The development of a vaccine specific to severe acute respiratory syndrome coronavirus 2 Omicron has been hampered due to its low immunogenicity. Here, using reverse mutagenesis, we found that a phenylalanine-to-serine mutation at position 375 (F375S) in the spike protein of Omicron to revert it to the sequence found in Delta and other ancestral strains significantly enhanced the immunogenicity of Omicron vaccines. Sequence FAPFFAF at position 371–377 in Omicron spike had a potent inhibitory effect on macrophage uptake of receptor-binding domain (RBD) nanoparticles or spike-pseudovirus particles containing this sequence. Omicron RBD enhanced binding to Siglec-9 on macrophages to impair phagocytosis and antigen presentation and promote immune evasion, which could be abrogated by the F375S mutation. A bivalent F375S Omicron RBD and Delta-RBD nanoparticle vaccine elicited potent and broad nAbs in mice, rabbits and rhesus macaques. Our research suggested that manipulation of the Siglec-9 pathway could be a promising approach to enhance vaccine response.

由于其免疫原性低，严重急性呼吸综合征冠状病毒 2 Omicron 特异性疫苗的开发受到阻碍。在这里，我们利用反向诱变发现，Omicron 刺突蛋白第 375 位（F375S）的苯丙氨酸到丝氨酸突变使其恢复为 Delta 和其他祖先菌株中发现的序列，显着增强了 Omicron 疫苗的免疫原性。Omicron 刺突中第 371-377 位的序列 FAPFFAF 对巨噬细胞摄取受体结合域 (RBD) 纳米颗粒或含有该序列的刺突假病毒颗粒具有有效的抑制作用。Omicron RBD 增强了与巨噬细胞上 Siglec-9 的结合，从而损害吞噬作用和抗原呈递并促进免疫逃避，这可以通过 F375S 突变消除。二价 F375S Omicron RBD 和 Delta-RBD 纳米颗粒疫苗在小鼠、兔子和恒河猴中引发了有效且广泛的 nAb。我们的研究表明，操纵 Siglec-9 通路可能是增强疫苗反应的一种有前途的方法。