Differential Binding and Neutralising Antibody Responses Across COVID-19 Severity in a Saudi Multicentre Cohort

Background: Humoral immune responses to SARS-CoV-2 are well documented, yet the immunopathogenic mechanisms distinguishing severe from critical disease remain incompletely defined, particularly in Middle Eastern populations. We investigated antibody responses across levels of clinical severity in a Saudi Arabian cohort. Methods: In this multicentre study, we analysed 406 participants stratified into five clinical groups: controls, asymptomatic, mild, severe, and critically ill requiring intensive care unit (ICU) admission. SARS-CoV-2-specific IgG and IgM levels were quantified alongside surrogate ACE2-RBD neutralisation activity. Associations between humoral markers, demographic factors, comorbidities, and disease severity were assessed. Results: SARS-CoV-2-specific IgG and IgM levels differed significantly across disease severity groups (p < 0.001), with higher levels observed in groups with greater clinical severity. No significant difference in IgG or IgM levels was observed between the severe and ICU groups (IgG p = 0.384; IgM p = 0.768). While binding antibody levels were associated with severity, surrogate ACE2-RBD neutralising activity did not differ significantly across groups (p = 0.209). Increasing age (χ2 = 44.5) and the presence of comorbidities (χ2 = 31.9) were associated with more severe clinical categories, whereas sex was not. Conclusions: These findings suggest that antibody levels provide useful information about exposure and immune activation, but antibody quantity alone does not fully explain the transition from severe to critical disease. The results support interpreting serological measures alongside clinical factors such as age and chronic illness.