Severity-Dependent IgG Epitope Profiling in COVID-19 Reveals Differential Recognition of Pathogen-Derived Antigens Lais Alves do Nascimento 1

Lais Alves do-Nascimento¹Nicolle Rakanidis Machado¹João Vitor da Silva Borges²Beatriz Oliveira Fagundes¹Isabella Siuffi Bergamasco²Fábio da Ressureição Sgnotto²André Bachi²Maria Notomi Sato¹Jefferson Russo Victor^1*

• ¹School of Medicine - University of São Paulo (FM-USP), São Paulo, Brazil
• ²Universidade de Santo Amaro, São Paulo, Brazil

Background: The contribution of antibody-mediated responses to COVID-19 outcomes remains unclear, particularly regarding cross-reactivity with unrelated pathogens. While co-infections are known to influence disease progression, the broader landscape of IgG reactivity during SARS-CoV-2 infection has not been systematically explored. Methods: We employed a high-density peptide microarray containing 4,344 linear epitopes from 37 viruses, 27 bacteria, 17 parasites, and 8 fungi to characterize serum IgG repertoires from individuals with moderate (n = 39) or severe (n = 40) COVID-19. Controls included pre-pandemic healthy donors and a pooled intravenous immunoglobulin (IVIg) formulation. Data analysis included intensity ranking, epitope mapping, and comparative analysis of mean signal intensities for each epitope between the COVID-Mod and COVID-Sev groups. Results: COVID-19 patients showed widespread IgG reactivity against diverse pathogens, with patterns differing by disease severity. Severe cases displayed broader and more intense reactivity, notably against hepatitis C virus (HCV), SARS-CoV-1, influenza A, Mycobacterium tuberculosis, and Plasmodium falciparum. Moderate cases showed preferential recognition of epitopes from HTLV-I, Neisseria meningitidis, and Trypanosoma cruzi. These findings suggest that SARS-CoV-2 infection modulates pre-existing humoral memory, possibly through epitope spreading or immune reprogramming. Conclusions: SARS-CoV-2 infection reshapes the IgG epitope repertoire in a severity-dependent manner, extending to antigens from unrelated pathogens. This phenomenon may reflect underlying immune dysregulation or idiotype-driven interactions. Comprehensive profiling of pathogen-related IgG responses may reveal potential biomarkers of disease severity. This phenomenon may inform future investigations aimed at improving personalized management strategies for co-infected or immunocompromised patients.