Among the 100 million people worldwide who have fought coronavirus infections, scientists are turning to the case of a 45-year-old COVID-19 patient in Boston to understand how the virus is able to trick humans.
During his 154-day illness – one of the longest on record – the patient’s body became a melting pot of rampant viral mutation. He offered the world one of the first sightings of a key mutation in the virus’s spike protein, which set off the alarm when it was later found in strains in the United Kingdom, South Africa and Brazil.
In the UK strain, the genetic change known as N501Y is believed to help increase the transmissibility of the virus by about 50%. In the South African strain, it can reduce the effectiveness of COVID-19 vaccines and treatments. Tests of its effect on the Brazil variant are still ongoing.
The Boston patient is now being seen as an important herald of the coronavirus’ ability to produce new and more dangerous versions of itself. Although he died in the summer, the medical file he left behind is helping experts to anticipate the emergence of new strains, focusing on the role of a growing population of immune-compromised patients battling the virus for months.
Among COVID-19’s most ill patients, this population of “long haulers” appears to play a key role in the incubation of new variants of the coronavirus, some of which can change the path of the pandemic.
The mutations that emerged from this single patient are “a microcosm of the viral evolution that we are seeing globally,” said Dr. Jonathan Z. Li, an infectious disease specialist at Brigham and Women’s Hospital in Boston who treated him. “He showed us what can happen” when a germ with a talent for genetic change in shape stumbles under conditions that reward him for it.
In fact, situations in which patients fail to eliminate a viral infection are “the worst possible scenario for the development of mutations,” said Dr. Bruce Walker, an immunologist and founding director of the Ragon Institute in Boston.
As weeks of illness turn into months, a virus copies itself millions of times. Each copy is an opportunity to make random mistakes. As it triggers new mutations, the virus can target those that help you resist drugs, evade your immune system and come back stronger.
SARS-CoV-2, the coronavirus that causes COVID-19, is an unpredictable adversary. The chance to witness its transformation in near real time and see where and how it mutates in a single host can guide the design of vaccines and drugs that will not lose their effectiveness over time, Walker said.
COVID-19 patients were just beginning to occupy the beds at Brigham and Women’s Hospital in the spring of 2020, when the Boston patient was first admitted. He had fever, nausea and a “frosted glass” lung scan of the new disease, said Li, who was part of a team that detailed the man’s case in the New England Journal of Medicine.
But COVID-19 was just one of its challenges. For 22 years, he suffered from a rare disease called antiphospholipid syndrome, which caused his immune system to attack his own organs and generate dangerous blood clots throughout his body.
To prevent his dishonest immune system from killing him, the patient needed an arsenal of immunosuppressive drugs. But in their fight against the coronavirus, these drugs kept the patient’s punch arm strapped to his back.
The Boston patient tested positive for SARS-CoV2 infections four separate times over 22 weeks. He was admitted to the hospital six times, including stints in intensive care. Doctors treated him with three courses of the antiviral drug remdesivir and once with Regeneron’s experimental monoclonal antibody cocktail.
Swabs removed from his nose and throat during his second hospital stay provided the first indication of the surprising rate of genetic transformation of the virus: compared to a sample collected during his first hospitalization, 11 letters in the sequence of 30,000 letters of the coronavirus were inverted and nine such nucleotides were eliminated.
His next trip to the hospital took him to the ICU. Tests revealed that another 10 letters in the virus’ genetic code changed and another one was deleted in a period of just five weeks. Three weeks later, after appearing to be recovering, the test came back positive and was placed on a mechanical ventilator to help him breathe. This time, the researchers found 11 more letter changes and 24 more exclusions in the virus genome.
Scientists were unable to say whether the Boston patient was unable to kick the virus or whether it was changing so completely that his immune system could not recognize it.
One thing was clear: more than half of the changes occurred in a section of the genetic code that dictates the structure of the virus’s spike protein, the lump that clings to human cells and initiates an infection. The virus’ “receptor-binding domain” – essentially the key that opens the lock on a human cell – accounts for only 2% of the virus’s genetic code. But 38% of the mutations generated during the Boston patient’s prolonged illness were concentrated only in that location.
In late December, British scientists speculated that just such a scenario involving an immunocompromised patient somewhere in England may have spawned the mutations that distinguish the strain from the UK.
Walker said he feared there would be many more patients of this type, including people with untreated HIV infections. Immunocompromised by HIV, patients with COVID-19 and receiving drugs that reward SARS-CoV-2 for developing “escape” mutations, these people can become crucibles of viral mutation.
South African scientists share this anxiety.
“In South Africa, the country with the largest HIV epidemic in the world, a concern has been prolonged viral replication and intra-host evolution in the context of HIV infection,” wrote the authors of a preliminary study that alerted the world for the new variant in early December.
To date, there is no evidence that HIV patients are more likely to have long-term COVID-19 cases. And even if they were, a long chain of immunocompromised patients probably would have been needed to generate the countless mutations that distinguish the strain from South Africa, their discoverers said.
Scientists are still trying to understand how certain mutations like the N501Y emerged in so many places at once. Has the growing scale of the pandemic given the virus many opportunities to change? Or are these mutations appearing in a small number of people, like the Boston patient, and somehow hitchhiking around the world?
Both factors are likely to be at work, and the longer and more intense the pandemic, the more likely the virus is to develop random mutations.
The Boston patient shows why this can be so dangerous. In his case, the snippets of the genetic code that were most likely to alter the affected structures that the COVID-19 vaccines and drugs were designed to recognize. Now, there is evidence that the changes may undermine the value of these drugs.
Tulio de Oliveira, an infectious disease researcher at the University of KwaZulu-Natal in South Africa, sees a pattern in which uncontrolled spread and long-distance infections work together to fuel coronavirus mutations.
Many of the places where new variants have been identified – including South Africa, Britain and California – have experienced two waves of outbreaks spread over just a few months. This, De Oliveira suspects, is no coincidence.
In the first wave, he said, the proliferation of infections gives the virus ample opportunity to take on genetic changes that can remain in the bodies of immunocompromised patients. As a second wave begins, new variants that were incubating on these long-haul trucks also began to circulate. When they encounter a large number of new hosts, the result is a fertile environment for the strains to establish themselves – if their genetic modifications confer some advantage.
The best way to prevent further mutations from occurring is to expand vaccinations and do more to protect people with compromised immune systems, said Oliveira.
“If we keep the virus for a long time, we will be giving it more opportunities to overcome us,” he said.
This story originally appeared in the Los Angeles Times.