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Influenza has gone by many names, including catarrh, grippe, and sweating sickness. Its modern name stems from the 14th-century Italian phrases influenza di stelle or influenza di freddo, meaning “influence of the stars” and “influence of the cold,” respectively.

Astrologers of the time believed that the disease’s periodic return was influenced by the location of the stars. Medical texts — including Avicenna’s The Canon of Medicine — linked it to environmental changes, such as shifts in weather and temperature. Medieval physicians attributed these recurring outbreaks to imbalances in the four humours, which in turn were influenced by seasonal changes. Spring meant an excess of blood; winter meant an increase in phlegm. Some observers also viewed periodic influenza outbreaks as divine punishments, with religious texts by Saint Augustine and others interpreting them as calls for repentance or moral rectitude.

In 1918, influenza swept across six continents and killed between 17 and 100 million people, as much as 5 percent of the global population.¹ In 1957 and 1968, large influenza pandemics struck again, each killing more than one million people. Similar deadly episodes stretch back to ancient Greece and China. For much of modern history, flu pandemics have emerged every 10 to 50 years.

During the 1918 pandemic, most scientists believed bacteria caused influenza. The influenza virus was not isolated until 1933, when an epidemic in London enabled British researchers Wilson Smith, Christopher Andrewes, and Patrick Laidlaw to collect human influenza virus from patients’ throat washings.

Once they identified the cause, scientists in New York City and elsewhere hurried to create a vaccine. They ran extensive trials and experiments to inoculate people against this perennial killer. American researchers tested the first flu vaccines on military personnel in the early 1940s, with a civilian rollout following in 1945.

Over the last century, however, researchers have consistently struggled to make highly effective influenza vaccines. Receiving the seasonal vaccine reduces the risk of infection by just 40 percent on average. By contrast, smallpox and measles vaccines are more than 95 percent effective at preventing disease, a level sufficient to have eradicated smallpox entirely. If the less-than-a-coin toss efficacy weren’t bad enough, influenza evolves so quickly that a novel virus emerges each flu season, necessitating a newly-formulated vaccine every year.

Advances in everything from disease surveillance to the development of next-generation adjuvants have, for the first time, brought so-called “universal” flu vaccines within reach. Such a vaccine would enable people to receive a single shot conferring lifelong immunity against any strain of flu: past, present, or future. This could even eradicate influenza for good.

So how do we make it happen?

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Plagues and Peril

The dawn of flu vaccines coincided with discoveries about how to grow viruses.

In 1931, Ernest Goodpasture, a pathologist at Vanderbilt University, and Alice Woodruff, a laboratory technician, devised a method to culture various viruses in fertilized chicken eggs. Eggs, they reasoned, offered a perfect medium: protein and nutrient-rich, and extremely inexpensive.

The duo selected eleven-day-old fertilized chicken eggs, just the right age to support viral growth. After sterilizing the egg shells with a germicide, they pricked each one with a needle and injected a drop of virus-laden liquid into the amniotic sac. The inoculated eggs were incubated, allowing the virus to multiply. The pair then re-sterilized the shells and carefully burned a small hole in the top of each one with a precision blow torch. This delicate process prevented contamination while offering access to the fluid inside. Finally, Goodpasture and Woodruff siphoned out this fluid, now teeming with virions, and purified it for further vaccine development.

Around 1940-1941, Thomas Francis Jr., a physician and epidemiologist at the University of Michigan, decided to make a vaccine using these egg-grown viruses. However, the U.S. Army initially feared that doing so would cause viruses to mutate and inadvertently repeat the 1918 pandemic. In response, Francis’ team, which included a young Jonas Salk, developed a method to inactivate viruses with formaldehyde, allowing them to be recognized by the immune system without causing disease and contagion.

Formaldehyde had precedent in medicine. Gaston Ramon, a French veterinarian, had used it to inactivate pathogens while developing diphtheria and tetanus vaccines in the late 19th and early 20th centuries. Formaldehyde transforms the toxins produced by bacteria into toxoids by cross-linking the proteins and nucleic acids of the pathogen. This transformation preserves the immune-stimulating properties of the pathogen while eliminating its virulence​. Armed with these neutralized viruses, Francis asked Salk to prepare a “killed-virus” flu vaccine.

This first flu vaccine worked, as most subsequent flu vaccines have, by training the immune system to make antibodies that neutralize hemagglutinin, a protein protruding from the virus’ surface. When antibodies bind to hemagglutinin, they physically block viruses from attaching to and entering human cells, thus shutting down the infection cycle. Viruses tagged by antibodies become easy targets for white blood cells like macrophages and neutrophils, which engulf and digest them.

Most seasonal flu vaccines today are still made with a nearly identical method as those pioneered by Francis and Salk in 1941. Thanks to improved surveillance and forecasting, though, we can now create “trivalent” or “quadrivalent” vaccines by injecting multiple viral strains into eggs to confer broader immunity. The 2024-2025 seasonal vaccines include three viruses; two influenza A strains (H1N1 and H3N2) and an influenza B virus. The World Health Organization selects these strains months in advance based on global surveillance data.

Because viral strains keep shifting, vaccines have to be administered every year to be effective. And their efficacy varies greatly from one year to the next. The 2014-2015 seasonal vaccine, for instance, was only 19 percent effective due to a mismatch between the selected strain and the circulating one. Even in good years, such as 2010-2011, the vaccine tops out at about 60 percent efficacy.

After nearly a century, influenza vaccines remain hit-or-miss.

Viral Evaders

Viruses mutate rapidly, and influenza’s constant genetic shifts make it hard for vaccines to keep up. The strains used for each year’s vaccine must be predicted a full 6-8 months in advance to give vaccine manufacturers time to ramp up production ahead of the next flu season. But it’s difficult to make accurate predictions so early when viruses mutate every day.

Flu viruses mutate up to 1,000 times faster than human genomes. RNA polymerase — the enzyme responsible for replicating influenza’s genetic material — lacks proofreading abilities, meaning that mutations aren’t corrected and can rapidly accumulate. Some mutations weaken the virus, but others help it evade immunity.

These mutations can cause physical changes in the virus that are difficult for the immune system to recognize, a phenomenon called “antigenic drift.” Mutations often occur in hemagglutinin and neuraminidase (NA), the primary targets of the immune system’s antibodies. Even across strains of influenza A viruses, the structure of hemagglutinin proteins can vary by more than 50 percent, meaning antibodies that bind to one strain may not work against another. Over time, antigenic drift leads to new strains that partially or completely evade pre-existing immunity in the population.

“Antigenic shift,” though, poses an even greater threat. It occurs when two or more different flu viruses infect the same host and exchange genetic material, thus creating an entirely new strain. The 2009 H1N1 “swine flu,” for example, emerged when human, avian, and swine strains mixed inside pigs. This flu strain was highly pathogenic and, at times, lethal, leading to between 151,700 and 575,400 deaths worldwide during the first year of the outbreak, mostly in Africa and Southeast Asia.

Animal reservoirs complicate things further. Influenza A infects not only humans but also bats, cats, dogs, birds, horses, and pigs. These animals can harbor viruses even when humans aren’t infected, allowing flu to lurk in the background and later spill back into human populations. Eradicating influenza, therefore, is much tougher than eliminating a virus that uniquely infects humans, like smallpox (which was eradicated in 1980).

Challenging the Immune System

Quirks of the human immune system — arguably the most complex part of the body outside of the brain, as science writer Ed Yong has opined — are another bottleneck for making broadly-effective flu vaccines.

During an infection, two things quickly occur. First, an immune cell coated with antibodies stumbles upon — and binds to — an antigen, or small protein that is distinctly “foreign” in nature. Then, once that immune cell binds to the antigen, it sets off a molecular cascade that signals the body to make more antibodies capable of the same, slowly building up its arsenal against the new disease. These focused antibodies can stick to the original antigen 10,000x more strongly than the initial immune cell that encountered the pathogen.

In the case of influenza, antibodies usually target hemagglutinin because it’s more exposed, protruding out from the virus like a scoop of ice cream on a waffle cone. But unfortunately, the top part of hemagglutinin — called the “head” — also varies widely between influenza strains and mutates rapidly, meaning that most antibodies quickly become ineffective. The stalk region, by contrast, is more conserved across strains.

Another challenge is “antigenic sin,” the immune system’s frustrating tendency to reuse existing antibodies rather than craft new ones for each new strain — even when they’re not the best match. Once the immune system makes antibodies against H5N1, for example, it keeps recycling them for newer strains, undermining the efficacy of updated vaccines. Annual flu shots still matter, though, because they boost the supply of “old” antibodies. While these may only weakly bind to newer strains, in large enough quantities they can offer some protection — just not for long. That’s why our century-old approach to seasonal flu vaccination can’t deliver lasting immunity.

In short, a truly universal vaccine must overcome a virus’s shapeshifting abilities, deliver high efficacy, and protect against multiple strains — a daunting task.

Making Universal Vaccines

Though none are yet approved, at least 207 universal flu vaccine candidates are in development, with 165 in preclinical trials and 42 in clinical trials, according to the Universal Influenza Vaccine Tracker. Scientists are trying a range of strategies, from nasal sprays to antigen-coated nanoparticles. A successful universal vaccine must have two features, though: broad protection against influenza strains and high potency, such that it confers protection for several years.

There are a few ways to make antibodies with broad protection against influenza variants. One approach — adopted by about ten “universal” flu vaccines currently under development — is to train the immune system solely on hemagglutinin protein stalks, rather than heads. Stalks are more similar between strains and are slower to mutate, meaning they could theoretically coax the body to make antibodies that recognize a wider range of viruses. In one study testing this hypothesis, these stalk-directed immune responses elicited significantly higher antibody titers than a seasonal comparator against multiple H1 flu strains as well as an H5 flu strain.

Another strategy is to synthesize “chimeric” antigens by mix-and-matching different hemagglutinin proteins — none of which naturally infect people. These chimeras carry different head regions and only one stalk region. If hemagglutinin is like an ice cream cone, with the ice cream scoop as the head and the sugar cone as its stalk, then a chimeric vaccine is like putting multiple ice cream flavors all on the same cone. Repeated doses of chimeric vaccines can be delivered while continually swapping in new ice cream flavors, further diluting the immune response to the head region while boosting the broadly-protective response against the stalk region, since the cone stays the same each time.

Researchers at the Mount Sinai School of Medicine have tested a chimeric vaccine in a Phase I trial, and it has now moved into Phase 2. Early results showed some flu protection, but manufacturing these complex proteins is challenging.²

Another approach is to mix antigens together without combining them into a single molecule. This is the strategy being used at Centivax. The company is making a “multivalent” vaccine that mixes hemagglutinin proteins from up to 30 different flu strains in a single shot; it’s akin to having thirty different ice cream cones with different flavors and is a more straightforward way of enabling higher antigen numbers than the 3-6 antigens chimeric vaccines can offer. When the vaccine is administered, antibodies that target conserved regions of hemagglutinin are exposed to a 30x greater dose than antibodies just targeting variable regions.

Publicly available data from animal studies show that Centivax’s broad-spectrum vaccine triggers a broadly protective antibody response against a panel of 36 strains of flu, including all pandemic strains from the past hundred years, as well as multiple strains not present in the vaccine. It’s still in preclinical development, but the hope is to move into clinical trials soon.

Another way to make broad-spectrum vaccines is to layer antigens onto nanoparticles, thus mimicking the natural structure of viruses and, possibly, enhancing the immune system’s response. Studies show that antibodies bind antigens more effectively when the antigens are anchored to a physical object instead of floating freely. Nanoparticles can also display multiple hemagglutinin proteins on a single particle — so-called “mosaic” nanoparticles — to enhance the immune response’s breadth.

The FluMos-v1 flu vaccine candidate, for example, is a mosaic nanoparticle vaccine that displays four hemagglutinin proteins at once. It recently wrapped up a Phase I clinical trial, but results aren’t public yet.

Broad protection is great, but for a vaccine to be truly “universal,” it must also be potent and offer lasting protection against all these different strains; ideally for several months or years.

One way to strengthen long-term immunity might be to inhale vaccines, rather than receive them via injection. Delivered through the nose or mouth, these “mucosal vaccines” set up defenses in the respiratory tract, where influenza typically enters. If the human body is a castle, this is like blocking the virus at the moat. Stopping infection at its entry point also curbs transmission and reduces viral mutations. Plus, because inhaled vaccines are needle-free, they tend to be more appealing to people, possibly boosting adoption.

Developing effective mucosal vaccines, however, is tricky. The immune response they trigger in the lungs can fade quickly unless it’s strong enough to spill over into the body’s systemic defenses. The vaccine must cross the mucosal barrier, ignite a robust immune response, yet not cause excessive inflammation. There is only one FDA-approved intranasal vaccine for any disease: the FluMist Quadrivalent flu vaccine, which uses weakened forms of viruses to trigger an immune response.

In 2004, a study on an intranasal flu vaccine given to people in Switzerland resulted in 46 cases of Bell's palsy, a short-lived paralysis that causes half the face to sag. Researchers now believe the issue stemmed from the vaccine’s adjuvants — or the chemical additives that act as inflammatory agents to amplify the body’s immune response — rather than from the vaccine itself.

Think of adjuvants as the vaccine’s “boosters.” They help the immune system recognize antigens more readily and hold on to that memory, potentially strengthening and prolonging protection. Creating new adjuvants has historically been difficult because they need to cause enough inflammation to effectively boost the immune response, but not so much as to cause undue side effects, like Bell’s palsy. Striking this balance is particularly difficult because what stimulates an immune response in one person might cause excessive inflammation in another.

Recent advances in adjuvant technology, though, are promising to unlock new levels of vaccine efficacy, especially from a class of molecules called saponins. Derived from the bark of the Quillaja saponaria tree, native to South America, saponins have been used in veterinary vaccines for decades. They are potent activators of the immune system, but the cruder preparations used in veterinary medicine can cause serious side effects in humans.

Saponins have been refined to reduce irritation, though, and are becoming more common. Saponin adjuvants have been used in several commercially available vaccines, including the RTS,S and R21 malaria vaccines, as well as Shingrix (which offers over 90 percent efficacy) and Novavax’s coronavirus vaccine.

The Century Ahead

Most efforts to create universal flu vaccines have achieved only incremental improvements over seasonal vaccines. But importantly, no one has yet tried merging all these new strategies into a single vaccine.

In theory, it should be possible to create a vaccine that uses a computationally-optimized mix of hemagglutinin proteins in a mosaic nanoparticle (for maximum breadth), is delivered intranasally (for mucosal immunity), and contains next-generation saponin adjuvants (to boost potency). Such a vaccine could even be mixed with additional, non-hemagglutinin antigens to expand its coverage.

Even if such an ambitious vaccine becomes a reality, though, there are still major obstacles to surmount before we can benefit from it. Intellectual property concerns, along with the fear of expensive failures in clinical trials, could deter researchers from launching early-stage tests of these next-generation vaccines.

Vaccines, unlike most medications, must be tested on healthy people. That drives stricter approval hurdles, especially for new adjuvant formulations. There’s also the question of how to prove a vaccine defends against multiple strains of flu when only one or two circulate each year.

One way to get around that problem could be to intentionally infect volunteers with different strains of influenza — known as a challenge trial — to directly measure broad-spectrum protection.

Regulatory agencies like the FDA and the European Medicines Agency are increasingly recognizing the value of such trials, and the FDA is exploring more flexible approval pathways for vaccines that address critical, unmet medical needs. This shift includes considering accelerated approval pathways that rely on immunogenicity data and challenge trial results, rather than the long-term outcome studies typically required in traditional trials. By easing the regulatory process, these shifts may motivate more companies to invest in ambitious vaccine designs.

A universal flu vaccine may seem elusive, but consider that in the 1920s, many doctors believed curing bacterial infections was impossible. There was, as Thomas Hager writes in The Demon Under the Microscope, a sense that "medicine had reached its limits" — a collective resignation to the belief that infectious diseases would continue to claim lives unchecked. Scientists at the time knew that dozens of different bacteria could cause disease and couldn’t imagine how a small number of drugs could possibly combat them all. Influenza and pneumonia alone caused nearly 30,000 deaths amongst U.S. Army soldiers during World War I, comprising more than half of the 52,000 non-combat deaths recorded.

That defeatism dissolved in the early 1930s when a small research team at IG Farben in Elberfeld, Germany — led by a meticulous pathologist named Gerhard Domagk — made the first commercially-available antibiotic. By combining an azo dye with a sulfonamide side chain, chemists made sulfamidochrysoïdine (sold as Prontosil), a molecule that is remarkably effective at treating infections caused by both staphylococcal and streptococcal microbes.

Just as the prevailing pessimism of the pre-antibiotic era gave way to a new age of medicine, so too could today’s challenges with influenza yield a breakthrough in pan-vaccine research down the line. With enough ingenuity, the dream of a one-shot "universal" flu vaccine won’t remain out of reach forever.

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Ryan Duncombe is an independent contractor working in biosecurity and pandemic preparedness. He previously worked on universal flu and COVID vaccines at Alvea and on vaccine policy at 1Day Sooner. He received his Ph.D. in immunology at the University of Chicago.

Jasmin Kaur is an independent consultant in biosecurity and health policy. She previously led the pandemic preparedness and human challenge studies program at 1Day Sooner, co-founded a health security and advocacy non-profit, and developed AI imaging pipelines as Disruptive Technologies Lead at GSK. She received her master's in biochemistry from University of Warwick.

Cite: Duncombe R. & Kaur J. “The Quest for Universal Flu Vaccines.” Asimov Press (2025). DOI: 10.62211/41po-45gh

Lead image by Ella Watkins-Dulaney.

This article was published on January 26, 2025.

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Footnotes

1. Mortality estimates for the 1918 flu pandemic vary widely but have tended to increase over the years.
2. Each protein in the vaccine must be individually engineered; mixing them together can then lead to unpredictable stabilities for each protein.