Monovalent Omicron COVID-19 vaccine triggers superior neutralizing antibody responses against Omicron subvariants than Delta and Omicron bivalent vaccine

The continuous evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses a challenge to determine the optimal updated composition of the coronavirus disease 2019 (COVID-19) vaccine. The present study aimed to investigate the immunogenicity of the Delta monovalent vaccine, the Omicron monovalent vaccine, and the Delta and Omicron BA.1 bivalent vaccine. Three COVID-19 vaccines were designed using the heterologous DNA prime-protein boost strategy, with each vaccine containing either Delta receptor-binding domain (RBD) of the spike protein, Omicron RBD, or both Delta and Omicron antigens. Temporal serum antibody binding titers and neutralizing antibody titers induced by the three vaccines in New Zealand White rabbits were analyzed. To further dissect the vaccine elicited antibodies (mAb) responses at the molecular level, a panel of rabbit monoclonal antibodies (RmAbs) was generated by a high-throughput single B cell sorting and discovery pipeline and further comprehensively characterized. The Omicron monovalent vaccine induced higher antibody binding titers and neutralization activities than the Delta and Omicron bivalent vaccine. Four RmAbs with robust neutralization capacity were isolated from rabbits immunized with the Omicron or Delta monovalent vaccine. Notably, 9E11 isolated from the Omicron monovalent vaccine group neutralized all the Omicron subvariants with an IC₅₀ value ranging from 1.5 to 503.6 ng/mL; thus, this vaccine could serve as a prophylactic and therapeutic intervention. Given the increasing incidence of COVID-19 cases due to the Omicron variant, RBD from the Omicron strain could serve as a candidate immunogen that can induce higher neutralization activities against the SARS-CoV-2 Omicron sublineages.

严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变异株的持续演化，为确定新型冠状病毒肺炎（COVID-19）疫苗的最优更新配方带来了挑战。本研究旨在评估德尔塔单价疫苗、奥密克戎单价疫苗以及德尔塔与奥密克戎BA.1双价疫苗的免疫原性。本研究采用异源DNA初免-蛋白加强免疫策略设计了三款新冠疫苗，每款疫苗分别包含刺突蛋白的德尔塔受体结合域（RBD）、奥密克戎RBD，或同时包含德尔塔与奥密克戎抗原。研究分析了三款疫苗在新西兰白兔体内诱导的时序性血清抗体结合滴度与中和抗体滴度。为进一步在分子层面解析疫苗诱导的抗体应答，本研究通过高通量单B细胞分选与发现流程制备了一组兔单克隆抗体（RmAbs），并对其进行了全面的特性鉴定。奥密克戎单价疫苗诱导的抗体结合滴度与中和活性均高于德尔塔与奥密克戎双价疫苗。从奥密克戎单价疫苗或德尔塔单价疫苗免疫的白兔体内，共分离得到4株具备强效中和活性的兔单克隆抗体。值得注意的是，从奥密克戎单价疫苗组分离得到的9E11可中和所有奥密克戎变异株，其半数抑制浓度（IC₅₀）范围为1.5~503.6 ng/mL；因此该疫苗可作为预防与治疗性干预手段。鉴于奥密克戎变异株导致的新冠病例数持续攀升，奥密克戎毒株的RBD可作为候选免疫原，诱导针对SARS-CoV-2奥密克戎亚谱系的更高水平中和活性。