Broadly Neutralizing Antibodies Against Omicron Variants of SARS-CoV-2 Derived from mRNA-Lipid Nanoparticle-Immunized Mice

The COVID-19 pandemic continues to threaten human health worldwide, as new variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged. Currently, the predominant circulating strains around the world are Omicron variants, which can evade many therapeutic antibodies. Thus, the development of new broadly neutralizing antibodies remains an urgent need. In this work, we address this need by using the mRNA-lipid nanoparticle immunization method to generate a set of Omicron-targeting monoclonal antibodies. Five of our novel K-RBD-mAbs show strong binding and neutralizing activities toward all SARS-CoV-2 variants of concern (Alpha, Beta, Gamma, Delta and Omicron). Notably, the epitopes of these five K-RBD-mAbs are overlapping and localized around Y453 and F486 of the spike protein receptor binding domain (RBD). Chimeric derivatives of the five antibodies (K-RBD-chAbs) neutralize Omicron sublineages BA.1 and BA.2 with low IC50 values that range from 5.7 to 12.9 ng/mL. Additionally, we performed antibody humanization on a broadly neutralizing chimeric antibody to create K-RBD-hAb-62, which still retains excellent neutralizing activity against Omicron. Our results collectively suggest that these five therapeutic antibodies may effectively combat current and emerging SARS-CoV-2 variants, including Omicron BA.1 and BA.2. Therefore, the antibodies can potentially be used as universal neutralizing antibodies against SARS-CoV-2.Funding Information: This research was funded by Academia Sinica, Key and Novel Therapeutics Development Program for Major Diseases (AS-KPQ-111-KNT) and the Emerging Infectious and Major Disease Research Program (AS-KPQ-111-EIMD) to HCW.Declaration of Interests: Related to this work, the Institute of Cellular and Organismic Biology and Biomedical Translation Research Center (BioTReC), Academia Sinica have filed a patent application on which H.C.W., R.M.L., W.Y.C. and H.T.L. are named as inventors. The other authors declare no conflict of interest.Ethics Approval Statement: All animal experiments were approved by the Academia Sinica Institutional Animal Care and Use Committee (IACUC protocol No. 20051468).