Hello again from The Checkup!
This week the Nobel Committee for Physiology or Medicine honored two scientists whose research into messenger RNA (mRNA) technology paved the way for much-lauded covid-19 vaccines. Katalin Karikó and Drew Weissman figured out how to tweak mRNA to prevent it from setting off an inflammatory reaction. Their discovery, first published in 2005, was key to developing the mRNA vaccines from Moderna and Pfizer/BioNTech, part of a vaccination strategy that saved millions of lives.
The Nobel shouldn’t have come as a surprise to them. The pair has won other prestigious prizes, and many have predicted a Nobel was imminent. (We flagged mRNA vaccines as one of the top 10 breakthrough technologies in 2021). But they still couldn’t believe the news.
“Kati texted me this cryptic message at four in the morning: ‘Did Thomas call?’” Weissman said at a press conference on Monday morning. “I texted her back and said, ‘No, who’s Thomas?’ She says: ‘Nobel Prize.’” They suspected a prank, and said they didn’t fully embrace the win until the public announcement.
Most vaccines train the immune system by supplying the pathogen against which they’re meant to protect—either the entire pathogen or some crucial component. The mRNA vaccines work a bit differently. They provide genetic code that cells within the body can translate into proteins. In the case of covid-19, the vaccines contain mRNA that codes for the “spike” protein found jutting from the outer surface of the virus. The body then produces copies of that protein, and the immune system learns to recognize it.
The idea of using mRNA in vaccines has been around for decades, but scientists hit a major stumbling block early on. Antonio Regalado recounted some of this history in his 2021 MIT Technology Review feature on mRNA. When researchers injected mRNA into mice, the animals got sick. “Their fur gets ruffled. They lose weight, stop running around,” Weissman told Regalado. Larger doses proved fatal. “We quickly realized that messenger RNA was not usable,” he said.
When foreign mRNA are injected into the body, the immune system spots a threat and creates inflammation. Karikó and Weissman found that by tweaking the genetic code slightly, they could nearly eliminate this problem. When the pandemic began in 2020, scientists had already been using their method to develop mRNA vaccines for other infectious diseases, so it was relatively simple to pivot to covid-19.
What makes mRNA a game changer? The vaccines are so easy to produce. When manufacturers wanted to update their covid vaccines this fall, they simply had to swap in a new code. By swapping in different codes, they should be able to target different pathogens.
Moderna has already filed for regulatory approval of an mRNA vaccine for the respiratory syncytial virus (RSV), a cold-like illness that can be severe in infants and older adults. The company also has an mRNA flu vaccine in late-stage clinical trials. An interim analysis in September showed that the shot outperformed traditional flu shots across all age groups, according to Moderna. Pfizer is also testing an mRNA flu vaccine, as are Sanofi Pasteur and GlaxoSmithKline, in partnership with CureVac. And several of the companies are also working on combination vaccines that protect against covid-19 and the flu.
There are a couple of reasons multiple companies are focusing their mRNA efforts on the flu. First, current flu vaccines rely on viruses grown in chicken eggs or cells, a laborious process that takes months. Using mRNA for flu vaccination would eliminate the need to grow the virus and speed the process substantially. That might allow for a better match between the vaccine and circulating flu strains (because the strains could be selected closer to flu season) and a quicker response should an influenza pandemic occur.
The other reason is that researchers can add in mRNA for many different flu strains to create a vaccine that might provide broader protection. Last year, a team at the University of Pennsylvania tested an mRNA vaccine containing antigens from all 20 known influenza subtypes that infect humans. In mice and ferrets, the vaccine protected against strains that matched the vaccine and strains that didn’t. This year, the National Institutes of Health launched a clinical trial to test another mRNA flu vaccine that doesn’t contain multiple antigens, but is designed to elicit a response to a portion of the virus that isn’t as likely to change from year to year.
Flu is just the beginning. The list of diseases for which mRNA vaccines are being developed goes on (and on and on): malaria, HIV, Zika virus, Epstein-Barr virus, cytomegalovirus, herpes, norovirus, Lyme disease, Nipah virus, C. difficile, hepatitis C, leptospirosis, tuberculosis, shingles, acne, chlamydia, and many others.
But wait! There’s more. mRNA could be a powerful way to treat diseases, not just prevent them. In fact, it was originally envisioned as a therapeutic. mRNA-based therapies for cancer have been in trials for a decade. The idea here is to provide mRNA that codes for proteins on the surface of the tumor. The immune system would then learn to recognize these antigens, and it can more effectively detect and attack cancer tissue.
Companies are also working on mRNA therapies for rare diseases, like cystic fibrosis. People with this disease have mutations in a gene called CFTR, the cystic fibrosis transmembrane conductance regulator. These mutations mean that the CFTR protein, which helps water move in and out of cells, doesn’t function correctly, leading to sticky mucus that clogs the lungs and causes recurring respiratory infections.
Vertex, in collaboration with Moderna, has developed mRNA that is designed to be inhaled. Once inside the lungs, cells translate the code into functional CFTR. Late last year, the Food and Drug Administration (FDA) gave Vertex the green light to launch a trial to test mRNA for cystic fibrosis. Moderna has also launched clinical trials to test therapies for methylmalonic acidemia, a disease that affects the function of the liver, and propionic acidemia, a rare metabolic disorder.
Not all of these efforts will succeed. In fact, many won’t. But the mRNA bonanza is sure to yield some wins. When Karikó and Weissman made their breakthrough discovery in 2005, “I told Kati our phones are going to ring off the hook,” Weissman said in an interview with Boston University’s alumni magazine in 2021. “But nothing happened. We didn’t get a single call.” Today, I think it’s safe to assume their phones won’t stop ringing.
Read more from our archive
And this year, Jessica Hamzelou looked at how mRNA might boost flu vaccines and treat cancer.
Plus, listen to an interview with Dave Johnson, the chief data and artificial intelligence officer at Moderna, who told the history of how Moderna’s covid-19 vaccine came to be.
From around the web
The story of how Nobel winner Katalin Karikó got demoted and persevered. (X)
The Centers for Disease Control and Prevention says a common antibiotic could protect some people against sexually transmitted infections when taken after sex. (New York Times)
Why is life expectancy falling in the US? Blame chronic diseases. (Washington Post)
Novavax, the oft-overlooked covid-19 vaccine manufacturer, gets FDA approval for its updated protein-based shot. (FDA)
The World Health Organization issued its second malaria vaccine recommendation, a move that is expected to ease supply constraints. (WHO)