Abstract: bioRxiv preprint doi: https://doi.org/10.1101/2022.02.15.480166; this version posted February 16, 2022. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. SARS-CoV-2 Omicron BA.2 Variant Evades Neutralization by Therapeutic Monoclonal Antibodies Hao Zhou1,*, Takuya Tada1,*, Belinda M. Dcosta1,* and Nathaniel R. Landau1,# Affiliation: 1 Department of Microbiology, NYU Grossman School of Medicine, New York, NY, USA. *These authors contributed equally. #Corresponding author: Nathaniel R. Landau, Ph.D. NYU Grossman School of Medicine 430 East 29th Street, Alexandria West Building, Rm 509, New York, NY 10016 Email: nathaniel.landau@med.nyu.edu Phone: (212) 263-9197 1 bioRxiv preprint doi: https://doi.org/10.1101/2022.02.15.480166; this version posted February 16, 2022. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Keywords: SARS-CoV-2 variants, Omicron BA.2, monoclonal antibodies, spike protein, Sotrovimab, Evusheld. 2 bioRxiv preprint doi: https://doi.org/10.1101/2022.02.15.480166; this version posted February 16, 2022. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Monoclonal antibody therapy for the treatment of SARS-CoV-2 infection has been highly successful in decreasing disease severity; however, the recent emergence of the heavily mutated Omicron variant has posed a challenge to this treatment strategy. The Omicron variant BA.1 has been found to evade neutralization by the Regeneron and Eli Lilly therapeutic monoclonal antibodies, while Sotrovimab and the Evusheld monoclonal antibody cocktail retain significant neutralizing activity. A newly emerged variant, Omicron BA.2, containing the BA.1 mutations plus an additional 6 mutations and 3 deletions, 3 of which lie in the receptor binding domain, has been found to be spreading with increased transmissibility. We report here, using a spike protein-pseudotyped lentivirus assay, that Omicron BA.2 is not neutralized with detectable titer by any of the therapeutic monoclonal antibodies, including Sotrovimab and the Evusheld monoclonal antibodies. The results demonstrate the difficulty of identifying broadly neutralizing monoclonal antibodies against SARS-CoV-2 and the importance of the T cell response from which immunoevasion is more difficult. 3 bioRxiv preprint doi: https://doi.org/10.1101/2022.02.15.480166; this version posted February 16, 2022. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Main text The BA.2 variant of the highly mutated Omicron SARS-CoV-2 variant identified in late 2021 in patients in countries including Denmark, South Africa and India (1) and since then, in more countries including the United States. BA.2 has been found to be 1.5-fold more transmissible than the already highly transmissible BA.1 variant and is thus expected to continue to increase in prevalence (2). The BA.2 spike protein has all of the mutations of BA.1 plus an additional 6 mutations and 3 deletions, three of which lie in the receptor binding domain (3) (Supplemental Figure 1A). Of the monoclonal antibodies authorized by the Food and..