Comparative Analysis of Nucleocapsid- and Spike-Specific Isotype Humoral Immune Responses Following Natural SARS-CoV-2 Infection and Vaccination with Sinopharm, Sinovac, and AstraZeneca

The diversity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine platforms and widespread natural exposure have created a complex landscape of humoral immunity requiring detailed characterization. Here, we compare nucleocapsid (N)- and spike (S)-specific antibody responses in sera from infected humans (IH) during the first pandemic wave (April–August 2020) and in vaccine recipients (Sinopharm, Sinovac, or AstraZeneca) using commercial ELISA kits. Among naturally IH, the IgG-positivity rate was higher for N (80.9%) than S (42.8%), with significantly elevated N-specific IgG levels compared to prepandemic controls ( p -value <0.05), while IgM responses showed no significant differences. Strong positive correlations were observed between S- and N-specific antibody responses, particularly for IgG and its subclasses. Vaccinated cohorts exhibited high IgG positivity rate (83–100%) against both antigens with low IgM levels, and overall IgG and subclass responses were significantly elevated relative to pre-pandemic controls ( p -value <0.05), with consistently strong inter-antigen correlations across groups. Overall, natural infection induces a coordinated humoral response biased toward the nucleocapsid antigen, supporting its utility as a marker of recent infection, whereas vaccination elicits a robust multi-subclass antibody response with platform-dependent differences in antigen recognition and subclass distribution.