The race is on. Vaccines against the virus that causes Covid-19 are needling into shoulders around the world, the tip-of-the-hypodermic spear of a year-long scientific triumph. But that protean virus, like all the things that infect humans and make them sick, jukes and dodges.
Virology versus epidemiology. Vaccinology versus evolution. Mutation versus mutation, transmission versus infection, virus versus vaccine. Start! Your! Engines! The past (horrible, tragic, no-good, very bad) year might have seemed like a straightforward battle between scientists and a virus to find new drugs and vaccines. But this wasn’t just a stand-up fight; it was also a bug hunt—a subtle push-pull across a dozen different vectors. Viruses aren’t exactly alive, but they still follow the same rulebook as every living thing on Earth: Adapt or die. Understanding those more occult forces—how viruses evolve inside us, their hosts, and how they change the ways they get from one person to the next—will define the next phase of the pandemic.
It’s easy to freak out about new variants of the SARS-CoV-2 virus, with their science-fiction nomenclature. There’s B.1.1.7, which looks to be a whiz at infecting new people. And you’ve got B.1.351 and P.1—maybe not any better at transmission from host to host, but better at evading an immune response (a natural one, or the kind a vaccine induces). A bunch of the immune-escaping ones share the same single mutation, even if they’re only distantly related. That, as the saying goes, is life. “The way the virus evolves, the fundamentals of evolution, are the same. What’s different is that’s playing out on a very, very large scale. There’s just so many people who are infected, and each person has a lot of viruses in them. So there are a lot of opportunities for the virus to make mutations and try new things,” says Adam Lauring, a virologist at the University of Michigan who studies viral evolution. “Every now and then one of those takes off. It’s a rare event, but when the virus has so many opportunities to game this out, it’s just going to happen with increasing frequency.” This is as much a game of epidemiology, in other words, as it is one of evolutionary biology.
So while it can seem like these variants have some kind of evil intention—to make people sicker, to kill all humans!—that’s not what’s going on. Viruses don’t want anything; they’re just verbs. Infect, reproduce, infect. A virus that kills too efficiently doesn’t get to be a virus for very long, because dead hosts can’t walk around breathing on uninfected-but-susceptible suckers. So one hypothesis says that these successful mutations are mostly changes in the way the virus infects. That is, they improve the way the virus gets into a human, or gets into a human cell, or reproduces in that cell (because the more virus a person makes, the more they give off, and the more likely it is to get to some other person).
That’s probably why all these similar variants seem to be arising all at once, and quickly. Viruses are just nubbly little dollops of proteins wrapped around big molecules of code, of genetic material. In SARS-CoV-2, that material is RNA. And some viruses pop mutations more frequently than others.
Viruses evolve because they reproduce—in fact, that’s pretty much their whole shtick—and mistakes creep into that genetic material in the process. Over the course of generations, sometimes those random or “stochastic” mistakes actually make the virus better at doing its thing; sometimes they make it worse. Which is to say, the circumstances of a virus’s life, or sort-of-life, play out against random changes to the code underlying its genes. (SARS-CoV-2 seems to mutate at about the same pace as other RNA viruses, even though like other coronaviruses in its family it has a built-in error-correction mechanism. It needs it, because its genome is so big, relatively speaking—three times the size of the genome in HIV, the virus that causes AIDS, for example. “Without proofreading, it would likely create too many mutations per virus replication event to remain viable,” says Katrina Lythgoe, an evolutionary epidemiologist at the Big Data Institute at Oxford University. That kind of genomic suicide is called crossing the “error catastrophe threshold.”)
Assuming that SARS-CoV-2 lived in some other animal before it started killing humans—bats, probably; pangolins, probably not—it must’ve been well-adapted for that other unlucky critter. Evolutionary biologists imagine what they call a “fitness landscape,” a pretend mountainous terrain of evolutionary success where the valleys are full of maladapted underperforming mutants and the rarified peaks are reserved for the expensive homes of successful genomic powerhouses. But the thing is, for winners on the peaks, any mutation is likely to be one that makes them less successful. The losers in the valleys pretty much have nowhere to go but up. Almost any mutation is more likely to be beneficial.
When a virus jumps a species barrier—like when an avian influenza jumps to ferrets, let’s say—the adaptations that made it a peak-living high-flyer in the bird fitness landscape no longer obtain in the new immune environment of the ferret. It tumbles down the mountain. But in the valley, a whole bunch of new stochastic mutations are likely to be high performers against the immune system and living conditions of the ferret. So what’s going on in humans, a year after the SARS-CoV-2 virus met us? “My pet theory is that what’s been going on is the virus is just trying to be a better virus. That often means being able to find the next host,” Lauring says. “Are you better at getting in there and replicating, copying yourself? I think that’s what’s going on.”
Many of the mutations in the so-called variants of concern are in the SARS-CoV-2 spike protein, the place a host’s immune system often attacks. But the spike is also the grappling hook and battering ram that the virus uses to attach to and invade host cells. “Because the mutations are in the spike—even though they’re being selected because maybe they make the virus grow or spread better—and because the spike is the main thing we target with our immune system and vaccines, that’s also going to change how the virus is recognized,” Lauring says. It’s a two-fer. Yay! (If you’re Team Virus.)
If you’re Team Humans, though, this is a bummer, because a virus has a lot of ways to become more transmissible. “In B.1.1.7, we hypothesize that it’s more transmissible because there’s more viral load,” Lythgoe says. Simply, that variant makes more of itself. While nobody knows how much virus it takes for someone to get infected, if Lythgoe’s team is right, people infected with B.1.1.7 just walk around in a bigger Pigpen cloud of virions. On the other hand, maybe that strain is just better at getting inside cells. Or maybe people with that variant are infectious for longer, so they have more chances to run into uninfected folks. It’s another unknown.
Stochastic mistakes aren’t the only way viruses change, though. A virus exists amid a sea of troubles—changes in context and conditions that apply selective pressures to every new mutant. Every emerging generation manifests new YOLO genetic tricks; the immune system of the host is what makes some of them better fitness landscape climbers. And since the virus is moving from within-host dynamics to host-host dynamics, and more of those hosts have already been infected … well, things are tough all over. “What’s happening over time is, the host environment is changing. An increasing fraction of the population has memory immune responses that are basically impeding the growth of the virus,” says Sarah Cobey, an epidemiologist and evolutionary biologist at the University of Chicago. “So there’s this growing selective pressure also to escape that immune response.”
Some strains replicate better than others, but that rate gets affected by the immune system of the host. “The fundamental dynamic is the same,” Cobey says, “but now the strains that replicate better are also those that can avoid some of that immune response.”
Acute, short-duration infections like influenza viruses or noroviruses (gross) don’t have as much time to reproduce and mutate. But chronic infections like HIV or hepatitis C, let’s say, give a virus population plenty of time to change. Covid-19 is an acute infection for most people, but for some people, it’s chronic. (These aren’t “long-haulers,” who for still unknown reasons have symptoms even after they clear the virus from their bodies; people with chronic infections have detectable viral loads for a long time, maybe because their immune systems are compromised for unrelated reasons.) A chronic infection can give new variants enough time to start climbing the fitness landscape. “After a while, the main selective pressure is immunity in the host population,” says Katia Koelle, an evolutionary biologist at Emory University. “What you see are antigenic changes, because those give you the biggest gains in fitness.”
Things get even more complicated for our poor SARS-CoV-2 variant, though. Not only does no one know how many individual viral particles it takes to get sick with Covid-19, but different pathogens have different “transmission bottlenecks.” That’s the number of those virions that actually land, hit the target, and give rise to new viral populations. Maybe only people with huge viral loads also have a lot of interesting mutations. But if the transmission bottleneck is small, “that means that if a beneficial mutation arises in an individual, especially in an acute infection like SARS-CoV-2, then it’s very unlikely to transmit. It basically slows down adaptive evolution,” Koelle says. “It seems to me that SARS-CoV-2 is more like flu. Flu, we know, has a very small transmission bottleneck.”
Once the viral variants climb to the top of the peaks in the human fitness landscape, they’ll face trade-offs, where improvements in their ability to transmit might compromise their ability to evade the immune system (Team Humans!) or kill the hosts too quickly for them to transmit (Team Virus, sort of!). “Early on—and by ‘early on’ I mean in the first couple years—the virus can make big improvements, and that might be what we’re seeing, that it’s adapting to people. But then over time, that should slow down,” Lauring says. “Sometimes the virus works its way into a corner, where there aren’t any new options available. We don’t know how that’s going to play out.” Covid-19 could become a seasonal problem like influenza, or mild but endemic like the common cold.
The major change to the immunity of all the hosts SARS-CoV-2 is likely to try to infect will be, of course, vaccination. That’s human ingenuity fighting viral expertise, but it can also exert a kind of direct adaptive pressure on the virus. History has examples of so-called leaky vaccines—those that aren’t effective enough to prevent all infections or all transmission, and allow better-adapted variants of whatever bug they’re trying to squish to live to fight another day.
In fact, one group of researchers has a model that suggests that could even happen with the new batch of vaccines against Covid—especially those that require two doses and seem to confer different levels of immunity depending on how far apart they’re administered, or whether someone skips the second one. Here’s how: If one extreme is a population totally naive to a new virus, completely vulnerable and with no immunity, and the other extreme is a population with perfect sterilizing immunity, what happens to a population in between? If a vaccine allows infection but no transmission, the virus doesn’t have a chance to evolve. But if a vaccine or vaccination strategy allows some infection and some transmission? “The ones that are the best at getting around the host’s defenses are the ones that are most likely to persist,” says Caroline Wagner, a bioengineer at McGill and one of the people working on the model. If that’s all true, a leaky vaccine or leaky vaccination strategy could actually drive antigenic drift and create even worse variants. McGill and her colleagues acknowledge that they don’t have enough data to put bounds on their model yet, but they worry about strategies like one proposed in the UK to abandon second doses as a way of speeding the process and husbanding scarce vaccine, or the way some countries are hoarding vaccine while others go without (potentially letting the virus, and variants, circulate and evolve freely).
Other researchers I spoke with weren’t as worried—one described that model as “hand-wavy.” All acknowledged the dangerous game of chicken that humanity is playing with viral evolution right now, but they also said that any vaccination was, at this point, better than none, or trying to game-theory the game. And so far, the vaccines against SARS-CoV-2 seem very effective. “I wouldn’t underestimate, evolutionarily speaking, what even a not-super-great vaccine can do. It’s like, yeah, maybe transmission happens, but maybe the bottleneck is tighter, or fewer viruses make it across. That might be enough to slow the virus down enough that it just peters out over time,” Lauring says. “You start reducing these numbers in every way, you cut down the chances for these mutations to take off. I’m not shedding as much, not as many viruses get across, other people have enough immunity that those few viruses, it’s like, boop, no problem.”
Pandemics only happen because chains of unlikely events—some biological and some social—create a population that’s vulnerable and circumstances that are lucky for the virus and unlucky for its host. But fighting a pandemic is a subtle battle; it only requires a little sabotage of all those chains. Understanding viral evolution will help scientists figure out whether a Covid vaccine will have to get re-upped every year like flu, or be a once-in-a-lifetime (or so) thing like measles. But either way, even if evolution makes the pandemic seem all the more terrifying now, understanding how it works will put humans higher up on that fitness landscape even sooner.
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