The coronavirus is on a serious self-improvement kick. Since infiltrating the human population, SARS-CoV-2 has splintered into hundreds of lineages, with some seeding new, fast-spreading variants. A more infectious version first overtook the OG coronavirus last spring, before giving way to the ultra-transmissible Alpha (B.1.1.7) variant. Now Delta (B.1.617.2), potentially the most contagious contender to date, is poised to usurp the global throne.
Alphabetically, chronologically, the virus is getting better and better at its primary objective: infecting us. And experts suspect that it may be a while yet before the pathogen’s contagious potential truly maxes out. “A virus is always going to try and increase its transmissibility if it can,” Jemma Geoghegan, an evolutionary virologist at the University of Otago, told me.
Other aspects of the virus’s unfolding bildungsroman, however, are much harder to forecast, or even get an initial read on. Researchers still don’t have a good handle on which variants might cause more cases of severe disease or death, a metric called virulence. And while a virus’s potential to transmit can sometimes heighten its propensity to kill, the two are by no means inextricably linked: Future coronavirus strains could trend more lethal, or less, or neither. We keep trying to pigeonhole specific variants as “more dangerous,” “more deadly,” or “more problematic,” but viral evolution is a humbling, haphazard mess—a plot-twisting story we have to watch play out in real time. “We cannot be complacent about ‘Oh, this is the end of the mutations,’” Akiko Iwasaki, a virologist and immunologist at Yale, told me.
As long as the virus has hosts to infect, it will keep shape-shifting in ways we can’t fully predict. That biological caprice makes it harder to anticipate the next pandemic hurdles we’ll need to clear, and assess the dangers still ahead. But our role in this relationship matters too: What the virus can accomplish also depends a great deal on us, which means its evolution does as well.
As desperately as we want to purge it, the coronavirus’s main objective is to get closer to us. Its biological imperative is to enmesh itself into a suitable host, reproduce, and disperse, then begin the process anew. In the past year and a half, SARS-CoV-2 has found its way into at least 180 million human hosts, and still the virus wants more. “The evolutionary pressure for a virus is transmissibility,” Iwasaki told me. Any changes that make more of it sooner will help it flourish, like a fast-growing weed settling into a new garden.
Most mutations that occur in the SARS-CoV-2 genome are inconsequential, even detrimental, to the virus’s propagation campaign. Occasionally, though, one virus will hit upon a smidgeon of advantage. All else held equal, this variant will have a leg up on its kin, and may outcompete them. Epidemiologists sampling the sick will see a sharp upswing in the proportion of people infected by a specific version of the virus—one too large and too sudden to be explained by chance. Such a spike tipped off public-health officials to the presence of Alpha shortly before it erupted across the globe. “It went from nothing to everything really quick,” Joseph Fauver, a genomic epidemiologist at Yale University, told me. Delta now appears to be following in its predecessor’s footsteps; it swept first through India and the U.K., overtaking more sluggish variants, then spilled over international borders.
Exactly how Alpha and Delta executed their meteoric rise is less clear: SARS-CoV-2 has likely hit upon multiple ways to spread more efficiently between hosts. Certain mutations might have helped Alpha more easily glom on to the outsides of cells; others might increase Delta’s ability to accumulate in the airway, the virus’s natural point of egress. Still other genetic changes could make specific variants hardier, perhaps allowing them to linger in the nose, so hosts stay contagious for longer.
These different possibilities can be teased apart in experiments in laboratory cells and animals, but they all converge on a single principle, Angela Rasmussen, a virologist at the Vaccine and Infectious Disease Organization in Saskatchewan, Canada, told me: “What we’re seeing is a virus that’s becoming more efficient at making more viruses.” Given sufficient time with a new host, most viruses can be expected to trend more transmissible; the coronavirus is probably no exception.
A more contagious virus might, at first pass, seem like a deadlier virus: Its enhanced invasion capabilities might allow it to grip more tightly onto its host, building up to levels high enough to overwhelm the body. “In that case, you could have transmissibility and virulence increasing in lockstep,” Paul Turner, an evolutionary biologist and virologist at Yale, told me—a neat, simple story. Some researchers have hypothesized that this could be the narrative behind the Alpha and Delta variants, both of which have been linked to bumps in hospitalization. But those patterns haven’t yet been conclusively nailed down, Turner said, and no evidence so far suggests that the coronavirus is systematically evolving to become more malicious. Viruses are microscopic entities hungry for spread, not carnage; the suffering of their host is not an imperative for them to persist. If a surge in virulence happens, it’s often incidental—collateral damage from an increase in contagiousness.
The march toward transmissibility doesn’t always drag virulence along. Many people have been found to silently carry tons of SARS-CoV-2 in their airways to no ill effect. On occasion, the two traits can even butt heads, forcing viruses to become tamer over time in service of speedier spread. The hypervirulent myxoma virus, a pathogen deliberately introduced into Australian rabbits in the 1950s as a form of biocontrol, for instance, appears to have become less lethal over time. Instead of killing rabbits instantly, it began to prolong its hosts’ sickness—and by extension, its own infectious window.
But myxoma is more exception than rule. Super-deadly or debilitating viruses such as Ebola and dengue, Fauver pointed out, don’t seem to be getting gentler; they already spread just fine. SARS-CoV-2 may have especially little reason to domesticate itself, since so much of its transmission happens before serious symptoms appear: “It’s not killing people before they can pass it on to someone else,” Rasmussen said. If the fates of SARS-CoV-2’s virulence and transmission aren’t tightly coupled, “there’s no responsible way to make any predictions about how virulence is going to change right now,” says Brandon Ogbunu, an evolutionary and computational biologist at Yale.
Alpha and Delta may still be, particle for particle, more formidable foes than other variants; if they’re consistently driving more disease, hospitalization, and death, those trends are certainly worth paying attention to. But definitively tying them to specific viral traits or mutations is difficult, in part because virulence itself is a murky concept. “It’s kind of a disastrous word,” Ogbunu told me. It’s meant to convey the damage caused to a host by a pathogen. But damage is subjective, and depends at least as much on the host as it does on the virus. While measuring transmissibility can mean simply asking whether a variant is present and to what extent, sussing out virulence is a more qualitative interrogation, of how virus and body interact, across a bevy of different environments. If variants are weeds, virulence asks how pernicious they are, and the answer can be heavily influenced by the delicacy of the garden plants they’re throttling.
Hospitalizations and deaths, some of the best real-world readouts for virulence, by themselves can be fraught metrics to use, says Müge Çevik, a virologist and infectious-disease expert at the University of St. Andrews, in the U.K. Not all places have the same standards of care, or the same access to treatments. Sick people might be admitted to a hospital because of a nastier form of the virus—or because of risk factors that made them more vulnerable to begin with. Immunity to SARS-CoV-2 has also been building over time, muddling susceptibility further. And much of the hardship caused by the coronavirus remains outside hospital walls. The difficulty of comparing populations may be part of the reason why different studies looking into variant severity have sometimes turned up discordant results. Ballooning case rates also have a way of reinforcing themselves: When many people suddenly get sick—perhaps because a more transmissible variant has emerged—medical infrastructure gets overwhelmed, and more people might die, even if the virus itself is no more harmful. “The epidemiology is so noisy, it’s so hard to say,” Vineet Menachery, a coronavirologist at the University of Texas Medical Branch, told me. (Researchers now generally agree that Alpha is deadlier than other variants; the news on Delta is less certain.)
That puts the onus on researchers to meticulously catalog not only the variants infecting us, but the characteristics of the people they most strongly affect, says Rebekah Honce, a virologist at St. Jude Children’s Research Hospital. “It’s a trifecta of host, agent, and environment—you can’t ignore any branch.”
COVID-19 will, inevitably, look different in the future. But our relationship with the virus won’t hinge solely on its genetic hijinks: We can expect the immune defenses we raise against SARS-CoV-2 to shape its evolutionary path.
With vaccines on the rise in many parts of the world, and fewer hosts to infect, the virus is starting to hit roadblocks and slowly sputter out. “By vaccinating, we’re making it less likely that new variants will emerge,” Çevik told me. Eventually, as our collective defenses build, SARS-CoV-2 might become no more a nuisance than a common-cold coronavirus, causing only fleeting and inconsequential symptoms in most people, whose bodies have seen some version of the pathogen before, Jennie Lavine, an epidemiologist and virologist at Emory University, told me. That, of course, makes equitable access to vaccines all the more important, so mutational hot spots don’t arise in unprotected places.
Left to its own devices, the virus could hypothetically bridle itself. But it may have no incentive to. “Counting on the virus to become less virulent on its own is a bad bet,” like waiting for an enemy to slacken its offense, Yale’s Iwasaki told me. The better move is to double down on our defense, the tools we already know best.
There is a curious caveat to the deployment of vaccines. While inoculations aren’t themselves the cause of SARS-CoV-2 mutations, the immunity they provide can nudge the virus onto new trajectories that we’ll need to keep monitoring. A less-than-stellar vaccine developed to block Marek’s disease in chickens goaded one virus into higher transmissibility and virulence, making the pathogen more dangerous to unvaccinated birds. (There’s no evidence that’s happening with SARS-CoV-2 and our current lineup of excellent vaccines, but the virus will continue to pose an especially big threat to those who aren’t immune.) Pressure from the vaccines could also drive the spread of variants that are better at eluding our defenses and, perhaps, stumping some of our shots. A handful of variants, including Delta, have already demonstrated the ability to dodge certain antibodies—another trait, Çevik said, that enables the virus to enter its host more easily.
In years to come, we’ll probably have to tinker with our vaccine recipes to keep pace with the fast-changing virus. But every vaccine we debut has the potential to block a route the virus might have otherwise taken. Viral genomes aren’t infinitely mutable—they can edit only the starting material they’ve been given, and they can’t make certain changes without hamstringing their precious capacity to spread. With time, we might be able to use shots strategically, to force SARS-CoV-2 onto more predictable evolutionary paths, Turner told me: “That’s the way we gain control.” If we’re going to live with this virus long-term—as we absolutely must—then vaccines are our key to building a sustainable relationship, one in which we turn the tables. We can make the virus’s evolution react to us, and not the other way around.