People with autoimmune rheumatoid disease who develop long COVID are more likely to have altered levels of inflammation-fueling antibodies specific to a coronavirus that causes the common cold, according to research led by HMS researchers at Brigham and Women’s Hospital, Massachusetts General Hospital, and the Ragon Institute of Mass General, MIT, and Harvard.

The results, published Sept. 6 in Science Translational Medicine, offer an important clue about the development of long COVID, a mystifying syndrome estimated to affect 65 million people worldwide.

Specifically, the analysis indicates that prior infection with a common cold coronavirus and elevated antibodies against it may prime the immune system and make certain individuals more likely to develop long COVID.

The researchers caution that this mechanism is not likely to account for all cases of long COVID, which may be fueled by different mechanisms that vary widely across individuals.

The authors also note that their study was restricted to individuals with rheumatic diseases, and further research is needed to determine whether these findings apply more widely to patients without autoimmune disorders. Nonetheless, the scientists say, the findings serve as an important indicator that a person’s pre-pandemic viral history could modulate one’s risk for long COVID.

“Our study offers evidence and explanation for why some of our patients may be experiencing the persistent and wide-ranging symptoms of long COVID.”

“Our study offers evidence and explanation for why some of our patients may be experiencing the persistent and wide-ranging symptoms of long COVID,” said study co-corresponding author Zachary Wallace, HMS assistant professor of medicine in the Division of Rheumatology, Allergy, and Immunology at Mass General. “Identifying a biomarker that helps us better understand current and previous infections could shed light on an inappropriate immune response that leads to some cases of long COVID.”

Starting with patients with rheumatic diseases, Wallace added, may allow researchers to develop biomarkers to understand who is at high risk for developing long COVID and strategically enroll individuals into clinical trials to either prevent long COVID or develop therapies to treat it.

“This study represents an important step in that direction,” Wallace said.

Up to 45% of individuals with rheumatic diseases, which include rheumatoid arthritis and other chronic autoimmune disorders that cause inflammation, experience persistent symptoms associated with long COVID 28 days after acute infection with SARS-CoV-2. Patients with rheumatic disease are also at risk for more severe disease and complications from acute infection.

Since the beginning of the pandemic, Wallace and his colleagues at Brigham and Women’s and Mass General have paid special attention to this group of patients to find insights that could help inform their treatment as well as the care of broader patient populations experiencing long COVID.

“At the very beginning of the pandemic, we joined forces to identify every rheumatic disease patient with COVID seen at our institutions so that we could follow their clinical course and collect survey and blood data,” said co-corresponding author Jeffrey Sparks, HMS associate professor of medicine in the Division of Rheumatology, Inflammation, and Immunity at Brigham and Women’s. “At first, we thought we might be doing this for a month or two, but the work continues today, and we are gaining important insights about a potential immune mechanism that may lead to long COVID, especially among patients with rheumatic disease.”

“When it comes to viruses, first exposure can shape lifelong immunity.”

Wallace, Sparks, and colleagues analyzed immunologic changes in patients with rheumatic disease who recovered from COVID-19. The investigators measured antibody responses against various parts of SARS-CoV-2, comparing patients who developed long COVID with those who did not. They looked for differences in the immunologic fingerprints left behind by previous infections. The team found an unexpected signal tied to OC43, a coronavirus that causes common cold-like symptoms. Individuals with long COVID were more likely to have antibody responses specific to this form of coronavirus.

“When it comes to viruses, first exposure can shape lifelong immunity,” said co-corresponding author Galit Alter, who contributed to this work while at HMS and the Ragon Institute before joining Moderna Therapeutics in October 2022. “We know that, in the setting of influenza, previous exposure to a viral strain can influence a person’s immune response to subsequent strains. This concept — which we call ‘original antigenic sin,’ may be at play for coronaviruses too and may influence risk of long COVID, especially among individuals with rheumatic disease.”

The researchers plan to further pursue biomarkers of long COVID, including the OC43 signature, which may be useful for developing diagnostics, therapeutics, and more targeted clinical trials to test interventions.

Authorship, funding, disclosures

Additional authors included Jonathan D. Herman, Caroline Atyeo, Yonatan Zur, Claire E. Cook, Naomi J. Patel, Kathleen M. Vanni, Emily N. Kowalski, Grace Qian, Shruthi Srivatsan, Nancy A. Shadick, Deepak A. Rao, Benjamin Kellman, Colin J. Mann, and Douglas Lauffenburger.

Support for this work was provided by Nancy Zimmerman, Mark and Lisa Schwartz, an anonymous donor (financial support), and Terry and Susan Ragon; by the SAMANA Kay MGH Research Scholars award, the Ragon Institute of Mass General, MIT, and Harvard, the Massachusetts Consortium on Pathogen Readiness, the National Institutes of Health (3R37AI080289-11S1, R01AI146785, U19AI42790-01, U19AI135995-02, U19AI42790-01, 1U01CA260476-01, CIVIC75N93019C00052, R01AR077607, P30AR070253, P30AR072577, K23AR073334, 1UL1TR002541-01, R03AR078938), the Gates Foundation, the Global Health Vaccine Accelerator Platform funding (OPP1146996 and INV-001650), the Musk Foundation, R. Bruce and Joan M. Mickey Research Scholar Fund, the Rheumatoid Research Foundation, and the Doris Duke Charitable Foundation.

Alter is an employee of Moderna Therapeutics and holds equity in Leyden Labs and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer unrelated to this work. Wallace reports research support from Bristol-Myers Squibb and Principia/Sanofi and consulting fees from Horizon, Sanofi, Viela Bio, Zenas BioPharma, Shionogi, and MedPace.

Adapted from a Mass General Brigham release. Originally published in Harvard Medical School News.