First, impressive vaccines for COVID. Next up: the flu.

As the world grapples with COVID-19, influenza is not getting much attention these days. But the flu’s global impact is staggering: 3 million to 5 million cases of severe illness every year and up to 650,000 deaths. Every few decades, a new flu strain spills over from animals and leads to a pandemic.

The deadly toll of influenza is all the more striking when you consider that we have had vaccines to fight it for eight decades. But they remain mediocre. A flu shot is good for only one flu season, and its effectiveness typically reaches somewhere between 40 per cent and 60 per cent. In some years, it is as low as 10 per cent.

But a new generation of highly effective flu vaccines may emerge in the next few years, based on the same mRNA technology that has protected hundreds of millions of people against COVID.

Although traditional influenza vaccines are grown for months in chicken eggs, mRNA vaccines are manufactured relatively quickly from scratch. In theory, their faster production may make them better matched to each season’s flu strains. And when they are injected into people, they may provoke a stronger immune response than traditional flu vaccines do.

Two companies — Moderna, the Massachusetts biotech company that produced one of the authorized mRNA vaccines for COVID, and Sanofi, a French maker of vaccines — began trials for mRNA flu vaccines this summer. Pfizer and BioNTech, the companies that produced the other mRNA COVID vaccine, started their own flu trial last month. And Seqirus, a vaccine producer based in England, is planning to test another mRNA vaccine for the flu early next year.

No one can say for sure how well any of these four seasonal flu vaccines will turn out, but many experts are optimistic. And further down the line, mRNA technology may be tailored to make vaccines that work for years against a wide range of influenza strains.

“I am beyond excited for the future of flu vaccination,” said Jenna Bartley, an immunologist at the University of Connecticut.

Not Good Enough

The 1918 influenza pandemic was the worst in modern history, killing between 50 million and 100 million people. As the death toll climbed, doctors responded by inoculating people by the thousands with an assortment of experimental vaccines. None of them worked.

Scientists at the time wrongly believed that disease was caused by bacteria, not viruses. That error led them to make vaccines from the microbes they gathered in the sputum of flu patients. The vaccines were useless at mounting an immune defense against the viral disease.

It was not until 1933 that British virologists isolated the influenza virus, finally making it possible to design an effective vaccine. Researchers injected influenza viruses into chicken eggs, where they multiplied. Once they had extracted and purified the new viruses, they killed them with chemicals and injected the inactivated viruses into people.

The United States licensed the first commercial influenza vaccine in 1945. The Nobel-prize-winning virus expert Wendell Stanley hailed the milestone, declaring that the vaccine would prevent influenza from ever again becoming “one of the great destroyers of human life.”

But the vaccine did not quite live up to Stanley’s hopes. Influenza outfoxed it with an awesome power to mutate.

During an influenza infection, cells in our airway begin copying the virus’s genome, allowing it to proliferate. The copying process results in lots of genetic errors. Sometimes these mutations will enable the virus to escape the body’s immune response spurred by a vaccine.

Flu viruses also have another route to rapid evolution. If two types of flu viruses infect the same cell, it can produce a genetic hybrid, which may evade vaccine-triggered immunity even more successfully.

This extraordinary capacity for change also explains why several strains of flu may circulate in a single flu season and new strains may rise to dominance the following year.

“The flu virus, for lack of a better word, is just kind of a jerk,” Bartley said.

Vaccine makers have responded by including up to four different strains in their annual formulations. But because producing vaccines in chicken eggs is such a slow process, scientists must choose which strains to include several months before a flu season, often leading to a mismatch when the shape-shifting virus actually arrives.

“It’s an educated guessing game,” said Dr. Alicia Widge, an immunologist at the National Institutes of Health’s Vaccine Research Center. “We’re always catching up with the virus.”

Between 2004 and 2019, the effectiveness of the flu vaccine ranged from as high as 60 per cent to as low as 10 per cent. Even that modest protection translates into a lot of benefit, however, because so many people get the flu every year. In addition to lowering the odds of getting infected, the vaccine also lowers the chances that people sick with the flu have to go to the hospital.

In the 2018-19 flu season, the flu vaccine — with an effectiveness of just 29 per cent — prevented an estimated 4.4 million illnesses in the United States alone, plus 58,000 hospitalizations and 3,500 deaths, according to one study.

If scientists could make more robust flu vaccines, they could potentially save thousands of additional lives.

“The bottom line is that the flu vaccines we have aren’t good enough,” said Nicholas Heaton, a virus expert at Duke University School of Medicine.

Immune Factories

In the 1990s, a few researchers set out on an entirely new course, making flu vaccines from mRNA.

The idea behind the technology was radically different from the chicken egg approach. In effect, the new shots would turn people’s own cells into vaccine factories.

Scientists would create an mRNA molecule with the instructions for making an influenza protein, then deliver it into cells. Those cells would then make copies of the viral protein, some of which would end up on their surface. Immune cells passing by would detect the alien proteins and respond with a defense against the virus.

In 1993, a team of French scientists conducted the first experiments on an mRNA vaccine for the flu. The vaccines produced promising responses in mice but were still primitive. For one thing, the animal’s cells sometimes responded to the vaccine’s mRNA by destroying it, as if it belonged to a foreign enemy. It took more than two decades of additional lab work before mRNA vaccines were ready for human trials.

When Moderna formed in 2010 to bring mRNA vaccines to the clinic, influenza was one of the first diseases it tackled. The company started with vaccines for two flu strains that normally infected birds but sometimes sickened people — exactly the kind of viruses that might give rise to new pandemics.

Moderna's first clinical trial results, in 2016, were encouraging. The volunteers produced antibodies against the viruses, although they also had side effects such as fever and fatigue. The results spurred Moderna to build a new factory in Norwood, Massachusetts, where the company could make large quantities of mRNA for more clinical trials.

The company began developing a new flu vaccine, this one for seasonal influenza rather than for pandemics. And the researchers worked on making the side effects of the vaccine less severe.

“You want folks to feel comfortable strolling into CVS and getting their shot, and not be worried about adverse events,” said Rose Loughlin, vice president for research and development strategy at Moderna.

But then in early 2020, just as they were hoping to begin a new flu trial, the scientists had to shelve the plan. A new coronavirus was exploding in China.

Combo Shots

Over the next year, Moderna made and tested a COVID mRNA vaccine with record speed. And its shot, like that of its primary competitor, Pfizer-BioNTech, was remarkably protective, with an efficacy rate around 95 per cent.

The success of mRNA vaccines delivered huge revenues to both companies. The Pfizer-BioNTech vaccine is on track to become the bestselling medicine of all time. And Moderna’s market cap since the beginning of the pandemic increased nineteenfold to around $123 billion.

Riding the mRNA wave, these companies, along with Sanofi and Seqirus, are moving on to seasonal flu projects.

Jean-François Toussaint, Sanofi Pasteur’s head of global research and development, cautioned that the success of mRNA vaccines against COVID did not guarantee similar results for influenza.

“We need to be humble,” he said. “The data will tell us if it works.”

But some studies suggest that mRNA vaccines might prove more potent than traditional ones. In animal studies, mRNA vaccines seem to provide a broader defense against influenza viruses. They prompt the animals’ immune systems to make antibodies against the virus and also train immune cells to attack infected cells.

But perhaps most importantly for the flu, mRNA vaccines can be made rapidly. The speed of mRNA manufacturing may allow vaccine makers to wait a few extra months before picking which influenza strains to use, potentially leading to a better match.

“If you could guarantee 80 per cent every year, I think that would be a major public health benefit,” said Dr. Philip Dormitzer, Pfizer’s chief scientific officer.

The technology also makes it easier for mRNA vaccine makers to create combination shots. Along with mRNA molecules for different strains of influenza, they can also add mRNA molecules for entirely different respiratory diseases.

At a Sept. 9 presentation for investors, Moderna shared results from a new experiment in which researchers gave mice vaccines combining mRNAs for three respiratory viruses: seasonal flu, COVID and a common virus called respiratory syncytial virus, or RSV. The mice produced high levels of antibodies against all three viruses.

Other researchers have been searching for a universal flu vaccine that could protect people for many years by fending off a broad range of influenza strains. Rather than an annual shot, people might need only a booster every few years. In the best-case scenario, one vaccination might even work for a lifetime.

At the University of Pennsylvania, a team of researchers led by Norbert Pardi is developing mRNA vaccines that encode proteins from influenza viruses that mutate only rarely. Experiments in animals hint that these vaccines could remain effective from year to year.

Although Moderna is not working on a universal flu vaccine at the moment, “it’s absolutely something we’d be interested in for the future,” said Dr. Jacqueline Miller, the company’s head of infectious disease research.

Even if mRNA flu vaccines live up to expectations, they will probably need a few years to gain approval. Trials for mRNA flu vaccines will not get the tremendous government support that COVID vaccines did. Nor will regulators be allowing them to get emergency authorization. Seasonal flu is hardly a new threat, and it can already be countered with licensed vaccines.

So the manufacturers will have to take the longer path to full approval. If the early clinical trials turn out well, vaccine makers will then have to move on to large-scale trials that may need to stretch through several flu seasons.

“It should work,” said Bartley of the University of Connecticut. “But obviously that’s why we do research — to make sure ‘should’ and ‘does’ are the same thing.”