When it comes to coronavirus infections, the third time is not the charm. What is?
In March, 2020, Chelsea Kay, a twentysomething music lover who lives in New York, went to see the Australian band Rüfüs Du Sol play a packed show at the Orpheum Theatre in the heart of New Orleans. At some point, a murmur rippled through the crowd: Tom Hanks had tested positive for SARS-CoV-2, the virus that causes COVID-19. Kay thought little of it until she learned, a few days later, that states were shutting down to slow the spread of the virus. After travelling to her parents’ home in Chicago, fatigue set in. Her mother pulled a batch of chocolate-chip cookies from the oven, and she thought, Uh, I can’t smell anything. A few weeks later, when the loss of smell became well-known as a symptom of COVID-19, she realized that she’d contracted the virus. “And that,” she told me, “was the first time I got it.”
Two years later, on a cold Monday in March, Kay woke up feeling exhausted—her breathing labored, her head pounding. Wow, she thought, I feel like shit. Though a COVID test came back negative, she developed fevers, chills, night sweats, and brain fog, and a second test returned positive. Kay was young, healthy, vaccinated, and boosted, yet she grew so short of breath that she had trouble climbing stairs. “I’d never experienced anything like it,” she told me. Her brain fog lasted weeks.
With that hard-won immunity, Kay assumed she’d earned a reprieve. “You deserve at least six months, right?” she told me. “I was, like, I’m good for a while now.” But, by the end of June, she again felt unwell, and her symptoms were much the same as in March. “It was shocking,” she said. “Like, COVID can happen again—anywhere, anytime.” One wonders whether the cycle could continue forever—whether many of us will eventually get COVID for a fourth time, or a fifth, or even a tenth.
During the first year of the pandemic, when reports of coronavirus reinfections started to trickle in, the phenomenon was considered exceedingly rare—“a microliter-sized drop in the bucket,” as one virologist put it. As of October, 2020, the world had recorded thirty-eight million coronavirus cases and fewer than five confirmed reinfections. Two years later, the bucket is overflowing. It’s now clear that not only will just about everyone contract the coronavirus, but we’re all likely to be infected multiple times. The virus evolves too efficiently, our immunity wanes too quickly, and, although COVID vaccines have proved remarkably durable against serious illness, they haven’t managed to break the chain of transmission.
As more of us experience repeat infections, we may sense that the virus remains a constant menace even when it is ignored, perhaps below the threshold of full-blown crisis but far more destructive than what we might have accepted in the Before Times. In the U.S., COVID is still on pace to kill more than a hundred thousand people per year; many of us share the reasonable worry that some future reinfection will be the one that causes longer-term harm to our health and quality of life. Has our battle with COVID-19 come to such a standstill that a slow burn of disruption, debility, and death will continue for years to come?
The specialists I consulted for this story shared a conviction that, despite the relentlessness of reinfections, our COVID woes are slowly starting to recede. They said that, although coronavirus infections will always carry risks, and we may still suffer periodic surges and new variants, infections should get less serious and less frequent as our immunity grows. Vaccines and therapeutics will also continue to improve, helping to lessen the worst effects of reinfection. But the duration and severity of this transitional period matters, too. How many times will we have to sit through quarantines and ride out symptoms, worrying how bad this one might be? How many more surprises could the coronavirus have in store?
The reinfection era began in earnest last winter, when the Omicron variant first spread around the globe. A recent study conducted in Serbia found that for people who were infected in the first twenty months of the pandemic, the risk of reinfection rose steadily but slowly: at six months, around one in a hundred had been reinfected; at twelve months, one in twenty; and at eighteen months, one in five. But Omicron sent reinfections skyrocketing. Nearly ninety per cent of all reinfections occurred in the study’s final month, January, 2022. (The researchers found that one in a hundred reinfections led to hospitalization, and one in a thousand resulted in death.) By some estimates, the initial Omicron outbreak caused ten times as many reinfections as the earlier Delta variant. And Omicron now circulates in the form of even more contagious subvariants, such as BA.4 and BA.5.
How often is the coronavirus reinfecting us now? “We’re probably all getting reinfected all the time,” Marcel Curlin, an infectious-disease physician at Oregon Health & Science University, told me. “If you put me in a room with someone with COVID, and a little virus lands in my nose and infects one cell and makes new viruses, but then my immune system immediately wipes it out—well, I’ve been infected. It’s just that it’s not clinically recognized as an infection.” Seen in this way, infections could be considered less of a binary than a spectrum: the virus can replicate inside our bodies even if it doesn’t cause symptoms or show up on less-sensitive tests. “I bet if we did a PCR test on every person every four days, we’d see a sky-high rate of reinfection,” Curlin said.
Fundamentally, our risk of reinfections depends on three main factors: how much our immunity has waned, how much the virus has changed, and how much of it we encounter. Our collective immunity increases with infections, reinfections, and vaccines. Booster shots are meant to slow the drawdowns in our immunity, and the recently approved bivalent vaccines, which target the Omicron subvariants BA.4 and BA.5, may be particularly helpful. But the immune system must be judicious: it encounters countless threats and can’t maintain enormous standing armies for each one. Over time, our bodies pare back their defenses, and whether we’re reinfected depends partly on how quickly and intensely they remobilize during the next encounter.
Our immune protections also exert pressure on the virus to evolve around them. Viruses can change so much that the body has trouble recognizing and subduing them. The original Omicron variant had at least thirty-two mutations on its spike protein—twice as many as Delta—and, in recent months, its subvariants have accumulated many more. SARS-CoV-2 is mutating faster than any of its cousin coronaviruses—faster, even, than the world’s dominant flu strain.
Finally, the chance you’re reinfected is a function of “viral dose.” It’s more than just a numbers game: our immune cells have to be stationed in the right places. “It’s like real estate in Manhattan,” Florian Krammer, a virologist at Mount Sinai’s Medical School, told me. “Location really matters.” COVID vaccines injected into muscle produce relatively high levels of antibodies in the blood and lungs, but not in the nose, mouth, and upper airways, where the coronavirus usually enters. (Natural infection seems to produce a longer-lasting immune response in the nasal cavity.) That’s why scientists are so interested in mucosal vaccines, which are administered in the nose or mouth. India and China recently authorized such vaccines, but it’s still not clear how effective they’ll be.
These three factors exist in a kind of equilibrium, but the balance can change, sometimes dramatically. Because Omicron is a more skilled infector of humans than prior variants, we need vastly higher levels of circulating antibodies to block it from infecting us. “The intrinsic transmissibility of Omicron has changed the rules of the game,” Dan Barouch, an immunologist at Harvard, told me—probably in a way that makes it impossible for us to win, if by winning we mean avoiding reinfection altogether. “Are we chasing our tails trying to continuously raise antibody titers against SARS-CoV-2 to levels that would fully block infection?” Barouch asked. “At this point, is preventing infection even a realistic goal?”
Aubree Gordon, an epidemiologist at the University of Michigan, has been following hundreds of households in Nicaragua to understand COVID risks over time. Gordon’s work has shown that, on average, a first infection lowers the severity of a second, and a second of a third. But, for some, COVID continues to present meaningful health risks. “I’d hoped that one or two reinfections would get us to a place where COVID was something like other coronaviruses,” Gordon told me. “It looks like it will take longer. But I expect we’ll still get there.”
Gordon believes that one day, SARS-CoV-2 will infect us far less frequently than it does now. She pointed to a paper published in Nature Medicine that examined how often people were infected by other coronaviruses. (Virtually everyone has antibodies against the four other coronaviruses that afflict humans, and they generally cause only mild cold symptoms.) The researchers followed ten healthy individuals for decades and found that, although reinfections can occur as soon as six months after a prior infection, the median time to reinfection was around three years. “And that’s for any infection, not symptomatic infection,” Gordon said. “My best guess would be—and this is just a guess—that symptomatic COVID infections will eventually occur every five years or so.” We could achieve this equilibrium within five years, and possibly sooner, she said. But that would still mean that many of us could get COVID ten times or more in our lifetimes.
Claudia, a special-education teacher with an easy smile and short, curly brown hair, was pregnant when the pandemic began. (She asked me to omit her last name to protect her privacy.) She and her husband stayed holed up in their Brooklyn apartment even after their daughter was born, in October, 2020. “Essentially the only time I left the house was for my postpartum visit,” she told me. But the couple decided to take PCR tests and spend Christmas, 2020, visiting her parents. Her results didn’t arrive until Christmas Eve, at which point Claudia and her mother were already cooing over the baby. “My mom was oh-my-God freaking out,” Claudia said. “We all had a moment of spinning our wheels. I felt totally fine, but somehow I had COVID?”
Her second positive test came a year later, when Omicron became the dominant variant and a wave of infections affected the school where she teaches. She had no symptoms and was surprised when a precautionary test came back positive. She’d been in close contact with many students and teachers, and the school closed early for winter break. “I inadvertently gave everyone that little Christmas gift,” she said.
Claudia’s third coronavirus infection, in September, was her worst—a reminder that infections and immunity do not always follow predictable patterns. Her daughter, now nearly two, developed a fever; Claudia soon experienced muscle pains, headaches, congestion, and fatigue, and then lost her sense of smell. When we spoke a few weeks later, it had mostly returned, but, she told me, “I’m constantly going around sniffing cinnamon, just to make sure.” Claudia feels grateful to have escaped these infections relatively unscathed, but she’s wary about long-term consequences. “I’m nervous about all these studies coming out saying, ‘Oh, you could get dementia, depression, any number of things after even mild COVID,’ ” she told me. “I’m, like, Well, shit, there’s nothing I can do about it now.”
People who are reinfected by the virus are much more likely to suffer a range of medical problems in subsequent months, including heart attacks, strokes, breathing problems, mental-health problems, and kidney disorders, according to a major new analysis of U.S. veterans. Compared with those who weren’t reinfected, they are twice as likely to die. “We did this paper because, for most people in the U.S., a first infection is now in the past,” Ziyad Al-Aly, the study’s lead author and chief of research and development at the V.A. St. Louis Health Care System, told me. “They’re thinking, I’ve had it once, I’m vaccinated, I’m boosted. Should I still go the extra mile to protect myself? Does reinfection really matter? The short answer is: yes, it absolutely does.”
There are some caveats. The study has not yet been published in a peer-reviewed journal, and many veterans are older men with multiple medical conditions, so they have a higher level of risk than the general population. It’s also possible that people who get reinfected are somehow dissimilar from those who don’t. Al-Aly was careful to note that a second infection isn’t necessarily worse than a first one—rather, that it’s worse than not getting reinfected at all. “But I think the idea that there’s some elevated risk that comes with reinfection isgeneralizable,” Al-Aly told me. Even when the health risks of any one infection go down, the cumulative risks of many infections should worry us.
People should still do their best to avoid contracting and transmitting the virus, Al-Aly said: mask on public transportation, stay home when sick, choose outdoor activities over indoor ones. Meanwhile, there’s more that policymakers must do: maintain testing and treatment programs, fund next-generation vaccines, invest in public-health departments, improve ventilation systems, support paid medical leave. “Without mitigation measures, it’s inevitable that most people will get reinfected,” Al-Aly said. “That’s the price we pay for moving toward normal. It’s an exorbitant price.”
Recently, I called Florian Krammer, the Mount Sinai virologist, and outlined a pessimistic scenario: a future in which COVID reinfections are common, dangerous, and inevitable. “When you say it like that, it sounds very bad,” Krammer admitted. “But I actually don’t see it that way.” There’s nothing special about the coronavirus, he argued. Yes, SARS-CoV-2 caused a global pandemic, but he thinks that was primarily because of its novelty. We perceive the virus as unique because we’re so focussed on it—it’s one of the most closely studied pathogens in human history—but it obeys the same general rules as other viruses.
Viruses have always caused a variety of immediate and lasting health problems. It’s just that “most people haven’t been paying attention,” Krammer said. Long before this pandemic, for example, viral infections were linked to diabetes, cancer, heart problems, and autoimmune conditions. Five years ago, in her book on the 1918 influenza pandemic, the journalist Laura Spinney wrote about people who suffered prolonged weakness, fatigue, brain fog, insomnia, and mood changes. “We were leaden-footed for weeks,” one woman recalled. “It also was very difficult to remember any simple thing, even for five minutes.” A train driver was “never . . . quite the same” after his illness, blacking out while driving and causing an accident. In parts of Africa, post-viral syndromes were so widespread among farmers that they’re thought to have triggered a famine. Recent researchsuggests that even non-pandemic influenza may be associated with protracted symptoms: according to researchers at Oxford, nearly a third of people who contract the flu virus today report symptoms that resemble long COVID, and could be suffering what might be called “long flu.”
Doesn’t this mean that we should worry about a higher baseline of illness going forward—that the risks of coronavirus reinfections will be layered atop a pre-pandemic level of disease? “Not necessarily,” Krammer told me. “In fact, I think we’re going to get back to more or less the same state we were in before the pandemic.” Krammer argued that respiratory viruses often compete with one another; one kind of infection could make others less likely, at least in the short term. (During the 2020-21 influenza season, flu cases fell so steeply that the C.D.C. was unable to calculate the virus’s burden.) After an infection, the cells in your respiratory tract remain in an antiviral state for some time, making it harder for other viruses to take up residence. It’s also likely that, during and after an illness, people change their behavior. They stay home from work, skip dinner with friends, forgo concerts and conferences. “In the long run, SARS-CoV-2 will be just another respiratory virus,” Krammer predicted.
Al-Aly was less sanguine. He sees little reason that COVID risks will necessarily drop to the level of influenza, and, in any case, we’re not there yet. “We have to balance the need for normalcy with the need to protect the health of the people,” he said. Still, he agreed with Krammer and the other experts on one thing: the added burden of a third, fourth, or fifth infection will probably be lower than the first or second. Each new infection may come with diminishing marginal pains. “There will come a point where reinfection will not add more risk,” Al-Aly said. “Whether that is the sixth or seventh or nth infection, we don’t know yet.”
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