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| A Long Covid patient at a hospital in Poland plays a virtual reality game to test reaction skills |
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.
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.
For patients, the
silence from NIH was distressing, especially as they struggled to find
care elsewhere. The scientists “took the data and left us hanging,” says
a person who traveled to NIH in the spring of 2021. “I have no
treatment, I have no idea what’s happening to my body.” Physicians,
several patients said, had nothing to offer and sometimes even declared
the symptoms imagined.
Nath told Science NIH facilities are not
equipped to treat large numbers of patients long-term. Says the health
care worker of the effort: “It’s too much for two people at the NIH to
do.”
The NIH data, which documented the patient cases, haven’t
been reported yet. Two top medical journals declined to publish a case
series of about 30 people, which Nath first submitted in March 2021.
Nath says he understands the rejection. The data weren’t “cut and dried;
it was observational studies.” This month, the scientists submitted a
case series of 23 people to a third publication, and Nath says his group
has submitted an amendment to a Long Covid protocol to include patients
with postvaccine side effects.
Science contacted regulators and
vaccinemakers about any information they’d gleaned on these side
effects. A Pfizer spokesperson wrote, “We can confirm it’s something
we’re monitoring.” Moderna, AstraZeneca, and Johnson & Johnson all
said they take side effects seriously and share reports they receive
with regulators. An FDA spokesperson said the agency “continues to
maintain a strong focus on monitoring the safety of the COVID-19
vaccines,” while the European Medicines Agency notes it “is taking steps
to use real-world data from clinical practice to monitor the safety and
effectiveness of COVID-19 treatments and vaccines.”
Other
researchers note the scientific community is uneasy about studying such
effects. “Everyone is tiptoeing around it,” Pretorius says. “I’ve talked
to a lot of clinicians and researchers at various universities, and
they don’t want to touch it.”
Still, her group and others are
pushing ahead. Prüss has detected autoantibodies in some patients with
postvaccine symptoms, although not in others. Several groups are
studying whether a patient’s postvaccination symptoms are due to
autoantibodies to the angiotensin-converting enzyme 2 (ACE2) receptor,
which the spike protein targets. Cheng and her colleagues are planning a
case series that includes sophisticated imaging and diagnostic tests
from a mix of Long Covid patients and those with postvaccine side
effects. And Pretorius and her colleague Chantelle Venter are hoping to
recruit at least 50 people to study clotting patterns before and after
vaccination.
At Yale, Iwasaki is planning to collaborate with
Nath and look at any potential link between Long Covid and postvaccine
effects, she says. She has spoken with affected patients and her lab
intends to collect samples from them, potentially of blood or saliva.
Murphy says more work is needed in animal models to trace the body’s
response to vaccination. “We need to look at this in controlled
situations,” he says.
Prüss is hunting for autoantibodies
following COVID-19 vaccination in mice. And he continues to care for
patients, both postvaccine and postinfection. His clinic hopes to soon
start a clinical trial of a treatment that removes most antibodies from a
patient’s blood. However, even if it works well, the procedure is
expensive and might not be widely available.
Patients in the middle
People
with lasting health problems after vaccination welcome any attention to
their plight. “You have this ugly stain on you, and you’re marginalized
and abandoned,” Brianne Dressen says. At first, “I was really afraid of
causing vaccine hesitancy,” she adds.
Other patients describe
vaccine opponents asserting that they deserve to die because they were
foolish enough to get vaccinated. Vaccine supporters tell them that by
speaking out they risk harming others, who may refuse to get vaccinated
and then die from COVID-19. “We’re stuck in this horrible in-between,”
says the patient who traveled to NIH last spring.
Brianne
Dressen, for her part, went public. She says she was frustrated when it
appeared that regulators, including FDA, were not promptly investigating
the apparent side effects. She took part in a June 2021 press
conference about vaccine side effects held by Senator Ron Johnson
(R–WI), who has been outspoken against COVID-19 vaccinations. “Talking
to politicians was not our plan A … not even close,” Brianne Dressen
says. “It was more like plan J.”
Jana Ruhrländer, too, feels
caught. After a single dose of the Moderna vaccine, the microbiology
graduate student in Kassel, Germany, developed symptoms including the
sensation of internal electric shocks Brianne Dressen experienced,
partial facial paralysis, muscle weakness that left her terrified she
was having seizures or a stroke, intense thirst, and wild swings in her
heart rate and blood pressure. Doctors dismissed her, saying their tests
found nothing wrong. She played detective, realizing her symptoms
overlapped with a hormonal system called the
renin-angiotensin-aldosterone system that regulates blood pressure and
fluid balance—and in which ACE2 plays a key role. She has recently
connected with doctors who are trying to learn whether autoantibodies
targeting that system might be causing her symptoms.
Despite her
experience, “I still think the vaccines are great,” Ruhrländer says. And
the mRNA technology “has so much potential.” But these side effects,
which for her have improved somewhat but haven’t disappeared, should be
acknowledged and understood, she says. “We have to speak openly about
it.”
Some of the patients who spoke with Science say medications
that tamp down the immune system have offered at least a measure of
relief. Nath noticed the same phenomenon. He hopes results from an NIH
clinical trial testing IVIG and intravenous steroids in Long Covid
patients “will be applicable to the vaccine-related complications.” None
of the patients with whom Science spoke has fully recovered.
Researchers
exploring postvaccine side effects all emphasize that the risk of
complications from SARS-CoV-2 infection far outweighs that of any
vaccine side effect. “You see 10, 100, 1000 times less risk from the
vaccine,” Prüss says. But understanding the cause of postvaccine
symptoms—and whether early treatment can help prevent long-term
problems—could be crucial for designing even safer and more effective
vaccines, Murphy says, as well as potentially providing clues to the
biology of Long Covid.
Cheng has heard from dozens of people who
describe chronic postvaccine problems, and she finds the overlap between
their symptoms and those of Long Covid compelling. Now, she wants to
move deliberately and scientifically in a search for answers. “We’ve got
to retain rigor,” she says. “There’s just this complete dearth of
data.” []
Source: Science.org
*) Update, 21 January, 12:45 p.m.: This story has been updated
with comments from the U.S. Food and Drug Administration and the
European Medicines Agency.