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 (i.e., 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).
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).
Table 1
| Monoclonal Antibody or Antiviral Drug | hCoV-19/Japan/UT-NCD1288-2N/2022 (Omicron/BA.2) | |
|---|---|---|
| Tested Value | Factor Increase as Compared with the Ancestral Strain | |
| Neutralization activity of monoclonal antibody† | ||
| LY-CoV016, etesevimab | >50,000 ng/ml | >2749 |
| LY-CoV555, bamlanivimab | >50,000 ng/ml | >10,661 |
| REGN10987, imdevimab | 68.65±8.84 ng/ml | 22.5 |
| REGN10933, casirivimab | 1666.19±771.77 ng/ml | 597.2 |
| COV2-2196, tixagevimab | 395.78±62.37 ng/ml | 206.1 |
| COV2-2130, cilgavimab | 4.44±2.72 ng/ml | 0.6 |
| S309, sotrovimab precursor | 1359.05±269.23 ng/ml | 49.7 |
| LY-CoV016 plus LY-CoV555 | >10,000 ng/ml | >794 |
| REGN10987 plus REGN10933 | 222.59±64.47 ng/ml | 63.1 |
| COV2-2196 plus COV2-2130 | 14.48±2.04 ng/ml | 4.2 |
| Viral susceptibility to drug‡ | ||
| GS-441524§ | 2.85±0.31 μM | 2.7 |
| EIDD-1931¶ | 0.67±0.22 μM | 1.3 |
| PF-07321332‖ | 6.76±0.69 μM | 1.9 |
Efficacy of Monoclonal Antibodies and Antiviral Drugs against the Omicron/BA.2 Subvariant in Vitro.*
*
Plus–minus values are means ±SD. The antibodies used in this analysis were produced in the authors’ laboratory and are not identical to the commercially available products. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant is denoted according to the World Health Organization labels for the Pango lineage.
†
The individual monoclonal antibodies were tested at a starting concentration of 50,000 ng per milliliter as a 50% focus reduction neutralization test (FRNT50) titer. The monoclonal antibody combinations were tested at a starting concentration of 10,000 ng per milliliter for each antibody. Shown is the factor increase in the FRNT50 titers of monoclonal antibodies against the omicron/BA.2 subvariant as compared with that against the ancestral strain, SARS-CoV-2/UT-NC002-1T/Human/2020/Tokyo (A).
‡
In this category, the value is the 50% inhibitory concentration (IC50) of the mean micromole value of triplicate reactions. The factor increase in the IC50 of drugs against the omicron/BA.2 subvariant as compared with that against the ancestral strain, SARS-CoV-2/UT-NC002-1T/Human/2020/Tokyo (A), is shown.
§
GS-441524 is the main metabolite of remdesivir, an RNA-dependent RNA polymerase inhibitor.
¶
EIDD-1931 is the active form of molnupiravir, an RNA-dependent RNA polymerase inhibitor.
‖
PF-07321332 (also known as nirmatrelvir) is a protease inhibitor.
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 (i.e., 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 (i.e., 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.
Notes
This letter was published on March 9, 2022, at NEJM.org.
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 Diseases, and 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 Development, and 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.
Supplementary Material
References
1.
World Health Organization. Weekly epidemiological update on COVID-19. February 1, 2022 (https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---1-february-2022).
2.
CoVariants. Overview of variants/mutations. February 3, 2022 (https://covariants.org/per-variant).
3.
Takashita E, Kinoshita N, Yamayoshi S, et al. Efficacy of antibodies and antiviral drugs against Covid-19 omicron variant. N Engl J Med 2022;386:995-998.
4.
Uraki R, Kiso M, Imai M, et al. Therapeutic efficacy of antibodies and antivirals against a SARS-CoV-2 Omicron variant. January 19, 2022 (https://assets.researchsquare.com/files/rs-1240227/v1/43f2453c-851d-4f87-ba4f-657687d73757.pdf?c=1642600701). preprint.
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Published online: March 9, 2022
Published in issue: April 14, 2022
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1National Institute of Infectious Diseases, Tokyo, Japan
2National Center for Global Health and Medicine, Tokyo, Japan
3University of Tokyo, Tokyo, Japan
4National Institute of Infectious Diseases, Tokyo, Japan
5University of Tokyo, Tokyo, Japan
6University of Wisconsin–Madison, Madison, WI
7National Institute of Infectious Diseases, Tokyo, Japan
8National Center for Global Health and Medicine, Tokyo, Japan
9University of Tokyo, Tokyo, Japan
10National Center for Global Health and Medicine, Tokyo, Japan
11National Institute of Infectious Diseases, Tokyo, Japan
12University of Tokyo, Tokyo, Japan
[email protected]
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