Antibodies against Spike protein correlate with broad autoantigen recognition 8 months post SARS-CoV-2 exposure, and anti-calprotectin autoantibodies associated with better clinical outcomes

Abstract

Autoantibodies to multiple targets are found during acute COVID-19. Whether all, or some, persist after 6 months, and their correlation with sustained anti-SARS-CoV-2 immunity, is still controversial. Herein, we measured antibodies to multiple SARS-CoV-2 antigens (Wuhan-Hu-1 nucleoprotein (NP), whole spike (S), spike subunits (S1, S2 and receptor binding domain (RBD)) and Omicron spike) and 102 human proteins with known autoimmune associations, in plasma from healthcare workers 8 months post-exposure to SARS-CoV-2 (n=31 with confirmed COVID-19 disease and n=21 uninfected controls (PCR and anti-SARS-CoV-2 negative) at baseline). IgG antibody responses to SARS-CoV-2 antigens were significantly higher in the convalescent cohort than the healthy cohort, highlighting lasting antibody responses up to 8 months post-infection. These were also shown to be cross-reactive to the Omicron variant spike protein at a similar level to lasting anti-RBD antibodies (correlation r=0.89). Individuals post COVID-19 infection recognised a common set of autoantigens, specific to this group in comparison to the healthy controls. Moreover, the long-term level of anti-Spike IgG was associated with the breadth of autoreactivity post-COVID-19. There were further moderate positive correlations between anti-SARS-CoV-2 responses and 11 specific autoantigens. The most commonly recognised autoantigens were found in the COVID-19 convalescent cohort. Although there was no overall correlation in self-reported symptom severity and anti-SARS-CoV-2 antibody levels, anti-calprotectin antibodies were associated with return to healthy normal life 8 months post infection. Calprotectin was also the most common target for autoantibodies, recognized by 22.6% of the overall convalescent cohort. Future studies may address whether, counter-intuitively, such autoantibodies may play a protective role in the pathology of long-COVID-19.

Overview of autoantibodies in COVID‐19 convalescents

“…showed reactivity for 37/102 (36.3%) targets, the comparison of the number of reactivity between the convalescent the control population showed an average of 2.9-fold increase in the number of autoreactive antibodies after SARS-CoV-2 infection. 46 An increase in autoantibodies' prevalence against immune system components, including cytokines, chemokines, complement, and cell surface proteins, was also documented in a cohort of 194 SARS-CoV-2 infected patients compared to uninfected individuals. 49 However, the analysis involved only patients in the acute phase of the disease, with no long-term evaluation during recovery and no assessment of the relationship to the post-COVID-19 syndrome.…”

“…The emergence of the former may result from increased antigen presentation during the SARS‐CoV‐2 infection since calprotectin levels were found to be elevated in COVID‐19, particularly in more severe disease forms 110,111 . The relevance of these antibodies remains explored, but the authors note that their presence was associated with better clinical outcomes 46 . The persisting IgG autoantibodies against centromeric protein CENP‐B were also found in 16% of analyzed convalescent patients.…”

“…The IgG antibodies against calprotectin that persisted for 8 months were also reported in COVID-19 convalescent, with no seroprevalence in noninfected controls (n = 21). 46 The emergence of the former may result from increased antigen presentation during the SARS-CoV-2 infection since calprotectin levels were found to be elevated in COVID-19, particularly in more severe disease forms. 110,111 The relevance of these antibodies remains explored, but the authors note that their presence was associated with better…”

“…An interesting analysis was performed by Moody et al, who aimed to assess the antibodies to various autoantigens found in COVID‐19 convalescents and their correlation with sustained anti‐SARS‐CoV‐2 immunity 46 . Autoantibodies for human proteins were evaluated in 31 patients, predominantly females (81%), 8 months after COVID‐19, and the results were compared with a group of 21 uninfected individuals.…”

“…Although no such case was found in the group of patients after COVID-19 without no post-acute symptoms, the finding of an uncommon occurrence of anti-IFN antibodies does not support the theory of their involvement in the pathogenesis of long COVID and responsibility for its symptoms 43. An interesting analysis was performed by Moody et al, who aimed to assess the antibodies to various autoantigens found in COVID-19 convalescents and their correlation with sustained anti-SARS-CoV-2 immunity 46. Autoantibodies for human proteins were evaluated in 31 patients, predominantly females (81%), 8 months after COVID-19, and the results were compared with a group of 21 uninfected individuals.…”