Original Antigenic Sin Key in Humoral Immune Response to SARS-CoV-2 Immunity

Among individuals with neurologic post-acute sequelae of SARS-CoV-2 infection (neuroPASC), an original antigenic sin is key in influencing a patient’s humoral immune response to COVID-19 immunity, according to study results presented at the 2023 American Academy of Neurology (AAN) Annual Meeting, held from
April 22 to 27, in Boston, Massachusetts.

Although considered mainly a respiratory pathogen, SARS-CoV-2 can also impact the central nervous system (CNS). It is well known that COVID-19–associated CNS issues can occur during the period of acute infection, but CNS disturbances can be reported at a distance from respiratory disease as well — that is, as neuroPASC.

Recognizing that the pathogenesis of neuroPASC remains to be elucidated, researchers sought to establish the role played by a patient’s antibodies and innate immune response in the pathologic process of neuroPASC. They used a systems serology approach to conduct an in-depth profile of antibody responses against SARS-CoV-2 and other viruses, such as the common coronavirus, in the serum of individuals infected with COVID-19 who did or did not develop neuroPASC. Among those who did develop neuroPASC, they compared serum and antibody responses, in an effort to identify those factors predictive of a good outcome compared with a bad outcome.

A total of 94 patients with COVID-19 did not develop any neurologic complications after an infection, compared with 18 individuals with neuroPASC who did exhibit lower systemic antibody responses against SARS-CoV-2. These responses included antibody-dependent complement deposition, natural killer cell activation, and Fc gamma receptor binding. However, there were no differences reported in these patients’ antibody responses to Epstein-Barr virus, herpes simplex virus type 1 (HSV-1), or influenza.

The researchers noted that neuroPASC demonstrated expanded antibody responses to other common coronaviruses, thus implying an original antigenic sin in which preexisting immune responses against related viruses shape a person’s response to a current infection.

They also found that in individuals who did develop neuroPASC, all antibody isotypes/subclasses were detected in their serum. In contrast, the cerebrospinal fluid (CSF) in these patients revealed the presence of immunoglobulin (Ig)G1, but the absence of IgM. This suggests compartmentalized humoral responses within the CSF via the selective transfer of antibodies from the serum to the CSF across the blood-brain barrier, as opposed to intrathecal synthesis.

In addition, SARS-CoV-2 responses observed in the CSF were selectively increased among patients who reported a good outcome, and systemic responses against other common coronaviruses were enriched in patients who reported a bad outcome.

“These data point to the potential critical importance of original antigenic sin in shaping the humoral response to SARS-CoV-2 immunity, representing a key prognostic biomarker, especially in the CSF, of neuroPASC disease,” the researchers concluded.