Vaccination has come a long way since physician Edward Jenner used pus from an infected blister to create the first vaccine against smallpox in 1796. Even so, vaccines have almost always used a part of a pathogen itself—until COVID-19 brought an emerging technology into the spotlight. Now, some experts predict the tech will lead to new vaccines against viruses from seasonal influenza to HIV.
The technology is based off messenger RNA, a molecule that carries genetic code; the two COVID-19 vaccines authorized for emergency use in the U.S. rely on it. Created separately by Moderna and a collaboration between Pfizer and BioNTech, both vaccines were developed in mere days and both were shown to be highly protective in clinical trials. (Find out more about how mRNA vaccines work.)
Some experts see mRNA vaccines as the key to faster or more effective vaccine programs, tackling multiple viruses with a single shot or providing protection against difficult diseases.
“The technology has been proven to be safe and effective, and everybody on planet Earth knows it, except for the anti-vaxxers,” says Derrick Rossi, a biologist and biotech entrepreneur who co-founded Moderna and has since left the company. “But I drank the Kool-Aid a long time ago.”
In January, Moderna pledged new programs to develop mRNA vaccines against Nipah virus, HIV, and influenza, adding to its vaccine pipeline that already included more than 20 mRNA efforts. Pfizer is also working on additional mRNA-based vaccines, including one for seasonal influenza, says Phil Dormitzer, the company’s chief scientific officer and vice president of viral vaccines. Dozens of other manufacturers and labs around the world are working on similar efforts.
But while it’s tempting to look at the technology as some kind of scientific savior, some experts caution that only so much can be extrapolated from the success of the COVID-19 vaccines and that mRNA won’t answer all vaccine prayers. Here is how experts think mRNA could change the landscape of vaccines in the future—and the many hurdles they will face as they are developed.
The method behind mRNA
Traditional vaccines use weakened viruses or viral protein fragments to teach the immune system to recognize and fight an invader. Scientists wagered mRNA could teach the same lesson, if only they could get it to stick around. When used in a vaccine, mRNA is a mobile molecule that delivers instructions to our bodies to make the components of a virus that will trigger an immune response. But it’s a temporary message: The body quickly degrades mRNA after reading it—a problem for scientists who wanted to use it in vaccines.
Drew Weissman, a professor of medicine at the University of Pennsylvania, and Katalin Karikó, a biochemist behind Pfizer and BioNTech’s COVID-19 vaccine, helped solve that puzzle in 2015. Their team discovered that enveloping mRNA in a coating of lipid nanoparticles not only delivered the message, it produced a vaccine adjuvant, a substance that promotes antibody production. (Also find out about the scientists who spent 12 years unlocking another vital part of the first mRNA vaccines authorized for human use.)
With this delivery system, mRNA vaccines can teach our bodies to make and fight a viral protein without ever encountering the pathogen. What’s more, the same basic ingredients can be used each time, adding only one unique component—an mRNA sequence—to produce the required protein.
In the Moderna and Pfizer-BioNTech COVID-19 vaccines, that ingredient is the sequence that codes for the coronavirus’s spike protein, which is what allows the virus to enter human cells. In theory, you could swap that spike protein sequence for one that makes an HIV antigen, and you’d have an HIV vaccine, says Weissman. Finding the right protein is the challenge, but the method is always the same. “That’s why they call it ‘plug and play,’” he says.
The future of vaccines (maybe)
With mRNA, scientists can go from “discovering the sequence of the virus to having something in a vial within weeks,” says Anna Durbin, a professor of international health at Johns Hopkins Bloomberg School of Public Health in Maryland. Moderna, for example, created its COVID-19 vaccine within two days of getting the sequence. And on the heels of such clinical successes for the technology, scientists are redoubling efforts to create mRNA-based vaccines for a host of other ailments.
Weissman’s lab is working on about 30 mRNA vaccines, he says, including a universal influenza vaccine that would work against all strains of flu and a pan-coronavirus vaccine that would fight against all coronaviruses, from the original Severe Acute Respiratory Syndrome (SARS) to Middle East Respiratory Syndrome (MERS).
Weissman says that mRNA vaccines could even fight multiple pathogens in a single shot by targeting what are called conserved sequences, portions of viral genomes that don’t mutate at all or as rapidly and that are consistent across multiple pathogens and their variants. Conserved sequences don’t often elicit an immune response, which is why some previous vaccines have not been effective against them. For example, influenza vaccines target the hemagglutinin, a protein made of a head and stalk. Past flu vaccines elicited immune responses against the quickly mutating head but not the conserved stalk.
But thanks to the adjuvant that mRNA creates when it’s enveloped in lipid nanoparticles, it’s able to target and create a strong immune response against the stalk, Weissman explains.
If successful in human clinical trials, Weissman’s universal flu vaccine could mean getting a shot every decade instead of every year, he says. And some scientists, including Weissman, believe that because mRNA can elicit powerful immune responses against parts of viruses that are usually less responsive, these vaccines could also hold the key to previously unsolvable puzzles, such as HIV.
But mRNA vaccines are hardly a “magic bullet,” Dormitzer cautions. And they will face many hurdles, some experts say, before they can become mainstream and accepted by the masses.
Hurdles and hardships
Pfizer’s COVID-19 vaccine, for example, must be stored at −70 °C, a temperature much colder than some health centers can accommodate. That’s because of the lipid nanoparticles used to deliver the mRNA, Weissman says. Lipid nanoparticles are like fat: When a fat droplet is kept cold, it holds its shape. But when fat droplets are left out or heated, they liquify and combine. Lipid nanoparticles do the same thing, and once they do, they don’t work.
Other scientists are working on different delivery systems that would avoid lipid nanoparticles; Pfizer and Weissman’s labs are working on freeze drying mRNA vaccines, which Weissman says could allow them to be stored in a refrigerator or even at room temperature. But it’s a costly process, and ensuring that it works takes a lot of time.
“To know that something is stable in the refrigerator for a year, you have to put it in the refrigerator for a year and wait,” Dormitzer explains.
Scientists also don’t yet know how long the immune response will last after receiving an mRNA vaccine. But the Pfizer-BioNTech COVID-19 vaccine was the first of its kind authorized outside of clinical settings, so scientists simply don’t have enough data from clinical trials.
The COVID-19 vaccines have also caused some uncomfortable reactions. For example, about 90 percent of people report arm soreness after getting the shot, compared with about 60 percent of people who have arm pain after receiving a flu vaccine. These mild reactions may be tolerable in a pandemic, says Durbin, but they might be less acceptable outside of crises or for less threatening pathogens. “We have a hard enough time getting people vaccinated for the flu now,” she says.
More troubling are the anaphylactic reactions some people experience after getting a COVID-19 vaccine. A little more than two of every million people who have received the Moderna shot experienced anaphylaxis, a severe, potentially life-threatening allergic reaction, while Pfizer and BioNTech reported about 11 cases of anaphylaxis for every million doses of its vaccine. Statistically speaking, the risk is low and can be managed. But it’s still higher than for other vaccines, and the reactions may be caused by lipid nanoparticles—the very things that allow mRNA to go into the body without degrading.
Nicole E. Basta, an associate professor and infectious disease epidemiologist at McGill University in Montreal, says that people often weigh the risk versus the benefit when deciding whether to be vaccinated. For COVID-19 vaccines, their high efficacy—as much as 95 percent in Pfizer’s vaccine and about 94 percent for Moderna’s—should tip the scales away from risk and toward benefit, she says.
And while new technology often means changing or conflicting information comes out quickly, Basta says it provides a unique chance for scientists to help people become more comfortable with the technology and better understand it.
“I really encourage people to continue to keep an eye on what's happening in the field of vaccines, because vaccines are most beneficial when a large number of people get them,” she says. “I think the discourse and discussion about mRNA vaccines is a really positive thing for public health, and I'm hopeful this is going to improve vaccine trust.”
Pumping the brakes
While the technology is promising, Pfizer’s Dormitzer questions whether mRNA will be the problem-solver many believe.
“There are some diseases that are really, really susceptible to immunization,” he says, and that includes SARS-CoV-2. “Others are quite hard. Flu is a hard one. And some have been pretty impossible up until now,” including HIV and hepatitis C. Some viruses may prove impervious to the technology. Other vaccines are so effective now—like the measles, mumps, and rubella (MMR) vaccine—that Dormitzer says it would be pointless to change them.
Whether or not mRNA vaccines become the vaccines of the future, one thing is almost certain: The next ones to hit the market won’t be developed nearly as fast. While the COVID-19 vaccines were created at record-breaking speeds, “the severity of the pandemic really put the gas pedal on these products,” says Rossi, who is no longer affiliated with Moderna.
The crisis also removed several barriers to typical vaccine production, with every manufacturer prioritizing the same goal and many conducting phases of clinical trials in parallel, rather than years apart. Previous mRNA vaccines had already been made against other viruses, including coronaviruses, though none have been brought to market.
“What people have to realize is that we’ve been working on mRNA for 15 years, and on mRNA vaccines for eight years,” Weissman says.
Dormitzer says there are lessons vaccine-makers can learn from the pandemic, such as tweaking their processes to do trials in concert or more efficiently. “I think we can do some acceleration,” he says. But not all scientists will be focused on a singular vaccine moving forward.
“We're going to get back to normal and have our normal range of interesting concerns,” he says. “And so, things won't be quite like this, nor would we want them to be quite like this.”