Covid-19 cases and hospitalizations are rising as the BA.5 subvariant of omicron takes root.

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The pattern has become all too familiar: A new version of the SARS-CoV-2 virus emerges and begins to dominate new Covid-19 cases, until it’s replaced by an even more contagious version of the virus.

This year, subvariants of the omicron variant of the virus have ruled cases in the US. The BA.1 subvariant started the omicron wave. Then in April, BA.2 formed the majority of cases. By May, BA.2.12.1 took over. Now BA.5 is in the lead, triggering a rise in hospitalizations across the country. It may be the most contagious version of the virus to date.

Why does this keep happening?

It’s evolution. The more a virus spreads, the more opportunities it has to mutate, and eventually some of those mutations will confer a transmission advantage to the virus.

Omicron showed that it was adept at causing reinfections among people who were previously exposed to Covid-19. BA.5 appears to have an especially potent mix of mutations that evade protection from the immune system.

The good news is that Covid-19 vaccines still provide good protection against severe illness caused by BA.5 and are keeping death rates down. But because BA.5 spreads so readily, the small fraction of people getting seriously sick is adding up, an especially frustrating development for everyone who has been diligent about getting vaccinated, masking, and social distancing.

Scientists are now zeroing in on what’s making BA.5 so prevalent even in an era of widespread immunity. What they learn could help contain the current surge and counter the next one, potentially allowing them to devise booster vaccines that better shield against newer versions of the virus.

And SARS-CoV-2 isn’t done evolving. Figuring out how a variant as strange as omicron arose and how it fine-tuned into BA.5 could unlock tools for predicting and preventing other variants in the first place.

Why BA.5 is good at dodging our immune systems

If viruses have a purpose, it’s to make copies of themselves. They don’t have the tools to do that on their own, so they have to hijack cells from a host (i.e., us) in order to reproduce. The copying process can be sloppy, especially with viruses that use RNA as their genetic material, like SARS-CoV-2, so mutations abound.

Most of these changes are detrimental to the virus or have no effect, but some can make the virus cause more severe disease, infect more people, or better hide from the immune system. When lots of people have been vaccinated or previously infected, mutations that conceal the virus have a huge advantage.

“The high level of immunity in the population is likely exerting selection pressure on the virus and the virus is evolving to try to get around that immunity,” said Daniel Barouch, director of the Center for Virology and Vaccine Research at the Beth Israel Deaconess Medical Center.

With SARS-CoV-2, when a version of the virus accumulates a distinct grouping of mutations and is deemed a public health threat, it’s classified as a variant and receives a Greek letter designation from the World Health Organization.

Smaller grouping of mutations within a variant are classified as subvariants, often described by letters and numbers based on their genetic heritage, though the line between variant and subvariant can be blurry. Adding to the confusion, SARS-CoV-2 can undergo recombination, where it blends traits from two different lineages. As researchers have improved their tracking of the virus’s genome, they’re seeing changes at a faster rate.

“What is striking is the speed at which we’re seeing the virus evolve,” Barouch said.

Omicron exemplifies how major and minor changes in the virus can take root. When it first cropped up in late 2021, it stood out for its suite of distinct mutations that set it far apart from other Covid-19 variants. Scientists couldn’t figure out its heritage since it didn’t closely resemble the major variants in circulation. Its closest known ancestor dates back to 2020, ancient times in terms of the virus’s evolution.

There are some theories, however. Omicron or a predecessor may have been circulating undetected. It may have evolved in a patient with a compromised immune system, granting the virus an unusually long amount of time to replicate and acquire mutations in a single host. It may also have jumped back into humans from another animal.

On the virus’s phylogenetic tree, a diagram that illustrates the evolutionary relationship among different versions of the virus, omicron is on a remote branch from the other variants. The dots represent reported sequences, and the distance between them reflects the number of mutations that divide them:

Compared to the original version of SARS-CoV-2 that arose in Wuhan, China, in 2019, omicron has more than 50 mutations. Thirty of these mutations are in the spike protein of the virus. These are the pointy bits that stick out from the virus and give it its crown-like appearance under a microscope.

The spikes directly attach to human cells to begin the infection process. They are also the main attachment point for antibodies, proteins from the immune system that recognize and inhibit the virus. So changes to the spike protein can alter how efficiently the virus can reproduce and how well the immune system can stop it.

Since omicron arose, SARS-CoV-2 genetic sequences show that the virus has undergone more subtle changes. There are only a handful of mutations that separate BA.5 from earlier subvariants like BA.2, but they’re enough to give the virus a massive advantage. BA.4 and BA.5 actually have almost identical spike proteins and differ in mutations in other parts of the virus.

Antibodies are very picky about the parts of the virus they will stick to, so small changes in these portions can make antibodies much less efficient. This is bad news for some antibody-based treatments for Covid-19, some of which are no longer recommended for use against omicron. But other drugs like Paxlovid still work against the newer subvariants.

A narrow group of subvariants taking over the world is a shift from how the virus mutated earlier in the pandemic. “[T]he fact that these omicron subvariants are becoming so dominant and sweeping worldwide is different from what we saw with, for example, delta, where its subvariants (which never got separate letters) never dominated in the same way,” said Emma Hodcroft, a molecular epidemiologist at the University of Bern, in an email. Even omicron subvariants have undergone recombination.

It’s partly a consequence of the global increase in exposure to the virus. There are few immune systems left that don’t have any familiarity with SARS-CoV-2. So BA.5’s most important trait for its success is how well it can elude the antibodies and white blood cells of people who were previously infected or vaccinated.

Barouch and his collaborators recently reported in the New England Journal of Medicine that existing immunity has a much harder time countering BA.5 compared to earlier omicron subvariants. So even people previously infected with omicron can get infected with BA.5. It may also spread more readily between people, though it doesn’t appear to cause more severe disease.

BA.5 may be in the lead now, but future Covid-19 threats could look vastly different

The fact that omicron is still spreading with just small tweaks to its genome compared to earlier variants shows that its combination of mutations is highly effective at spreading. But that doesn’t mean that future versions of SARS-CoV-2 will just iterate from BA.5. A completely different version of SARS-CoV-2 could yet emerge and start the process all over again.

“While things do seem to be at least somewhat different with omicron, in that [it’s] given rise to so many successful subvariants, I don’t think we can rule out that there may be another variant appearing unexpectedly,” Hodcroft said.

What can we do about this?

The best strategy is to limit the spread of the virus, denying it opportunities to mutate. Getting vaccinated and boosted if eligible remains critical, not just in the US, but around the world. Though vaccinated people can still get infected with BA.5, their chances are lower than those who are not immunized, they are less likely to spread it to others, and most importantly, are far less likely to get dangerously sick.

It’s also worth noting that BA.5 was actually detected in South Africa back in February, but only in the past month has it gained momentum in the US. This highlights the importance of surveillance. That means tracking genetic changes to the virus and public health monitoring to catch surges before they erupt.

The concern now is that, in the US, vaccination rates have hit a plateau even though most of the population is now eligible for a Covid-19 shot. Public health measures like social distancing and mask mandates are almost gone. And with the rise of at-home testing, many cases are going unreported. So while BA.5 may not cause the same devastation as earlier versions of omicron, it can still cause a lot of misery as hospitals fill up.

Even now, in its third year, the trajectory of the pandemic remains murky, and the virus could still bring unpleasant surprises. “What this is telling us: we need to remain vigilant,” Barouch said.