When the pandemic virus emerged a year ago, one refrain from scientists provided reassurance: It’s not mutating so quickly—the pathogen looks pretty stable. But recent news from the UK suggests that SARS-CoV-2 might be more of a moving target than we thought. Sequencing data from that nation described in a research manuscript posted online but not yet formally published in a scientific journal suggests that a widespread variant of the virus accumulated 17 new mutations in a short time span. Now virologists are scrambling to figure out whether these mutations render the virus more transmissible, a possibility that has already led 40 nations to implement travel restrictions against the UK.
The emergence of this worrying variant comes at a pivotal moment in the course of the pandemic: Public health officials are just now trying to decide who should be prioritized to receive the first Covid-19 vaccines approved for distribution in the US. Reports that so many mutations have arisen all at once in the new coronavirus—and that these mutations could have epidemiological consequences—add an important, but so far unappreciated, wrinkle to these deliberations. The pathogen likely has more opportunity to develop mutations in immunocompromised individuals than in other carriers. As a result, to guard against the emergence of new and more dangerous variants of SARS-CoV-2, we should consider moving immunocompromised people—who are themselves at higher risk of dying from Covid-19—closer to the front of the vaccination line.
Scientists are still puzzling over how the streak of new mutations arose in the UK variant. It could just be a fluke of how the virus has been tracked, where they somehow missed a gradual accumulation of changes as it passed from person to person through the population. But the abruptness with which the suite of new mutations cropped up has left researchers worried that all or most of the changes developed in a single person. When an active infection lingers in someone’s body, an arms race may develop between the virus and the immune system. Over time, mutations that allow the virus to evade successive waves of defenses such as antibodies could stack up; and the longer an infection lasts in a person, the more opportunities the virus has to add such variants.
Since early in the pandemic, doctors have suspected that people who are immunocompromised are particularly prone to just that kind of extended illness. Most people with Covid-19 are thought to stop shedding infectious virus after around 10 days from the time they were infected, but numerous outlier cases have been identified. These tend to involve people with weakened immune systems. A 71-year-old woman who became infected with the virus at a Washington nursing home in February, and who had a kind of cancer that limited her antibody production, ended up harboring the coronavirus for at least 105 days and being infectious for at least 70.
Could the virus mutate rapidly under such conditions? It’s certainly pretty stable over the course of a normal, shorter bout of Covid. A study posted online, which has not yet been formally reviewed and published in a journal, found very little viral mutation occurring in a general sampling of more than 1,000 people with the disease. At the same time, studies that have closely followed immunocompromised individuals have been less reassuring. Michigan researchers followed a 60-year-old man with cancer who was on medication to suppress his immune system’s B cells, which normally produce antibodies. Over the four months that they tracked him, the researchers found that SARS-CoV-2’s spike protein, which is the principal target of Covid vaccines, remained unchanged. However they did observe other mutations that popped up elsewhere in the virus, unrelated to the spike protein.
Meanwhile, scientists who studied the immunocompromised woman from the Washington nursing home “observed marked within-host genomic evolution of SARS-CoV-2 with continuous turnover of dominant viral variants.” In other words, the virus was definitely evolving variants—including those with changes to the spike protein sequence—during the course of her infection.
Another group, writing in The New England Journal of Medicine earlier this month, detailed the trajectory of the virus in a 45-year-old man with an autoimmune disorder for which he was receiving immunosuppressants. In this case they found there was “accelerated” evolution of the virus in the individual, and many of the mutations were in the spike protein. Most immunocompromised people clear SARS-CoV-2 infections without major complications, they wrote, but “this case highlights the potential for persistent infection and accelerated viral evolution associated with an immunocompromised state.”
The same phenomenon has been observed in other conditions where the immune system is hampered. HIV attacks immune function, which allows it to evolve at an astoundingly high rate, making it even harder for the body to keep producing antibodies that bind and neutralize the virus. By the same mechanism, HIV infections allow other viruses in the individual to last longer and morph. Herpes simplex virus can evolve unusual drug-resistance in AIDS patients, for example.
Still, we need a better understanding of exactly which immunocompromised patients are most vulnerable to long-lasting SARS-CoV-2 infection. The category of "immunocompromised" captures such a wide range of different conditions, and they may not all confer the same risk of persistent Covid-19. Brian Wasik, a virologist at Cornell University, points out that the term may include people born with rare disorders that diminish their ability to fight off pathogens, as well as those who are taking immunosuppressants to allow for a transplant or quell an autoimmune disease.
Evidence for the links between immunocompromised individuals and persistent SARS-CoV-2 infections, and between persistent infections and viral evolution, is compelling enough to be considered in discussions about vaccine priority. On Sunday, a panel from the US Centers for Disease Control and Prevention recommended that immunocompromised people be placed in “Phase 1c”—the third wave—of vaccine rollout. That means they’re due to receive the injections at the same time as those with cancer, coronary heart disease, or obesity, among other conditions. That decision was meant to address the particular risks posed by Covid-19 to people with immune system issues, but it left out the possibility that vaccinating these individuals could help prevent the development of new SARS-CoV-2 variants that would make this pandemic even worse than it already is. For that reason, even though there are only a handful of directly relevant case reports, public health officials should consult with virologists about whether it might be wise to move immunocompromised people into the earlier Phase 1b group.
At the very least, we need better monitoring of potential changes to SARS-CoV-2. The US government should do more to help organize viral sequencing efforts. The CDC has a program nicknamed Spheres that has tried to capture sequence data during the pandemic, but it’s falling short: Where the UK has sequenced an estimated 10 percent of its Covid-19 cases, the US has only managed 0.3 percent. “It’s a little bit patchy,” says Adam Lauring of the University of Michigan Medical School, who adds that his team has uploaded around 2 percent of the sequence variant data in the US. “There are vast swaths of the country where there aren’t people who are spending a lot of time and effort” on this task. Better monitoring of viral evolution might also help to clarify the question of exactly where—in which sick people—these changes are most likely to accumulate.
As we monitor for SARS-CoV-2 mutations, we have to acknowledge that understanding their epidemiological and clinical significance requires further work. Meanwhile, the virus is still rampant, which provides more opportunities for it to mutate even as it spreads from person to person. But the long-lasting infections in some immunocompromised individuals, and the associated potential for viral evolution, should be a focus of attention.
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