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

As the omicron 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 affiliates have been at the top of the variant rankings since last winter. Before that, the delta reigned supreme.

Scientists have some ideas about how new variants appear. One involves people with persistent infections — people who test positive for the virus over a long 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.

That long-running infection first came onto epidemiologist Nathan Grubaugh’s radar in the summer of 2021. His team had been analyzing strains of the coronavirus in patient samples from Yale New Haven Hospital when Grubaugh noticed something he had seen before. Known only as B.1.517, this version of the virus never got a name like delta or omicron, nor did it rage through communities like its infamous relatives.

Instead, after appearing somewhere in North America in early 2020, B.1.517 was used in 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 lines that ignite and then burn.

B.1.517 could have been long forgotten, set aside by the latest variant to stake a claim on local communities. “And yet we were still seeing it,” Grubaugh says. Even after B.1.517 had spread across the country, his team noticed it showing up in patient samples. The same descent, every few weeks, like clockwork, for months.

One clue was the sample ID of the sample. The code in the B.1.517 samples was always the same, Grubaugh’s team noted. All had come from a single patient.

That patient, a man in his 60s with a history of cancer, returned in November 2020. That’s when they tested positive for SARS-CoV-2. After seeing B.1.517 show up consistently in their samples, Grubaugh worked with a clinician to get the patient’s permission to analyze their data.

Ultimately, the patient remained infected for 471 days (and counting), Grubaugh, Yale postdoctoral researcher Chrispin Chaguza and their team reported last month in a preliminary study posted on medRxiv.org. Due to declining health and a desire to maintain anonymity, the patient was unwilling to be interviewed, and Grubaugh has no direct contact with them.

But all those samples collected over all those days told an incredible story of viral evolution. Over the course of about 15 months, at least three genetically distinct versions of the virus had rapidly evolved within the patient, the team’s analysis suggested.

Each version had dozens of mutations and appeared to coexist in the patient’s body. “Honestly, if any of these showed up in a population and started to transmit, we would call it a new variant,” Grubaugh says.

This scenario is probably rare, he says. After all, many protracted infections likely occurred during the pandemic and only a small fraction of worrisome variants emerged. But the work suggests that persistent viral infections could provide a playground for rapid evolutionary experiments — perhaps taking advantage of weakened immune systems.

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

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

Together, the studies determine how such infections can potentially drive the emergence of the next omicron.

“I am very convinced that people with persistent infection are important sources of new variants,” says Friedrich.

Who exactly develops these infections remains mysterious. Yes, the virus can strike people with weakened immune systems, but “not every immune-compromised person develops a persistent infection,” says Viviana Simon, a virologist at the Icahn School of Medicine at Mount Sinai, who worked on the study. of omicron infection.

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

Studying patients with prolonged infections can also tell scientists where SARS-CoV-2 evolution is going, Friedrich says. Just because the virus evolves within a person does not mean it will spread to other people. But if certain viral mutations tend to show up in many people with persistent infections, that could hint that the next big variant might evolve 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.

Beyond viral forecasting, Grubaugh says identifying people with lingering infections is important so doctors can 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 countries in the world are not designed to detect these infections and do not have access to vaccines or treatments. And even when these are available, some patients withdraw. The patient in Grubaugh’s study received an infusion of monoclonal antibodies about 100 days after their infection, then refused all other treatments. They are not vaccinated.

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

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

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