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In 25 months, the novel-coronavirus has infected 320 million people worldwide and killed 5.5 million of them. 

But the SARS-CoV-2 virus could have been worse. The latest Omicron variant is highly transmissible, but not as deadly for vaccinated people. The previous Delta variant is usually more severe, owing to its tendency to attack the lungs rather than stay in the throat like Omicron does. But mercifully, Delta doesn’t spread as fast as Omicron does.

Now imagine a coronavirus that’s both deadly and highly transmissible. It’s certainly within the realm of possibility.

To head off a potentially worse coronavirus pandemic, a University of Illinois at Chicago scientist named Changchuan Yin is looking for warning signs. Genetic hints of the plague to come. But experts warned his proposed system might be flawed, because it assumes coronaviruses will evolve in predictable ways.

There are lots of coronaviruses out there in the animal kingdom; scientists have named 46 of them so far. Any one could leap to the human — and a bunch already have. We’ve suffered through outbreaks of SARS-CoV-1, MERS and now SARS-CoV-2 — all coronaviruses with their distinctive spikes and tendency to cause respiratory infections. 

Yin and other experts warned it’s inevitable there will be a SARS-CoV-3 that, at some point in the near future, will cross over from animals to people. “We are experiencing a new coronavirus outbreak every eight to 10 years,” said Kevin Saunders, director of the Human Vaccine Institute at Duke University. 

Our odds of beating the next coronavirus could improve if we see the virus coming. We could develop new therapies and vaccines and put in place public-health strategies to limit the pathogen’s spread. But that means spotting the new virus well in advance of its leap from the original animal host to the human population.

Identifying the likeliest viral culprit is a tough gig that, at present, involves a lot of guesswork. In a preprint of a new study, not yet peer-reviewed, Yin proposes a system for surveilling and assessing coronaviruses. One that could give us the early warning we need, assuming we collect and genetically-sequence enough samples from bats, civets and other coronavirus-prone animals.

The science is complicated, but it boils down to this: viruses that are making peace with their human hosts – infecting them but usually not killing them – tend to accumulate a lot of a certain kind of mutation called a “homopolymeric nucleotide repeat,” or “HP repeat.” 

An HP repeat occurs when our antibodies and T-cells attack a virus and the virus adapts that attack. Every HP repeat is a sort of genetic scar from the pathogen’s battle with our immune systems as the two try to strike a truce of sorts. 

That truce makes evolutionary sense. Generally speaking, a pathogen evolves to be just virulent enough to thrive and spread, but not so virulent that it kills its hosts … and itself. 

“This is basic evolutionary biology where viruses become attenuated or weakened with serial passage through human or animal hosts,” said Paul Ananth Tambyah, president of the Asia Pacific Society of Clinical Microbiology and Infection in Singapore. “That is how live-virus vaccines are — you simply infect and reinfect successive generations of animals until you select for mutations which render the virus relatively harmless.” 

A virus with a low number of HP-repeats probably hasn’t been exposed to people, possibly ever. 

“A low HP score suggests that the virus is in a more native state,” Yin explained. That’s a giant red flag. The pathogen has never known human beings so it doesn’t know how to avoid making them really, really sick or killing them. It infects human cells and just goes nuts.

So how many HP repeats is a sign of a virus that has the potential to surprise our immune systems and cause a pandemic? Six or fewer, according to Yin. “I think if a virus has lower HP … it could be a dangerous virus,” Yin said.

A coronavirus called Human-CoV/HKU1, which causes mild, cold-like symptoms, has 10 HP-repeats. SARS-CoV-2, which is obviously much more dangerous, has six. A coronavirus called SZ3 that’s found in civets, a cat-like tropical mammal, has four of the mutations — meaning it just might be even more dangerous to people than SARS-CoV-2. The worrying bat coronavirus HKU9-1 has only three HP repeats. 

If virologists find a coronavirus with just a couple HPs — look out. Our antibodies and T-cells aren’t ready to battle that virus all on their own.

But there’s a possible flaw in Yin’s system. As Yin points out, Omicron actually has .2 fewer HP repeats than the very first strain of SARS-CoV-2 that infected people starting way back in December 2019. Omicron gradually evolved over two years and yet it has fewer of the telltale mutations. 

Yin assumes a human-infecting virus stacks up more HP repeats over time, but Omicron bucked that trend. And it underscores an important truth about coronaviruses: This type of pathogen is unpredictable.

Omicron has an alarming assortment of roughly 50 key mutations, around 30 of which are on the spike protein that helps the virus grab onto our cells. “These major mutations that have occured with Omicron — people said that can’t happen,” said Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota. “That was a mega leap.” 

If coronaviruses behaved the way we expect viruses in general to behave, they’d become steadily less harmful over time. But Omicron muddied our expectations and befuddled experts by being both better and worse than Delta – vastly more transmissible and yet somewhat less lethal. “All of us got variant evolution wrong,” said Edwin Michael, an epidemiologist at the Center for Global Health Infectious Disease Research at the University of South Florida.

Omicron’s lower-than-expected HP-repeat count seems to undermine Yin’s design for a pandemic early-warning system, and has made some of his fellow scientists skeptical. “There are some who would disagree” with Yin’s surveillance design, Osterholm said. 

Yin acknowledges the limits of his system. The HP repeats “cannot directly infer” a virus’s virulence in people or, by extension, its potential to cause a pandemic. No, it’s an indirect warning of a possible nasty pathogen. “It is of importance for tracking, virulence assessment and controlling the outbreak of a coronavirus,” Yin said. But it’s not foolproof.

Given the circumstances, even a flawed system like Yin’s might be better than nothing. SARS-CoV-3 is coming for us, eventually. “Therefore, strict epidemic surveillance is indispensable,” Yin wrote. Maybe the risk of a false alarm, based on an imperfect search for one kind of mutation, is better than no alarm at all.