Moderna's flu data offer a clear lesson: mRNA isn't magic
Last fall, as their Covid-19 vaccine crossed the finish line, Moderna unveiled plans to take its newly proven mRNA platform and use it to effectively change how the world blocks humanity’s most persistent viral foes.
In addition to their pre-existing vaccine programs, executives announced new ones for flu, where vaccines have chronically underperformed, and HIV, which has eluded every inoculation effort over nearly 40 years. In flu, the other mRNA vaccine companies — BioNTech (with Pfizer), Translate Bio (under Sanofi), and CureVac (with GSK) — all had similar ambitions, hoping to make shots that were as high as 80% effective.
Friday morning, though, cast doubt on those lofty hopes. Moderna became the first company to release data on an mRNA flu candidate, and they looked, well, fine.
The company showed the shot could successfully induce antibodies against the four families of flu viruses that current killed virus and protein-based vaccines do. But nothing in the early data suggested it was any better at inducing those antibodies, experts said.
Effectively, the company reproduced the same old shot in fancy new clothes.
“It’s just as good as what we have right now,” said Peter Palese, who studies flu and flu vaccines at the Icahn School of Medicine. “But I don’t think what we have seen so far is breaking new territory or really opening up a completely new technology.”
Or, as his colleague Florian Krammer put it on twitter: “mRNA is not a silver bullet.”
Yep, looks like regular seasonal vaccines, but probably more reactogenicity. mRNA is not a silver bullet. https://t.co/Jqq6saI1cD
— Florian Krammer (@florian_krammer) December 10, 2021
An mRNA version of the existing flu shots could still be useful and offer a couple advantages, but they also come with their own often over-looked shortcomings. Chief among them is the shot’s reactogenicity — i.e., its tendency to cause significant headaches, fever and other unpleasant side effects in the days after inoculation.
Moderna’s data showed that, like its Covid-19 vaccine, its flu shot caused more adverse reactions than protein-based or live virus vaccine. On a conference call, analysts argued that could stand in the way of Moderna’s greater ambition of building a single seasonal shot that combines flu, RSV and Covid-19 vaccine — a vision that’s only feasible with mRNA.
If just the flu and coronavirus shot each triggered such side effects on their own, SVB Leerink’s Mani Foroohar noted, how reactogenic would they be combined?
But just an mRNA flu shot alone could pose safety questions, Palese said. The lipid nanoparticles that carry the mRNA to cells also act as an adjuvant, stimulating the innate immune system. That boosts the protection people receive, but it could have long-term effects if given annually.
The flu vaccines most people currently receive are not adjuvanted. Generally, only those over 65 receive an adjuvanted flu vaccine such as Fluzone.
“I think there has been provisionally a reluctance to use adjuvants for vaccines against influenza, because one doesn’t want to give an adjuvant every year, continuously for 60 or 70 years of someone’s life,” he said.
Moderna executives cautioned against making too sweeping of a comparison between vaccines before results came in from a head-to-head trial. And they pointed to other areas experts agree mRNA could have an advantage.
For example, mRNA can be made faster than traditional egg or cell-grown flu shots. In theory, that could give Moderna and other mRNA companies more time to make sure the flu strains in the vaccine match the flu strains circulating in the fall, chipping away at a problem that in some years can make the seasonal shot as little as 19% effective.
How much they chip away will depend on how fast Moderna can make the shot. Palese doubted the advantage will be significant, but Moderna president Stephen Hoge noted the company already plans to manufacture an Omicron-specific variant in 100 days. Today, by contrast, officials have to select strains in February.
Ultimately, though, the impact of Moderna’s technology — or Translate’s or BioNTech’s — may come down to whether they can do more than just make mRNA versions of other shots.
Those efforts present far greater technical chances but also far greater opportunity. The biotech said Friday it would now advance a candidate that it designed similarly to proposed “universal” flu vaccines that can protect against all strains, a long-sought holy grail that has had mixed results in the clinic.
The company is also working to advance its program for an HIV vaccine, the greatest prize in vaccinology for more than three decades. Louis Picker, an immunologist at Oregon Health and Science University focused on HIV, cautioned anyone against getting their hopes up on it.
“At this point mRNA vaccine technology, by itself, does very little to counter the major obstacles to HIV vaccine efficacy,” he said in an email.
But mRNA can be very helpful, he said. For the last 12 years, the HIV vaccine field has been trying to build shots that can elicit ultra-rare antibodies that can neutralize all of the many diverse strains of HIV.
mRNA, Picker said, is unique in allowing researchers to quickly and iteratively design new constructs and test them in hopes of eventually hitting on the right design. Moderna is now putting the first such blueprint in Phase I, though Picker is pretty confident the first shot on goal is going to miss.
“Real success is not a foregone conclusion,” he said, “And if it happens is quite a way off in the future.”
Other researchers agree. Hildegund Ertl, who has worked on HIV vaccines at the Wistar Institute, pointed in an email to an NIH paper from this week studying Moderna’s HIV shot in monkeys. The monkeys were given the vaccine and then exposed to HIV. Most weren’t infected but those who were didn’t seem to suppress the virus at all, suggesting a very poor response.
“I’m not holding my breath,” Ertl said.