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It’s impossible to say how the coronavirus will continue to evolve. Those changes, after all, are a result of random mutations.

But there are some fundamental principles that explain why the virus has morphed as it has, principles that could guide our understanding of its ongoing evolution — and what that means for our future with the pathogen.

The great fear is that nature could spit out some new variant that completely saps the power of vaccines and upends the progress we’ve made against the pandemic. But to virologists and immunologists, such a possibility seems very unlikely.

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That’s not to say variants won’t impair immune protection. Already, it appears Delta is causing breakthrough infections and symptomatic cases at higher rates than other variants. But vaccines have shown they don’t lose much oomph at protecting people from hospitalization and death, no matter the variant they’re up against. The way the vaccines work leaves experts optimistic that mutations won’t suddenly leave everyone vulnerable again.

“I don’t think that we’ll end up with variants that completely escape antibodies or vaccine-induced immunity,” said vaccinologist Florian Krammer of Mount Sinai’s Icahn School of Medicine. Already, Krammer said, we’ve seen the immune system’s ability to neutralize viral variants drop — to the greatest degree with the Beta variant — but it still persists. Because of that, vaccines haven’t lost major steps at protecting people from the worst outcomes of Covid-19.

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Something unexpected could happen, scientists caution — another twist in a pandemic full of them. Already, they’ve had to reassess their thinking about the coronavirus’ evolution. This family of viruses proofreads itself as it replicates, which means it picks up mutations more slowly than viruses like influenza. For the first several months of the pandemic, the virus didn’t seem to be changing in dramatic ways. But now, variants are dominating the conversation.

“This virus has been surprising us,” said Ramón Lorenzo-Redondo, a molecular virologist at Northwestern University’s Feinberg School of Medicine.

Below, STAT outlines some of the key questions about the virus’ evolution — and what it means going forward.

Why does the virus keep getting more transmissible? 

When the coronavirus started circulating among people in late 2019, it was already quite the spreader. Cases overwhelmed Wuhan and led China to impose what were then jaw-dropping lockdowns.

But to the virus, people were a new host. A change in its RNA genome had enabled it to infect our cells, replicate inside them, and jump to other people, but the pathogen hadn’t had much of a chance to figure us out yet. It had a lot of room to get better at using us to proliferate.

That meant there were a lot of low-hanging fruit mutations that the virus could pick up and that would give it a competitive advantage over other iterations of the virus. It’s not that the virus was knowingly figuring out which mutations would make it a better spreader. But as the virus made copies of itself, sometimes it made errors. And by chance, some of those errors gave it a boost over its siblings, helping it outcompete them.

It’s happened throughout the pandemic. An early change dubbed D614G led to a strain that was better at spreading than the very first version, enabling that variant to sweep around the world. For a while, that strain was dominant, but then Alpha appeared, and now Delta. Each subsequent iteration was a more effective spreader than the strains before it, so it outran the others. (One note about Alpha: scientists believe it emerged from a person who was immunocompromised and had a rare chronic Covid-19 infection, which allowed the virus to pick up a lot of mutations in a relatively quick period in one host, and then spread from there.)

One way to think about a virus’ transmissibility is on a curve, one that rises fast and tapers off toward some peak ability. It’s going to get better at spreading comparatively quickly, particularly when there’s been uncontrolled transmission for a year and a half. Over time, it could evolve more slowly, with fewer new combinations of mutations that might increase its transmissibility. Some scientists have questioned whether Delta is so transmissible that the virus might be nearing the flatter part of the curve. But to virologist Adam Lauring of the University of Michigan, “We just don’t know where we are in terms of that leveling off.” It’s possible then, that the virus could still stumble upon mutations that help it spread even more efficiently.

The virus could change in other ways too. If there’s one silver lining about Delta, it’s that it’s so transmissible that it’s crowded out other variants that are more worrying from an immune perspective, namely Beta, as well as Gamma. But scientists caution that there’s no fundamental reason why a variant couldn’t emerge that combines Delta’s spreading prowess with Beta’s ability to partially sneak around immune responses.

Such a variant might look different than we would imagine. Sometimes combining mutations that would seem to maximize transmissibility and immune-dodging abilities actually leads to a virus that fizzles out. Variants that can escape the immune response might be inept at hacking into cells to cause infections. But more worrisome variants are possible, and the best way to prevent them, experts say, is cutting transmission.

How will all this change as more people are protected? 

Because basically everyone on the planet was susceptible to Covid-19 at first, the fastest-spreading variant has been able to outrun others. But as the environment changes, the pressures that select for certain characteristics do as well. And instead of a sprinter like Delta, a bulldozer could eventually get the advantage.

Take Beta and Gamma. These variants, which respectively appeared in South Africa and Brazil, emerged in areas that had massive first waves. That’s led to one hypothesis that the variants took off because they could circulate better among people who had previous infections. Viruses that didn’t have those features couldn’t find as many new cells to infect, and fell back.

Scientists can’t say for sure that’s what happened with Beta and Gamma — perhaps they were just more transmissible in other ways. But it still holds that variants that have some ability to get around the immune response will get the upper hand in populations with greater levels of protection. They might not be causing severe disease in people who are protected — whether from vaccination or past infection — but if they can cause infections in at least some of those people and transmit from there, their prevalence will increase over other variants that have a harder time causing infections in protected people. (This appears to be happening with Delta to an extent, given that it’s now known that some vaccinated people transmit the variant.)

When populations have high levels of immunity, “it favors [variants] that have some sort of escape mutation that doesn’t throw a monkey wrench in the transmission side of things,” said Michael Worobey, a professor of evolutionary biology at the University of Arizona.

Now, you may be wondering: If that’s the case, does that mean a population that’s largely vaccinated will actually encourage the virus to evade protection?

Different forces are at play here. But one key factor is that by cutting how much the virus replicates — both through preventing infections and by shortening the infections that do occur — vaccines limit the likelihood of additional, more dangerous variants. People who are protected against the virus can act as evolutionary dead ends.

“The pressure is there, but the opportunity is not,” said Jeremy Kamil, a virologist at Louisiana State University Health Shreveport. “The virus has to replicate in order to mutate, but each virus doesn’t get many lottery tickets in a vaccinated person who’s infected.”

How will the virus’ future evolution affect vaccine protection?

The nightmare scenario is the virus changes in ways that completely escape immune response but that preserve its lethality and transmissibility. But many experts say that a sudden appearance of such a strain seems exceedingly unlikely. Variants could dent some of the defenses vaccines give us, but the immune response should still generally be able to protect us against severe disease.

“A virus just can’t change a couple amino acids and completely evade the totality of the immune response,” said virologist Angela Rasmussen of the University of Saskatchewan’s Vaccine and Infectious Disease Organization, referring to the building blocks that make up the virus.

Our first line of defenders is antibodies, some of which are trained to recognize specific pieces of the virus and prevent it from infecting cells. If mutations change those components — akin to putting on a fake mustache and sunglasses — then perhaps the antibodies geared to identify the virus’ upper lip or eyes might be fooled. The virus could gain a toehold and start an infection. But the vaccines have primed our bodies to recognize other parts of the virus, and to have waves of responders. Antibodies that latch on to other parts of the virus could kick in, and immune cells that help clear out infections before they cause much damage could arrive as reinforcements.

No vaccine is perfect. A small number of people get hospitalized with Covid-19 or even die after being vaccinated, often those with other health conditions. And it’s possible that variants could cause the vaccines to lose some of their effectiveness: perhaps they cause symptomatic disease at higher rates, and even increase the rate of severe disease or death by a hair. Concerns about the immune response waning in general, combined with the partial escape potential of Delta, are driving the debate about boosters, at least for certain groups of people. But overall, the vaccines are so protective that many virologists — while cautioning they can’t guarantee it — don’t see some variant arriving that alone upends the power of the shots.

One future for the virus is that it reaches some stability but then continues to change in small ways. People could become susceptible to an infection over time (whether that’s every year or after several years isn’t known and will likely vary) but will still generally be protected from worse outcomes. And with every exposure to the virus, including exposure-mimicking vaccines, our bodies will get better at warding it off, maybe even without symptoms. In that way, SARS-CoV-2 will eventually become another endemic respiratory virus.

“The indications are that immunity is really protective against hospitalization and death, even if we’re going to be stuck in a groundhog day world where the virus keeps infecting people year after year even after they’ve been exposed,” Worobey said.

A lab study, published as a preprint this month, found that even if a variant emerged that could escape the immune protection people have — a scenario that study author and virologist Paul Bieniasz of Rockefeller University called “extremely unlikely to happen suddenly” — a booster shot could raise antibody levels to the point where people could fend off the evolved virus. Similarly, if the virus continues to evolve and leads to a more gradual erosion of immune protection, an extra jab could handle it, perhaps one that’s tweaked to better suit the changes in the virus.

“Even if the virus acquires those resistance mutations, it’s possible to generate an immune response that’ll cope with that,” Bieniasz said.

Helen Branswell contributed reporting.

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