DIVERGENT ADAPTIVE IMMUNE RESPONSES DEFINE 2 TYPES of LONG COVID

ABSTRACT

Background: More than 10% of patients infected with SARS-CoV-2 experience a Long COVID syndrome, characterized by the persistence of a diverse array of symptoms where fatigue predominates. The role of the adaptive immune response in Long COVID remains poorly understood, with contrasting hypotheses suggesting either an insufficient antiviral response or an excessive immune response that would trigger autoimmune damage. To address this issue, we set to characterize humoral and cellular responses in Long COVID patients prior to SARS-CoV-2 vaccination. Methods: Long COVID patients (n=36) were included based on (1) an initial SARS-CoV-2 infection documented by PCR or the conjunction of two major signs of COVID-19 and (2) the persistence or resurgence of symptoms for over 3 months. They were compared to convalescent COVID patients with resolved symptoms (n=23) and uninfected control individuals (n=20). IgG and IgA antibodies specific to the SARS-CoV-2 spike were detected by a sensitive S-flow assay, which measures antibody binding to spike-expressing 293T cells. For CD4+ T cell response analyses, cytokine production was measured by intracellular staining on primary T cell lines stimulated by immunodominant peptides derived from the S, M, and N viral proteins. Results: Antibody analyses revealed either strong or very low/undetectable amounts of spike-specific IgG in sera from Long COVID patients, thus distinguishing a seropositive and a seronegative group. Seropositive Long COVID patients (n=21) showed strong CD4 responses that tended to be of higher magnitude than those of convalescents (P<0.05 for 2 immunodominant peptides). In contrast, seronegative Long COVID patients (n=15) showed low or undetectable CD4+ T cells responses, with 4/15 patients showing responses above those observed in healthy donors. CD4+ T cell responses correlated with spike-specific IgG responses in seropositive Long COVID patients (P≤0.002) but not in convalescents, pointing to differences in immune memory persistence. Conclusion: These findings highlight divergent adaptive immune responses among Long COVID patients, with a group characterized by seroconversion and particularly strong CD4+ T cell responses, and a second group characterized by low or undetectable antibody and cellular responses. Further studies are warranted to determine whether the etiology and the duration of symptoms differ in these two groups of Long COVID patients.