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People with neurologic post-COVID sequelae showed immunologic imprinting from other common coronaviruses, suggesting that "original antigenic sin" -- immune responses shaped by an initial exposure to a related pathogen -- may play a role in long COVID.

Compared with people who did not develop neurologic complications after COVID, those with neurologic sequelae had lower systemic antibody responses against SARS-CoV-2, reported Marianna Spatola, MD, PhD, of the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard Medical School in Cambridge, Massachusetts.

Surprisingly, these people had significantly expanded antibody responses to other common coronaviruses, suggesting that pre-existing responses against similar viruses may have influences their response to SARS-CoV-2 infection, Spatola said in a press briefing in advance of her presentation at the 2023 American Academy of Neurology annual meeting.

At 6-to-8-month follow-up, cerebrospinal fluid (CSF) responses to SARS-CoV-2 were selectively elevated in people who had good outcomes after acute SARS-CoV- 2 infection. Systemic responses against other coronaviruses were enriched in people with bad outcomes.

The findings hint at a previously unappreciated role for immunologic imprinting from other coronaviruses that may induce defective antibody-mediated control of SARS-CoV-2, leading to systemic immune activation and neuroinflammation, Spatola noted.

"These common coronaviruses are pretty similar to SARS-CoV-2, but they are not exactly the same," she said. "The increased antibody responses were not specific to SARS-CoV-2, so they were probably less efficient to control the virus. This can lead to persistence of inflammation -- and if it happens within the brain, it can lead to neuroinflammation which can, by itself, be detrimental and cause neurological dysfunction."

The idea of original antigenic sin is not unique to SARS-CoV-2, Spatola observed. "Indeed, it is a concept that is relatively known in the field of vaccinology," she said. "For example, those who have been working to find the best vaccine for the flu virus or for HIV know it's very hard to find the perfect vaccine that can be protective for all the different types for the virus that evolve over time."

How SARS-CoV-2 affects the brain is not fully known. Prior research in hospitalized COVID patients has shown elevated levels of brain injury. Autopsies have demonstrated that the virus can persist in the brain and body, but with little evidence of inflammation or direct viral cytopathology outside the respiratory tract. Even among people with mild COVID, reports of tissue damage and loss of gray matter volume have emerged.

Spatola and colleagues used a systems serology approach to profile antibody responses against SARS-CoV-2 and other viruses, including common coronaviruses, in the serum of 112 SARS-CoV2-infected individuals who either did (18 people) or did not (94 people) have long COVID neurologic symptoms, also known as neurologic post-acute sequelae of COVID-19 or neuroPASC.

In the 18 people with neurologic symptoms, the researchers compared serum and CSF antibody responses and identified factors that might predict a good versus bad outcome.

People who had neurologic long COVID showed lower systemic antibody responses against SARS-CoV-2, including antibody-dependent complement deposition, NK cell activation, and Fcg receptor binding. No differences in antibody responses to Epstein-Barr virus, flu, or herpes simplex virus 1 emerged.

All antibody isotypes or subclasses of SARS-CoV-2 spike specific features were detected in the serum of people with neurologic long COVID. CSF profiles were characterized by immunoglobulin G1 (IgG1) and the absence of immunoglobulin M (IgM).

This may reflect compartmentalized, brain-specific responses against SARS-CoV-2 through antibodies selectively transferred from serum to CSF across the blood-brain barrier, Spatola noted. "What I have been able to see is that the antibodies within the brain are functionally different," she observed. "They are able to activate certain specific functions of the innate immune system."

The findings suggest a possible pathogenic mechanism that may contribute to long COVID and possible targets for therapeutic strategies, Spatola said.

However, it's not clear whether the findings represent long COVID mechanisms or prognostic biomarkers, she noted. A limitation of the study was its small sample size.

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