When COVID-19 Really Is 'Just Another Flu'

It's hard to imagine a day when people will be as nonchalant about getting their COVID-19 vaccine as they are about getting their flu shot, but it is one possible future reality, experts say.

Each year in the U.S., influenza kills between 12,000 and 60,000 people, and puts some 140,000 to 810,000 people in the hospital, according to the CDC. But that's a level we've come to live with -- there are no calls for social distancing or mask wearing, no shuttering the economy, to prevent transmission.

"Because influenza is so common, people figure it's no big deal. It's like driving a car. People will die, but not me because I'm a good driver. I'm in good health," said Pedro Piedra, MD, a respiratory virus specialist at Baylor College of Medicine in Houston.

Flu is generally survivable, with a population-wide mortality rate of 0.1%. Combine that with the varying efficacy of seasonal influenza vaccination -- from 30% in a bad year to 70% in a good year, according to Martin Blaser, MD, an infectious disease expert at Rutgers University in New Jersey -- and the laissez-faire attitude about influenza is hardly surprising. The 40% of adults who are vaccinated each year is largely driven by the 65+ age group, according to CDC data.

While 60,000 deaths a year pales in comparison to the 180,000+ caused by COVID in the U.S. since March, it's still a large number, infectious disease experts said.

"One might argue, shouldn't we be making a big investment in a better flu vaccine to save all those lives?" Blaser said. "I think the answer is yes. But that requires two things: a better vaccine and more people taking the vaccine."

Some experts think this question may be relevant to the future of COVID-19 as well.

Better Flu Vaccines?

Making a better flu vaccine is a big task that has been on the research radar for decades. In 1945, the first inactivated influenza vaccine was licensed for use in the general public. Just two years later, researchers realized that antigenic changes in circulating influenza virus made existing vaccines less effective, according to the CDC. By 1948, the World Health Organization was setting up methods for monitoring those changes.

Since then, experts have had to forecast strains for the following year's vaccine some 9 months ahead, because it takes that long to manufacture the hundreds of millions of doses needed each season. As a result, the choice of strains for the upcoming Northern Hemisphere season is based on those circulating early in the Southern Hemisphere's season.

A universal flu vaccine would change that, though it's seen as the more challenging solution, Blaser said.

"I'm not sure it's achievable but there are people who think that it is," he said. "Nature has selected for flu viruses that can vary their surfaces in a way that allows them to keep ahead of human immunity. The key is to try to understand, is there a part of the flu virus that is relatively invariant, that one could make a vaccine based on that and will offer some degree of protection?"

Some elements of the flu virus structure are conserved among strains, but efforts to base vaccines on them have not yet panned out.

The lower-hanging fruit, Piedra said, is improving annual vaccines through relatively prosaic means, such as increasing their immunogenicity and improving strain matching.

Developing a quadrivalent vaccine that contains two influenza A and two influenza B strains has been one such improvement, and a more potent dose has been made available to older adults, Piedra said.

Shortening vaccine production schedules would help improve prediction of circulating virus, Blaser said: "If we could improve production so it is only 3 months, we'd probably do a better job."

Even if a better vaccine is developed, getting more people to take the vaccine would be the next challenge, Blaser and Piedra said. Though the threat of pandemic influenza remains a real one, the fearless attitude of society toward the flu will continue to make uptake difficult.

COVID-19 As 'Just a Cold'?

It's hard to predict what will happen with COVID-19, experts said. Blaser said it's "theoretically possible to eliminate COVID-19 through a vaccination strategy if enough people get vaccinated and if the virus does not change its antigens to stay ahead of vaccine immunity, but it could go any way."

Thus far, it doesn't appear that SARS-CoV-2 mutates as rapidly as influenza, even though it is an RNA virus, which is more prone to mutation that DNA viruses, Blaser said.

Piedra cautioned, however, that respiratory viruses are generally harder to eradicate. "We aren't always able to make a vaccine that has the right response to prevent infection," he said. "That's different from preventing illness. By preventing infection, we're reducing the spread of the virus. That's a much more difficult hurdle."

Specifically, different immune responses are needed in the upper and lower respiratory tracts, and vaccines don't always provide such a coordinated response, he said, so they generally "afford protection against more severe disease rather than protection against the illness itself."

That points to the possibility of COVID-19 becoming endemic, Piedra said, like the four other coronaviruses in circulation in the U.S.: 229E, NL63, OC43, and HKU1.

In most cases, these viruses cause nothing more than common cold symptoms, though they can produce more severe infections, including pneumonia.

First identified in the 1960s, they're now suspected to have been around for hundreds of years, Piedra said.

"I think what's going to happen with these types of viruses, as they're introduced, is that it will take many years before they become fully adapted to humans -- and when they do that, they lose some of their potency," Piedra said. "It doesn't mean they lose all of their potency, but they do lose virulence" and cause fewer deaths.

While it's not a closed-book case, there is some evidence that this is what happened with OC43. A global pandemic in 1889-1890 that brought more than 1 million deaths globally has been attributed to influenza, but Belgian researchers have posited this was instead the initial outbreak of OC43.

People who caught the illness had more central nervous system symptoms than influenza usually brings, and one feature of OC43 is that it can attack the nervous system, those researchers said.

That could mean SARS-CoV-2 becomes a bad flu, or perhaps even just a cold, and that people may be indifferent about getting their COVID-19 vaccine -- but Blaser cautions that "how much COVID will vary over the years remains a wide open question."

Having a vaccine available with good uptake, having antivirals that can be given orally, and having good monoclonal antibody therapies will certainly diminish the fear factor of COVID-19, Piedra said.

He praised the speed at which the U.S. and the world has moved on those fronts. "Imagine from 1918 to 1940, it took 20-something years before we had a little bit of a handle on influenza viruses. For SARS-CoV-2 in a very short time, we knew what the virus was, we knew its genome, we developed vaccine candidates, we're starting to understand the immune response, we've developed antivirals."

"With this virus, it will take a while before we truly feel comfortable with it," he said. "The amount of death it is causing in the U.S. and worldwide is tremendous. We're going to have a major fear factor for a while."

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