mRNA: Deliverance, Dud, or Danger?

 by Bethany McLean

It’s hard to imagine, but just five years ago, very few people outside of a small group of extremely determined scientists had heard of mRNA. Then came the pandemic. The once obscure molecule was celebrated as our salvation, as it served as the basis for vaccines to fight Covid-19. The once-unknown scientists who had advanced mRNA technology won the Nobel Prize in 2023 for saving millions of lives. 

For mRNA, vaccines were just supposed to be the beginning. The technology was supposed to be the holy grail, the thing that would turn our bodies into factories for making the medicines that could cure us of—well, anything, from rare diseases to cancer. “Out of the horror of Covid will come remarkable advances,” said Jeremy Farrar, the then-director of Wellcome, a charitable trust dedicated to healthcare, in 2022.

Fast-forward to today, with mRNA now facing an implacable foe: Health and Human Services (HHS) secretary Robert F. Kennedy Jr. In 2021 RFK Jr. claimed that the Covid shot was “the deadliest vaccine ever made.” Two weeks ago he announced that the federal government was canceling nearly $500 million in government-funded mRNA research projects. Entrepreneurs who have founded companies to develop mRNA-based therapeutics say the government’s antipathy is causing investors to pull out. 

Moderna, the 15-year-old biotech company that was founded to exploit mRNA—its very name is a play on the molecule—has lost 95 percent of market value, and it plans to lay off 10 percent of its workforce. Even before Kennedy’s latest salvo, the government had canceled a $766 million contract with the Biomedical Advanced Research and Development Authority (BARDA) to develop several flu vaccines.

For mRNA true believers—and there are still plenty of them—these attacks on a molecule with such lifesaving potential is akin to Galileo’s trial in the seventeenth century for the heretical claim that the earth revolves around the sun, shutting down science and preventing progress.

Except that the truth, as is so often the case, is more complicated.

The knowledge that mRNA was a powerful part of our genetic code dates back to the discovery in 1953 of the structure of DNA. Scientists soon posited the existence of a molecule that served as a messenger of sorts, carrying out instructions for making the proteins that are responsible for nearly every task in our cellular life. The molecule came to be known as messenger RNA, or mRNA. 

Theoretically, mRNA could be a key for curing an extraordinary array of diseases; if it could deliver the “right” instructions to a person’s DNA, it could essentially instruct a misbehaving cell to behave. As Moderna executive Stephen Hoge told Science magazine in 2017, “If you can hack the rules of mRNA, essentially the entire kingdom of life is available for you to play with.”

But mRNA was a difficult molecule to control. For instance, it could provoke an immune reaction, which could itself be dangerous. What’s more, even when scientists found ways for mRNA to evade an immune response, there was another risk: toxicity. The more times you had to deliver the molecule, the higher the risk. And so on.

Vaccines were the proverbial low-hanging fruit. Since the very purpose of a vaccine is to trigger a response by the body’s immune system, mRNA’s inherent weakness would become a strength. In addition, an mRNA vaccine could be developed both faster and more easily than traditional vaccine-making.

Moderna never sold itself to investors as a vaccine company, however. Its vision was always more grandiose. CEO Stéphane Bancel used to say that “if mRNA works once, it will work many times,” reaching “hundreds of previously undruggable targets.” 

Yet by 2020, a decade after its splashy founding, Moderna hadn’t developed a single revenue-producing drug, or even a drug that had made it as far as a late-stage clinical trial—until Covid came along.

In a way, Covid-19 was tailor-made for mRNA. For decades, the National Institutes of Health, under the leadership of Barney Graham, MD, PhD, had been studying how to approach the spike protein that all coronaviruses had—and the government, through BARDA, had also helped to fund Moderna. When the pandemic hit, it all came together. “You had a framework on file,” said Akash Tewari, the global head of biotech research at Jefferies, an investment banking and capital market firm. “The analogy is if Covid was a house, there was only one door, and if you can’t use the key, you can’t enter.”

In other words, Covid didn’t so much prove mRNA’s widespread utility but rather offered a specific opportunity for a specific vaccine. Through its “Operation Warp Speed” project to develop a vaccine quickly, the government spent billions subsidizing the crash research efforts of not only Moderna but a half-dozen other pharma companies all racing to make a vaccine.

Maybe it shouldn’t be surprising that, given a long-standing mistrust of vaccines in some quarters combined with our rancorous times, that the opposition to an mRNA vaccine started up even before the vaccine was approved. First, it was the Democrats—yes, the Democrats—saying it was untrustworthy. In September 2020, as President Donald Trump’s first term was winding down, then–New York governor Andrew Cuomo said that the state would conduct its own review of the vaccines once they became available. “We can no longer trust the federal government,” he said.

But then the narrative flipped. Out of office, Trump began to distance himself from the vaccine when he realized that many in his base opposed vaccination. Meanwhile, the Biden administration wildly oversold the vaccine. It was no longer just a pretty incredible scientific discovery; it was a miracle! It would prevent transmission and make sure none of the virtuous vaccinated ever got Covid again. Those who did get Covid—well, it was their own fault. In July 2021, Rochelle Walensky, the former head of the Centers for Disease Control (CDC), told NPR: “This is becoming a pandemic of the unvaccinated.”

The Biden administration spent $1 billion on a campaign supporting the vaccine.

If all the promises had been true, then the various things the Biden administration did, from vaccine mandates to pushing a booster regimen for anyone over six months old—a regimen, it should be pointed out, that no other country followed—might have been understandable. But most of it wasn’t true. The mandates were predicated on the notion that the mRNA vaccine stopped transmission. It didn’t. Nor did it prevent someone from getting Covid again. Given the type of infection that Covid is, “We should have made it very clear that a vaccine is not going to last long, nor is it going to protect against mild or moderate disease,” Paul Offit, MD, an infectious disease specialist at Children’s Hospital in Philadelphia, told me. What it did do was help to prevent severe infections.

“I frankly told my family you don’t need a booster every year if you’re in good health,” a former Warp Speed official told me. He added, “If I had a six-month-old, I would not immunize them. The recommendation was too broad in the U.S. in regard to boosters.”

What about the concerns, like those expressed by RFK Jr., that the shot is dangerous? A study of 99 million vaccinated people by the Global Covid Vaccine Safety Project found “previously identified rare cases of myocarditis and pericarditis following first and second doses of mRNA vaccines.” But the study didn’t turn up any shocking hidden dangers; Offit told me that he has not seen anything worrisome. 

HHS, in announcing the cancellation of the mRNA funding, cited research supposedly backing up its assertion that this technology is dangerous. But Endpoints News, a biotech trade publication, reached many of the cited scientists and multiple authors, who said that the government misinterpreted their findings. All drugs come with some risk; the fact that that is true of the mRNA vaccine doesn’t mean it is evil. It’s why responsible doctors don’t prescribe medications for people who don’t need them.

Into that froth of discontent and uncertainty stepped RFK Jr., with his long-standing opposition to vaccines. Of course, maybe he would have nuked mRNA research funding even if it hadn’t been so hyped by the Biden administration. But it also gave real scientists who were critical of the government’s approach to the pandemic, like the Stanford epidemiologist Jay Bhattacharya, an opening. (Bhattacharya is now the director of the NIH.) Last week, in a Washington Post column in support of the decision to curb mNRA funding, he wrote, “The platform has failed a crucial test: earning public trust.” His argument misstates who was, ahem, calling the shots—the lack of trust isn’t because a molecule did something wrong, but because the public health establishment never explained to the public the vaccine’s limitations. 

The complicated history of mRNA also helps explain why, despite all the hype, no mRNA-based drug other than the Covid vaccine has been approved by the FDA. The evidence from clinical trials currently underway for any mRNA therapeutic is at best mixed. Scientists laugh at the idea that mRNA was ever going to be a kind of plug and play for different diseases. “There is no technology in biotech that is the best in every single disease state,” says Tewari. “It’s an impossible bar.”

The application that the FDA has approved is a vaccine for respiratory syncytial virus (RSV), a respiratory virus that can be dangerous for the very young and the very old. Moderna’s data doesn’t show any health benefits over the already approved vaccine from Pfizer, which is not mRNA-based. The Advisory Committee on Immunization Practices, which advises the CDC on vaccines, has not given a preference to Moderna’s product. “It’s categorically a failure as the next frontier,” one biotech investor told me.

Moderna is also working on a vaccine for cytomegalovirus (CMV), a latent virus that can be passed from pregnant women to their babies, but it has been delayed for unclear reasons. “They haven’t released the full data set, but broadly speaking, people think it doesn’t work,” said the investor. Separately, Moderna’s clinical trial for a vaccine for norovirus was paused by the FDA last winter after one outbreak of a rare neurological condition. The timing is still unclear. Vaccines for the flu are in process, but given that there are existing shots, the data will have to be great to move the market. mNRA bulls claim these products will someday generate billions in sales, but skeptics aren’t sold. “No one who is short the stock is worried about any of these products being a hit,” says the investor, meaning that investors who are skeptical of Moderna don’t think the stock is going to soar because of these products. 

(“The flexibility and adaptability of our mRNA platform allows for constant innovation,” said a Moderna statement. “Our commitment to patients and advancing mRNA medicine has never been stronger.”)

You can also see that mRNA isn’t the holy grail by looking at BioNTech’s portfolio. BioNTech is the German company that collaborated with Pfizer on its mRNA vaccine. Back in 2013 it hired Katalin Kariko, the scientist whose mRNA discoveries won her and her partner, Drew Weissman, a Nobel prize in 2023. (Kariko left the company in 2022 and is now an adviser.) BioNTech’s official pipeline still includes mRNA-based vaccine candidates, but Tewari said most of the value that investors are ascribing to the company’s pipeline is because of a non-mRNA-based drug that might work for solid cancer tumors.

None of this is a surprise to investors in the field. As several pointed out to me, Moderna has long been a heavily shorted stock, meaning that many are betting against the company’s biggest claims. “Why was Moderna’s stock struggling before Covid?” asked hedge fund manager Justin Simon. “Because the biotech specialist investors had already vetted the tech biology and found it to be pedestrian in terms of applicability to meaningful end-market therapies.”

The big question mark is cancer. The hope has always been that mRNA can be designed quickly and cheaply as individualized cancer therapeutics. Moderna has been working on a vaccine that would trigger an immune response in patients with melanoma and be used in combination with a Merck drug; that is now in Phase 3 trials and Merck has sounded optimistic about it, said an investor who follows the company closely. But just as mRNA’s utility for Covid didn’t mean it could be a perfect vaccine for everything else, even success with melanoma won’t mean that individualized therapies for every kind of cancer will be here tomorrow, or ever.

Another gauge of the uncertainty surrounding mRNA is that large pharmaceutical companies haven’t started mRNA programs en masse—which surely would have happened if it were the miracle compound it’s been cracked up to be.

On one level, the government’s highly publicized retreat from mRNA doesn’t mean that much. Even mRNA’s believers say that having the government involved in mRNA as a platform for viral infections isn’t critical anymore. “We achieved 90 percent of the progress,” said someone who was involved with Warp Speed. “Nothing can undo that.”

But at the same time, another lesson from the story of mRNA is that politics and science corrupt each other. Even with the private sector funding the research, politics could still be at play if an otherwise promising drug gets jammed up at the Food and Drug Administration, or if an investor who might be inclined to put money into a drug candidate says no because of the mRNA stigma.

Although mRNA trials have disappointed so far, a breakthrough is still possible. At this point, we just don’t know. Meanwhile, the broader campaign against mRNA, and all vaccines—and maybe even science itself—is a dumb and dangerous distraction. As evidenced by the recent deadly measles outbreak—which is taking place because too many parents are refusing to immunize their children against the illness—vaccine skepticism can come with a very high cost. “It’s going to make vaccines more feared, less available, and more expensive,” said Offit. In fact, even this administration has tried to expand the usage of vaccines against RSV and the flu in the elderly. Cut the funding, maybe. But also cut the rhetoric.

https://www.thefp.com/p/mrna-deliverance-dud-or-danger-science-tech-vaccine