A 471-day-old case of COVID-19 reveals how the coronavirus mutates

As omicron’s BA.5 subvariant continues to fuel the spread of the coronavirus in the United States, I’ve been thinking about what might come next. Omicron and its offshoots have topped the variant charts since last winter. Before that, the delta reigned supreme.

Scientists have several ideas about how new variants emerge. One involves people with persistent infections – people who have tested positive for the virus for an extended period of time. I will tell you about the curious case of a person infected with SARS-CoV-2 for at least 471 days and what can happen when infections go unchecked.

This lingering infection first caught the radar of epidemiologist Nathan Grubo in the summer of 2021. His team was analyzing coronavirus strains in patient samples from Yale New Haven Hospital when Grubo noticed something he had seen before. Known only as B.1.517, this version of the virus was never given a name like delta or omicron, nor did it run rampant through communities like its infamous relatives.

Instead, after emerging somewhere in North America in early 2020, B.1.517 spread to a handful of regions around the world, even causing an outbreak in Australia. But after April 2021, B.1.517 seemed to sputter, one of who-knows-how-many viral lineages that flare up and then eventually fizzle out.

B.1.517 may have been long forgotten, abandoned by the latest option for staking claims in local communities. “And yet we were still seeing it,” says Grubo. Even after B.1.517 disappeared across the country, his team noticed it showing up in patient samples. The same line, every few weeks, like clockwork, for months.

One clue was the identification number of the samples. The B.1.517 sample code was always the same, Grubaugh’s team noticed. All were from one patient.

This patient, a man in his 60s with a history of cancer, relapsed in November 2020. This was right around the time he first tested positive for SARS-CoV-2. After seeing B.1.517 show up again and again in their samples, Grubaugh worked with a clinician to get permission from the patient to analyze their data.

Ultimately, the patient remained infectious for 471 days (and growing), Grubaugh, postdoctoral researcher Crispin Chaguza and their team reported last month in a preliminary study published on medRxiv.org. Due to ill health and a desire to remain anonymous, the patient did not wish to be interviewed and Grubo has no direct contact with them.

But all those samples collected over all those days told an incredible story about the evolution of the virus. Over about 15 months, at least three genetically different versions of the virus evolved rapidly in the patient, the team’s analysis showed.

Each version had dozens of mutations and seemed to coexist in the patient’s body. “Honestly, if one of these shows up in a population and starts to be transmitted, we’ll call it a new variant,” Grubo says.

That scenario is probably rare, he says. After all, many long-lasting infections likely occurred during the pandemic, and only a few worrisome variants emerged. But the work suggests that persistent viral infections may provide a platform for rapid evolutionary experiments—perhaps by taking advantage of weakened immune systems.

Grubaugh’s work is “probably the most detailed look we’ve had at a single, persistent SARS-CoV-2 infection to date,” said Tom Friedrich, a virologist at the University of Wisconsin-Madison who was not involved in the work.

The study supports an earlier finding in a different immunocompromised patient – ​​one with persistent omicron infection. In this work, the researchers documented the evolution of the virus over 12 weeks and showed that its offspring infected at least five other people.

Together, the studies lay out how such infections could potentially stimulate the emergence of the next omicron.

“I’m quite convinced that people with persistent infection are important sources of new variants,” says Friedrich.

Exactly who develops these infections remains a mystery. Yes, the virus can wipe out people with weakened immune systems, but “not every immunocompromised person develops a persistent infection,” says Viviana Simon, a virologist at the Icahn School of Medicine at Mount Sinai who worked on the Omicron infection study.

In fact, doctors and scientists have no idea how common these infections are. “We just don’t have the numbers,” says Simon. That’s a huge gap for researchers, and one that Mount Sinai’s Pathogen Surveillance Program is trying to overcome by analyzing real-time infection data.

Examining patients with long-term infections can also tell scientists where the evolution of SARS-CoV-2 is going, Friedrich says. Just because a virus evolves in a person doesn’t mean it will spread to other people. But if certain viral mutations tend to show up in multiple people with persistent infections, it could suggest that the next big variant could develop in a similar way. Knowing more about these mutation patterns could help researchers predict what’s to come, an important step in designing future coronavirus vaccine boosters.

In addition to predicting viruses, Grubaugh says identifying people with lingering infections is important for doctors to provide care. “We need to give them access to vaccines, monoclonal antibodies and antiviral drugs,” he says. These treatments can help patients clear their infections.

But identifying persistent infections is easier said than done, he points out. Many places in the world are not set up to detect these infections and do not have access to vaccines or treatments. And even when they are available, some patients refuse. The patient in Grubaugh’s study received an infusion of a monoclonal antibody about 100 days after infection, then refused all other treatments. They are not vaccinated.

Although the patient remained infectious throughout the study, their variants never spread in the community, as far as Grubaugh knows.

And while untreated chronic infections can give rise to new variants, they can also emerge in other ways, such as from animals infected with the virus, from person-to-person transmission to groups of people that scientists haven’t observed, or from ” something else that maybe none of us have thought of yet,” he says. “SARS-CoV-2 continues to surprise us with its evolution.”

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