We were so close to conquering COVID-19.

Now, as delta sweeps the world, experts worry: What future version of the virus could expand its infectious empire?

“The big concern is that the next variant that might emerge — just a few mutations potentially away — could potentially evade our vaccines,” Centers for Disease Control and Prevention Director Dr. Rochelle Walensky said this week.

All viruses constantly change into new versions of themselves. With each generation, they make random genetic errors.

They don’t mean to cause trouble. They have no dreams of greatness, said Dr. Joel Ernst, professor of medicine and chief of the Division of Experimental Medicine at UC San Francisco.

“All they want to do is replicate,” he said. Citing the pioneering work of Stanford microbiologist Stanley Falkow, Ernst said, “the goal of a virus is to become viruses.”

Early on, we weren’t too worried about changes to the SARS-CoV-2 virus’s genetic makeup, stored in a single strand of RNA. Compared with flu and HIV, the virus changes slowly as it spreads. Thanks to a ‘proofreading’ enzyme that corrects potentially fatal copying mistakes, it typically accumulates only two single-letter mutations per month in its genome — a rate of change about half that of influenza and one-quarter that of HIV.

We watched it blunder. One of the earliest variants, named D614G, carried a mutation that made it easier for the virus to dock onto human cells. But that mutation also made it more vulnerable to our antibodies.

“That was a dumb variant,” said Ernst. “It had its day, but it didn’t knock us off.”

But now we know that any change can have serious consequences.

Delta serves as a textbook example. Its genetic code not only carries some of the successful mutations of earlier variants but also the ability to spread twice as fast, churning out many more progeny.

Data indicate that delta is 40%-60% more transmissible than alpha and almost twice as transmissible as the original Wuhan strain of SARS-CoV-2. Furthermore, it grows at higher levels inside the throat and lungs than did earlier versions of the virus.

With only 49.3% of the U.S. population fully vaccinated, this trait is proving key to the delta’s continued evolution and spread. That is why it has quickly become California’s dominant strain, accounting for 84.4% of all new sequenced cases, up from 53% in June.

“It’s sobering,” said virologist Shane Crotty of the Vaccine Discovery Division at La Jolla Institute for Immunology. Variants “alpha and delta are six months apart from each other. Each managed to become much more infectious.

“That definitely makes it less certain about what the virus can do in the future,” he said.

Scientists are racing to understand what specific mutations are causing transmission to soar.

There is particular attention to changes that involve the virus’s spike protein, which lets the virus latch onto human cells and gain entry, causing infection.

“The concern is that each mutation might make it a little bit more able to bind” tightly to cells, said infectious disease expert Dr. Julie Parsonnet, professor of medicine at Stanford University.

Or maybe there’s some other part of the virus that excels at its job.

“Ninety percent of the genome of the virus controls for everything else,” such as rate of replication, Crotty said. “And so it’s plausible that a decent part of this increased transmissibility is coming from parts of this virus that we don’t understand yet.”

Perhaps it involves an enzyme called RNA polymerase, which is responsible for copying genetic code as the virus reproduces, suggested Ernst.

“With influenza, we know that there are variants of RNA polymerase that will make more viruses, because the viral polymerase works better,” he said.

Changes to two other traits — virulence and vaccine evasion — also could transform the pandemic.

So far, the virus has been notably uncreative at evading our vaccines, with just a limited repertoire of changes. For instance, despite being separated by thousands of miles, the delta variant first discovered in India and a variant most common in California used the same mutation to try to dodge our antibodies. Variants that independently emerged in South Africa and Brazil also share a mutation.

“There are a handful of ways that the virus has mutated to avoid some of the antibody response,” none of them very effective, said Crotty. “And it keeps coming up with them over and over again. And so far, that doesn’t appear to be a big problem.”

But there are troubling signs of increased virulence. The death rate associated with alpha, or the U.K. variant, was about 64% higher than previous variants. Now, compared to alpha, the delta variant doubles the risk of hospitalization among the unvaccinated, based on new Scottish data. Scientists don’t know if that is because of a genetic change or simply because it grows so rapidly.

It is unlikely to suddenly morph into a virus that kills quickly, scientists add. The pandemic has exploded because the virus is so sneaky, multiplying in unvaccinated people who feel fine and continue to socialize.

“Evolutionarily, killing your host is not a very smart thing for a virus to do,” said UCSF infectious disease expert Dr. Monica Gandhi. 

To quickly detect the next mutation that could alter the trajectory of the pandemic, the U.S. must more fully harness the power of genomics, the experts agreed.

Only close surveillance through gene sequencing will tell us if the virus has taken another big jump, alerting us to prepare.

“At some point,” said Ernst, “it’s likely that the virus will reach the point that it’s tried out everything. And we respond.”

“There will be some equilibrium,” he said, “but I don’t know where that is.”