflammation. The answer turned out to be additional substances such as carbon atoms to mRNA without changing its function. "When you change the structure of some of those RNA bases, you get rid of the inflammatory potential of the RNA," Weissman says.
These additions block sensors on cells from overreacting to the newly injected mRNA. This understanding has been incorporated into the vaccines Moderna and Pfizer/bioNTech are testing. (Karikó is the senior vice president of bioNTech; Weissman is an advisor to bioNTech.)
This month both Moderna and Pfizer/bioNTech aim to begin studies of their mRNA vaccines in about 30,000 people apiece, hoping to show their vaccines are safe in large groups of people and effective at building some immunity to the coronavirus. If these studies show positive results, the world could be one step closer to its first mRNA vaccine and a way to slow the COVID-19 pandemic.
Sara Suliman, an immunologist at Harvard, says the sheer scale of the COVID-19 pandemic means that multiple vaccine types will be necessary—mRNA and otherwise. “In the case of COVID we can’t put all our eggs in one basket,” Suliman says. “Ideally, you want to give the whole world this vaccine.” arguing that no single company can meet a global vaccine demand.
In less extreme times, Suliman says, companies would not manufacture millions of vaccine doses without solid proof that a vaccine will enable long-lasting immunity. With COVID-19, though, companies may start to produce millions of doses based on less-solid evidence so they can be ready for distribution as soon as governmental groups like the FDA approve them.
Drew Weissman sees a big future for mRNA vaccines after the pandemic, too. Perhaps, he says, one day a single mRNA vaccine (sometimes supplemented with booster shots) could replace the 20 or so vaccines children receive today. Suliman, though, is more cautious, pointing out that the measles vaccine already works well as is and doesn’t need reconfiguring. She says we should save mRNA for new vaccines to face new threats—not reinvent the wheel.