All of these findings collectively indicate that COVID-19 vaccination predominantly induces IgG1, whereas natural infection can elicit responses in both IgG1 and IgG3 subclasses.<h4>Conclusion</h4>The findings highlight RBD-specific IgG3 as well as nucleocapsid IgG as crucial markers for differentiating between vaccination and natural infection and suggest these assays have utility for longitudinal monitoring of vaccinations and for establishing SARS-CoV-2 correlates of protection. Here, IGHG3 is linked to infection.