Emerging SARS-CoV-2 variants, notably Omicron, continue to remain a formidable challenge to worldwide public health. The SARS-CoV-2 receptor-binding domain (RBD) is a hotspot for mutations, reflecting its critical role at the ACE2 interface during viral entry. Here, we comprehensively investigated the impact of RBD mutations, including 5 variants of concern (VOC) or interest—including Omicron (BA.2)—and 33 common point mutations, both on IgG recognition and ACE2-binding inhibition, as well as FcγRIIa- and FcγRIIIa-binding antibodies, in plasma from two-dose BNT162b2-vaccine recipients and mild-COVID-19 convalescent subjects obtained during the first wave using a custom-designed bead-based 39-plex array. IgG-recognition and FcγR-binding antibodies were decreased against the RBD of Beta and Omicron, as well as point mutation G446S, found in several Omicron sub-variants as compared to wild type. Notably, while there was a profound decrease in ACE2 inhibition against Omicron, FcγR-binding antibodies were less affected, suggesting that Fc functional antibody responses may be better retained against the RBD of Omicron in comparison to neutralization. Furthermore, while measurement of RBD–ACE2-binding affinity via biolayer interferometry showed that all VOC RBDs have enhanced affinity to human ACE2, we demonstrate that human ACE2 polymorphisms, E35K (rs1348114695) has reduced affinity to VOCs, while K26R (rs4646116) and S19P (rs73635825) have increased binding kinetics to the RBD of VOCs, potentially affecting virus–host interaction and, thereby, host susceptibility. Collectively, our findings provide in-depth coverage of the impact of RBD mutations on key facets of host–virus interactions.

新兴的 SARS-CoV-2 变种，特别是 Omicron，仍然对全球公共卫生构成巨大挑战。SARS-CoV-2 受体结合域 (RBD) 是突变的热点，反映了其在病毒进入过程中在 ACE2 界面上的关键作用。在这里，我们全面研究了 RBD 突变的影响，包括 5 个关注变体 (VOC) 或感兴趣的变体（包括 Omicron (BA.2)）和 33 个常见点突变，均对 IgG 识别和 ACE2 结合抑制以及 FcγRIIa 产生影响- 和 FcγRIIIa 结合抗体，来自两剂 BNT162b2 疫苗接种者和轻度 COVID-19 恢复期受试者的血浆，在第一波期间使用定制设计的基于珠子的 39 重阵列获得。与野生型相比，针对 Beta 和 Omicron 的 RBD 以及在几个 Omicron 亚变体中发现的点突变 G446S 的 IgG 识别和 FcγR 结合抗体有所减少。值得注意的是，虽然针对 Omicron 的 ACE2 抑制显着降低，但 FcγR 结合抗体受到的影响较小，这表明与中和相比，针对 Omicron 的 RBD 的 Fc 功能性抗体反应可能会更好地保留。此外，虽然通过生物层干涉测量法测量 RBD-ACE2 结合亲和力表明所有 VOC RBD 对人类 ACE2 的亲和力增强，但我们证明人类 ACE2 多态性 E35K (rs1348114695) 对 VOC 的亲和力降低，而 K26R (rs4646116) 和 S19P (rs73635825) 增加了与 VOC 的 RBD 的结合动力学，可能影响病毒与宿主的相互作用，从而影响宿主的易感性。总的来说，我们的研究结果深入探讨了 RBD 突变对宿主与病毒相互作用的关键方面的影响。