Jonathan Wosen , 2025-05-21 17:25:00
Messenger RNA vaccines fueled the response to the worst pandemic the world has faced in a century and led to a Nobel Prize. This week, they’re set to face intense scrutiny from critics doubtful of the safety and efficacy of these shots.
On Wednesday, a subcommittee of the Senate Homeland Security and Governmental Affairs Committee is holding a hearing on, in its own words, “The Corruption of Science and Federal Health Agencies: How Health Officials Downplayed and Hid Myocarditis and Other Adverse Events Associated with the COVID-19 Vaccines.”
The hearing comes as some state legislatures look to ban mRNA vaccines, and as the Trump administration is gathering information about mRNA research funded by the National Institutes of Health, triggering fears that grants for such work could soon be terminated. The federal government recently announced plans to focus NIH’s own work on universal flu and coronavirus vaccines employing chemically inactivated whole viruses.
These developments have imperiled the future of mRNA, a once-dismissed technology that rocketed to prominence during the pandemic and has the potential to power cancer vaccines, gene-editing therapies, and rare disease medicines. Recent events have also resurfaced basic questions about the safety and efficacy of vaccines built with these snippets of genetic code.
Nearly five years after regulators cleared the first mRNA vaccines for use, researchers have more data than ever to answer those questions. Here’s a quick breakdown of what we know — and how we know it.
What is mRNA, and why use it in vaccines at all?
mRNA molecules are snippets of genetic code that exist in all the cells of our body. Without them, we wouldn’t be alive. That’s because our DNA doesn’t do anything on its own. Those chemical instructions need to be read and used to produce proteins, which carry out the bulk of a cell’s operations. mRNA makes that possible by carrying genetic information out of a cell’s nucleus and to its protein-making machinery, where amino acids link together to build a new protein.
Researchers first discovered mRNA in 1961, when they found that treating bacteria with a chemical that blocked RNA synthesis halted protein production. That finding raised the tantalizing possibility that researchers might be able to design mRNA to make any protein they wanted — like a viral protein meant to teach the immune system to fight off infection.
mRNA is especially convenient for vaccine development because it can be manufactured the same way regardless of what protein it codes for. Researchers only have to change the molecular sequence, and that can be done quickly — a helpful feature when trying to keep up with fast-mutating viruses.
“If you were going to try to do that in a traditional vaccine, you have to grow up very, very large vats of proteins made from viruses … inactivate them, purify them, and test them. And by the time you do all that, you may miss the window when the vaccine is going to be most useful,” said Robert “Chip” Schooley, an infectious disease expert at the University of California, San Diego.
That’s a key reason why Moderna and Pfizer turned to mRNA at the start of the Covid-19 pandemic, building on decades of foundational work. Since then, federal regulators have approved a Moderna vaccine for respiratory syncytial virus. Companies are also working to develop mRNA-based flu vaccines, and there are earlier-stage studies underway testing an mRNA vaccine for HIV, a virus that has thwarted vaccinologists for decades.
How do we know mRNA vaccines work?
Moderna and Pfizer’s Covid-19 vaccines were cleared for use based on large studies that enrolled tens of thousands of volunteers. Moderna’s trial enrolled more than 30,000 volunteers, while Pfizer’s recruited more than 43,000. Some volunteers were randomly assigned to receive a vaccine designed to trigger an immune response to the coronavirus’s spike protein, a surface molecule that allows the virus to latch onto and slip inside of cells. Other participants got a placebo injection. To avoid biasing the study, volunteers weren’t told whether they were given vaccine or placebo, and medical staff administering the shots didn’t know which group their patients were in.
Randomized controlled trials such as these are the gold standard of evidence in clinical research, and they showed that the vaccines initially had more than 90% efficacy in preventing illness. Similarly, in a late-stage trial of nearly 37,000 people across 22 countries, Moderna’s RSV vaccine showed 83.7% efficacy against lower respiratory tract disease caused by the virus.
A vaccine’s efficacy, how it performs in a clinical trial, doesn’t always match its effectiveness, how it performs in the real world. But researchers have now studied the effectiveness of mRNA vaccines extensively, often by analyzing electronic health records and insurance claims. Such studies have shown that protection against infection or mild disease has decreased substantially as the virus has changed and as immune responses sparked by the vaccines have waned.
For instance, a 2021 study of Kaiser Permanente members in Southern California found that two doses of Moderna’s mRNA vaccine were more than 86% effective against infection with most coronavirus variants. But a study published the next year based on the health system’s data found that the shots were only 44% protective against infection with the Omicron variant of the virus. Numerous studies have shown similar trends. Another reason the observed benefits of vaccination have narrowed compared to the early days of the pandemic is that many unvaccinated people have now had Covid-19 and thus have natural immunity to the virus.
Protection against severe disease, however, has held strong. A Centers for Disease Control and Prevention analysis of data from hundreds of hospitals and Medicare claims found that, from 2023 to 2024, Covid-19 vaccines reduced immunized adults’ risk of ending up in an intensive care unit or dying from the disease by almost 70% during the first two months after vaccination and by half up to 10 months after vaccination.
“They continue to hold up if your measure of success is keeping you out of the hospital or keeping you from dying of Covid. And for the last five years, the majority of people who died of Covid have been unvaccinated, or at least under-vaccinated. The proof is in the pudding,” said Mark Sawyer, an infectious disease expert at Rady Children’s Hospital. He and UCSD’s Schooley have both served as members on the FDA’s vaccine advisory committee.
How do we know these vaccines are safe, especially in the long term?
Hundreds of millions of people in the U.S. have gotten mRNA vaccines, and billions of doses have been administered worldwide. That has allowed researchers to scour for side effects too rare to show up in a 30,000-person clinical trial, or that might appear after more than a few months.
“The number of people that could be evaluated for the vaccine and [adverse] reactions was enormous, much larger than we’ve ever been able to do,” said Kathryn Edwards, scientific director of the Vanderbilt Vaccine Research Program.
Researchers have turned to countries with large, centralized health systems to assess global safety, such as Canada, England, South Korea, and Israel. In the U.S., safety databases such as the Vaccine Adverse Event Reporting System, or VAERS, co-managed by the CDC and Food and Drug Administration, and V-safe, a vaccine safety tracking system managed by the CDC, have amassed hundreds of thousands of data points. The CDC also tracks adverse events though the Vaccine Safety Datalink, a collaborative project with health care organizations across the country. And the Department of Defense maintains its own system for monitoring adverse events after vaccination among military members and others affiliated with DOD.
Some of these systems, such as VAERS and V-safe, allow vaccinated people to self-report how they feel after their shots. That comes with a caveat: These reports can’t definitely prove that a person’s symptoms were caused by a vaccine. But researchers can look for signs there is a possible vaccine side effect that needs to be studied more closely.
That was how researchers first saw hints that mRNA Covid-19 vaccines were linked with a slightly increased risk of inflamed heart muscle, or myocarditis, in younger adults, particularly young men. A 2022 study reported that the Pfizer and Moderna vaccines led to an additional 22 and 31 myocarditis cases, respectively, for every million 18- to 29-year-olds in the U.S. Most of these rare cases were mild and didn’t cause more than brief chest pain. By comparison, SARS-CoV-2 infection causes myocarditis at much higher rates than vaccination, with the CDC reporting 150 cases per 100,000 Covid-19 patients.
Edwards noted that vaccine-associated myocarditis cases have dropped since the early days of the vaccine rollout. One possible reason why: While people got their first two doses of mRNA vaccine within three to four weeks, boosters are administered far less frequently. She added that in Canada, which spaced out the first two mRNA vaccine doses more than in the United States, myocarditis rates were lower than in the U.S.
Edwards served on the data and safety monitoring board for Pfizer’s Covid-19 vaccine trial, and she was a reviewer of an extensive report by the National Academies of Sciences, Engineering, and Medicine on Covid-19 vaccine safety. Apart from myocarditis, the more than 300-page report did not find major safety risks connected with the mRNA vaccines. By comparison, side effects such as stroke, bleeding, and Guillain-Barré syndrome, a rare autoimmune condition, were linked to AstraZeneca’s vaccine, which uses a modified cold virus to shuttle genetic information coding for the SARS-CoV-2 spike protein into cells.
Is tissue from aborted fetuses used in mRNA vaccines? And can these vaccines integrate into our DNA?
No and no. These vaccines contain mRNA encased in lipid nanoparticles, fatty bubbles that protect the mRNA until it’s safely delivered into a cell. The shots don’t contain fetal components. During the early stages of research and development, Moderna and Pfizer tested their vaccines in the lab using HEK 293 cells, a cell line originally derived from a 1973 abortion in the Netherlands. HEK 293 is one of the most widely used cell lines in biomedical research today, and working with these cells does not require harvesting additional fetal tissue. Scientists simply allow existing cells to grow and divide in the lab.
mRNA can’t integrate into the genome since it doesn’t enter the nucleus, the part of a cell where DNA is stored. The molecule only enters the cytoplasm, the watery inner space that fills most of a cell and where protein production takes place.
Outside of vaccines for infectious disease, what else is mRNA used for?
There’s a wide range of other potential uses for mRNA. Plenty of biopharma companies are working on cancer vaccines that use mRNA to teach the immune system to target proteins expressed by malignant cells but which are not found on healthy cells. Moderna and Merck have reported that pairing a cancer vaccine tailored to each patient with an immunotherapy drug could reduce the risk of recurrence in patients with advanced melanoma.
Researchers are also developing mRNA therapies that teach patients’ cells to produce proteins that are missing or defective. Vertex is in the process of testing that strategy in cystic fibrosis, with the goal of reaching the 10% of patients who can’t be treated with the company’s existing therapies. And companies like Intellia Therapeutics are working on therapies that use mRNA to code for Cas9, a key component of the gene-editing tool CRISPR that precisely cuts DNA. The biotech has reported promising results on this strategy from a couple of trials, raising hopes this strategy could lead to lasting therapies for a host of genetic diseases.
Coming out of the pandemic, biopharma leaders and academics were especially hopeful that Covid-19 vaccines would only be the beginning of mRNA’s future. That optimism has been replaced by profound uncertainty, with investors saying they’d need to see stellar data to make an investment in mRNA given the current political environment. The Trump administration is reevaluating a $590-million contract with Moderna for developing an mRNA-based bird flu vaccine; the company’s stock, which trades under the ticker “MRNA,” is down 36% this year.