key: cord-0975665-lb1ptujt
authors: Yamasoba, Daichi; Kosugi, Yusuke; Kimura, Izumi; Fujita, Shigeru; Uriu, Keiya; Ito, Jumpei; Sato, Kei
title: Sensitivity of novel SARS-CoV-2 Omicron subvariants, BA.2.11, BA.2.12.1, BA.4 and BA.5 to therapeutic monoclonal antibodies
date: 2022-05-03
journal: bioRxiv
DOI: 10.1101/2022.05.03.490409
sha: fcd9c562a521409512ffb3807c41fe9698c501a3
doc_id: 975665
cord_uid: lb1ptujt

As of May 2022, Omicron BA.2 variant is the most dominant variant in the world. Thereafter, Omicron subvariants have emerged and some of them began outcompeting BA.2 in multiple countries. For instance, Omicron BA.2.11, BA.2.12.1 and BA.4/5 subvariants are becoming dominant in France, the USA and South Africa, respectively. In this study, we evaluated the sensitivity of these new Omicron subvariants (BA.2.11, BA.2.12.1 and BA.4/5) to eight therapeutic monoclonal antibodies (bamlanivimab, bebtelovimab, casirivimab, cilgavimab, etesevimab, imdevimab, sotrovimab and tixagevimab). Notably, we showed that although cilgavimab is antiviral against BA.2, BA.4/5 exhibits higher resistance to this antibody compared to BA.2. Since mutations are accumulated in the spike proteins of newly emerging SARS-CoV-2 variants, we suggest the importance of rapid evaluation of the efficiency of therapeutic monoclonal antibodies against novel SARS-CoV-2 variants.

F486V and R493Q ( Figure 1B) . In particular, the L452R and L452Q substitutions 45

were detected in Delta and Lambda variants, and we demonstrated that the L452R/Q 46 substitution affects the sensitivity to vaccine-induced neutralizing antibodies. 1,2 47

Therefore, it is reasonable to assume that these new Omicron subvariants reduces 48 sensitivity towards therapeutic monoclonal antibodies. To address this possibility, 49

we generated pseudoviruses harboring the S proteins of these Omicron subvariants 50

and derivatives and prepared eight therapeutic monoclonal antibodies. Consistent 51 with previous studies, 3-5 bamlanivimab, casirivimab, etesevimab, imdevimab and 52 tixagevimab were not functional against BA.2 ( Figure 1C) . These five antibodies did 53 not work against new Omicron subvariants, while the BA.2 S bearing R493Q 54 substitution was partially sensitive to casirivimab and tixagevimab ( Figure 1C and 55 Figure S1 ). Interestingly, bebtelovimab was ~2-fold more effective against BA.2 and 56

all Omicron subvariants tested than the parental virus ( Figure 1C) . Although 57 sotrovimab was ~20-fold less antiviral against BA.2 than the parental virus, the 58

Omicron subvariants bearing L452R substitution including BA.2.11 and BA.4/5 were 59 more sensitive to sotrovimab than BA.2 ( Figure 1C) . Cilgavimab was also antiviral 60 against BA.2, while the L452R/Q substitution rendered ~2-5-fold resistance to this 61 antibody. Notably, BA.4/5 exhibited ~30-fold more resistance to cilgavimab 62 compared to BA.2 ( Figure 1C) . 63

Since mutations are accumulated in the S proteins of newly emerging 64 SARS-CoV-2 variants, we suggest the importance of rapid evaluation of the 65 efficiency of therapeutic monoclonal antibodies against novel SARS-CoV-2 variants. 66 

SARS-CoV-2 B.1.617 mutations L452R 84 and E484Q are not synergistic for antibody evasion

The SARS-CoV-2 Lambda variant exhibits 87 enhanced infectivity and immune resistance

Serum neutralization of SARS-CoV-2 90

Omicron sublineages BA.1 and BA.2 in patients receiving monoclonal 91 antibodies

Efficacy of Antiviral Agents 93 against the SARS-CoV-2 Omicron Subvariant BA.2

Resilience of S309 and AZD7442 96 monoclonal antibody treatments against infection by SARS-CoV-2 Omicron 97 lineage strains

 (bamlanivimab, bebtelovimab, casirivimab, cilgavimab, etesevimab, imdevimab, 116 sotrovimab and tixagevimab) were tested. The assay of each antibody was 117 performed in sextuplicate at each concentration to determine the 50% neutralization 118concentration. The log2 fold changes of resistance versus the parental virus (circle 119 size) or BA.2 (color) are respectively shown. Representative neutralization curves 120 are shown in Figure S1 in the Supplementary Appendix. 121