Five things to know about this year’s ‘tripledemic’

The Perelman School of Medicine’s E. John Wherry and Scott Hensley discuss the season’s confluence of COVID-19, influenza, and RSV and how our bodies are responding.

two young people wearing lie under a blanket on a couch, looking sick
Image: iStock/Srdjanns74

Call them a triple threat? Influenza and RSV (short for respiratory syncytial virus) descended upon the U.S. population in late fall, joining a steady stream of COVID-19 infections. What has come to be referred to as the “tripledemic” has laid low millions across the nation during the last few months.

Misconceptions about this wave of infection have abounded, with some blaming vaccines or the SARS-CoV-2 virus itself for tampering with immunity. To clear up some of the science related to COVID, other respiratory viruses, and associated vaccines, Penn Today spoke with two scientists from the Perelman School of Medicine: immunologist E. John Wherry and influenza virus expert Scott Hensley. These are some of their top takeaways.

‘Immunity theft’? Not really a thing, but immunity debt may be

“The idea of immunity theft, that either infection with SARS-CoV-2 or vaccination against it have made our immune systems weaker—there’s no good evidence for that,” says Wherry. “Immunity debt is a different thing. I don’t love the term, but from a colloquial standpoint it captures some of what has happened over the last two to three years.”

In a sense, the population’s immunity is in “debt” from a few years of social distancing, masking, and reduced travel, Wherry says. We have not had the same exposures to RSV and influenza as we typically would and thus have not mounted an immune response against them recently. Notably, young children, most of whom would normally be exposed to RSV or flu in their first three years, may have skirted that exposure due to pandemic-related changes in social behavior.

A large part of the spike in illnesses we’ve seen this past fall and early winter, therefore, may be a partial payment toward that “debt.”

“Population immunity was very low against these viruses,” Hensley says. “Once the spark occurred, there was just this huge, immunologically naïve population out there. That’s why RSV and influenza viruses have spread so rapidly.”

That’s not to say some viral infections have no impact on the immune system. Some, like HIV and measles, are known to suppress immunity. But thus far this hasn’t been shown with COVID-19, the researchers say. Instead, a third phenomenon, dubbed “immune stealing,” may come into play in cases of severe or long COVID-19.

“In severe cases we’ve seen COVID-19 be associated with immune miswiring, causing the immune system to fight against the things that it uses to communicate with itself, like cutting phone lines,” says Wherry. “This can lead to autoimmunity. It’s something we’re worried about and an area that’s now being studied.”

RSV and flu came early this year—flu may make another appearance

Generally, RSV infections would gain steam in the fall and peak in the period from December to February. Flu generally peaks a bit later. This year, however, “RSV and flu were happening in a synchronous way,” says Wherry, and the RSV peak occurred unusually early, in November.

Flu cases are falling off now, but Hensley notes there may be a second wave to come. While the initial peak is driven by viruses that fall into the category known as influenza A, often a second peak in late winter or early spring involves influenza B viruses, which can cause severe disease. Hensley notes that last week saw an uptick in influenza B numbers in the Philadelphia area, though it remains to be seen how widespread those infections will grow.

Meanwhile, a new variant of SARS-CoV-2, XBB.1.5, which arose from two Omicron subvariants, is behind many new cases in the Philadelphia region. Some experts believe this version of the SARS-CoV-2 to be more transmissible than prior strains.

Viruses can co-infect one person, sometimes competing for dominance

With so many viruses circulating, sometimes one person can pick up multiple infections at once. Documenting how often this occurs is difficult, however, says Wherry. More often, a viral infection coexists with a bacterial one, like a sinus infection or pneumonia arising during a bout with a viral respiratory infection. “Especially in older people, that secondary infection, sepsis or pneumonia, can come with real negative consequences,” Wherry says.

Another dynamic that can occur is competition between viruses. “Studies have shown that if you infect an animal with flu, RSV will not take hold,” Hensley says. “And epidemiological evidence supports those findings.”

This can occur as part of the innate immune response, a general “fight” reaction against foreign invaders.

Adding COVID-19 to the mix, Hensley says it’s possible that this aspect of competition could prompt changes in how flu infects populations. “Last winter when the Omicron variant came on the scene, we saw COVID cases shooting up and flu cases going down,” he says. “We’ll need more years of data to understand whether competition was playing a role in that dynamic, but it will be interesting to see how SARS-CoV-2 shakes up our normal epidemiological curves for flu.”

Vaccines are doing their jobs, and there’s still reason to take caution around COVID

All signs indicate that the bivalent boosters that began rolling out in late summer are working. According to recent scientific papers and reports from the Centers for Disease Control and Prevention, these boosters effectively enhance immune protection that may have waned since individuals received the earlier iterations of vaccines that immunized against a single strain of virus. A December CDC publication, for example, found that the bivalent vaccine provided 73% additional protection against hospitalization among immunocompetent people older than 65 compared with earlier COVID-19 vaccines.

“It’s very likely that the booster is also preventing or limiting infection in folks under 65,” Wherry says.

From a variety of studies, he says, it seems that a booster dose every four to six months from the last exposure to SARS-CoV-2—be it in the form of infection or vaccination—will continue to offer good protection.

And with so many people lacking immunity to influenza from past years, Hensley says, “if there’s ever a time to get a flu vaccine, this is it.” This year’s flu vaccine formula appears to be a good match for the circulating influenza A and B viruses.

Next-generation vaccines may protect against a huge swath of viruses

In collaboration with Drew Weissman’s group, Hensley and colleagues recently published a paper in Science on a multivalent vaccine capable of inducing a baseline level of immunity against all 20 subtypes of influenza. The vaccine uses mRNA, like the COVID vaccines, from a hemagglutinin protein from each of these flu strains.

“Influenza virus subtypes currently circulating in birds and pigs could enter the human population and cause a pandemic, but it’s impossible to predict which one will,” Hensley says. “The vaccine we created contains immunogens from every subtype. In animal models, our vaccine does not necessarily prevent all viral infections, but it does limit severe disease caused by diverse influenza virus strains.”

The multivalent vaccine showed promising results in animals in the lab, and Hensley and Weissman are making plans to start a phase 1 clinical trial in people. It’s a strategy that researchers are pursuing with coronaviruses as well.

“Think back to the start of this COVID pandemic, when many of us were staying home and washing our groceries,” Hensley says. “If we had a pan-coronavirus vaccine that could prevent severe disease and death, that would have completely changed the course of the pandemic.”

Scott Hensley is a professor of microbiology in the University of Pennsylvania Perelman School of Medicine.

E. John Wherry is the Richard and Barbara Schiffrin President’s Distinguished Professor, chair of the Department of Systems Pharmacology & Translational Therapeutics, director of the Colton Center for Autoimmunity, and director of the Institute for Immunology in Penn’s Perelman School of Medicine.