Mechanism of a rabbit monoclonal antibody broadly neutralizing SARS-CoV-2 variants

Abstract

Due to the continuous evolution of SARS-CoV-2, the Omicron variant has emerged and exhibits severe immune evasion. The high number of mutations at key antigenic sites on the spike protein has made a large number of existing antibodies and vaccines ineffective against this variant. Therefore, it is urgent to develop efficient broad-spectrum neutralizing therapeutic drugs. Here we characterize a rabbit monoclonal antibody (RmAb) 1H1 with broad-spectrum neutralizing potency against Omicron sublineages including BA.1, BA.1.1, BA.2, BA.2.12.1, BA.2.75, BA.3 and BA.4/5. Cryo-electron microscopy (cryo-EM) structure determination of the BA.1 spike-1H1 Fab complexes shows that 1H1 targets a highly conserved region of RBD and avoids most of the circulating Omicron mutations, explaining its broad-spectrum neutralization potency. Our findings indicate 1H1 as a promising RmAb model for designing broad-spectrum neutralizing antibodies and shed light on the development of therapeutic agents as well as effective vaccines against newly emerging variants in the future.

Engineered Multivalent Nanobodies Efficiently Neutralize SARS-CoV-2 Omicron Subvariants BA.1, BA.4/5, XBB.1 and BQ.1.1

“…Several prior studies have demonstrated the presence of conserved epitopes on the RBD, whether in the RBM region or the non-RBM region, highlighting the potential to use the RBD as an effective target for developing potent and broadly neutralizing antibodies [33][34][35][36]57,58]. In this study, our aim was to initially develop robust nanobodies that target diverse epitopes on the RBD and effectively inhibit various Omicron subvariants.…”

“…Notably, the majority of spike glycoprotein mutations in Omicron are concentrated in the RBD region, significantly impairing the potency of most RBD-targeting neutralizing antibodies [32]. Recently, several broadly neutralizing antibodies have been reported to demonstrate potent efficacy in neutralizing BA.4/5, BQ, and XBB subvariants by binding to highly conserved RBD epitopes [33][34][35][36]. These studies have demonstrated that the RBD still contains protective and conserved epitopes, which can serve as viable targets for the development of potent and broadspectrum neutralizing antibodies.…”

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

“…Following the fitting of the curve, the dissociation constant (K D ) value was calculated after the background was removed. 27 …”