Breakthrough infections by SARS-CoV-2 variants become the global challenge for pandemic control. Previously, we developed the protein subunit vaccine ZF2001 based on the dimeric receptor-binding domain (RBD) of prototype SARS-CoV-2. Here, we developed a chimeric RBD-dimer vaccine approach to adapt SARS-CoV-2 variants. A prototype-Beta chimeric RBD-dimer was first designed to adapt the resistant Beta variant. Compared with its homotypic forms, the chimeric vaccine elicited broader sera neutralization of variants and conferred better protection in mice. The protection of the chimeric vaccine was further verified in macaques. This approach was generalized to develop Delta-Omicron chimeric RBD-dimer to adapt the currently prevalent variants. Again, the chimeric vaccine elicited broader sera neutralization of SARS-CoV-2 variants and conferred better protection against challenge by either Delta or Omicron SARS-CoV-2 in mice. The chimeric approach is applicable for rapid updating of immunogens, and our data supported the use of variant-adapted multivalent vaccine against circulating and emerging variants.

SARS-CoV-2 变种的突破性感染成为全球大流行控制的挑战。此前，我们基于原型SARS-CoV-2的二聚体受体结合域（RBD）开发了蛋白亚单位疫苗ZF2001。在这里，我们开发了一种嵌合 RBD-二聚体疫苗方法来适应 SARS-CoV-2 变体。原型 Beta 嵌合 RBD 二聚体最初被设计用于适应耐药 Beta 变体。与其同型形式相比，嵌合疫苗引发了更广泛的变体血清中和，并为小鼠提供了更好的保护。嵌合疫苗的保护作用在猕猴身上得到了进一步验证。这种方法被推广到开发 Delta-Omicron 嵌合 RBD 二聚体以适应当前流行的变体。同样，嵌合疫苗引发了更广泛的 SARS-CoV-2 变体血清中和，并为小鼠提供了更好的保护，以抵抗 Delta 或 Omicron SARS-CoV-2 的攻击。嵌合方法适用于免疫原的快速更新，我们的数据支持使用针对循环和新出现的变体的变体适应多价疫苗。