As omicron subvariant BA.5 continues to drive the coronavirus’ spread in the United States, I’ve been thinking about what could come next. Omicron and its offshoots have been topping the variant charts since last winter. Before that, delta reigned.
Scientists have a few ideas for how new variants emerge. One involves people with persistent infections — people who test positive for the virus over a prolonged period of time. I’m going to 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 roil away uncontrolled.
That lengthy infection first came onto epidemiologist Nathan Grubaugh’s radar in the summer of 2021. His team had been analyzing coronavirus strains in patient samples from Yale New Haven Hospital when Grubaugh spotted 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 rampaged through communities quite like its infamous relatives.
Instead, after springing up somewhere in North America in early 2020, B.1.517 tooled around in a handful of regions around the world, even sparking an outbreak in Australia. But after April 2021, B.1.517 seemed to sputter, one of the who-knows-how-many viral lineages that flare up and then eventually fizzle.
B.1.517 might have been long forgotten, shouldered aside by the latest variant to stake a claim in local communities. “And yet we were still seeing it,” Grubaugh says. Even after B.1.517 had petered out across the country, his team noticed it cropping up in patient samples. The same lineage, every few weeks, like clockwork, for months.
One clue was the samples’ specimen ID. The code on the B.1.517 samples was always the same, Grubaugh’s team noticed. They had all come from a single patient.
That patient, a person in their 60s with a history of cancer, relapsed in November of 2020. That was right around when they 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 the patient’s permission to analyze their data.
Ultimately, the patient has remained infected for 471 days (and counting), Grubaugh, Yale postdoctoral researcher Chrispin Chaguza and their team reported last month in a preliminary study posted at medRxiv.org. Because of deteriorating health and a desire to maintain their anonymity, the patient was not willing to be interviewed, and Grubaugh has no direct contact with them.
But all those samples collected over all those days told an incredible tale of viral evolution. Over about 15 months, at least three genetically distinct versions of the virus had rapidly evolved inside the patient, the team’s analyses suggested.
Each version had dozens of mutations and seemed to coexist in the patient’s body. “Honestly, if any one of these were to emerge in a population and begin transmitting, we would be calling it a new variant,” Grubaugh says.
That scenario is probably rare, he says. After all, lots of prolonged infections have likely occurred during the pandemic, and only a handful of concerning variants have emerged. But the work does suggest that persistent viral infections can provide a playground for speedy evolutionary experimentation — 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 with the work.
The study supports an earlier finding about a different immunocompromised patient — one with a persistent omicron infection. In that work, researchers documented the evolution of the virus over 12 weeks and showed that its descendant infected at least five other people.
Together, the studies lay out how such infections could potentially drive the emergence of the next omicron.
“I am pretty well convinced that people with persistent infection are important sources of new variants,” Friedrich says.
Who exactly develops these infections remains mysterious. Yes, the virus can pummel 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 really have the numbers,” Simon says. That’s a huge gap for researchers, and something Mount Sinai’s Pathogen Surveillance Program is trying to address by analyzing real-time infection data.
Studying patients with prolonged infections could also tell scientists where SARS-CoV-2 evolution is heading, Friedrich says. Just because the virus evolves within a person doesn’t mean it will spread to other people. But if certain viral mutations tend to arise in multiple 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 forecast what’s to come, an important step in designing future coronavirus vaccine boosters.
Beyond viral forecasting, Grubaugh says identifying people with prolonged infections is important so doctors can provide care. “We need to give them access to vaccines, monoclonal antibodies and antiviral drugs,” he says. Those treatments could help patients clear their infections.
But identifying persistent infections is easier said than done, he points out. Many places in the world aren’t set up to spot these infections and don’t have access to vaccines or treatments. And even when these are available, some patients opt out. The patient in Grubaugh’s study received a monoclonal antibody infusion about 100 days into their infection, then refused all other treatments. They have not been vaccinated.
Though the patient remained infectious over the course of the study, their variants never spread to the community, as far as Grubaugh knows.
And while untreated chronic infections might spawn new variants, they could emerge in other ways, too, like from animals infected with the virus, from person-to-person transmission in groups of people scientists haven’t been monitoring, or from “something else that maybe none of us has thought of yet,” he says. “SARS-CoV-2 has continued to surprise us with its evolution.”