Concerning SARS-CoV-2 variants emerging from chronic COVID infections, study finds

Concerning coronavirus variants emerge from chronic, long-term COVID infections in people who may be immune and unable to clear the virus, a new study strongly suggests. Frontiers in virology published the findings of scientists from Emory University and the University of Oxford.

“Rather than evolving from chains of transmission of acute COVID infections in hundreds of millions of people, our results show that the variants of concern come from rare cases where someone may have an active infection for months, says Daniel Weissman, a corresponding author and Emory professor of biology and physics specializing in the quantitative theory of evolution.

A key take-home message is that it is important to find those people who are chronically infected and provide them with support to recover. In many cases, they may be asymptomatic and not even realize they are infected with COVID despite actively shedding the virus.”

Mahan Ghafari, first author of the article and postdoctoral researcher, University of Oxford

Ghafari graduated from Emory in 2018 with a master’s degree in physics.

Other authors of the paper include Aris Katzourakis, professor of evolution and genomics at the University of Oxford; Qihan Liu, an Emory graduate student in physics; and Emory undergraduate Arushi Dhillon.

Viruses like SARS-CoV-2 are constantly evolving due to occasional mutations in the genetic code that can occur during their replication. “When a virus copies itself, it doesn’t always make perfect copies,” says Weissman.

Usually, such random mutations do not benefit the virus or cause concern for scientists who monitor these changes. Sometimes, however, mutations result in a variant of the virus that can make it more transmissible, harder to detect and treat, and even more deadly.

The World Health Organization defines a concerning variant of SARS-CoV-2 as one that is more likely to cause infections, even in vaccinated people or in those who have already been infected.

“In the early months of the pandemic, it didn’t look like the coronavirus was going to adapt to a worrying variant,” Weissman says. “But then, boom, boom, boom! Not only did the coronavirus evolve into a VOC, but it did so three times in a row at the end of 2020.”

The World Health Organization dubbed these first three variants of concern alpha, beta, and gamma.

Why did these three VOCs appear around the same time and apparently in three distant regions of the world?

Another mystery was why large clusters of mutations occurred in VOCs. “A key thing that distinguishes these COVs from other virus lineages that were circulating is that each of them has a very high number of mutations,” Ghafari notes. “That’s a major point of distinction in terms of evolution.”

At least some of the COV mutations had been detected in chronic cases of COVID, leading to the hypothesis that these long-term cases could be the source of the COVs. The other leading theory was that COVs emerged from sustained transmission of acute infections in areas of the world with poor genomic surveillance of the virus.

Ghafari, Weissman and their collaborators were among the first teams to methodically test these theories surrounding the emergence of alpha, beta and gamma VOCs.

The researchers built a mechanistic and theoretical model to study the problem, using existing data and software they developed. The resulting model rules out the theory that VOCs originated from sustained transmission of acute infections and fully supports the theory that each variant evolved in a single chronically infected individual.

The model shows how multiple mutations were required, each of which may have been neutral or slightly advantageous for viral fitness. In this way, a variant eventually acquires a constellation of mutations that allow it to become more transmissible.

Although the current paper relies on data for alpha, beta, and gamma variants, the resulting theoretical model also explains the subsequent independent emergence of delta and omicron VOCs. Delta appeared in India at the end of 2020, quickly sweeping this country and spreading around the world. Delta subsided after the emergence of omicron, which is not a descendant of the delta variant, in South Africa in late 2021. Omicron quickly became the dominant global VOC.

The researchers have made their model and software available to the public for others to study the evolution of SARS-CoV-2 variants.

“Ideally, we would like to be able to eventually quantify when new variants might emerge in the future,” Weissman said. “This has huge implications from a public health perspective.”

Studies have shown that some immunocompromised people, such as those taking medication for other chronic conditions, have had active COVID infections for a year or even longer. Identifying these people, the researchers point out, is critical not only to help them seek treatment for COVID, but also to perform genomic surveillance of the SARS-CoV-2 viruses they carry.

“Who knows which variant might boil up next in a chronically infected individual?” said Ghafari. “Our study shows that from an evolutionary perspective, we can expect something completely different from previous COVs. If we want to stay ahead of this virus, we need to more actively identify and monitor those affected chronic infections.”

The work was funded by the National Science Foundation, the Simons Foundation, the Sloan Foundation, the Biotechnology and Biological Science Research Council and the European Research Council.


Journal reference:

Ghafari, M. et al. (2022) Investigating the evolutionary origins of the first three SARS-CoV-2 variants of concern. Frontiers in virology.

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