The Vanishing Variants: Lessons from Gamma, Iota, and Mu

In early 2021, Colombian scientists discovered a disturbing new variant of the coronavirus. This variant, later known as Mu, had several troubling mutations that experts believe could help it evade the defenses of the immune system.

Over the following months, Mu spread rapidly in Colombia, fueling a new wave of Covid-19 cases. By the end of August, it had been detected in dozens of countries and the World Health Organization had designated it as a “variant of interest”.

“Mu was starting to make noise globally,” said Joseph Fauver, a genomic epidemiologist at the University of Nebraska Medical Center and author of a recent study on the variant.

And then it collapsed. Today, the variant has practically disappeared.

For every Delta or Omicron there is a Gamma, Iota or Mu, variants that have resulted in local surges but never achieved global dominance. And while understanding Omicron remains a key public health priority, there are lessons to be learned from these lesser lineages, experts say.

“This virus has no incentive to stop adapting and evolving,” said Joel Wertheim, a molecular epidemiologist at the University of California, San Diego. “And seeing how he’s done that in the past will help prepare us for what he might do in the future.”

Studies of the also-rans have shed light on surveillance shortcomings and policy errors – providing more evidence that international travel bans in America were not effective – and on what makes the virus successful, suggesting that in the first phase of the pandemic, transmissibility was more important than immune evasion.

The research also underscores how much context matters; variants that have an impact in some places never take hold in others. As a result, it is difficult to predict which variants will become dominant, and staying on top of future variants and pathogens will require comprehensive, near real-time monitoring.

“We can gain a lot by looking at the viral genomic sequence and saying, ‘This one’s probably worse than another one,'” Dr Wertheim said. “But the only way to really know is to watch it spread, because there are many potentially dangerous variants that have never caught on.”

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

Both were true of Mu as it spread in Colombia. “It had a few mutations that people were watching very closely,” said Mary Petrone, a genomic epidemiologist at the University of Sydney and author of Mu’s new paper. Several of its spike protein mutations had been documented in other immuno-evasive variants, including Beta and Gamma.

In the new study, which has yet to be published in a scientific journal, the scientists compared the biological characteristics of Mu to those of Alpha, Beta, Delta, Gamma and the original virus. Mu did not replicate faster than any other variant, they found, but it was the most immuno-evasive of the group – more resistant to antibodies than any known variant apart from Omicron, Dr Fauver said. .

By analyzing the genomic sequences of Mu samples collected around the world, the researchers pieced together the spread of the variant. They concluded that Mu likely emerged in South America in mid-2020. It then circulated for months before being detected.

Genomic surveillance in many parts of South America was “patchy and incomplete”, said Jesse Bloom, an expert in viral evolution at the Fred Hutchinson Cancer Research Center in Seattle. “If there had been better surveillance in these areas, it might have been easier to make a quicker assessment of concern about Mu.”

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

This complication has created delays in the public sharing of Mu footage. The time that elapsed between when a virus sample was taken from a patient and when it was made public on GISAID was consistently longer for Mu cases than for Delta cases, the researchers found. .

“The genome itself was essentially creating artificial surveillance gaps,” Dr. Fauver said. “This resulted, at least in our experience, in us not getting data for weeks when we normally try to get it within days.”

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

Combine these oversight gaps with Mu’s immune evasion and the variant seemed poised to take off. But that’s not what happened. Instead, Mu radiated from South and Central America to other continents, but did not circulate widely once it got there, the scientists found. “It was an indication that this variant was not necessarily as suitable for North American and European populations as we had anticipated,” Dr. Petrone said.

It’s probably because Mu found himself in competition with an even more formidable variant: Delta. Delta wasn’t as good at dodging antibodies as Mu, but he was more transmissible. “So ultimately Delta spread more widely,” Dr. Bloom said.

Studying successful variants only tells half the story. “Variants that don’t become dominant are, in a way, negative controls,” Dr. Petrone said. “They tell us what went wrong, and in doing so, help to fill knowledge gaps about variant fitness.”

Delta has surpassed several immuno-evasive variants in addition to Mu, including Beta, Gamma, and Lambda. This pattern suggests that immune evasion alone was not enough to allow one variant to outcompete a highly transmissible version of the virus – or at least that was not the case at the start of the pandemic, when few people were immune.

But vaccinations and multiple waves of infection have changed the immune landscape. According to the scientists, a highly immuno-evasive variant should now have more benefits, which probably partly explains the success of Omicron.

Another recent study suggested that in New York, immuno-evasive Gamma tended to do better in neighborhoods with higher pre-existing immunity levels, in some cases because they were hit hard when first Covid wave. “We cannot see a new variant in a vacuum, because it arises in the shadow of all the variants that came before it,” said Dr. Wertheim, who was one of the study’s authors.

Indeed, the clash of past variants reveals that success depends strongly on the context. For example, New York City may have been the birthplace of the Iota variant, which was first detected in virus samples collected in November 2020. “And so it gained a foothold very early on” , said Dr. Petrone. Even after the arrival of the more transmissible Alpha variant, Iota remained the dominant variant in the city for months, before finally disappearing.

But in Connecticut, where Iota and Alpha both appeared in January 2021, things turned out differently. “Alpha kind of took off immediately, and Iota didn’t have a chance,” said Dr. Petrone, who led a study of the variants in the two regions.

A similar pattern is already beginning to play out with the multiple lineages 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 experiencing a new surge.

That’s another reason to study the variants that have declined, said Sarah Otto, an evolutionary biologist at the University of British Columbia. A variant that was mismatched at a certain time and place could take off in another. Indeed, Mu’s misfortune could simply have been that he appeared too soon. “Maybe there weren’t enough immune people to really give this variant a boost,” says Dr. Otto.

But the next variant of concern could be a descendant or something similar to an immune-evasive line that never really caught on, she said.

A look back at previous variants can also provide insight into what worked – or didn’t work – to contain them. The new Gamma study provides further evidence that international travel bans, at least as the United States has implemented them, are unlikely to prevent the global spread of a variant.

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

Because Gamma has never dominated the world, studying its spread has provided a “clearer” picture of the effectiveness of travel bans, said Tetyana Vasylyeva, a molecular epidemiologist at the University of California, San Diego and author of the study. “When it comes to studying variants like, say, Delta – something that has 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 rapidly evolving virus, there is an understandable impetus to focus on the future, Dr Fauver said. And as the world’s attention turned to Delta and then Omicron, he and his colleagues discussed whether to continue their study of old Mu news.

“We were like, ‘Does anyone care more about Mu?'” Dr. Fauver recalled. “But we think there’s still room for high-quality studies that ask about previous variants of concern and try to unravel what happened.”

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