ABSTRACT
Heterologous ChAdOx1-BNT162b2 vaccination induces a stronger immune response than BNT162b2-BNT162b2. Here, we investigated the molecular transcriptome, germline allelic variants of immunoglobulin loci, and anti-Omicron antibody levels in 46 office and lab workers from the Republic of Korea following ChAdOx1-BNT162b2 vaccination. Anti-spike-specific IgG antibody levels against the ancestral SARS-CoV-2 strain increased from 70 AU/ml to 14,000 AU/ml to 142,000 AU/ml one, three and seven days following the second vaccination. Titers against VOC, including Omicron, were two-fold to three-fold lower, yet higher than those measured following BNT162b2-BNT162b2 vaccination. RNA-seq of peripheral immune cells demonstrated activation of interferon pathways with increased IGHV clonal transcripts encoding neutralizing antibodies. scRNA-seq revealed enriched B cell and CD4+ T cell responses in both ChAdOx1-BNT162b2 and BNT162b2-BNT162b2 recipients, but a stronger clonal expansion of memory B cells with ChAdOx1-BNT162b2. In summary, heterologous ChAdOx1-BNT162b2 provides an innate and adaptive immune response that exceeds homologous BNT162b2 vaccination.