The Mutating Nature of COVID-19: A Surprising Twist
In the early days of the COVID-19 pandemic, scientists offered a reassuring message: the SARS-CoV-2 virus mutates relatively slowly. This led to the belief that the virus would not evolve into a more dangerous form quickly and that vaccines would provide long-lasting protection. However, reality had other plans. The virus began to mutate rapidly, first becoming more transmissible and later evading human immunity, leading to breakthrough infections and reinfections. Five years later, with a flurry of alphabetically named variants, most people have contracted COVID-19 at least once. Vaccines are still being updated to keep up with new variants, and the virus continues to evolve.
Scientists were both right and wrong about the virus’s mutation rate. While the virus does not mutate especially quickly as it spreads from person to person, they overlooked a critical factor: when SARS-CoV-2 infects an immunocompromised patient, it can linger for months, accumulating mutations at an accelerated pace. If such a highly mutated virus spreads to others, it can have significant consequences. This is likely how the Omicron variant emerged in late 2021, boasting over 50 mutations in a remarkably short period. Omicron’s mutations allowed it to infect even vaccinated individuals, causing a massive wave of infections.
Chronic Infections and the Rise of Variants
Researchers now believe that immunocompromised patients with chronic COVID-19 infections are key drivers of new variants, including Omicron. Even as the urgency of COVID-19 surveillance has diminished, scientists are closely monitoring these chronic infections for clues about future variants.
The connection between chronic infections and mutant variants became clearer early in the pandemic. In 2020, researchers in New York, including geneticist Harm van Bakel, studied cancer patients with prolonged COVID-19 infections. These patients remained positive for up to two months because their weakened immune systems, compromised by cancer treatments, could not clear the virus. A December 2020 study suggested that immunocompromised patients might need extended isolation periods to prevent spreading the virus.
Around the same time, a UK-based study led by Ravindra Gupta found that an immunocompromised patient with a lingering infection developed curious new mutations after receiving antibody treatments from COVID survivors. These mutations gave the virus a slight advantage in evading antibodies and infecting cells. The study proposed that immunocompromised hosts provide an ideal environment for viral evolution: their weakened immune systems cannot eliminate the virus entirely, but they apply enough pressure for the virus to adapt and acquire new tricks.
While the virus from that patient likely did not spread widely, similar chronic infections worldwide could lead to the same battle-tested mutations appearing in different parts of the globe. For example, mutations observed in the UK patient later appeared in variants like Alpha and Omicron, which spread globally. In 2021, multiple concerning variants were found to carry mutations first identified in immunocompromised patients in New York early in the pandemic.
The Evolutionary Patterns of Chronic Infections
None of the most notorious COVID-19 variants have been directly traced to a single immunocompromised patient. However, indirect evidence strongly suggests that many variants emerge from chronic infections. These infections produce a distinct pattern of mutations: an overabundance of changes in the spike protein, which the virus uses to penetrate human cells, but relatively few changes elsewhere. This pattern is evident in Omicron subvariants BA.1 and BA.2, as well as the variant responsible for the JN.1 surge last winter.
Jesse Bloom, a viral evolution expert at the Fred Hutchinson Cancer Center, says he now has “very high confidence” that these variants originated from chronic infections. While the evidence for other variants is less clear, it is possible they evolved similarly.
A Glimpse into the Future of COVID-19
Long before the COVID-19 pandemic, Bloom studied the evolution of influenza viruses in immunocompromised patients. He found that mutations in these patients could predict future changes in seasonal flu. This idea was groundbreaking at the time, but it has since become highly relevant for understanding SARS-CoV-2.
Chronic COVID-19 infections are now being studied as potential harbingers of the virus’s future evolution. Viviana Simon, a microbiologist at the Icahn School of Medicine at Mount Sinai, says, “Those will actually teach us a lot about the future tricks SARS-CoV-2 will come up with.” To uncover these insights, Simon and van Bakel are leading a research project to develop better tools for sequencing viruses from chronic infections and identifying which immunocompromised patients are most at risk of harboring them. The findings from this research could serve as a preview of what the future of COVID-19 might hold.
As the pandemic continues to evolve, understanding the role of immunocompromised patients in the development of new variants is crucial for preparing for what’s to come. With ongoing research, scientists hope to anticipate the next wave of mutations and stay one step ahead of the virus.
