A new study is currently enrolling people with long COVID who have not yet been vaccinated. The work could tell researchers what’s driving the condition and offer clues to treatment. 

HHMI scientists are joining many of their colleagues worldwide in working to combat the new coronavirus. They’re developing diagnostic testing, understanding the virus’s basic biology, modeling the epidemiology, and developing potential therapies or vaccines. We will be sharing stories of some of this work.

HHMI Investigator Akiko Iwasaki

Within the last few months, some people with lingering COVID-19 symptoms have been reporting something surprising: vaccination seems to improve their condition. These patients, known as “long haulers” or people with “long COVID,” suffer from a host of full-body symptoms that can make it difficult to walk, concentrate, and breathe.

Now, scientists have launched a new study to examine just how vaccination affects these individuals, and whether the vaccine can offer clues to treatment. Researchers are currently recruiting people over 18 who have not yet been vaccinated and have had COVID-19 symptoms for more than two months since their initial infection, announced study leader Akiko Iwasaki, a Howard Hughes Medical Institute Investigator at Yale University.

Iwasaki’s team will collect blood and saliva samples before and after vaccination and look at participants’ immune responses. That could tell researchers what’s driving long COVID, and even suggest therapies likely to treat it.

The Centers for Disease Control and Prevention already recommends vaccination for people who have had COVID-19, but developing treatment options for long COVID is crucial, Iwasaki says – especially now, as cases continue to rise. “Even after the pandemic is contained, millions of people in the U.S. are going to be left with long-term symptoms,” she says. “Unfortunately, this is the next phase of COVID, and we need to come up with a solution.”

Listening to patients

Iwasaki’s new study was inspired, in part, by discussions on social media. Since the pandemic’s beginning, Iwasaki, an immunologist, has been at the forefront of COVID-19 science communications. On Twitter, where she goes by the handle @VirusesImmunity and has more than 130,000 followers, Iwasaki has shared the latest coronavirus research, laid out the details of her own COVID-19 studies, and proposed theories for why, in some cases, disease symptoms stick around.

She’s also been listening. Earlier this year, Iwasaki began hearing hints that COVID-19 vaccination seemed to help some long haulers feel better. Infectious disease physicians she follows noticed that, in some patients, symptoms eased after vaccination. And a survey of 931 long haulers from the grassroots organization Survivor Corps found that 42 percent reported improvements post-vaccination. (About 14 percent of survey respondents felt worse, and the rest didn’t notice a difference before and after vaccination.) Studies have yet to examine this phenomenon, but “evidence from the community has been accumulating that the vaccines might be doing something,” Iwasaki says.

Long COVID, also known as post-acute sequelae of SARS-CoV-2 (PASC) and post-acute COVID-19 syndrome (PACS), is still largely a medical mystery. Scientists know that the condition can persist nine months or more after initial infection, and can spark a sometimes incapacitating collection of symptoms, including fatigue, “brain fog,” headache, and muscle pain. It’s unclear exactly how many people infected with coronavirus develop long COVID, though the World Health Organization estimates about 10 percent.

Even people with mild COVID-19 cases, or those who were asymptomatic, can be affected. Several studies have suggested that long COVID is more likely to affect women than men, and young people are not without risk. “A lot of people assume that if you’re healthy and in your twenties or thirties, you’re going to be fine without the vaccine,” Iwasaki says. “That is not true.” She’s seen young, active women with no underlying conditions hit inexplicably with relentless, energy-sapping symptoms. “All of a sudden, they’re just debilitated with long-haul disease,” Iwasaki says.

There are currently no established long COVID diagnostic tests, and treatment options are limited. David Putrino, a physical therapist and neuroscientist at Mount Sinai Health System, has worked with long COVID patients for months developing a rehabilitation program. Twice weekly physical therapy for an average of 65 days can reduce fatigue by 30 percent, his team reported in April on the preprint site Research Square.

“Patients who couldn’t climb the stairs are now getting up and running,” he says. “That’s encouraging.” But the program is intense, and the gains are relatively modest, he notes. “Anything that takes 65 days to rehabilitate is concerning.”

Looking for treatments

The critical need for effective long COVID treatments has ignited interest within the scientific community. In February, Francis Collins, director of the National Institutes of Health, announced a $1.15 billion initiative to identify the causes of long COVID and find ways to prevent and treat the illness.

“So little is known right now,” Putrino says. “If we’re going to develop therapies that work more effectively, we need to understand the pathophysiology of this condition.” In other words, scientists need to unearth the underlying roots of long COVID, and why it arises in some patients and not others.

Iwasaki has a few theories. After infection, people with the condition may not be clearing the virus from their bodies. Virus could persist in hidden reservoirs that aren’t detected by a nasal swab. This stealth virus replicates, the body fights, and the cycle ­– and COVID-19 symptoms ­– continues. Lasting symptoms may also stem from bits of SARS-CoV-2 RNA or protein: “viral ghosts” that linger in the body once the primary infection has passed. These viral specters are just leftover fragments that are not infectious but could still spur the immune system into continued action, prompting long-term inflammation. Or COVID-19 could trigger an autoimmune disorder that prompts the body to continually attack itself.

There’s some evidence for these theories, and they’re not mutually exclusive, Iwasaki wrote in an article on Medium in March. Her team and others have already discovered “autoantibodies” – immune proteins that target the body instead of the virus – in some patients with COVID-19.

Iwasaki has teamed up with Putrino to examine whether people with long COVID are more prone to producing these autoantibodies. They’ll also look for other oddities in the immune response. This study, which began collecting blood samples last week, is running parallel to the one for which Iwasaki is currently recruiting participants.

To figure out how COVID-19 vaccines may be affecting long haulers, Iwasaki’s team plans to enroll patients near her lab in New Haven, Connecticut, who have not yet been vaccinated. The researchers have begun recruiting participants locally but hope to open the study up nationally. They’ll monitor participants’ immune responses before and after vaccination to see whether any immune factors correlate with improvements in symptoms.

The vaccine could, for example, temporarily trick the immune system, diverting rogue immune cells away from attacking the body. It’s also possible that the vaccine ramps up production of antibodies or immune cells that root out any lingering virus. “That would be amazing – a permanent cure,” Iwasaki says.

No matter what the team finds, Iwasaki is certain they’ll learn something new about the disease process. “We haven’t even scratched the surface” of understanding long COVID, she says. “Ultimately we hope to protect people and provide relief from their symptoms.”


People interested in participating in Dr. Iwasaki’s long COVID study can contact to learn more.

Video source: HHMI employee town hall on COVID-19 vaccines, April 7, 2021. Moderator: Aileen O'Hearn, science editor for HHMI's Tangled Bank Studios and public media.

Media Contact

Jim Keeley 301-215-8858