In early 2021, scientists in Colombia discovered a disturbing new variant of the coronavirus. This variant, eventually known as Mu, had several troubling mutations that experts believed might help it evade the immune system’s defenses.
In the following months, Mu quickly spread to Colombia, Fueling a new wave of Covid-19 cases. By the end of August, it had been detected in dozens of countries and in the World Health Organization had designated him 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 vanished. Today, the variant has almost disappeared.
For each Delta or Omicron there is a Gamma, Iota or Mu, variants that have led the local waves but have never reached global domination. 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 at San Diego. “And seeing how he has done it in the past will help us prepare for what he might do in the future.”
The also-rans studies shed light on surveillance gaps and policy errors – providing further evidence that American international travel bans were not effective – and what makes the virus effective, suggesting that in the early stages of the pandemic, the transmissibility was more important than immune evasion.
The research also highlights how important context is; variations that impact in some places never catch on in others. As a result, it is difficult to predict which variants will achieve dominance, and keeping abreast of future variants and pathogens will require comprehensive, near-real-time surveillance.
“We can gain a lot by looking at the viral genomic sequence and saying, ‘This is probably worse than another,’” said Dr. Wertheim said. “But the only way to really know is to see it spread, because there are a lot of potentially dangerous variants that have never caught on.”
Here is Mu
The coronavirus is constantly evolving and most of the new variants are never noticed or named. But others raise alarms, either because they quickly become more common or because their genomes seem threatening.
Both were true of Mu when it spread to Colombia. “It contained a couple of mutations that people had been looking at very closely,” said Mary Petrone, a genomics epidemiologist at the University of Sydney and author of Mu’s new paper. Many of the mutations in its spike protein had 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, the scientists compared the biological characteristics of Mu with 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 immune evasive of the group – more resistant to antibodies than any known variant besides Omicron, said Dr. Fauver said.
By analyzing the genomic sequences of Mu samples collected from around the world, the researchers reconstructed the spread of the variant. Those who concluded that Mu had likely surfaced in South America in mid-2020. It then circulated for months before being detected.
Genomic surveillance in many parts of South America was “incomplete and incomplete,” he said Jesse Bloom, a viral evolution expert at the Fred Hutchinson Cancer Research Center in Seattle. “If there had been better surveillance in those regions, perhaps it would have been easier to make a quicker assessment than to worry about Mu.”
Mu also presented another challenge. A type of mutation, known as a frameshift mutation, occurred which was rare in coronavirus samples. Those mutations were flagged as errors when scientists, including Dr. Fauver, tried to upload their Mu sequences to GISAIDan international repository of viral genomes used to keep tabs on new variants.
That complication created delays in the public sharing of Mu sequences. The researchers found that the time elapsed between when a virus sample was collected from a patient and when it was made publicly available on GISAID was consistently longer for Mu cases than for Delta cases.
“The genome itself was fundamentally creating artificial surveillance gaps,” said Dr. Fauver said. “The result, at least in our experience, is that we haven’t gotten any data for weeks when we normally try to get it out in a few days.”
(GISAID’s quality control systems are important, the researchers pointed out, and the repository solved the problem.)
Combine these surveillance gaps with Mu’s immune evasion 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 it got there, the scientists found. “This was an indication that this variant was not necessarily suitable perhaps for North American and European populations as we expected,” said Dr. Petrone said.
Probably because Mu found himself competing with an even more formidable variant: Delta. Delta wasn’t as good at dodging antibodies as Mu, but it was more transmissible. “So eventually Delta spread more widely,” said Dr. Bloom said.
Right variant, right time
Studying successful variants only tells half the story. “The variants that do not become dominant are, in a sense, negative controls,” says Dr. Petrone said. “They tell us what went wrong, and in doing so, they help bridge the knowledge gaps about variant fitness.”
Delta has overcome several immune variants besides Mu, including Beta, Gamma, and Lambda. This model suggests that immune evasion alone was not enough to allow a variant to pass a highly transmissible version of the virus, or at least it was not during the initial phase of the pandemic, when few people had immunity.
But vaccinations and multiple waves of infection have changed the immune landscape. An evasive highly immune variant should now have a greater advantage, the scientists said, which is likely part of why Omicron has been so successful.
Another recent study suggested that New York City evasive immune range tended to do better in neighborhoods with higher levels of pre-existing immunity, in some cases because they were hit hard by the first wave of Covid. “We can’t see a new variant in a vacuum, because it comes in the shadow of all the variants that preceded it,” said Dr. Wertheim, author of the study.
Indeed, the clash of past variants reveals that success is highly context-dependent. For example, New York City may have been the birthplace of the Iota variant, which was detected for the first time in virus samples collected in November 2020. “And so it caught on early on,” said Dr. petrolium. Even after the arrival of the more transmissible Alpha variant, Iota remained the dominant variant of the city for months, before fading away.
But in Connecticut, where Iota and Alpha both appeared in January 2021, things turned out differently. “Alpha just took off immediately and Iota didn’t stand a chance,” said Dr. Petrone, who was driving a study of the variants in the two regions.
A similar pattern is already starting to manifest with Omicron’s multiple lineages. In the United States, BA.2.12.1, a sub-variant first identified in New York, took offwhile in South Africa, BA.4 and BA.5 are leading a new wave.
This is another reason to study the variants that have decreased, said Sarah Otto, an evolutionary biologist at the University of British Columbia. A variant that is mismatched for one time and place may take hold in another. Indeed, Mu’s misfortune may have simply been that it emerged too soon. “There may not have been enough people who had immunity to really give that variant a boost,” Dr. Otto said.
But the next variant of concern could be a descendant or something similar to an immune-evasive lineage that never caught on, he said.
Looking back at previous variations can also provide insight into what worked, and didn’t, in containing them. The new Gamma study provides further evidence that international travel bansat least as far as the US has implemented them, they are unlikely to prevent a variant from spreading globally.
Gamma was first identified in Brazil in late 2020. In May of that year, the United States banned most non-U.S. citizens from traveling to the country from Brazil, a restriction that has remained in place until November 2021. Yet Gamma was detected in the United States in January 2021 and soon spread to dozens of states.
Since Gamma has never come to dominate all over the world, the study of its diffusion has provided a “cleaner” picture of the effectiveness of travel bans. said Tetyana Vasylyeva, a molecular epidemiologist at the University of California at San Diego and author of the study. “When it comes to studying variants like, say, Delta – something that has caused a major outbreak in every location – sometimes it’s really hard to find models, because it happens on a very large scale and very fast,” she said.
In an ongoing global health emergency, with a rapidly changing virus, there is an understandable urge to focus on the future, Dr. Fauver said. And as the world’s attention shifted 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 is still room for high-quality studies that ask questions about previous variants of concern and try to look back on what happened.”