Clear bottles on a production line.

Ingredients for the mRNA vaccine made by CureVac.Credit: Guillaume Souvant/AFP via Getty

It’s only a small chemical tweak, but it has triggered huge division in the mRNA research community.

Proponents argue that a simple chemical modification to the backbone of mRNA is crucial to the success of mRNA vaccines, allowing them to trigger a potent immune response without massive side effects. Exhibit A: the blockbuster COVID-19 vaccines made by Pfizer–BioNTech and Moderna, both of which have this modification. But some mRNA manufacturers have long held that unmodified mRNA elicits a superior immune response to pathogens — a rift with implications for mRNA vaccine development.

Now the biggest champion of the unmodified approach has changed its tune. CureVac — which is one of the world’s oldest mRNA specialty companies and is based in Tübingen, Germany — is ditching unmodified mRNA, and embracing the modified version for its entire infectious-disease vaccine portfolio after disappointing results from COVID-19 vaccine trials.

Modified mRNA is the “best-performing technology for prophylactic vaccines”, Franz-Werner Haas, CureVac’s outgoing chief executive, said in a conference call last week to announce the company’s strategic shift — a retreat from a position it has held since its founding in 2000.

The company’s about-face should help put to rest the decades-long debate among scientists over which type of mRNA is best to protect against influenza, SARS-CoV-2 and other viral threats. CureVac’s pivot in the respiratory-disease arena leaves only a few late-stage products reliant on unmodified mRNA, all of which are COVID-19 vaccine candidates under development in Asia.

The mod squad

Vaccines designed around mRNA work by giving the body instructions on how to make viral proteins. Those proteins then train the immune system to produce antibodies that can disarm invading pathogens. But the process only works if the immune system doesn’t see the vaccine mRNA itself as a threat.

That’s where modifications come in. In the mid-2000s, scientists discovered that swapping one of RNA’s four basic building blocks, called nucleotides, for a related analogue helped to make the mRNA less conspicuous to the immune system. Vaccines could then be given at higher doses, allowing for maximal antibody responses with fewer of the icky side effects — fevers, chills, aches — that result from immune reactions to the mRNA itself.

For decades, CureVac thought that it could achieve the same effect by fine-tuning the mRNA sequence to avoid tripping the immune alarm. The company claimed that its ‘optimized’ mRNA could elicit the full breadth of desired immune responses without any major safety issues1. But in late-stage testing, CureVac’s experimental jab didn’t yield enough antibodies to thwart emerging variants of SARS-CoV-22. The general consensus: CureVac’s dose was too low but couldn’t be raised because of tolerability concerns.

The company created a next-generation jab that, although still built around unmodified mRNA, seemed to generate more robust immune responses at the same dose used for its earlier vaccine3. The product entered clinical trials in March 2022. But around the same time, a shift in mindset was taking hold at the company.

As Haas told Nature in an interview that month, “There should not be a kind of religious way to see” the issue of mRNA modifications. CureVac and its co-development partner, GSK of London, decided to give modified mRNA a real try, with the idea being, as Haas put it, to “let the data talk”.

In August, another COVID-19 vaccine candidate from CureVac entered clinical trials, this one updated to reflect the circulating Omicron variant of SARS-CoV-2 — and now with modified mRNA.

Chemical conversion

On 6 January, CureVac reported preliminary-trial data comparing the two next-gen jabs. At the same dose, a shot of the modified mRNA elicited about the same number of coronavirus-foiling antibodies as the next-generation vaccine based on unmodified mRNA. But importantly, it also caused many fewer side effects, allowing CureVac to safely up the dosage for maximal immune protection.

The data in favour of modifications were “very compelling”, says Phil Dormitzer, global head of vaccines research and development at GSK. “Modified RNA has really proven itself.” CureVac, in collaboration with GSK, is now moving forward with high-dose modified mRNA for both of its COVID-19 and flu vaccine programmes.

CureVac is not the first firm to run trials of mRNA vaccine candidates, with and without modifications. Other companies, including BioNTech in Mainz, Germany, and Sanofi, headquartered in Paris, have also done so — but none had disclosed their full results. “That’s why the CureVac study is so helpful,” says vaccinologist Norbert Pardi at the University of Pennsylvania Perelman School of Medicine in Philadelphia.

The data might be preliminary, but “this is the first head-to-head comparison led by the same company”, he says. And, according to Pardi, it clearly shows that “modified RNA is the way to go”.

Another long-time proponent of ‘natural’ mRNA, the company Translate Bio, now a subsidiary of Sanofi, ditched the approach last year. That leaves only a handful of newer mRNA players still advocating for unmodified mRNA in respiratory vaccines. Among them is the company Abogen Biosciences of Suzhou, China, which is furthest along with its late-stage trials of a COVID-19 vaccine developed using unmodified mRNA. Few scientists expect the vaccine to perform much better than CureVac’s first product did.

“The industry has pretty much all aligned with using modified nucleotides,” says Michael Heartlein, a co-founder of Translate Bio.

A role for natural products

That’s true for infectious diseases at least, and with current formulations. There are other, as-yet unproven ways to deliver mRNA vaccines that might not need the chemical switcheroo. And in the realm of oncology, unmodified mRNA-based vaccines might be useful for ‘therapeutic vaccines’, which treat disease, rather than prevent it.

Cancer vaccines help the immune system to recognize tumour cells so that killer T cells can mount an attack. In this context, natural-mRNA vaccines’ tendency to trigger the production of immune-revving molecules can be beneficial.

The same molecules could suppress the types of antibody response needed to combat infectious-disease agents, notes Katalin Karikó, the biochemist who first demonstrated the importance of mRNA modifications for avoiding unwanted immune responses, and who now works a consultant for BioNTech. However, she adds that for cancer, killer immune cells are the key.

A test should come soon: later this year, both BioNTech, whose cancer vaccines use unmodified mRNA, and Moderna, which uses modified, will report full data on their vaccines’ performance in treating melanoma.