It’s flu season. At state health departments and academic medical centers, and at the US Centers for Disease Control and Prevention, epidemiologists are intently watching two sets of data: the number of flu cases and the number of Americans taking flu shots.
So far, the balance between them looks good. In most of the US, the occurrence of illnesses that look like the flu—ones that cause a fever and sore throat but haven’t been confirmed by a lab test—is low. Out of the viral samples taken from sick people and sent to labs for confirmation, only 2 percent have turned out to be flu. And at this point, more than 142 million Americans have taken the shot, using up most of the 156 to 170 million that manufacturers predicted they would deliver this fall.
But there’s one more piece of data that will let analysts know how this flu season will unroll: whether the vaccine actually works. Last year, for instance, the shot was 54 percent effective. The year before, it prevented illness in only 36 percent of those who took it. Since 2009, the vaccine’s effectiveness has been as high as 60 percent and as low as 19 percent.
This variability speaks to the biggest challenge of fighting the flu: its restless, endless mutation. Every year, vaccine makers in each hemisphere build a new formula based on whatever is circulating. But they can never be confident that the strain they pick in a lab as that year’s target will look the same after six more months in the wild—or whether something entirely new will pull ahead of the pack.
So every summer, as the northern hemisphere’s flu season approaches, public health people fretfully anticipate the data. Will manufacturers deliver the shot in time? Will enough people take it? How effective will it be? And every year, as they watch the numbers settle, at least some of them long for something that could short-circuit the waiting: a vaccine that works no matter how the virus changes and that could be produced far enough in advance to prevent a fall vaccination crunch.
That goal is known as a universal influenza vaccine. For immunologists, it has been an end-of-the-rainbow phantasm for more than a decade, a deeply desired treasure that manages to stay just out of reach. Recently, though, the pursuit of a better flu shot has notched promising achievements. A vaccine candidate developed by the National Institutes of Health has entered its second Phase 1 clinical trial (which tests whether a compound is safe for humans). Other candidates developed by Moderna, based on the mRNA technology that allowed rapid development of Covid vaccines, are in Phase 1/2 and also Phase 3 trials (which test for efficacy). And novel constructs developed by teams at Mount Sinai School of Medicine and the University of Pennsylvania have delivered promising results in mice. They are all feats of engineering and imagination, deploying the latest virological tools against an ancient foe.
But hard work lies ahead. Flu is a tricky, unstable virus that has eluded lasting containment since the first vaccine against it was released in 1945. It remains so challenging that some of the scientists leading the search for better tools have started to rename what they are looking for. “We have stopped calling it a ‘universal flu vaccine,’” says Masaru Kanekiyo, a vaccine immunologist who leads the molecular immunoengineering section of the NIH’s Vaccine Research Center. “We have been using ‘super seasonal vaccine,’ which would essentially be an improvement on the current seasonal vaccine.”
To understand why improving the vaccine is so crucial, it’s important to consider the flu’s public health burden. Just in the US, the CDC estimates that it sickens up to 41 million people each year and kills anywhere from 12,000 to 52,000 depending on the severity of the season. Globally, there are up to 1 billion cases and 650,000 deaths a year, according to the World Health Organization. And that’s with current flu shots controlling the disease’s impact—though public health planners acknowledge that the vaccines are largely a rich-country phenomenon and are much less available in emerging economies.
Flu wreaks such havoc because it is such a unique virus. First, in a quirk that it shares with SARS-CoV-2, RSV, and common cold viruses, it doesn’t create perfect immunity; we retain immunological memories of it but not enough to prevent reinfection. Second, it’s a relentlessly mutating organism, making slight changes all the time. Even if we gained durable immunity to one strain, that might not protect us against a successor that arrives the next year. And since durable and broad immunity don’t occur in natural infection, it’s a big ask to try to create those with a vaccine.
Drugmakers create fresh flu vaccine formulas each year, matching them to the circulating flu strains detected by a worldwide surveillance network led by the WHO. But getting from strain detection to a finished formula isn’t quick. “If we are making a vaccine for 2023, we have to follow a [strain] recommendation made in February 2023,” says Peter Palese, a professor of microbiology at the Icahn School of Medicine at Mount Sinai and one of the deans of universal flu vaccine research. “By the time the vaccine is made, manufactured by industry, and distributed to CVS [pharmacies] and pediatricians, there is a gap of six to eight months, which is used by the virus to change.”
To work better than current formulas, a superior vaccine would need to anticipate the genetic drift of mutation and protect against more strains than circulate in a single season, plus confer protection for more than a handful of months. In a research agenda it first set in 2018, the NIH defined the goal of a universal vaccine as being at least 75 percent effective for at least one season, and preferably longer, against at least the group of viruses known as influenza A, which cause most recorded cases. (There’s also a second group, influenza B; the current seasonal vaccine contains both A and B viruses.)
In the dream scenario, a universal vaccine would also protect against pandemic viruses, which fall outside the slightly mutated progression of flu that occurs from year to year, and instead contain such dramatic genetic changes that they make many more people sick. Ideally, researchers would like to see manufacturing change, too; the current process, which relies on growing the vaccine-strain viruses in billions of live chicken eggs, is known to introduce unwanted mutations.
Here’s the central challenge of making a better vaccine. The portion of the virus that our immune systems react to, a protein on the surface called hemagglutinin (HA for short), is also the part that drifts genetically from season to season. When we develop an infection, antibodies that we produce bind and block that HA. “The first viral exposure you have shapes how you respond in the future,” says Jenna Guthmiller, an immunologist and assistant professor at the University of Colorado Anschutz School of Medicine and a collaborator with Palese’s lab. “In a few years, you see a drifted version of this, something that's mutated just ever so slightly. That antibody may still be able to recognize it, but the strength of that binding is now reduced.”
To solve the twin problems of mutations always racing ahead and our response lagging behind, teams have pursued two concepts. One simultaneously presents the immune system with multiple HAs, a scenario that never occurs naturally. The other executes a maneuver that slides a different part of the flu virus into contact with the immune system first.
The second path is the strategy that Palese and his group have followed. Traditional flu vaccines deliver portions of the flu virus, or entire killed or weakened viruses, to prompt the immune system to respond. As a first step, the Mount Sinai research tinkers with the internals of the virus by tailoring its HA, disassembling the lollipop-shaped antigen into its component parts. By removing the head—the much-mutating part that engages with our cells—they allow the supporting stalk, which changes less, to come to the fore. Because the HA needs a head to invoke an immune response, the team creates a chimera, swapping in HA heads from flu varieties that don’t infect humans. Palese calls them “funny hats.”
“They fit very well; we can make intact viruses,” he says. “The important thing is that the stalk is always the same. So if you give two doses with different hats, they will always see the stalk, which is conserved.” So far, that construct has been given to mice, delivered either as a live-attenuated vaccine or as a killed virus with an immune-boosting adjuvant.
Projects that follow the other path are in human trials at the NIH and Moderna. Flu-MOS, the NIH construct, uses a self-assembling nanoparticle developed at the University of Washington to cram together multiple fragments of HAs from several flu strains: four in its first iteration, which is ongoing, and six in the trial that began last September. Both trials are looking for safety signals, such as reactions to the shot, but they also are attempting to measure immune responses, taking periodic blood samples from the human volunteers to look for antibody production.
“This is our current hypothesis, that if you start generating antibodies and overall protection against one strain there is a possibility that you are generating cross-strain protection as well,” says Richard Wu, a physician and principal investigator for the Flu-MOS clinical trial. “How much protection is still under study. But the idea of being exposed to multiple strains, allowing you to confer a larger overall protection, would be a nice strategy toward a universal flu vaccine.”
Similarly to the NIH, Moderna has adopted an iterative strategy, beginning with a 4-HA formula using the company’s mRNA technology, which induces the immune system to make its own copies of an antigen (and then manufacture antibodies against it). The earliest candidate, dubbed mRNA-1010, passed safety benchmarks in February in a Phase 3 trial; but in measurement of immune responses, it scored higher than existing vaccines only against the influenza A strains it contained, not the B strains. The company updated the formula and re-enrolled the trial, while moving forward with several expanded formulas that contain additional HAs from other strains. Several also add neuraminidase, a protein on the surface of the flu virus that controls how viral copies break free from cells. Neuraminidase, or NA, is rarely included by itself in current flu shots.
“The reason you would target additional antigens like the NA is that you have a certain level of redundancy of protection, essentially targeting the virus at multiple stages of its lifecycle,” says Raffael Nachbagauer, Moderna’s program leader and executive director for infectious disease development. “It’s similar to how HIV drugs have shown that if you only target one of the proteins, you have quick escape of the virus and it doesn't work. But if you have, essentially, cocktails of different drugs that target different proteins, it works incredibly well.”
The candidates containing NA, which Moderna has dubbed 1020 and 1030, have been in a Phase 1-2 trial since April 2022, examining safety and immune response. If they succeed in later trials, that could pave the way to incorporating even more flu-virus proteins that are more conserved from strain to strain than either HA or NA—and that might constitute the first steps toward a truly universal vaccine.
Still, the flu is endlessly surprising. Like other researchers, Nachbagauer is cautious about not overpromising when the whole field’s limited successes have already taken so long. “Our ultimate goal is not to have three different vaccines and every customer has to pick and choose,” he says. “Our ultimate goal is to combine all those features and slowly build up to a broad vaccine that has the latest strain recommendation and is better matched to what's currently circulating. The question is when you can get to that point—and I do think that within the next few years, you can actually get there.”
That would be a much better vaccine—but, he acknowledges, not the universal one that researchers have dreamed of. “It's so easy to set really high bars for what you need to achieve for total universality,” he says. “And just never get there because it's such an incredibly high bar that you might never cross.”