Heterologous ChAdOx1-BNT162b2 vaccination in a Korean cohort induces a robust genetic immune and antibody response that includes Omicron

Heterologous ChAdOx1-BNT162b2 vaccination induces a stronger immune response than two doses of BNT162b2. Yet, the molecular transcriptome, the germline allelic variants of immunoglobulin loci and anti-Omicron antibody levels induced by the heterologous vaccination have not been formally investigated. Moreover, there is a paucity of COVID-19 vaccine studies including diverse genetic populations. Here, we show a robust molecular immune transcriptome and antibody repertoire in 46 office and lab workers from the Republic of Korea after heterologous vaccination, ChAdOx1 followed by BNT162b2. Anti-spike-specific IgG antibody levels against the ancestral SARS-CoV-2 strain increased from 70 AU/ml immediately following the first vaccination to 14,000 U/ml within three days after the second vaccination and 142,000 AU/ml after seven days. Antibody titers against more recent variants, including Omicron, were two- to three-fold lower, yet higher than those obtained after the second dose of a BNT162b2-BNT162b2 homologous vaccination. RNA-seq conducted on peripheral immune cells demonstrated a strong activation of interferon-induced genetic programs in the heterologous cohort and an increase of specific IGHV clonal transcripts encoding neutralizing antibodies was detected. Enrichment of B cell and CD4+ T cell responses was observed following both ChAdOx1-BNT162b2 heterologous and BNT162b2-BNT162b2 homologous vaccination using scRNA-seq, but clonally expanded memory B cells were relatively stronger in the heterologous cohort. In summary, a heterologous vaccination with ChAdOx1 followed by BNT162b2 provides an innate and adaptive immune response exceeding that seen in homologous BNT162b2 vaccination.相较于两剂BNT162b2（BNT162b2）疫苗接种，异源ChAdOx1（ChAdOx1）-BNT162b2疫苗接种可诱导更强的免疫应答。然而，目前尚未有研究对该异源疫苗接种诱导的分子转录组、免疫球蛋白基因座的种系等位基因变异以及抗奥密克戎抗体水平进行正式探究。此外，当前纳入多遗传人群的新冠疫苗相关研究仍较为匮乏。本研究对大韩民国46名办公室及实验室工作人员在接受先ChAdOx1后BNT162b2的异源疫苗接种后，开展了分子免疫转录组与抗体库的深度分析。针对原始严重急性呼吸综合征冠状病毒2（SARS-CoV-2）毒株的抗刺突特异性IgG抗体水平，从首剂接种后即刻的70 AU/ml升至第二剂接种后3天内的14000 U/ml，并在全程接种后7天达到142000 AU/ml。包括奥密克戎在内的近期变异株的抗体滴度较原始毒株低2至3倍，但仍高于接受两剂BNT162b2同源疫苗接种后所测得的抗体滴度。对外周免疫细胞开展的RNA测序（RNA-seq）结果显示，异源接种队列中干扰素诱导的基因程序被显著激活，同时检测到编码中和抗体的特异性免疫球蛋白重链可变区（IGHV）克隆转录本水平升高。通过单细胞RNA测序（scRNA-seq）分析发现，无论是ChAdOx1-BNT162b2异源接种还是BNT162b2-BNT162b2同源接种，均观察到B细胞与CD4阳性T细胞应答的富集；但异源接种队列中克隆扩增的记忆B细胞应答相对更强。总结而言，先接种ChAdOx1再接种BNT162b2的异源疫苗接种策略，所诱导的固有免疫与适应性免疫应答均优于两剂BNT162b2同源疫苗接种。