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

To the Editor:

The omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for coronavirus disease 2019 (Covid-19), has spread rapidly around the world and has already become the predominant variant circulating in many countries. As of February 2022, omicron variants have been divided into four distinct sublineages: BA.1, BA.1.1, BA.2, and BA.3.1 Most circulating omicron variants belong to sublineage BA.1; however, in Denmark, India, and the Philippines, the sublineage BA.2 is now becoming dominant.2

As compared with the Wuhan / Hu-1/2019 reference strain, the sublineage BA.2 of the omicron variant has 16 amino acid substitutions in the receptor-binding domain of the spike (S) protein of SARS-CoV-2,2 which is the primary target for monoclonal antibody – based therapy. The BA.2 and BA.1 variants share 12 of these 16 substitutions; however, BA.2 has four substitutions in the receptor-binding domain (ie, S371F, T376A, D405N, and R408S) that differ from those in BA.1. These findings suggest that there may be differences in the effectiveness of monoclonal antibodies against these different omicron sublineages.

Accordingly, we examined the neutralizing ability of therapeutic monoclonal antibodies that have been approved by the Food and Drug Administration, individually and in combination, against the omicron BA.2 subvariant hCoV-19 / Japan / UT-NCD1288-2N / 2022 (omicron / BA.2; NCD1288), which was isolated from a traveler who arrived in Japan from India. Whole-genome sequencing analysis of the NCD1288 virus stock confirmed that it had the 16 substitutions that are characteristic of the omicron variant in the receptor-binding domain of the S protein, as compared with the Wuhan / Hu-1/2019 reference strain (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).

Efficacy of Monoclonal Antibodies and Antiviral Drugs against the Omicron / BA.2 Subvariant in Vitro.

A live-virus focus reduction neutralization test (FRNT) showed that both LY-CoV016 (marketed as etesevimab) and LY-CoV555 (marketed as bamlanivimab), individually and in combination, lost neutralizing activity against omicron / BA.2 (NCD1288) (Table 1). These findings are similar to our previous findings with omicron / BA.1 (hCoV-19 / Japan / NC928-2N / 2021; NC928)3 and omicron / BA.1.1 (hCoV-19 / Japan / NC929-1N / 2021; NC929).4 BA.1.1, a subvariant of BA.1, has the R346K mutation in the S protein (Table S2). However, REGN10987 (marketed as imdevimab), which was previously shown to lose neutralizing activity against omicron / BA.1 (NC928) and omicron / BA.1.1 (NC929),3.4 had neutralizing activity against omicron / BA.2 (NCD1288).

In addition, the combination of REGN10987 and REGN10933 (marketed as casirivimab) also inhibited omicron / BA.2 but did not inhibit omicron / BA.1 or omicron / BA.1.1. However, the FRNT50 (the titer of monoclonal antibodies required for a 50% reduction in the number of infectious foci) value of this combination therapy was higher by a factor of 43.0 to 143.6 for omicron / BA.2 than for an ancestral strain – SARS-CoV-2 / UT-NC002-1T / Human / 2020 / Tokyo (NC002) – and other variants of concern (ie, the alpha [B.1.1.7]beta [B.1.351]gamma [P.1]and delta [B.1.617.2] variants).

REGN10933, COV2-2196 (marketed as tixagevimab), and COV2-2130 (marketed as cilgavimab) neutralized omicron / BA.2. The COV2-2196 – COV2-2130 combination inhibited omicron / BA.2 with a low FRNT50 value (14.48 ng per milliliter); however, the FRNT50 values ​​of this combination were higher by a factor of 1.4 to 8.1 for omicron / BA.2 than for the ancestral strain and other variants of concern.

S309 (the precursor of sotrovimab), which has been shown to have lower neutralizing activity against omicron / BA.1 and omicron / BA.1.1 than against the ancestral strain and other variants of concern,3.4 had even less neutralizing activity against omicron / BA.2 in our study. The FRNT50 value of this monoclonal antibody was higher by a factor of 12.2 to 49.7 for omicron / BA.2 than for the ancestral strain and other variants of concern.

The susceptibilities of omicron / BA.2 (NCD1288) to remdesivir, molnupiravir, and nirmatrelvir were similar to those of the ancestral strain and other variants of concern (ie, 50% inhibitory concentration values ​​for these three agents that differed by factors of 2.5 to 4.5, 0.7 to 1.6, and 1.5 to 3.3, respectively) (Table 1).3 Clinical studies are warranted to determine whether these antiviral therapies are indeed effective against omicron / BA.2 infections. Our data indicate that some therapeutic monoclonal antibodies (REGN10987 – REGN10933, COV2-2196 – COV2-2130, and S309) have lower neutralizing activity against omicron / BA.2 than against earlier variant strains.

Emi Takashita, Ph.D.
National Institute of Infectious Diseases, Tokyo, Japan

Noriko Kinoshita, MD
National Center for Global Health and Medicine, Tokyo, Japan

Seiya Yamayoshi, DVM, Ph.D.
Yuko Sakai-Tagawa, Ph.D.
University of Tokyo, Tokyo, Japan

Seiichiro Fujisaki, Ph.D.
National Institute of Infectious Diseases, Tokyo, Japan

Mutsumi Ito, DVM
Kiyoko Iwatsuki-Horimoto, DVM, Ph.D.
University of Tokyo, Tokyo, Japan

Peter Halfmann, Ph.D.
University of Wisconsin – Madison, Madison, WI

Shinji Watanabe, DVM, Ph.D.
National Institute of Infectious Diseases, Tokyo, Japan

Kenji Maeda, MD, Ph.D.
National Center for Global Health and Medicine, Tokyo, Japan

Masaki Imai, DVM, Ph.D.
University of Tokyo, Tokyo, Japan

Hiroaki Mitsuya, MD, Ph.D.
Norio Ohmagari, MD, Ph.D.
National Center for Global Health and Medicine, Tokyo, Japan

Makoto Takeda, MD, Ph.D.
Hideki Hasegawa, MD, Ph.D.
National Institute of Infectious Diseases, Tokyo, Japan

Yoshihiro Kawaoka, DVM, Ph.D.
University of Tokyo, Tokyo, Japan
[email protected]

Supported by grants from the Center for Research on Influenza Pathogenesis (HHSN272201400008C, to Dr. Kawaoka), and from the Center for Research on Influenza Pathogenesis and Transmission (75N93021C00014, to Dr. Kawaoka), funded by the National Institute of Allergy and Infectious Diseasesand by a Research Program on Emerging and Reemerging Infectious Diseases (JP20fk0108412 and JP21fk0108615, to Dr. Kawaoka; JP21fk0108104, to Dr. Watanabe), a Project Promoting Support for Drug Discovery (JP20nk0101632, to Dr. Kawaoka), the Japan Program for Infectious Diseases Research and Infrastructure (JP21wm0125002, to Dr. Kawaoka) from the Japan Agency for Medical Research and Developmentand a Grant-in-Aid for Emerging and Reemerging Infectious Diseases from the Ministry of Health, Labor, and Welfare, Japan (20HA2007, to Dr. Hasegawa).

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

This letter was published on March 9, 2022, at NEJM.org.

Drs. Takashita, Kinoshita, and Yamayoshi contributed equally to this letter.

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