In the spring of 1846, a Dutch physician named Peter Ludwig Panum arrived on the Faroe Islands, a volcanic chain about two hundred miles northwest of Scotland. He found the Faroes to be a harsh and unforgiving place. The islands’ eight thousand inhabitants, who were Danish subjects at that time, spent their days outdoors, buffeted by sea winds, fishing and tending sheep. The conditions, Panum wrote, were unlikely “to prolong the lives of the inhabitants.” And yet, despite the scarcity of medical care and a diet of wind-dried, sometimes rancid meat, the average Faroese life span was forty-five years, which matched or exceeded that in mainland Denmark. The islanders benefitted from a near-complete lack of infectious disease; many illnesses, including smallpox and scarlet fever, rarely reached them. Panum had arrived to study a measles epidemic—the first outbreak of that virus in the Faroe Islands in sixty-five years.
For the most part, the course of the outbreak was devastating and predictable. In six months’ time, more than three-quarters of the islands’ inhabitants were infected, and about a hundred people died. But the outbreak was also unusual in many ways. In mainland Europe, measles was typically a childhood infection. Few Faroese children died in the outbreak; instead, adults bore the brunt. Their mortality rates increased with every decade of life until about the age of sixty-five, and then dropped off. It turned out that those who’d been infected during the islands’ last measles epidemic, in 1781, were still protected by the immunity that they’d acquired decades before. Of these “aged people,” Panum wrote, “not one, as far as I could find out by careful inquiry, was attacked the second time.”
Panum’s study remains a striking demonstration of a remarkable fact: the body remembers. It learns to recognize the pathogens it encounters, and, in some cases, it can hold on to those memories for decades, even a lifetime. Ancient civilizations knew about immune memory long before they understood it; Thucydides, in his account of the plague of Athens, wrote that “the same man was never attacked twice—never at least fatally.” Many of us draw our ideas about the immune system from stories like these. We think of immunity as a binary state: without it, we’re vulnerable; with it, we’re safe.
For many pathogens, however, including coronaviruses, immunity is less clear-cut. The coronavirus family includes SARS-CoV-2, the virus responsible for COVID-19, along with four seasonal coronaviruses—HCoV-229E, HCoV-OC43, HCoV-HKU1, and HCoV-NL63—which together cause an estimated ten to thirty per cent of common colds. Today, these seasonal coronaviruses are the cause of common childhood infections, as measles was in Panum’s time. In sharp contrast to measles, though, adults are reinfected by seasonal coronaviruses every few years.
Much of what we know about these reinfections comes from the Common Cold Unit, a remarkable British research program whose studies of virus transmission and treatment involved more than eighteen thousand human volunteers over the course of forty-four years. In one of the unit’s last studies, published in 1990, fourteen healthy volunteers were exposed to seasonal coronavirus 229E by means of a nasal wash. They returned, a year later, to receive a second, identical dose. Of the nine people who were successfully infected the first time, six were infected again in the second exposure. The five volunteers who’d escaped the virus the first time were all infected, too. The fact of the reinfections might seem alarming, but the volunteers who’d been reinfected had fewer symptoms and were less likely to transmit the virus to others. They weren’t completely immune, but they retained a degree of immunity—low enough to allow for reinfection, but high enough to render the virus less potent.
This murky portrait of coronavirus immunity will shape our future as the U.S. brings COVID-19 under control. After getting the virus, the vaccine, or both, at least a hundred and sixty million Americans have acquired some form of immunity. Still, it is likely that the virus itself is here to stay. “I personally think that there’s essentially zero chance that SARS-CoV-2 will be eradicated,” Jesse Bloom, a virologist at the Fred Hutchinson Cancer Research Center, told me. (Bloom advised my Ph.D. research on influenza evolution.) Most viruses, including the four seasonal coronaviruses, other common-cold viruses, and the flu, haven’t been eradicated; scientists describe them as “endemic,” a term derived from the Greek word éndēmos, meaning “in the people.” Endemic viruses circulate constantly, typically at low levels, but with occasional, more severe outbreaks. We don’t shut out these endemic viruses with quarantines and stay-at-home orders; we live with them.
What will it be like to live with endemic SARS-CoV-2? That depends on the strength of our immune memories. How vividly will our bodies remember the virus or vaccine? How will waning immunity and the rise of variants—such as Delta, which is currently driving a spike in COVID cases around the world—affect our vulnerability to reinfection? We’re beginning to learn the answers to some of these questions, and to get a sense of the years to come.
On May 13, 2020, a fishing vessel left Seattle in search of hake. Before boarding, the ship’s hundred and twenty-two crew members were tested for the coronavirus, and also for antibodies against it, which indicate prior infection. Three crew members tested positive for antibodies before departure; everyone tested negative for the virus. But, while at sea, a member of the crew fell ill and tested positive. A ship at sea is an island, and the coronavirus spread rapidly. When the vessel returned to shore, after an eighteen-day voyage, a hundred and three crew members tested positive for the coronavirus. And yet none of the three crew members who’d possessed antibodies before boarding were infected a second time. In October, 2020, when these results were reported in the Journal of Clinical Microbiology, it wasn’t yet clear whether antibodies that formed during an initial infection could protect against reinfection. The vessel had brought home reassuring news.
Antibodies aren’t always the first line in our immune defense. When our cells encounter a new virus, they first respond by means of the so-called “innate” immune system, which shuts down many incipient infections quickly, before they grow out of control. This initial response is nonspecific; for the most part, it’s the same for every pathogen, novel or familiar. It’s only a few days later that the “adaptive” immune system—the home of immune memory—shifts into gear. Part of that ramping up involves B cells, which make antibodies. As a matter of course, our bodies produce millions of B cells, each tuned, in a more or less random way, to make a different kind of antibody; these antibodies are so diverse that one will inevitably match whatever pathogen might infect us. During an infection, the B cells that happen to be well suited to the new invader receive a signal to multiply. The antibodies they produce circulate in the bloodstream, binding to virus particles and disabling them.
The fishing-vessel study confirmed that the antibody response inspired by an initial SARS-CoV-2 exposure could protect against subsequent infections for some period of time. Immune memory had taken root. “Those B cells will, in many cases, persist through the rest of your life and keep cranking out antibodies, so your body will now remember whatever you’ve been exposed to,” Bloom, who was one of the authors of the study, said. And yet there are degrees of immune memory. Antibodies against certain viruses, such as measles, mumps, rubella, and smallpox, persist at extraordinarily stable levels for many decades; it’s because of that persistence that the “aged people” in Panum’s study were able to resist disease a lifetime later. But not all antibody responses are so durable. In 2007, researchers published a study of workers at the Oregon National Primate Research Center. The workers’ blood is tested regularly for exposure to animal diseases. The researchers found that, although some antibody levels stayed high, others fell over time. Antibodies against tetanus and diphtheria, two bacterial toxins, fell to half their previous levels in ten to twenty years.
The gradual erosion of antibody levels in the blood can lower protection and render us vulnerable to reinfection. An important unanswered question about SARS-CoV-2, therefore, is how long our antibody responses will last. “Long term, do your antibodies go to a stable plateau that persists for the rest of your life, or is it a downward-sloping line?” Bloom asked. For SARS-CoV-2, specifically, it’s too early to know. But long-term studies of its relatives, the viruses that cause SARS and MERS, have found that antibody levels can decline detectably in the two or three years after an infection. Time may erode levels of COVID antibodies as well.
Decline is not disappearance. Even if antibody levels go down from their initial post-infection peak, they may remain high enough to prevent a viral exposure from becoming an infection, or to keep an infection from progressing into severe disease. Onboard the fishing vessel, two of the three protected crew members had only modest antibody levels. The virus still left them untouched.
Immune memory isn’t inscribed in antibodies alone. “There is a whole array of memory cells that are just waiting to get reactivated,” Marion Pepper, an immunologist at the University of Washington, told me. In addition to the B cells that make antibodies, we possess T cells—marauding defenders capable of destroying the body’s own cells if they’ve been infected with a virus. Like antibodies, T cells come to circulate at lower levels over time. But both adaptive systems boot up faster upon reinfection. “It takes five to seven days to mount an adaptive immune response when you first see a virus,” Pepper said. “But it can take as little as two to four hours when you see it again.”
Last summer, Pepper’s lab conducted a detailed study of immunity in fifteen volunteers who’d had mild COVID-19 infections three months earlier. The researchers looked for antibodies, but also for so-called “memory” B and T cells—scouts that live in our tissue and bloodstream, monitoring for the reappearance of specific pathogens from the past. When these memory cells recognize an old foe, they sound the alarm, speeding the multiplication of pathogen-specific B and T cells. Memory cells are “little needles in a haystack,” Pepper told me, but the researchers still found ones tuned to the coronavirus, even though their research subjects had experienced only mild symptoms. “I have a lot of faith in the immune system,” Pepper said.
The immune system’s overlapping layers work together to strengthen its memory. But viruses aren’t static. As they accumulate mutations, their shapes shift, and they gradually become more difficult for the system to recognize. Survivors of the 1918 flu pandemic maintained strong antibody responses against that virus for almost ninety years. And yet adults still get the flu approximately once every five years, because the influenza virus’s rapid evolution insures that each year brings new variants. On average, flu viruses acquire half a dozen mutations each year; many of these alter the proteins that allow the viruses to enter and exit host cells. Antibodies that once bound tightly to a virus may have a weaker grip on its evolved form; the virus might escape the notice of certain T cells that used to recognize it.
“You can also ask the question for coronaviruses,” Bloom said. “How much of the ability to reinfect people might be driven by the virus changing?” Growing evidence suggests how much viral evolution might make us vulnerable to coronavirus reinfection. Recently, researchers in Bloom’s lab analyzed blood samples collected from people in the nineteen-eighties and nineties; the samples contained antibodies for the version of seasonal coronavirus 229E that circulated back then. Those same antibodies failed to recognize the descendants of the virus that had evolved in the intervening years. Coronaviruses mutate more slowly than viruses like influenza and H.I.V., but, over the course of a decade or two, they can still change enough to evade our immune memory.
Today, we are grappling with several coronavirus variants that are more transmissible—and possibly more deadly—than the original strain of SARS-CoV-2. Antibodies created in response to the initial virus or the current vaccines bind more poorly to several of these variants, creating opportunities for reinfection. The city of Manaus, in the Brazilian Amazon, is a case that has given researchers some reason for concern. In early 2020, the coronavirus spread there virtually unchecked; by October, tests showed that about half of the city’s inhabitants harbored antibodies, leading some scientists to declare that the area had reached herd immunity. But, in December, the city experienced a second coronavirus surge that was even more severe than the first, causing more hospitalizations and deaths than the initial wave.
