The Vanishing Variants: Lessons from Gamma, Iota and Mu

Scientists say studying the fading Coronavirus variants could help us prepare for what lies ahead.

An alarming new Coronavirus variant was discovered in Colombia in early 2021. Mu had several mutations that experts believed might help it evade the immune system’s defenses.

In the following months, Mu spread rapidly in Colombia, resulting in a new surge of Covid-19 cases. The World Health Organization had designated it a “variant of interest” by the end of August after it was detected in dozens of countries.

“The Mu variant was starting to make some noise globally,” said Joseph Fauver, a genomic epidemiologist at the University of Nebraska Medical Center.

Then it fizzled. The variant is all but extinct today.

Gamma, Iota, and Mu are variants of Delta or Omicron that drove local surges but never achieved global dominance. Despite the importance of understanding Omicron, experts say there are lessons to be learned from these lesser lineages.

Joel Wertheim, a molecular epidemiologist at the University of California San Diego, says the virus has no incentive to stop adapting and evolving. “Seeing how it has done that in the past will help us anticipate what it might do in the future.”

Studies of the also-rans have shed light on surveillance gaps and policy blunders — proving the ineffectiveness of American international travel bans — as well as what makes the virus successful, suggesting that transmissibility was more important than immune evasion in the early phases of the pandemic.

Additionally, the research emphasizes how context matters; variants that succeed in some places do not succeed in others. Due to this, predicting which variants will dominate is difficult, and keeping up with future variants and pathogens will require near-real-time surveillance.

Doctor said we can gain a lot by looking at the viral genomic sequence and saying, “This one is probably worse than that one.” The only way to know for sure is to watch it spread, since many potentially dangerous variants never appeared.

Here’s looking at Mu

It is well known that the Coronavirus is constantly evolving, and new variants often go unnoticed or unnamed. In contrast, others raise alarms, either because they are becoming more common or because their genomes appear ominous.

As Mu spread through Colombia, both were true. “There were a couple of mutations that people had been watching very closely,” said Mary Petrone, a genomic epidemiologist at the University of Sydney and an author of the new Mu paper. Other immune-evasive variants, including Beta and Gamma, have also been documented to have mutations in their spike protein.

A new study, which has not yet been published in a scientific journal, compared Mu’s biological characteristics to those of Alpha, Beta, Delta, Gamma, and the original virus. While Mu did not replicate faster than any other variant, Doctor said, it was the most immune-evasive of the bunch.

Researchers reconstructed the variant’s spread by analyzing genomic sequences of Mu samples collected around the world. Their conclusion was that Mu likely emerged in South America by the middle of 2020. After that, it circulated for months before being detected.

Jesse Bloom, an expert in viral evolution at the Fred Hutchinson Cancer Research Center in Seattle, said South American genomic surveillance was “patchy and incomplete.” Perhaps it would have been easier to determine how worried to be about Mu if there had been better surveillance in those regions.

Mu presented another challenge as well. The coronavirus sample exhibited a rare mutation known as a frameshift mutation. GISAID, an international repository of viral genomes used to keep track of new variants, flagged such mutations as errors when scientists, including Doctor, uploaded their Mu sequences.

Due to that complication, the public sharing of Mu sequences was delayed. A viral sample was collected from a patient and made public on GISAID consistently longer for Mu cases than for Delta cases, the researchers found.

According to Doctor, the genome itself created artificial surveillance gaps. “At least in our experience, it resulted in us not getting data out for weeks when usually we try to get it out in days.”

(GISAID’s quality-control systems are crucial, the researchers noted, and the repository has corrected the issue.)

As a result of these surveillance gaps and Mu’s immune evasiveness, the variant was poised to take off. However, that wasn’t the case. Scientists found that Mu spread from South and Central America to other continents but didn’t circulate widely once it reached them. Doctor noted that this variant was not as fit in the North American and European populations as expected.

Probably because Mu was competing with a variant even more formidable than it: Delta. Delta was not as adept at dodging antibodies as Mu, but it was more transmissible. Doctor explained that Delta spread more widely in the end.

Right variant, right time

The study of successful variants tells only half the story. According to Doctor, nondominant variants are in a sense negative controls. In doing so, they fill in knowledge gaps about variant fitness by telling us what didn’t work.”

In addition to Mu, Delta also surpassed Beta, Gamma, and Lambda as immune-evasive variants. Immune evasion alone wasn’t enough to allow a variant to outperform a highly transmissible virus in the early phases of the pandemic.

Vaccinations and multiple waves of infection have changed the immune landscape, however. Scientists believe Omicron’s success is due in part to a highly immune-evasive variant.

In New York City, immune-evasive Gamma tended to do better in neighborhoods with higher levels of preexisting immunity, possibly because they were hit hard by the first Covid wave. It is impossible to view a new variant in a vacuum, because it arises in the shadow of all the variants that preceded it, said Doctor.

As the clash of variants past demonstrates, success depends heavily on context. New York City may have been the birthplace of the Iota variant, first detected in virus samples collected in November 2020. In this way, it got a foothold early on, according to Doctor. Despite the arrival of the more transmissible Alpha variant, Iota remained the city’s dominant variant for months.

In Connecticut, however, where Iota and Alpha both appeared in January 2021, things unfolded differently. According to Doctor, who led a study of variants in the two regions, Alpha took off immediately.

Omicron’s multiple lineages are already beginning to follow a similar pattern. While BA.2.12.1, a subvariant first identified in New York, is taking off in the United States, BA.4 and BA.5 are gaining traction in South Africa.

This is another reason to study waning variants, said Sarah Otto, an evolutionary biologist at the University of British Columbia. It is possible for a variant that was poorly matched for one place and time to take off in another. Mu’s misfortune might have simply been that it emerged too soon. According to Doctor, there might not have been enough people with immunity to boost that variant.

She said the next variant of concern could be a descendant of, or something similar to, an immune-evasive lineage.

Taking a look back at previous variants can also provide insight into what worked and what didn’t. As the new Gamma study shows, international travel bans, at least as implemented in the United States, are unlikely to prevent the spread of a variant worldwide.

Brazil was the first country to identify Gamma in late 2020. In May of that year, the United States prohibited most non-Americans from entering the country from Brazil, a restriction that lasted until November 2021. Yet Gamma was detected in the United States in January 2021 and soon spread to dozens of states.

Tetyana Vasylyeva, a molecular epidemiologist at the University of California San Diego and one of the study’s authors, said studying Gamma’s spread provided a more accurate picture of the effectiveness of travel bans. When it comes to studying variants like Delta, which has caused a major outbreak everywhere, it can be difficult to find patterns because it occurs on such a large scale and so quickly,” she explained.

Doctor said that in a global health emergency with a virus that changes rapidly, it is understandable to focus on the future. He and his colleagues discussed whether to continue studying Mu as the world’s attention turned to Delta and then Omicron.

We asked ourselves, ‘Does anyone care about Mu anymore?’” recalled Doctor. There is still room for high-quality studies that ask questions about previous variants and look back at what happened.”

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