The immune system is very complicated. It works, roughly, like this.
The first of three phases involves detecting a threat, summoning help, and launching the counterattack. It begins as soon as a virus drifts into your airways, and infiltrates the cells that line them.
When cells sense molecules common to pathogens and uncommon to humans, they produce proteins called cytokines. Some act like alarms, summoning and activating a diverse squad of white blood cells that go to town on the intruding viruses—swallowing and digesting them, bombarding them with destructive chemicals, and releasing yet more cytokines. Some also directly prevent viruses from reproducing (and are delightfully called interferons). These aggressive acts lead to inflammation. Redness, heat, swelling, soreness—these are all signs of the immune system working as intended.
This initial set of events is part of what’s called the innate immune system. It’s quick, occurring within minutes of the virus’s entry. It’s ancient, using components that are shared among most animals. It’s generic, acting in much the same way in everyone. And it’s broad, lashing out at anything that seems both nonhuman and dangerous, without much caring about which specific pathogen is afoot. What the innate immune system lacks in precision, it makes up for in speed. Its job is to shut down an infection as soon as possible. Failing that, it buys time for the second phase of the immune response: bringing in the specialists.
Amid all the fighting in your airways, messenger cells grab small fragments of virus and carry these to the lymph nodes, where highly specialized white blood cells—T-cells—are waiting. The T-cells are selective and preprogrammed defenders. Each is built a little differently, and comes ready-made to attack just a few of the zillion pathogens that could possibly exist. For any new virus, you probably have a T-cell somewhere that could theoretically fight it. Your body just has to find and mobilize that cell. Picture the lymph nodes as bars full of grizzled T-cell mercenaries, each of which has just one type of target they’re prepared to fight. The messenger cell bursts in with a grainy photo, showing it to each mercenary in turn, asking: Is this your guy? When a match is found, the relevant merc arms up and clones itself into an entire battalion, which marches off to the airways.
Some T-cells are killers, which blow up the infected respiratory cells in which viruses are hiding. Others are helpers, which boost the rest of the immune system. Among their beneficiaries, these helper T-cells activate the B-cells that produce antibodies—small molecules that can neutralize viruses by gumming up the structures they use to latch on to their hosts. Roughly speaking—and this will be important later—antibodies mop up the viruses that are floating around outside our cells, while T-cells kill the ones that have already worked their way inside. T-cells do demolition; antibodies do cleanup.
Both T-cells and antibodies are part of the adaptive immune system. This branch is more precise than the innate branch, but much slower: Finding and activating the right cells can take several days. It’s also long-lasting: Unlike the innate branch of the immune system, the adaptive one has memory.
After the virus is cleared, most of the mobilized T-cell and B-cell forces stand down and die off. But a small fraction remain on retainer—veterans of the COVID-19 war of 2020, bunkered within your organs and patrolling your bloodstream. This is the third and final phase of the immune response: Keep a few of the specialists on tap. If the same virus attacks again, these “memory cells” can spring into action and launch the adaptive branch of the immune system without the usual days-long delay. Memory is the basis of immunity as we colloquially know it—a lasting defense against whatever has previously ailed us.
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Immune responses are inherently violent. Cells are destroyed. Harmful chemicals are unleashed. Ideally, that violence is targeted and restrained; as Metcalf puts it, “Half of the immune system is designed to turn the other half off.” But if an infection is allowed to run amok, the immune system might do the same, causing a lot of collateral damage in its prolonged and flailing attempts to control the virus.
This is apparently what happens in severe cases of COVID-19. “If you can’t clear the virus quickly enough, you’re susceptible to damage from the virus and the immune system,” says Donna Farber, a microbiologist at Columbia.
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There’s a further twist. Normally, the immune system mobilizes different groups of cells and molecules when fighting three broad groups of pathogens: viruses and microbes that invade cells, bacteria and fungi that stay outside cells, and parasitic worms. Only the first of these programs should activate during a viral infection. But Iwasaki’s team recently showed that all three activate in severe COVID-19 cases. “It seems completely random,” she says. In the worst cases, “the immune system almost seems confused as to what it’s supposed to be making.”
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There are also preliminary hints that some people might have a degree of preexisting immunity against the new coronavirus. Four independent groups of scientists—based in the U.S., Germany, the Netherlands, and Singapore—have now found that 20 to 50 percent of people who were never exposed to SARS-CoV-2 nonetheless have significant numbers of T-cells that can recognize it. These “cross-reactive” cells likely emerged when their owners were infected by other, related coronaviruses, including the four mild ones that cause a third of common colds, and the many that infect other animals.
But Farber cautions that having these cross-reactive T-cells “tells you absolutely nothing about protection.” It’s intuitive to think they would be protective, but immunology is where intuition goes to die. The T-cells might do nothing. There’s an outside chance that they could predispose people to more severe disease. We can’t know for sure without recruiting lots of volunteers, checking their T-cell levels, and following them over a long period of time to see who gets infected—and how badly.
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During an infection, antibodies are produced by two different groups of B-cells. The first group is fast and short-lived, and quickly unleashes a huge antibody tsunami before dying off. The second group is slower but long-lasting, and produces gentler antibody swells that continuously wash over the body. The transition from the first group to the second means that antibody levels usually decline over the course of an infection. “There’s nothing scary about it,” Krammer says.
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But “the fact that you don’t have measurable antibodies doesn’t mean that you aren’t immune,” Iwasaki says. T-cells could continue to provide adaptive immunity even if the antibodies tap out. Memory B-cells, if they persist, could quickly replenish antibody levels even if the current stocks are low. And, crucially, we still don’t know how many neutralizing antibodies you need to be protected against COVID-19.
Wang agrees: “There’s a common notion that antibody quantity is all that matters, but it’s more complicated than that,” she says. “The quality of the antibody is as important.” Quality might be defined by which part of the virus the antibodies stick to, or how well they stick. Indeed, many people who recover from COVID-19 have low levels of neutralizing antibodies overall, but some of them neutralize very well. “Quantity is easier to measure,” Wang adds. “There are more ways to characterize quality and we don’t know which ones are relevant.” (This problem is even worse for T-cells, which are much harder than antibodies to isolate and analyze.)
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In the meantime, anecdotal reports have described alleged reinfections—people who apparently catch COVID-19 a second time, and who test positive for the coronavirus again after months of better health. Such cases are concerning, but hard to interpret. Viral RNA—the genetic material that diagnostic tests detect—can stick around for a long time, and people can test positive for months after they’ve cleared the actual virus. If someone like that caught the flu and went to their doctor, they might get tested for coronavirus again, get a positive result, and be mistakenly treated as a case of reinfection. “It’s really hard to prove reinfection unless you sequence the genes of the virus” both times, Iwasaki says. “No one has that data, and it’s unreasonable to expect.”
Immunity lasts a lifetime for some diseases—chickenpox, measles—but eventually wears off for many others.
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If people endure a second bout with COVID-19, the outcome is again hard to call. For some diseases, like dengue, an antibody response to one infection can counterintuitively make the next infection more severe. So far, there’s no evidence this happens with SARS-CoV-2, says Krammer, who expects that any reinfections would be milder than the first ones. That’s because the coronavirus has a longer incubation time—a wider window between infection and symptoms—than, say, the flu. That could conceivably provide more time for memory cells to mobilize a new force of antibodies and T-cells. “Even if there’s some immunity loss in the future, it’s not that we’d have to go through this pandemic again,” Cobey says.
What will determine our future with the virus is how long protective immunity lasts. For severe coronaviruses like MERS and the original SARS, it persists for at least a couple of years. For the milder coronaviruses that cause common colds, it disappears within a year. It’s reasonable to guess that the duration of immunity against SARS-CoV-2 lies within those extremes, and that it would vary a lot, much like everything else about this virus. “Everyone wants to know,” says Nina Le Bert from the Duke-NUS in Singapore. “We don’t have the answer.”
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The virus could cause annual outbreaks. It might sweep the world until enough people are vaccinated or infected, and then disappear. It could lie low for years and then suddenly bounce back. All of these scenarios are possible, but the range of possibilities will narrow the more we learn about the immune system.
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