Serum And Cerebrospinal Fluid Antibody Signatures Track With Outcome Of Neurologic Post-Acute Sequelae Of SARS-Cov-2 Infection (NeuroPASC)
Marianna Spatola1, Alessandro Dinoto2, Silvia Bozzetti2, Vanessa Chiodega2, Sergio Ferrari2, Sara Mariotto3, Galit Alter1
1Ragon Institute of MGH, MIT and Harvard Medical School, 2Department of Neuroscience, Biomedicine and Movement Sciences, Section of Neurology, University of Verona, 3University of Verona

Determine the role of antibodies and innate immune responses in the pathogenesis of neurologic post-acute sequelae of SARS-CoV2 (neuroPASC).

Despite being primarily a respiratory pathogen, SARS-CoV-2 can also affect the central nervous system (CNS). SARS-CoV-2-related CNS disturbances have been observed during acute infection, but also at distance from respiratory disease, as neuroPASC. The pathogenesis of neuroPASC remains unclear. 
Using a systems serology approach, we deeply profiled the antibody responses against SARS-CoV-2 and other viruses, including common Coronaviruses, in the serum of SARS-CoV2-infected individuals who developed or not neuroPASC. In neuroPASC, we compared the serum and cerebrospinal fluid (CSF) antibody responses, and identified prognostic factors for good vs bad outcome. 

Compared to individuals who did not develop neurological complications following infection (n=94), those with neuroPASC (n=18) showed lower systemic antibody responses against SARS-CoV-2, including antibody-dependent complement deposition (ADCD), NK cell activation (ADNKA) and Fcg receptor binding. No differences in the antibody responses to EBV, Flu or HSV1 were observed. However, surprisingly, NeuroPASC showed expanded antibody responses to other common Coronaviruses, suggesting an original antigenic sin, where pre-existing immune responses against related viruses shape the response to current infection. Also, in neuroPASC, all antibody isotypes/subclasses were detected in the serum, whereas CSF was characterized by IgG1 (and absence of IgM), suggesting compartmentalized humoral responses within the CSF through selective transfer of antibodies from the serum to the CSF across the blood-brain-barrier, rather than intrathecal synthesis. Finally, CSF SARS-CoV-2 responses were selectively elevated in individuals with good outcome, whereas systemic responses against other common Coronaviruses were enriched in individuals with bad outcome.

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