Original antigenic sin influences humoral immune response to SARS-CoV-2

“Original antigenic sin” may play an important role in shaping the humoral immune response to SARS-CoV-2 immunity, and consequently could be a key factor in the pathogenesis of neurologic post-acute sequelae of SARS-CoV-2 (neuroPASC).

The pathogenesis of neuroPASC remains unclear. The current study concentrated on the role of the patient’s antibodies and innate immune response in the mechanisms of neuroPASC [1]. Using the serum of SARS-CoV2-infected patients, a systems serology approach enabled unbiased in-depth profiling of antibody responses against SARS-CoV-2 and other viruses (including non-Coronaviruses). Among those who developed neuroPASC, the researchers compared serum and antibody responses.

Of 112 patients with a SARS-CoV2 infection, 94 did not develop neurological complications, whereas 18 did. The results suggested that the antibody response to SARS-CoV2 is compartmentalised in the CSF of patients with neuroPASC. This was suggested by the fact that in these patients, all antibody isotypes/subclasses were detected in the serum, whereas CSF was mainly populated by less varied and less functional SARS-CoV2-specific antibodies (IgG), while IgM antibodies were absent. This suggests a sieve across the blood-brain-barrier rather than intrathecal synthesis.

Another finding was that patients with neuroPASC had a lower systemic antibody response against SARS-CoV-2. There were no differences in antibody responses to Epstein-Barr virus, influenza virus, or herpes simplex virus type 1. Surprisingly, there were expanded antibody responses to other common Coronaviruses in the neuroPASC-group, suggesting original antigenic sin (immunological imprinting). This refers to the phenomenon in which prior exposure to an antigen shapes the subsequent (suboptimal) immune response to a related antigen. This “off-target” antibody response was even more outspoken in neuroPASC patients with a poor outcome, suggesting it may serve as a prognostic biomarker. This skewed antibody activation may reduce viral clearance and increase neuro-inflammation, contributing to neurological symptoms.

1. 1. Spatola M. Serum and cerebrospinal fluid antibody signatures track with outcome of neurologic post-acute sequelae of SARS-Cov-2 infection (NeuroPASC). S21.006, AAN 2023 Annual Meeting, 22–27 April, Boston, USA.

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