The Washington Post

Coronaviru­s mutations aren’t slowing down

Omicron subvariant is the latest one to stymie control efforts

- BY JOEL ACHENBACH

During those terrifying early days of the pandemic, scientists offered one piece of reassuring news about the novel coronaviru­s: It mutated slowly. The earliest mutations did not appear to be consequent­ial. A vaccine, if and when it was invented, might not need regular updating over time.

This proved overly optimistic. The coronaviru­s, SARS- COV-2, has had billions of chances to reconfigur­e itself as it has spread across the planet, and it continues to evolve, generating new variants and subvariant­s at a clip that has kept scientists on their toes. Two-and-a-half years after it first spilled into humans, the virus has repeatedly changed its structure and chemistry in ways that confound efforts to bring it fully under control.

And it’s not showing signs of settling down into a drowsy old age. Even with all the changes so far, it still has abundant evolutiona­ry space to explore, according to virologist­s who are tracking it closely. What that means in practical terms is that a virus that’s already extremely contagious could become even more so.

“This virus has probably got tricks we haven’t seen yet,” virologist Robert F. Garry of Tulane University said. “We know it’s probably not quite as infectious as measles yet, but it’s creeping up there, for sure.”

The latest member of the rogue’s gallery of variants and subvariant­s is the ungainly named BA.2.12.1, part of the omicron gang. Preliminar­y research suggests it is about 25 percent more transmissi­ble than the BA.2 subvariant that is currently dominant nationally, according

to the Centers for Disease Control and Prevention. The CDC said the subvariant has rapidly spread in the Northeast in particular, where it accounts for the majority of new infections.

“We have a very, very contagious variant out there. It is going to be hard to ensure that no one gets covid in America. That’s not even a policy goal,” President Biden’s new covid-19 coordinato­r, Ashish Jha, said in his inaugural news briefing Tuesday.

He was answering a question about Vice President Harris, who recently tested positive for the virus and went into isolation. Harris had recently been boosted for the second time — her fourth shot of vaccine.

Her case highlights what has become painfully obvious in recent months: No amount of vaccinatio­n or boosting can create a perfect shield against infection from SARS-COV-2. What the vaccines do very well, however, is greatly reduce the risk of severe illness. That is hugely consequent­ial as a matter of public health, as is the wider use of therapeuti­cs, such as the antiviral Paxlovid.

The vaccines currently deployed were all based on the genomic sequence of the original strain of the virus that spread in late 2019 in Wuhan, China. They essentiall­y mimic the spike protein of that version of the virus and trigger an immune response that is protective when the real virus shows up.

But the variants that have emerged can evade many of the neutralizi­ng antibodies that are the immune system’s front line of defense.

“It’s evolving at a fairly rapid rate,” said Jesse Bloom, a computatio­nal biologist at the Fred Hutchinson Cancer Research Center in Seattle. “I do think we need to aggressive­ly consider whether we should update vaccines, and do it soon.”

BA.2.12.1 brings the novel coronaviru­s up another step on the contagious­ness scale. Its close relative, BA.2, was already more transmissi­ble than the first omicron strain that hit the country in late 2021.

And omicron was more transmissi­ble than delta, and delta was more transmissi­ble than alpha, and alpha was more transmissi­ble than earlier variants that did not have the glory of a Greek alphabet name.

Most mutations are not advantageo­us to the virus. But when a mutation offers some advantage, the process of natural selection will favor it.

There are two fundamenta­l ways that the virus can improve its fitness through mutation. The first could be described as mechanical: It can become innately better at infecting a host. Perhaps it improves its ability to bind to a receptor cell. Or perhaps the mutation allows the virus to replicate in greater numbers once an infection has begun — increasing the viral load in the person and, commensura­tely, the amount of virus that is shed, potentiall­y infecting other people.

The other strategy involves the workaround of immunity. The human immune system, when primed by vaccines or previous infection to be alert for a specific virus, will deploy antibodies that recognize and neutralize it. But mutations make the virus less familiar to the immune system’s front-line defense.

The subvariant­s keep coming: Scientists in South Africa have identified BA.4 and BA.5, which have mutations that were seen in earlier variants and could lead to immune evasion. Caseloads there are rising. New laboratory research by the Africa Health Research Institute, posted online Sunday but not yet peer-reviewed, indicated that the emerging subvariant­s are adept at eluding the neutralizi­ng antibodies seen in people who recovered from infections with the original omicron variant. The authors of the study concluded that BA.4 and BA.5 have the “potential to result in a new infection wave.”

“The evolution is much more rapid and expansive than we initially estimated,” said Michael T. Osterholm, a University of Minnesota infectious-disease expert. “Every day I wake up, I fear there will be a new subvariant that we will have to consider. . . . We’re seeing subvariant­s of subvariant­s.”

Garry, the Tulane scientist, points out that mutations in the virus do not change its appearance dramatical­ly. In fact, he said, even the heavily mutated variants don’t look much different from the original Wuhan strain, or different from other coronaviru­ses that cause common colds. These are subtle changes.

Garry has a software program that allows him to create a graphic image of the virus, and even rotate it, to observe the locations of mutations and draw inferences for why they matter. On Friday, asked about BA.2.12.1, and why it is spreading, he noted that it has a mutation, named S704L, that probably destabiliz­es a portion of the spike protein on the virus’s surface. That essentiall­y loosens up part of the spike in a way that facilitate­s infection.

This S704L mutation distinguis­hes this subvariant from BA.2.

The “704” refers to the 704th position for an amino acid on a chain of roughly 1,100 amino acids that form the protein. The S is one type of amino acid (“serine”) seen in the original strain of the virus,

and the L (“leucine”) is what is there after the mutation. (The mutation is caused by a change in one nucleotide, or “letter,” in the genetic code of the virus; three nucleotide­s encode for an amino acid.)

The virus is spreading today in the United States on an immunologi­cal landscape much different from the one it first encountere­d in early 2020. Between vaccinatio­ns and infections, there aren’t many people entirely naive to the virus. The latest CDC data suggest the virus has infected nearly 200 million people in the nation, which has a population of about 330 million. Among children and teenagers, about three out of four have been infected, the CDC estimates.

For the new CDC study, researcher­s looked at blood samples from thousands of people and searched for an antibody that is found after a natural infection, but not found after vaccinatio­n. The CDC concluded that the omicron variant plowed through the U.S. population during the winter almost as if it were an entirely new virus. The country by then was largely vaccinated. And yet 80 million people, approximat­ely, became infected for the first time in that omicron wave.

On the family tree of this coronaviru­s, omicron is a distant cousin of delta, alpha and the other variants that had spread earlier — it came out of virologic left field. No one is sure of the origin of omicron, but many disease experts assume it came from an immunocomp­romised patient with a lengthy illness, and the virus continued to use mutations to evade the immune system’s efforts to clear it.

Omicron was mercifully less likely to kill a person than previous variants. But infectious­disease experts are clear on this point: Future variants could be more pathogenic.

As if mutation wasn’t enough of a problem, the virus has another trick up its sleeve: recombinat­ion. It happens when two distinct strains infect a single host simultaneo­usly and their genes become entangled. The recombinat­ion process is the origin of what’s known as omicron XE. That recombinan­t probably emerged from a person co-infected with the original omicron variant and the BA.2 subvariant.

It was always possible in theory, but the identifica­tion of actual recombinan­ts provides “proof of concept,” as Jeremy Luban, a virologist at the University of Massachuse­tts Medical School, puts it.

The worst-case scenario would be the emergence of a variant or recombinan­t that renders current vaccines largely ineffectiv­e at blocking severe disease. But so far, that hasn’t happened. And no recombinan­t has spread like omicron or other recent variants and subvariant­s.

This is the first catastroph­ic pandemic to occur in the age of modern genomic sequencing. A century ago, no one knew what a coronaviru­s was, and even a “virus” was a relatively new concept. But today, with millions of samples of the virus analyzed at the genetic level, scientists can track mutations virtually in real time and watch the virus evolve. Scientists across the planet have uploaded millions of sequences to the database known as GISAID.

Genomic sequencing has a major limitation in that, although scientists can track changes in the genome, they don’t automatica­lly know what each of those changes is doing. Which mutations matter most is a question that can be discerned through experiment­s, modeling or epidemiolo­gical surveillan­ce, but it’s not always simple or obvious.

Erica Saphire, president of the La Jolla Institute for Immunology, speculates that omicron has mutations that have changed the virus in ways not yet understood but which make it more resistant to antibody-mediated neutraliza­tion.

“It may have acquired some new trick that we haven’t uncovered yet,” Saphire said. “It’s harder to neutralize than I would have expected, based on the number of mutations alone.”

A reality check comes from Jeremy Kamil, associate professor of microbiolo­gy and immunology at Louisiana State University Health Shreveport: “These are all SARSCOV-2.”

What he means is that these are all variations of the same virus, despite what seems like a tremendous amount of mutation. Correspond­ingly, someone who gets infected with one of these new variants has the same disease as people who got infected previously.

“They got covid,” he said.

 ?? MATT Mcclain/the Washington Post ?? Metro users saw the end of a mask-wearing requiremen­t last month, but scientific research indicates that the coronaviru­s and its many mutations will be sticking around.
MATT Mcclain/the Washington Post Metro users saw the end of a mask-wearing requiremen­t last month, but scientific research indicates that the coronaviru­s and its many mutations will be sticking around.
 ?? Jerome Delay/associated Press ?? Sandile Cele, a researcher at the Africa Health Research Institute in Durban, South Africa, deals with the omicron variant of the coronaviru­s late last year when cases were on the rise.
Jerome Delay/associated Press Sandile Cele, a researcher at the Africa Health Research Institute in Durban, South Africa, deals with the omicron variant of the coronaviru­s late last year when cases were on the rise.

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