Lessons from Gamma, Iota and Mu

In early 2021, scientists in Colombia discovered a worrying new strain of the coronavirus. This variant, eventually known as mu, had several troubling mutations that experts believed could help evade the immune system’s defenses.

In the months that followed, mu quickly spread in Colombia, fueling a new wave of COVID-19 cases. By the end of August, it had been discovered in dozens of countries and the World Health Organization had labeled it an “interesting variety.”

“Mu started making some noise worldwide,” said Joseph Fauver, a genomic epidemiologist at the University of Nebraska Medical Center and an author of a recent study on the variant.

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And then it fizzes. Today, the variant has virtually disappeared.

For every delta or ommicron there is a gamma, iota or mu variant that caused local peaks, but never advanced to global dominance. And while understanding omicron remains a critical public health priority, there are lessons to be learned from these lesser lines, experts say.

“This virus has no reason to stop adapting and evolving,” said Joel Wertheim, a molecular epidemiologist at the University of California, San Diego. “And seeing how it did that in the past helps us prepare for what it could do in the future.”

Studies by the also-rans have shed light on surveillance gaps and policy blunders — providing more evidence that America’s international travel bans were ineffective — and on what makes the virus successful, suggesting that in the early stages of the pandemic, the transmissibility was more important than immune evasion.

The research also shows how important context is. Variants that have an impact in some places never gain a foothold in others. As a result, it is difficult to predict which variants will prevail, and to keep abreast of future variants and pathogens requires extensive, near real-time monitoring.

“We can gain a lot by looking at the viral genomic sequence and saying, ‘This one is probably worse than the others,'” Wertheim said. “But the only way to really know is to see how it spreads, because there are a lot of potentially dangerous variants that have never broken through.”

Here’s looking at mu

The coronavirus is constantly changing and most new variants are never noticed or mentioned. But others are sounding the alarm, either because they are quickly becoming more common or because their genomes look ominous.

Both were true of mu as it spread in Colombia.

“It contained a number of mutations that people had been closely monitoring,” said Mary Petrone, a genomic epidemiologist at the University of Sydney and author of the new mu paper. Several of the mutations in the spike protein have been documented in other immune-evasive variants, including beta and gamma.

In the new study, which has not yet been published in a scientific journal, scientists compared the biological characteristics of mu with those of alpha, beta, delta, gamma and the parent virus. Mu replicated no faster than any other variant, they found, but it was the most immune-evasive of the bunch — more resistant to antibodies than any known variant, besides omicron, Fauver said.

By analyzing the genome sequences of mu samples from around the world, the researchers reconstructed the distribution of the variant. They concluded that mu had likely surfaced in South America in mid-2020. Then it circulated for months before being discovered.

Genomic surveillance in many parts of South America has been “patchy and incomplete,” said Jesse Bloom, an expert on viral evolution at the Fred Hutchinson Cancer Research Center in Seattle. “If there had been better surveillance in those regions, it might have been easier to estimate more quickly how concerned you are about mu.”

Mu also presented another challenge. It happened to have a type of mutation known as a frameshift mutation that was rare in coronavirus samples. Such mutations were flagged as errors when scientists, including Fauver, attempted to upload their mu sequences to GISAID, an international repository of viral genomes used to track new variants.

That complication caused delays in the public sharing of mu series. The time that elapsed between the time a virus sample was collected from a patient and the time it was made publicly available on GISAID was consistently longer for mu cases than for delta cases, the researchers found.

“The genome itself basically created artificial gaps in surveillance,” Fauver said. “It has led, at least in our experience, to not getting any data out for weeks when we normally try to get it in days.”

(GISAID’s quality control systems are important, the researchers emphasized, and the repository has solved the problem.)

Combine these gaps in guard with mu’s immune-evasive ability and the variant looked poised to take off. But that’s not what happened. Instead, mu radiated from South and Central America to other continents, but didn’t circulate widely once there, the scientists found.

“That was an indication that this variant might not be as suitable for the North American and European populations as we expected,” Petrone said.

That was probably because mu competed with an even more formidable variant: delta. Delta wasn’t as adept at evading antibodies as mu, but it was more transmissible. “So eventually the delta spread more widely,” Bloom said.

Right variant, right time

Studying successful variants only tells half the story.

“Variants that don’t become dominant are, in a sense, negative controls,” Petrone said. “They tell us what didn’t work and in doing so help fill the knowledge gaps around variant fitness.”

Delta overtook several immune-evasive variants in addition to mu, including beta, gamma, and lambda. This pattern suggests that immune evasion alone was not enough for a variant to outperform a highly transmissible version of the virus — or at least not during the early phase of the pandemic, when few people had immunity.

But vaccinations and multiple waves of infection have changed the immune landscape. A highly immune-evasive variant should now have more of an edge, scientists said, which is likely part of why omicron has been so successful.

Another recent study suggested that immune-evasive gamma in New York City tended to fare better in neighborhoods with higher levels of pre-existing immunity, in some cases because they were hit hard during the first wave of COVID-19.

“We can’t look at a new variant in a vacuum, because it comes about in the shadow of all the variants that preceded it,” said Wertheim, author of the study.

Indeed, the clash of past variants reveals that success is highly dependent on context. New York City, for example, may have been the birthplace of the iota variant, which was first detected in virus samples collected in November 2020. “And that’s how it got a foothold early on,” Petrone said. Even after the more portable alpha variant arrived, iota remained the dominant variant of the city for months, before finally fading away.

But in Connecticut, where iota and alpha both appeared in January 2021, things were different.

“Alpha just took off right away and iota didn’t stand a chance,” said Petrone, who led a study on the variants in the two regions.

A similar pattern is already starting to play out with the multiple lines of omicron. In the United States, BA.2.12.1, a subvariant first identified in New York, has taken off, while in South Africa BA.4 and BA.5 are creating a new wave.

That’s another reason to study variants that declined, said Sarah Otto, an evolutionary biologist at the University of British Columbia. A variant that was poorly coordinated for a certain time and place could get off the ground in another. Mu’s misfortune might indeed be that it showed up too early.

“There may not have been enough people with immunity to really boost that variant,” Otto said.

But the next variant of concern could be a descendant of, or something similar, from an immune-evasive lineage that never really took hold, she said.

Looking back at previous variants can also provide insight into what did or didn’t work in curbing them. The new gamma study provides further evidence that international travel bans, at least as implemented by the United States, are unlikely to prevent the global spread of a variant.

Gamma was first identified in Brazil at the end of 2020. In May of that year, the United States banned most non-US citizens from traveling to the country from Brazil, a restriction that remained in effect until November 2021. Still, gamma was detected in the United States. States in January 2021 and quickly spread to dozens of states.

Because gamma never dominated globally, studying its distribution provided a “cleaner” picture of the effectiveness of travel bans, said Tetyana Vasylyeva, a molecular epidemiologist at the University of California, San Diego and an author of the study.

“When it comes to studying variants like, say, delta — something that’s caused a major outbreak everywhere — sometimes it’s really hard to find patterns because it’s happening on a very large scale and very quickly,” she said. .

In an ongoing global health emergency, with a virus rapidly changing, there is an understandable impulse to focus on the future, Fauver said. And as the world’s attention turned to delta and then ommicron, he and his colleagues discussed whether to continue their study of old-news mu.

“We were like, ‘Does anyone care about mu?'” Fauver recalls. “But we think there’s still room for high-quality studies that ask questions about past variants of care and try to look back at what happened.”

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