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How healthy innate immune systems adapt to viral mutations - Feb 2021

The Body Is Far From Helpless Against Coronavirus Variants The Atlantic Feb 12 , 2021


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To locate some of the world’s most superpowered cells, look no further than the human immune system. The mission of these hometown heroes is threefold: Memorize the features of dangerous microbes that breach the body’s barriers. Launch an attack to bring them to heel. Then squirrel away intel to quash future assaults.

The immune system is comprehensive, capable of dueling with just about every microbe it meets. It’s archival, ace at memorizing the details of its victories and defeats. It might be complicated, but it is also, simply put, cool as hell.

Now, a year into a pandemic, our immune systems face a new challenge. The coronavirus has picked up mutations that boost its ability to hop from human to human and thwart some of the antibodies that have reliably conquered it before. The protection offered by vaccines appears riddled with holes. Viruses evolve fast—faster than humans ever could. If the pandemic is a race, the coronavirus seems, at times, on the verge of lapping us.

But the immune system is not doomed to be discombobulated by a never-ending barrage of shape-shifting variants. For every trick the virus plays, the immune system arguably has an equally impressive one. Vaccines remain an essential ally, armoring the body before it encounters the virus. And although the variants have opened up gaps in that chain mail, the pliancy built into our bodies can at least buy time to repair them.

“Yes, we should be concerned,” Ali Ellebedy, an immunologist at Washington University in St. Louis, told me. “But I think we should also be optimistic.”

When any infectious interloper hits, the body’s first responders—the less specialized cells of the innate immune system—rush in to wallop it. Those cells also gather information on the invader and ferry it to the lymph nodes, where they parade pieces of the pathogen in front of the body’s longer-term defenders, the cells of the adaptive immune system.

Among these adaptive cells are B cells, each wired to recognize a slightly different hunk of foreign matter. During their development, individual B cells will mix and match segments of genes that encode antibodies, generating billions or trillions of unique combinations. The result is a multitude of Y-shaped molecules that can collectively “respond to any foreign pathogens they see,” says Kim Jacobson, an immunologist at Monash University in Australia. The focus of these antibodies is so laser-sharp that they can differentiate even the individual nooks and crannies that decorate a virus’s surface.

The large majority of B cells won’t be triggered by the chunks of virus shuttled in during any given infection. But the few that are will begin to rapidly copy themselves in hopes of joining the fray. Some will immediately transform into antibody factories, pumping out gobs of the Y-shaped molecules to run rapid viral interference. Others, however, will remain in the lymph nodes to further study the virus.

Here they will split themselves into more B cells, deliberately introducing errors into their genetic code. If the original genetic scramble created antibodies prepared to take on all manner of pathogens, these random but more subtle tweaks have a chance of enhancing the ability to vanquish the specific virus at hand. The process is a bit like evolution on steroids: Mediocrity gets repeatedly weeded out, leaving only the sharpest and strongest killers behind. By the time a virus has vacated the body, the antibodies being produced against it are, on average, more precise and potent.

Much of this painstaking refinement continues after the virus itself is gone: Certain innate cells will cling to scraps of viral corpses—macabre souvenirs of maladies past—to keep the B cells’ boot camp open in the lymph nodes. In a study published last month in the journal Nature, researchers found that the antibodies of COVID-19 survivors continue to strengthen their grip on the coronavirus for several months.

“Over time, our antibodies just become better,” Ellebedy said.

After infection is cleared, most of the B cells that rallied to the fore will die off, their life purpose fulfilled. But some cloister themselves in the bone marrow, eking out small quantities of antibodies. Others—the so-called memory contingent—will drift quietly throughout the body like sentinels, scanning the blood and tissues for trace signals that the same virus has returned to trouble them again. Called back into action, these memory B cells can immediately start pumping out antibodies. Or they can reenter training centers in the lymph nodes to continue their education on the virus, honing their defensive skills further.

Read: Immunology is where intuition goes to die

In epic tales of the immune system, B cells and their antibodies tend to hog the limelight. Antibodies, which are proteins that drift through the blood, are easy to capture and measure; they’re sometimes powerful enough to waylay a virus before it has the chance to break into a cell. But no antibodies would be produced without the help of T cells, which coax B cells into maturing and play vital roles in their training regimen—loyal wingmen at the ready. T cells are also formidable foes in their own right, capable of recognizing virus-infected cells and forcing them to self-destruct.

T cells don’t undergo the same supercharged mutation process that their B-cell colleagues do. They are stuck with the pathogen sensors they’re born with. But the starting repertoire of T cells, and the number of bugs they can recognize, is similarly massive. And like their B-cell counterparts, T cells are capable of remembering past pathogenic encounters—and their discerning gaze is especially difficult to elude.

When viruses undergo a substantial costume change, it can disrupt this iterative process. It’s a big part of why flu vaccines have to be updated every year, Ellebedy said: “We are always trying to catch up with the virus.”

But coronaviruses mutate far more slowly than flu viruses do. And this new one has yet to undergo a makeover that fully neuters the vaccines we’ve developed against it. “I think there’s probably a very small probability that there will be complete escape,” David Masopust, an immunologist at the University of Minnesota, told me.

B cells and T cells develop so many unique ways of recognizing a given virus that any one mutation, or even a handful, won’t fully thwart them. A change to the equivalent of a virus’s elbow, for example, will have little impact on a T cell’s ability to recognize its earlobe. Memory cells will rapidly seize upon commonalities between the two versions of the virus; in some people, this alone could be enough to nip an infection in the bud.

Certain memory cells—especially T cells—might have enough flexibility to recognize a modified version of their viral target. Experts call this “cross-reactivity,” and it’s a crucial part of the T cell way of life, Laura Su, an immunologist at the University of Pennsylvania, told me. Some scientists have hypothesized that T cells previously marshaled against other coronaviruses, such as those that cause common colds, might even play a small role in quelling this new one.

Even in the complete absence of memory and cross-reactivity, the body still has a huge reserve of backup cells—the multitude of B and T cells that were not triggered by the first go-round with the virus, Su said. The war against variants is not a fight just for veterans: Chances are, rookies are waiting in the lymph nodes to be called to the front lines. Depending on the extent of the virus’s metamorphosis, another infection, perhaps another illness, may be possible. But the body is not left wholly defenseless.

In South Africa, where an immunity-dodging coronavirus variant was recently identified, drops in vaccine efficacy showcase the tight foxtrot between the virus’s mutability and the immune system's adaptability. Johnson & Johnson’s numbers fell from 72 to 57 percent; Novavax’s, from 89 to 49 percent (though this last number ticked up to 60 percent when the researchers considered only people who were not living with HIV, a virus that blunts the immune system). But neither vaccine’s efficacy plummeted to zero—not even close. Most vaccinated immune systems, it seems, have yet to be fully flummoxed by the variant.

“The biggest misconception is these immune responses are all or none,” Marc Jenkins, an immunologist at the University of Minnesota, told me. But as my colleague Sarah Zhang has written, vaccines function more like a dimmer than a light switch, tuning down the risk of serious COVID-19 along a hazy spectrum. Importantly, the vaccines still seem to largely ward off severe disease and death—a hint that residual antibodies and T cells are still making a dent, Jenkins said. The stunning data from Moderna’s and Pfizer’s trials, which suggest that their vaccines are about 95 percent effective at preventing COVID-19, also leave more wiggle room for unexpected hurdles. (Scientists also expect that these vaccines will undergo mild to moderate dips in efficacy against the variants, based on early data from laboratory experiments.)

The protection offered by vaccines doesn’t need to be bulletproof to have an effect. “Even if vaccination does not prevent infection, the B cells and T cells will prevent severe disease and bolster immunity, which is incredibly important,” Smita Iyer, an immunologist at UC Davis, told me.

One unusual phenomenon that’s been documented with flu viruses did give a few immunologists pause. In some cases, immune cells may be so taken with one version of a virus that they struggle to react to another. Although memory cells might still react strongly to parts of the virus that are familiar, their responses to the changed bits will be considerably lackluster—the result of a kind of stubborn imprinting that leaves cells “stuck in the past,” as Su described it. Scientists aren’t sure exactly why or how this bias occurs. But the cells’ recalcitrance can imperil the body’s ability to catalog new versions of a virus and guard against them in the future.

Nothing yet suggests that this problem is cropping up with the new coronavirus, Ellebedy said. But researchers will be on the lookout as the variants continue to disperse across the globe.

Vaccine makers are already starting to retool their formulations to account for the new variants: Some have set their sights on strain-specific boosters, while others tinker with recipes that could tackle multiple virus versions at once. But the vaccines we have still work—and rolling them out widely and rapidly will help starve the virus of new hosts, and new opportunities to mutate and surge further ahead.

“Viruses evolve—that is a fact,” Iyer told me. “The best solution is to stop the viruses from spreading.”

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