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A Long Covid patient at a hospital in Poland plays a virtual reality game to test reaction skills. - BARTOSZ SIEDLIK/AFP VIA GETTY IMAGES |
Published: January 20, 2022
By: Jennifer Couzin-Frankel, Gretchen Vogel
In late 2020, Brianne Dressen began to spend hours in online communities for people with Long Covid, a chronic, disabling syndrome that can follow a bout with the virus. “For months, I just lurked there,” says Dressen, a former preschool teacher in Saratoga Springs, Utah, “reviewing post after post of symptoms that were just like my own.”
Dressen had never had COVID-19. But that November, she’d received a dose of AstraZeneca’s vaccine as a volunteer in a clinical trial. By that evening, her vision blurred and sound became distorted—“I felt like I had two seashells on my ears,” she says. Her symptoms rapidly worsened and multiplied, ultimately including heart rate fluctuations, severe muscle weakness, and what she describes as debilitating internal electric shocks.
A doctor diagnosed her with anxiety. Her husband, Brian Dressen, a chemist, began to comb the scientific literature, desperate to help his wife, a former rock climber who now spent most of her time in a darkened room, unable to brush her teeth or tolerate her young children’s touch.
As time passed, the Dressens found other people who had experienced serious, long-lasting health problems after a COVID-19 vaccine, regardless of the manufacturer. By January 2021, researchers at the National Institutes of Health (NIH) began to hear about such reports and sought to learn more, bringing Brianne Dressen and other affected people to the agency’s headquarters for testing and sometimes treatment.
The research was small in scale and drew no conclusions about whether or how vaccines may have caused rare, lasting health problems. The patients had “temporal associations” between vaccination and their faltering health, says Avindra Nath, clinical director at the National Institute of Neurological Disorders and Stroke (NINDS), who has been leading the NIH efforts. But “an etiological association? I don’t know.” In other words, he does not know whether vaccination directly caused the subsequent health problems.
NIH’s communications with patients faded by late 2021, though Nath says the work continues behind the scenes. The pullback caused bewilderment and dismay among patients who spoke with Science, who said the NIH researchers were the only ones helping them. Now, a small number of other researchers worldwide is beginning to study whether the biology of Long Covid, itself still poorly understood, overlaps with the mysterious mechanisms driving certain postvaccine side effects.
More discrete side effects connected to COVID-19 vaccines have been recognized, including a rare but severe clotting disorder that occurs after the AstraZeneca and Johnson & Johnson vaccines and heart inflammation, documented after the messenger RNA (mRNA) vaccines manufactured by Pfizer and Moderna. Probing possible side effects presents a dilemma to researchers: They risk fomenting rejection of vaccines that are generally safe, effective, and crucial to saving lives. “You have to be very careful” before tying COVID-19 vaccines to complications, Nath cautions. “You can make the wrong conclusion. … The implications are huge.” And complex and lingering symptoms like Dressen’s are even more difficult to study because patients can lack a clear diagnosis.
At the same time, understanding these problems could help those currently suffering and, if a link is nailed down, help guide the design of the next generation of vaccines and perhaps identify those at high risk for serious side effects. “We shouldn’t be averse to adverse events,” says William Murphy, an immunologist at the University of California, Davis. In November 2021 in The New England Journal of Medicine, he proposed that an autoimmune mechanism triggered by the SARS-CoV-2 spike protein might explain both Long Covid symptoms and some rare vaccine side effects, and he called for more basic research to probe possible connections. “Reassuring the public that everything is being done, researchwise, to understand the vaccines is more important than just saying everything is safe,” Murphy says. Like others, he continues to urge vaccination.
Echoes of Long Covid?
How frequently side effects like Dressen’s occur is unclear. Online communities can include many thousands of participants, but no one is publicly tracking these cases, which are variable and difficult to diagnose or even categorize. The symptoms also include fatigue, severe headaches, nerve pain, blood pressure swings, and short-term memory problems. Nath is convinced they are “extremely rare.”
Long Covid, in contrast, affects anywhere from about 5% to 30% of those infected by SARS-CoV-2. Researchers are making tentative progress with several ideas about the underlying biology. Some studies suggest the virus may in certain cases linger in tissues and cause ongoing damage. Other evidence indicates aftereffects of the original infection might play a role even after the body clears the virus.
For example, evidence from animal studies supports the idea that antibodies targeting the SARS-CoV-2 spike protein—the same protein that many vaccines use to trigger a protective immune response—might cause collateral damage, notes Harald Prüss, a neurologist at the German Center for Neurodegenerative Diseases (DZNE) and the Charité University Hospital in Berlin. In 2020, while hunting for antibody therapies for COVID-19, he and his colleagues discovered that of 18 antibodies they identified with potent effects against SARS-CoV-2, four also targeted healthy tissues in mice—a sign they could trigger autoimmune problems.
"We shouldn’t be averse to adverse events."
WILLIAM MURPHY - UNIVERSITY OF CALIFORNIA, DAVIS
Early clinical data point in a similar direction. Over the past year, research groups have detected unusually high levels of autoantibodies, which can attack the body’s own cells and tissues, in people after a SARS-CoV-2 infection. In Nature in May 2021, immunologists Aaron Ring and Akiko Iwasaki at Yale School of Medicine and their colleagues reported finding autoantibodies in acute COVID-19 patients that target the immune system and brain; they are now investigating how long the autoantibodies persist and whether they can damage tissues. This month, Cedars-Sinai Medical Center cardiologist Susan Cheng and protein chemist Justyna Fert-Bober wrote in the Journal of Translational Medicine that autoantibodies could last up to 6 months after infection, although the researchers did not correlate autoantibodies’ persistence with ongoing symptoms.
In part to understand whether these autoantibodies harm people, DZNE is checking the cerebrospinal fluid of Long Covid patients for antibodies that react to mouse brain tissue—if they do react, they might attack human neural tissues as well. In a paper Prüss and his colleagues are about to submit, they describe finding autoantibodies that attack mouse neurons and other brain cells in at least one-third of those patients. A group at Northwestern University, meanwhile, reported in an August 2021 preprint that in people with neurological complications after COVID-19, a subset of T cells is persistently activated as would happen with an ongoing SARS-CoV-2 infection, suggesting some sort of aberrant immune response or lingering virus.
Some researchers are looking at another possible culprit for Long Covid: tiny clots in the blood. In an acute SARS-CoV-2 infection, small clots can form that can damage cells that line blood vessels. Resia Pretorius, a physiologist at Stellenbosch University in South Africa, and her colleagues published preliminary evidence in August in Cardiovascular Diabetology that microscopic clots can linger after an infection clears. They might interfere with oxygen delivery, which could explain some Long Covid symptoms such as brain fog. Pretorius is now teaming up with colleagues to develop diagnostics for this microclotting and study ways to treat it in Long Covid.
Pretorius says she and her colleagues have also seen patients—fewer than 20, she estimates—with chronic problems following vaccination. She says these include Long Covid–like symptoms such as brain fog as well as other clotting concerns such as deep vein thrombosis. The cause of the very rare but severe clotting after the AstraZeneca and Johnson & Johnson vaccines remains unknown, but Pretorius suspects all COVID-19 vaccines might also sometimes trigger subtler clotting issues. She says she has preliminary evidence that vaccination can lead to microclots, although in most cases they go unnoticed and quickly disappear—an effect she and a colleague saw in their own blood and that of eight other healthy volunteers, which they sampled after their vaccinations.
A touchy topic
Long Covid research also brought the Dressens to Nath. In January 2021, Brian Dressen sought help from Nath, who had been studying Long Covid. Nath responded quickly and asked Brianne Dressen to join an ongoing study he leads on the natural history of inflammatory diseases of the nervous system.
Dozens more patients describing postvaccine complications found their way to Nath and Farinaz Safavi, an NINDS neurologist. “I promise you we will report your issue and other cases we are reviewing now,” Safavi wrote to Danice Hertz in March 2021. Hertz, a retired gastroenterologist who lives in Southern California, had developed debilitating side effects after one dose of the Pfizer vaccine. Senior officials at the U.S. Food and Drug Administration (FDA), the Centers for Disease Control and Prevention, and Pfizer, among others, were copied on the email, which Hertz shared with Science.
Over the first half of 2021, Nath and Safavi invited Brianne Dressen and others to NIH for testing and, in some cases, short-term treatment, for example with high-dose steroids or intravenous immunoglobulin (IVIG), which can quell or modulate immune responses. The patients spent at least several days undergoing neurological, cardiac, and other tests, including lumbar punctures and skin biopsies.
The NIH researchers were “trying to help people,” says a health care worker whose symptoms began after the Pfizer vaccine, one of four people in the study who spoke to Science. Nath says 34 people were enrolled on the protocol, 14 of whom spent time at NIH; the other 20 shipped their blood samples and in some cases cerebrospinal fluid.
As time passed, however, the patients say the NIH scientists pulled back. A September visit Brianne Dressen had scheduled for additional neurologic testing was converted to a telemedicine appointment. In December, Nath asked her to stop sending patients his way. “It is best for such patients to receive care from their local physicians,” he wrote to her.
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