Here, we present a comparative molecular-level investigation of the polyclonal plasma IgG response to the SARS-CoV-2 S glycoprotein, whether elicited by natural infection (primary ancestral SARS-CoV-2 virus or pre-Omicron VOC breakthrough [BT] infection), vaccination (stabilized ancestral Wuhan-Hu-1 S), or their combination. The gene discussed is ART4; the disease is infection.