During the annual flu season, many people experience the usual symptoms: a runny nose, sneezing, body aches, and fever. Flu can also be deadly. In the United States alone, influenza viruses cause hundreds of thousands of hospitalizations and tens of thousands of fatalities each year. During the pandemic, however, a drastic change occurred: there was a precipitous drop in infections with influenza and other respiratory viruses—and in some parts of the world, some of these pathogens are nowhere to be found.
“It’s really dramatic how the flu disappeared this year,” says Ellen Foxman, an immunologist at Yale University. At Yale-New Haven Hospital, where Foxman works, there were around 3,000 confirmed flu cases in the first three months of 2020, Foxman tells The Scientist. “This year, from the first of January until now, there’s zero.”
Mask wearing, social distancing, and other restrictions implemented to stave off SARS-CoV-2 are thought to be the primary culprits in the decline in other respiratory pathogens in circulation. As such measures are lifted, though, scientists are expecting the missing viruses to return—and are pondering what will happen when that occurs.
Scientists suspect that the lack of exposure to influenza over the course of this pandemic means that people’s immune systems are now more vulnerable than usual to infection. At the same time, not being able to circulate has led to a striking reduction in the genetic diversity of circulating influenza viruses, which are constantly undergoing mutations—but it’s not yet clear what implications this has for human health.
“I think everyone appreciated not having colds and flus this year,” Foxman says. “It would be really nice to keep that going. The question is, what is it going to take?”
Many scientists expected the strict measures put in place during this pandemic would lead to a reduction in infections from other respiratory viruses, and indeed, signs that influenza was being kept at bay began emerging early in the pandemic. Last April, Ben Cowling, an infectious diseases epidemiologist at Hong Kong University, and his colleagues used surveillance and hospitalization data to estimate that in Hong Kong, flu transmission within the general community declined by 44 percent after measures to limit SARS-CoV-2’s spread were implemented last January.
A few months later, Rachel Baker, an epidemiologist at Princeton University, published a similar study based on data from the US on outbreaks of seasonal influenza as well as respiratory syncytial virus (RSV), a pathogen that circulates in infants and young children, sometimes causing severe illness. She and her colleagues examined surveillance data collected in the US between 2016 and March 2020, the month during which the US government declared COVID-19 a national emergency. Their work revealed that by the end of March, RSV transmission had fallen by an estimated 20 percent, and that even though the 2019–2020 flu season was more severe than average, after the state of emergency was announced—and measures to control SARS-CoV-2’s spread were put in place in many states—influenza outbreaks, too, showed signs of subsiding.
Similar trends have emerged elsewhere as well. In Australia, for example, investigators reported that compared to similar periods during pre-COVID years, RSV and influenza infections in children dropped by more than 98 percent between April and August 2020.
As those early studies predicted, the spread of influenza and RSV was significantly stymied was over the course of the pandemic, to the point where, as Foxman notes, some hospitals have seen almost no cases this year.
“To have us completely miss the flu and the RSV season is unprecedented,” Baker says. Such a drop-off has not been seen in recent history. The closest example might be the 1918 influenza pandemic, during which public health inventions appeared to drive a change in the seasonality of measles in London due to an estimated 38 percent reduction in contacts among susceptible and infected individuals, according to recent research.
Why did distancing measures stop influenza and RSV, while COVID-19 continued to spread? Scott Hensley, a viral immunologist at the University of Pennsylvania, says one reason is that there was a large susceptible population to COVID-19—because SARS-CoV-2 was a new virus—whereas for viruses such as influenza, populations have higher levels of immunity, because many people have had prior infections. Another possibility, Hensley adds, is that SARS-CoV-2 is simply more transmissible, though he notes that the relative transmissibility of these viruses has yet to be tested.
“All the measures that have been put in place to limit the spread of SARS-CoV-2 have effectively limited the spread of influenza and other airborne viruses,” Hensley says. “As we start relaxing some of the social distancing and restrictions, it’s expected that these viruses will return.”
A diversity bottleneck
A key question that scientists have now is what those viruses will look like when they return.
During the pandemic, not only have flu case numbers plummeted in parts of the world, but influenza viruses has also become significantly less diverse—so much so that some variants of the virus may have disappeared. “What we’ve seen is a major collapse in the genetic diversity of [flu] viruses,” Hensley says.
A key question that scientists have now is what those viruses will look like when they return.
There are four types of influenza viruses: A, B, C, and D. The viruses responsible for seasonal flus fall into types A and B. Type A viruses are split into subtypes named for the identity of two of its surface proteins, hemagglutinin (H) and neuraminidase (N)—H1N1, for example. Type B viruses, by contrast, are divided into two lineages, B/Victoria and B/Yamagata. Both subtypes and lineages can be further divided into clades and subclades based on their genetics.
“In the past 18 months, the B/Yamagata lineage has disappeared,” says Cowling. In addition, among the clades of H3N2 viruses—of which of around half a dozen usually circulate each season—there now appear to be only two major clades, according to Hensley. “Very few flu viruses have been able to make it out of the COVID pandemic unscathed.”
It’s not yet clear why some subgroups of these viruses survived, while others have gone off the map, but Hensley says that there are a few potential explanations. “Some people have speculated that those viruses were just sort of in the right place at the right time,” he tells The Scientist. Alternatively, “maybe the viruses that have squeaked by during the pandemic have something special about them—maybe they are able to evade human immunity more effectively or transmit more effectively.”
Scientists are also wondering: Are these lost variants of the influenza virus really gone, or are they just biding their time, waiting to spread? John McCauley, the director of the World Influenza Centre at the Francis Crick Institute in the UK, notes that the viruses that appear to have disappeared could still be in circulation at low levels somewhere in the world. Viral infections tend to spread exponentially—so even if the rate of transmission of a virus currently appears slow, numbers could rapidly increase later on. Scientists don’t know how quickly one of these currently undetectable flu variants could take over, “but it’s starting from a lower base [number of infections] than would be normal,” McCauley adds.
Thus, the significant drop in the diversity of the influenza virus may just be temporary. If there is a severe flu season, Cowley says, then “that would give the opportunity for the virus to evolve—and maybe develop some diversity—again.”
There are already signs that some of these viruses are beginning to return. Although there have not yet been large outbreaks of flu in places where levels dropped drastically over the past year and a half, some areas are already seeing surges in RSV. “We’ve seen RSV come back in many countries now—flu hasn’t come back, so there’s a bit of a puzzle there,” Baker says. One possible explanation for this is that RSV has returned because it circulates mostly in young children, and while some kids are going back to daycare, many adults are still working from home. Another is the fact that seasonal patterns in transmission are stronger for flu than for RSV, and it’s no longer flu season in the Northern Hemisphere.
“It’s an unprecedented time in flu history,” Hensley says. “But influenza viruses have this uncanny ability to change and adapt, and I would expect that once life sort of gets back to normal, we’ll see flu get back to normal as well.”
After almost two years of having to fend off few to no infections with influenza and other respiratory viruses, some scientists are worried that the lack of infections may had led to a decrease in immunity to some of these pathogens. “There’s never been a time in recent history where the human population was as immunologically naive as it is here in 2021,” Hensley says.
I would expect that once life sort of gets back to normal, we’ll see flu get back to normal as well.—Scott Hensley, University of Pennsylvania
Cowling and his colleagues found signs that this was happening in Hong Kong: after prolonged school closures, colds caused by rhinoviruses exploded upon return to the classroom, despite a requirement for students and staff to wear masks at all times and strict distancing measures such as limits on group activities. “We were kind of surprised, because we didn’t think that anything could spread” under those conditions, Cowling says. Because the schools had been closed, “we think that led to a loss of immunity, and so there were even more infections than ever before.”
Most of the worry regarding the lowering of immune defenses is related to the adaptive immune system, which remembers prior infections and launches specific responses to pathogens. “When you see [a virus] again, it sort of tickles the memories so that those memory responses are easier to trigger,” Foxman explains. “There’s a concern that it’s been a while since we’ve seen most of the common respiratory viruses going around, and so our memory responses might be worse.”
Foxman adds that the innate immune system—which launches rapid, nonspecific responses to fight off pathogens—may have also been affected. “We haven’t had either the boosting of adaptive immunity or the normal level of innate immunity you just get from getting infections all the time, especially for kids,” Foxman tells The Scientist. “Both are reasons why people are worried about the respiratory viruses being worse this year.”
Studies from Foxman’s group and others suggest that when common cold viruses are circulating, they may provide protection against other viruses, such as SARS-CoV-2. While more research is needed to establish whether this phenomenon is real, researchers have documented several instances, in both humans and animals, when infection with one virus appeared to reduce the chances of getting infected with another. “Once a cell in your airway gets infected, it triggers these defenses and tells all the cells around to switch on your antiviral program,” Foxman says. “So common cold triggers these defenses pretty fast. Then those are still on to protect against the viruses that are better at blocking those defenses.”
In addition to the possible reduction in immune defenses among older children and adults, there is also now an extra year’s worth of babies who have never been exposed to some of these viruses, Foxman says. Kids are thought to be vectors that spread viruses to other members of society—so more immune-naive youngsters may mean that there’s more potential for the pathogens to spread and for the infants themselves to fall ill.
The good news is that while our immune defenses to influenza may be lowered, there is a way to boost them: with vaccines. The best way to prevent flu’s worst effects, including death, is by getting vaccinated, Foxman says.
Many unknowns remain about what this prolonged period of reduced activity has meant for influenza and other viruses that many of us have been able to evade during the pandemic. But one thing is clear: the public health interventions designed to stave off respiratory pathogens worked. The question now is to what extent we should continue implementing some of those measures, Baker says. Keeping some of these rules in place at the population level will likely be difficult, but “at the individual level, wearing a cloth mask in dense public transit areas, on airplanes, or in the supermarket is a good way to at least help minimize your risk of getting the flu during flu season,” she adds. “I think maybe some of those measures, now we know that they work, will linger in society, and hopefully that will have a positive impact on the future burden of influenza.”