On March 22 the World Health Organization announced that the Omicron subvariant BA.2 had become the dominant form of SARS-CoV-2, the virus that causes COVID, worldwide. BA.2 shares many genetic similarities with its close relative BA.1, which fueled a global resurgence in COVID infections in recent months. But BA.2 is between 30 percent and 50 percent more contagious than BA.1.
Now, as this latest version of SARS-CoV-2 sweeps the planet, pandemic-weary people everywhere are asking the same question: Is society doomed to confront a succession of new viral variants, each one more contagious than the last?
“We still don’t know the full capacity of this virus to evolve and make radically new types of variants,” says Jeffrey Shaman, an infectious disease modeler at Columbia University’s School of Public Health. According to Shaman and other scientists, SARS-CoV-2 still has a lot of genetic leeway left in terms of how it infects human cells and skirts the immune system. New variants can emerge from stepwise changes in the viral sequence. But heavily mutated versions of SARS-CoV-2 that bear little resemblance to their predecessors “have also come from out of the blue,” says Ralph Baric, a virologist at the University of North Carolina at Chapel Hill. “And if any of these variants are better at infecting cells or evading immunity than their predecessors, then you’ll see increased transmission over the strains that came before.”
The Omicron subvariants were all detected around the same time last November in South Africa. These new and dramatically different versions of SARS-CoV-2 were jolting to many scientists, who had anticipated that the next major variant would descend incrementally from the Delta variant. BA.1 quickly overtook Delta as the dominant strain worldwide, while BA.2 lingered behind, “likely in a rural area where it didn’t have as much initial opportunity to spread,” says Bette Korber, a computational biologist who studies viral diseases at the Los Alamos National Laboratory in New Mexico. But after BA.2 got into bigger, more interconnected communities, “it began moving fast.” As soon as it could jump to other countries, BA.2 exploded across Africa, Europe and Asia, and it currently accounts for nearly 55 percent of all new SARS-CoV-2 infections in the U.S., according to latest data from the Centers for Disease Control and Prevention.
In the likeliest scenario, BA.1, BA.2 and a third Omicron subvariant that never took off—BA.3—evolved over the course of chronic infections in a small population of immune-compromised people. Stephen Griffin, a virologist at the University of Leeds School of Medicine in the England, says that bouncing back and forth among the members of this population likely provided “a training ground for the virus,” allowing SARS-CoV-2 to probe and test new mutations that allowed it spread more efficiently.
BA.1 wound up acquiring 60 mutations that are not found in the ancestral SARS-CoV-2 that first surfaced in Wuhan, China. Among them are 32 genetic changes located specifically in the virus’s iconic spike protein, which is a target for immune cells and vaccines. BA.2 shares many of those same mutations but also has 28 unique genetic changes of its own, four of them in the spike protein.
According to Baric, Omicron is the first SARS-CoV-2 variant to evolve in the context of mounting immunity in the population—the result of vaccines and prior infection with other forms of the virus. Earlier variants, namely Alpha, Beta, Gamma and Delta, competed for dominance primarily on the basis of how well they infect human cells in high numbers and transit efficiently among people. But Omicron acquired the further advantage of being able to resist immune defenses against the variants that came before, thereby increasing the number of susceptible people in the population. The difference in neutralizing antibody responses against Omicron, compared with prior variants, “is massive,” Baric says. Neutralizing antibodies deflect SARS-CoV-2 from binding to ACE2 receptors, the virus’s entry point into human cells. “We’re talking about a 15- to 50-fold drop in antibody levels, depending on who runs the assay and how recently you’ve been infected or boosted,” Baric says.
Identifying the mutations that allow Omicron to “escape” neutralizing antibodies is now the focus of intense research. At least some of those mutations appear to affect parts of the spike protein that bind to ACE2. In the ancestral virus, those mutations would have interfered with the microbe’s ability to initiate an infection. But Omicron appears to tolerate the changes without losing its capacity for binding to ACE2. Ram Sasisekharan, a biological engineer at the Massachusetts Institute of Technology, says that, so long as these mutations persist in the virus, “we can expect that Omicron-like variants will continue to emerge, driven primarily by immune evasiveness rather than enhanced intrinsic infectivity.”
But infectivity and immune escape are also deeply intertwined, and determining their respective roles in viral spread is exceedingly challenging. That is especially true at this current stage of the pandemic. Dozens of vaccines have been deployed against SARS-CoV-2, and numerous forms of the virus have swept the globe. Infections and vaccines are contributing to immunity through a dizzying array of combinations, and “this is all getting messier and messier for the scientific community to tease out,” Baric says.
Fortunately, evidence so far indicates that disease symptoms caused by BA.2 are not more severe than those caused by BA.1 in vaccinated people or people who were previously infected with SARS-CoV-2, according to Sasisekharan.
BA.1 clearly won out against Delta, largely on account of its capacity for immune escape. But to what degree does immunity from prior infection with BA.1 protect against BA.2?
Early evidence suggests that reinfections with BA.2 after BA.1 do occur but are rare. “If you were infected with BA.1, then you’re probably well protected from BA.2,” Griffin says. “But the protection is not complete.” Scientists anticipate that places where BA.1 has already peaked at high levels might avoid subsequent surges of BA.2. The BA.1 peak decayed rapidly in South Africa last December, and BA.2 in that country is “not much of a problem,” says Juliet Pulliam, an epidemiologist who directs the DSI-NRF Center of Excellence in Epidemiological Modelling and Analysis at South Africa’s Stellenbosch University. “Our case numbers are currently quite low.”
Experts are carefully tracking BA.2’s trajectory in the U.S., where BA.1 also ran rampant earlier this year. COVID cases in this country have dropped by 35 percent in recent weeks, even as BA.2 has become the dominant strain. Parts of the U.S., including some northeastern states, are seeing an uptick in SARS-CoV-2 infections. But whether a national surge will follow is unknown. “We’re in a gray area right now,” Baric says.
Other factors also govern BA.2’s transmission: vaccine and booster coverage, public health countermeasures and the average age of the population all play a role. Hong Kong’s dramatic surge in BA.2 cases has been attributed in part to vaccine hesitancy among the elderly. John Moore, a virologist at Cornell University’s Weill Cornell Medicine College, believes BA.2 has spiked in European countries and the U.K. largely as a result of easing COVID restrictions. “Governments in those countries, particularly in the U.K., said that ‘Covid is over; let’s party,’” he says. “That’s all a highly transmissible variant needs.”
If the succession of ever more transmissible variants has any silver lining, it is that they are evolving in tandem with population immunity. Each new variant may cause fewer deaths simply because more people are able to thwart infection and severe disease. But Shaman points out that SARS-CoV-2 is also far more liable to change than the other respiratory viruses we have learned to live with. The transmissibility of new SARS-CoV-2 variants should eventually hit a plateau, just as the coronaviruses that cause the common cold did. But in the meantime, “we don’t know what the next decade is going to look like with this virus,” Shaman says. “So we’ve got to keep an eye on it.”