We’ve never seen a virus evolve like this. Here’s why COVID’s future is still a mystery

We’ve never seen a virus evolve like this. Here’s why COVID’s future is still a mystery

When scientists find a new disease-causing virus in humans, the first question they want answered is: Can this thing spread easily from person to person? And if not, will it someday?

Avian influenza can infect humans, but it’s not very good at passing from one person to another. Same with the coronavirus that causes MERS, another severe respiratory illness. Though hundreds of cases of both have been reported over the past two decades, neither virus seems inclined to evolve toward efficient person-to-person transmission.

In less than three years, the coronavirus that causes COVID-19 has mastered it.

SARS-CoV-2 has accumulated a suite of mutations over an astonishingly short period of time that have made it now one of the most infectious human pathogens on the planet. And for the first time ever, scientists have the tools and the knowledge to closely track that evolution in near-real time, studying the small but mighty genomic mutations that have transformed the virus to the point where it hardly resembles the strain that began infecting humans in China in late 2019.

Mapping the evolution of this virus has fed academically curious minds in every nation, and it’s had real world implications too. Identifying and describing new variants has helped guide public health responses and is now informing the next generation of vaccines and drug therapies.

The coronavirus’ rapid evolution also is helping scientists anticipate the future of the pandemic, and what mutations may make it a less — or more — formidable foe in years to come.

“This is the first time in human history that we’ve been able to witness a global pandemic at the genomic, evolutionary level,” said Joe DeRisi, president of San Francisco’s Chan Zuckerberg Biohub, which has done genomic sequencing on the virus since the start of the pandemic.

Joe DeRisi, president of the Chan Zuckerberg Biohub, stands for a portrait on Thursday, Nov. 19, 2020, in San Francisco.

Noah Berger/Special to The Chronicle

What’s been especially fascinating, and at times alarming, is the speed of this virus’ evolution. That SARS-CoV-2 would mutate to better adapt to humans was always anticipated, but the pace of that adaptation has been breathtaking.

Scientists say that’s in large part due to the scale of the pandemic — more than half a billion infections worldwide have afforded the virus near-boundless opportunity to mutate. But it’s a matter of timing, too. As a human virus, SARS-CoV-2 is still in its infancy, developing rapidly to flourish in its new environment. Meanwhile, human immunity to the virus — due to infection and vaccination — has become increasingly complex, applying constant pressure to further evolve.

“It’s normal to see this kind of evolution — this constant battle between human and pathogen,” said Fenyong Liu, an infectious disease expert at UC Berkeley’s School of Public Health. “Each of us is focused on survival. We develop a better system to beat them, and they’re going to mutate and try to escape. It happens with all infectious diseases, but for COVID, the whole process really sped up because of the scale of it.”

Tanya Alexander waits in line for COVID-19 test with her grandson Sincere Perkins, 9, at Bayview Opera House in San Francisco on Thursday, Jan. 6, 2022.

Tanya Alexander waits in line for COVID-19 test with her grandson Sincere Perkins, 9, at Bayview Opera House in San Francisco on Thursday, Jan. 6, 2022.

Brontë Wittpenn/The Chronicle

Predicting how evolution will shape the next iterations of this virus is tricky, and scientists lack the technology to do it with any precision. How the virus has mutated over the past two and a half years provides some clues: Scientists have identified dozens of specific mutations — mostly associated with increasing infectiousness — that have recurred in multiple variants. Those mutations likely will keep showing up, re-sorting themselves in different combinations that give the virus further survival advantages. Some of the mutations could become permanently embedded in the virus’ genetic code. A few already have.

Recently, the virus has mutated to evade hard-won human immunity, and most experts in virology believe it will continue down that evolutionary path. It could also acquire new mutations that make it more infectious, though it’s already become so efficient at spreading among humans that it’s hard to imagine how much more gains it can make there, some scientists say.

The most critical question — and possibly the toughest to answer — is whether the virus will evolve to cause more or less severe disease in humans. Many experts believe that viruses tend to become more benign over time — one of the current coronaviruses that now causes the common cold may have been the source of a deadly pandemic in the late 1800s — but that’s not a sure thing, and no one can say how long such evolution may take. Omicron and its subvariants are causing milder disease than their predecessors, but it would be naïve to assume a future variant couldn’t arrive with mutations that make it fiercer once again, experts say.

Social distancing circles at Dolores Park on Saturday, May 23, 2020, in San Francisco. The 10-foot circles, which were eight feet apart from each other, were an effort to curb coronavirus spread.

Social distancing circles at Dolores Park on Saturday, May 23, 2020, in San Francisco. The 10-foot circles, which were eight feet apart from each other, were an effort to curb coronavirus spread.

Santiago Mejia/The Chronicle

“Hopefully it will adapt and become a very mild seasonal disease, and our immune systems will adapt, too,” Liu said. “But in reality, the virus has unlimited capability to adapt and mutate.”

Scientists began tracking the evolution of SARS-CoV-2 almost immediately after the virus was isolated and identified in early January 2020. Once the first genomic sequence was complete and had been shared on a public database, infectious disease experts around the world started hunting for mutations, largely to keep tabs on how the virus was spreading.

Most people by now are familiar with the role mutations play in giving the virus certain advantages. But most mutations don’t actually have an obvious effect on the virus, they’re simply glitches in the code. Those mutations can serve as evolutionary breadcrumbs, though, allowing scientists to follow the virus’ trail as it travels widely around the globe. And throughout the pandemic, public health experts have used mutations to identify and control clusters of infections.

Still, scientists are most invested in tracking consequential mutations that may alter the public health response. For example, arrival of the incredibly infectious omicron led many officials to recommend people start wearing higher quality masks, and eventually triggered another universal mask mandate in California to help curb the spread.

The most influential mutations mostly have been identified in the spike protein, the section of the virus that projects out of the surface and latches onto the ACE2 receptor, a protein on the exterior of human cells through which SARS-CoV-2 gains entry.

The first significant mutation — known as D614G and nicknamed “Doug” — arrived sometime in spring 2020; it basically made the ACE2 receptor more accessible. “It was like putting a wedge in the door to keep it open,” said Shannon Bennett, chief of science at the California Academy of Sciences.

Shannon Bennett, chief of science for the California Academy of Sciences, studies infectious diseases that can be transmitted from animals to humans. Here, she plays her piano at her home on March 20, 2020, in Mill Valley, Calif.

Shannon Bennett, chief of science for the California Academy of Sciences, studies infectious diseases that can be transmitted from animals to humans. Here, she plays her piano at her home on March 20, 2020, in Mill Valley, Calif.

Paul Kuroda/Special to The Chronicle

That mutation granted the virus an early boost in infectiousness, and it has stuck around in every important variant since. Identifying a mutation of that significance was surprising, and exciting, Bennett said. It was the kind of early evolutionary shift that scientists have never been able to capture before. With earlier viruses — HIV, for example — by the time scientists identified and were able to study them closely enough to look for mutations, they were already well established in humans and had likely gone through years of vigorous adaptations.

After D614G, the virus quickly accumulated mutations that mostly improved its ability to transmit and infect. Scientists haven’t yet determined exactly what all those changes are doing, at the biological level, to increase infectiousness. Some may allow the virus to replicate faster in the nose or bind more tightly to the ACE2 receptor, making it harder for the immune system to shake off an early infection. Mutations could also make the virus more durable, for instance able to survive for longer periods in the air.

By the end of 2020, it was becoming apparent that the virus was evolving quickly in an environment of widespread transmission. Troubling new variants were emerging at regular intervals, each causing new waves of infection in the country in which they emerged and sometimes on a global scale. And each new variant seemed to be at least somewhat more infectious than the one preceding it. Alpha, which dominated in the U.S. in early 2021, was perhaps 50% more infectious than the original virus, and delta, which fueled the summer 2021 surge, was perhaps 90% more infectious than alpha.

Nurse practitioner Paige Yang mixes a dose of Evusheld, a preventative monoclonal injection, at Total Infusion in Oakland, Calif. on March 16, 2022. The medication is used to prevent COVID-19 among immunocompromised patients.

Nurse practitioner Paige Yang mixes a dose of Evusheld, a preventative monoclonal injection, at Total Infusion in Oakland, Calif. on March 16, 2022. The medication is used to prevent COVID-19 among immunocompromised patients.

Brontë Wittpenn/The Chronicle

Omicron, which carried dozens of new mutations, was again more infectious — up to fivefold over delta. And each of its subvariants has been more infectious still. The currently circulating strains, all offspring of omicron, are nearly as infectious as measles, which is the most contagious of all known human infections.

Scientists say the virus may have hit peak infectiousness, or close to it. Now, it’s evolving to get around the immune response, and that trend likely will continue. Early studies show that the two up-and-coming variants in the U.S. — BA.4 and BA.5, which currently make up roughly a third of cases — are the most immune evasive so far; people who are vaccinated or have already been infected, or both, may still be vulnerable.

“I think there’s a max in terms of how transmissible it can be,” said Nadia Roan, an investigator at the Gladstone Institutes in San Francisco who studies immunology. “Now almost the entire world has some form of immunity, whether from infection or vaccination or both, and that’s the big pressure. A virus that is able to take off right now has to be immune evasive.”

Scientist Xiaoyu Luo, postdoctoral scholar Julie Frouard, lead scientist Nadia Roan, PhD, and research assistant Matthew McGregor wear masks and lab coats while walking through the lab at Gladstone Institutes in San Francisco on Thursday, August 13, 2020.

Scientist Xiaoyu Luo, postdoctoral scholar Julie Frouard, lead scientist Nadia Roan, PhD, and research assistant Matthew McGregor wear masks and lab coats while walking through the lab at Gladstone Institutes in San Francisco on Thursday, August 13, 2020.

Jessica Christian/The Chronicle

Immune evasion is such a concern that many experts believe the world needs to focus resources on developing next-generation vaccines that will target parts of the virus less prone to mutations. Manufacturers of the two main U.S. vaccines — Pfizer and Moderna — are working to update their products to better match the currently circulating variants, but that’s difficult to do when the dominant variant changes every few months.

Ideally, scientists would develop a vaccine that neutralizes the virus — preventing it from ever taking hold and stopping transmission entirely — and doesn’t fade over time. The latter may not be possible, though. “It doesn’t seem that this coronavirus will be inducing the same immunity that polio and measles induces — that lasts for your entire life,” said Raul Andino, a UCSF virologist.

Eventually, the pace of evolution in SARS-CoV-2 may slow down, or at least produce fewer consequential mutations that cause fresh surges several times a year. But it’s tough to guess when that will happen.

“Virus evolution is relentless. The virus never takes a rest, never takes a break, and it never stops mutating,” DeRisi said. “The truce may come when we figure out what kind of yearly boosters we need, or what vaccination works.

“We want to get the virus to where it just doesn’t matter anymore,” he said. “We’re not there yet. But there’s reason to be optimistic, and also reason to be cautious and not let our guard down.”


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