The n e w e ng l a n d j o u r na l of m e dic i n e

C or r e sp ondence

Efficacy of Antiviral Agents against Omicron

Subvariants BQ.1.1 and XBB

To the Editor: Three sublineages of the B.1.1.529
(omicron) variant of severe acute respiratory syn-
drome coronavirus 2 (SARS-CoV-2) have serially
transitioned into globally dominant forms — first
BA.1, then BA.2, and then BA.5. As of October
2022, most circulating omicron variants belong
to BA.5. However, the prevalence of BQ.1.1 (a BA.5
subvariant) and XBB (a BA.2 subvariant) is in-
creasing rapidly in several countries, including the
United States and India. BA.2 and BA.5 variants
have been shown to have less sensitivity to certain
monoclonal antibodies than previously circulating
variants of concern.1-5 Notably, as compared with
BA.5 and BA.2, BQ.1.1 and XBB carry additional
substitutions in the receptor-binding domain of
the spike (S) protein, which is the major target for
vaccines and therapeutic monoclonal antibodies
for coronavirus disease 2019 (Covid-19). These
subvariants may, therefore, be more immune-
evasive than BA.5 and BA.2.
We assessed the efficacy of therapeutic
monoclonal antibodies against omicron BQ.1.1
(hCoV-19/Japan/TY41-796/2022; TY41-796) and XBB
(hCoV-19/Japan/TY41-795/2022; TY41-795), which
were isolated from patients. The BQ.1.1 isolate
had three more substitutions (R346T, K444T,
and N460K) in its receptor-binding domain than
a BA.5 (hCoV-19/Japan/TY41-702/2022) isolate (Fig.
S1A in the Supplementary Appendix, available with
the full text of this letter at NEJM.org). The XBB
isolate had nine more changes (G339H, R346T,
L368I, V445P, G446S, N460K, F486S, F490S, and
the wild-type amino acid at position 493) in its
receptor-binding domain than a BA.2 (hCoV-19/
Japan/UT-NCD1288-2N/2022) isolate (Fig. S1B).
To examine the reactivity of monoclonal anti-
bodies against these subvariants, we determined
the 50% focus reduction neutralization test
(FRNT50) titer of the monoclonal antibodies by
using a live-virus neutralization assay. REGN10987
(marketed as imdevimab), REGN10933 (marketed
as casirivimab), COV2-2196 (marketed as tixa­
gev­i­mab), COV2-2130 (marketed as cilgavimab),
and S309 (the precursor of sotrovimab) did not
neutralize the BQ.1.1 or XBB isolates even at the
highest FRNT50 value (>50,000 ng per milliliter)
tested (Fig. 1A and Table S1). LY-CoV1404 (mar-
keted as bebtelovimab), which effectively neu-
tralizes1,3-5 omicron BA.1, BA.2, BA.4, and BA.5,
had no efficacy against BQ.1.1 or XBB. Both com-
binations of monoclonal antibodies tested (i.e.,
imdevimab–casirivimab and tixagevimab–cil-
gavimab) failed to neutralize either BQ.1.1 or XBB.
These results suggest that imdevimab–casirivimab,
tixagevimab–cilgavimab, sotrovimab, and bebt-
elovimab may not be effective against BQ.1.1 or
XBB in the clinical setting.
The Food and Drug Administration approved
remdesivir (an inhibitor of the RNA-dependent
RNA polymerase [RdRp] of SARS-CoV-2) for the
treatment of Covid-19 and issued an emergency
use authorization for molnupiravir (an RdRp in-
hibitor) and nirmatrelvir (an inhibitor of the main
protease of SARS-CoV-2). We therefore tested
these antiviral drugs by determining the in vitro
50% inhibitory concentration (IC50) of each com-
pound against BQ.1.1 and XBB. Unlike the amino
acid sequence of the reference strain Wuhan/
Hu-1/2019, the BQ.1.1 and XBB isolates encode
the P3395H substitution in their main protease
(Fig. S1C and S1D). The BQ.1.1 and XBB isolates
also have two (Y264H and P314L) and three
(P314L, M659I, and G662S) substitutions in their
RdRp, respectively. The susceptibilities of BQ.1.1
and XBB to the three compounds were similar to
those of the ancestral strain (SARS-CoV-2/UT-
NC002-1T/Human/2020/Tokyo). For BQ.1.1, the
IC50 value was lower by a factor of 0.6 with rem-
desivir and higher by factors of 1.1 and 1.2 with
molnupiravir and nirmatrelvir, respectively. For
the XBB subvariant, the IC50 value was lower by a
factor of 0.8 with remdesivir, lower by a factor of
0.5 with molnupiravir, and higher by a factor of 1.3
with nirmatrelvir (Fig. 1B). These results suggest

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Ancestral strain: SARS-CoV-2/UT-NC002-1T/Human/2020/Tokyo Omicron BQ.1.1: hCoV-19/Japan/TY41-796/2022

Omicron BA.2: hCoV-19/Japan/UT-NCD1288-2N/2022 Omicron XBB: hCoV-19/Japan/TY41-795/2022
Omicron BA.5: hCoV-19/Japan/TY41-702/2022

A Neutralizing Activity of Monoclonal Antibodies

REGN10987 REGN10933 REGN10987–REGN10933
Imdevimab Casirivimab Imdevimab–Casirivimab
100 100 100
FRNT50 (ng/ml) FRNT50 (ng/ml) FRNT50 (ng/ml)
Ancestral: 34.4 Ancestral: 28.7 Ancestral: 29.4
80 BA.2: 1,840.6 80 BA.2: >50,000 80 BA.2: 2,606.9
Neutralization (%)

BA.5: 876.5 BA.5: >50,000 BA.5: 2,982.0

60 BQ.1.1: >50,000 60 BQ.1.1: >50,000 60 BQ.1.1: >50,000
XBB: >50,000 XBB: >50,000 XBB: >50,000
40 40 40

20 20 20

0 0 0
10–4 10–2 100 102 104 106 10–4 10–2 100 102 104 106 10–4 10–2 100 102 104 106

S309 LY-CoV1404 COV2-2196

Sotrovimab Precursor Bebtelovimab Tixagevimab
100 100 100
FRNT50 (ng/ml) FRNT50 (ng/ml) FRNT50 (ng/ml)
Ancestral: 1304.6 Ancestral: 16.5 Ancestral: 29.1
80 BA.2: >50,000 80 BA.2: 12.5 80 BA.2: 12,867.9
Neutralization (%)

BA.5: >50,000 BA.5: 14.3 BA.5: >50,000

60 BQ.1.1: >50,000 60 BQ.1.1: >50,000 60 BQ.1.1: >50,000
XBB: >50,000 XBB: >50,000 XBB: >50,000
40 40 40

20 20 20

0 0 0
10–4 10–2 100 102 104 106 10–4 10–2 100 102 104 106 10–4 10–2 100 102 104 106

COV2-2130 COV2-2196–COV2-2130
Cilgavimab Tixagevimab–Cilgavimab
100 100
FRNT50 (ng/ml) FRNT50 (ng/ml)
Ancestral: 79.0 Ancestral: 37.7
80 BA.2: 76.9 80 BA.2: 188.1
Neutralization (%)

BA.5: 258.0 BA.5: 633.6

60 BQ.1.1: >50,000 60 BQ.1.1: >50,000
XBB: >50,000 XBB: >50,000
40 40

20 20

0 0
10–4 10–2 100 102 104 106 10–4 10–2 100 102 104 106
Antibody Concentration (ng/ml)

B Inhibitory Activity of Antiviral Drugs

GS-441524 EIDD-1931 PF-07321332
Remdesivir Molnupiravir Nirmatrelvir
100 100 100
IC50 (µmol/liter) IC50 (µmol/liter) IC50 (µmol/liter)
Ancestral: 1.8 Ancestral: 2.5 Ancestral: 2.2
80 BA.2: 2.3 80 BA.2: 3.5 80 BA.2: 3.2
Inhibition (%)

BA.5: 2.3 BA.5: 4.6 BA.5: 2.9

60 BQ.1.1: 1.0 60 BQ.1.1: 2.8 60 BQ.1.1: 2.6
XBB: 1.4 XBB: 1.2 XBB: 2.9
40 40 40

20 20 20

0 0 0
10–4 10–2 100 102 104 106 10–4 10–2 100 102 104 106 10–2 10–1 100 101 102
Drug Concentration (µmol/liter)

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 Correspondence
Figure 1 (facing page). In Vitro Efficacy of Therapeutic
Monoclonal Antibodies and Antiviral Drugs against
Omicron Subvariants.
Panel A shows the neutralizing activity of monoclonal
antibodies against omicron subvariants. The antibod‑
ies used in this analysis were produced in the authors’
laboratories and are not identical to the commercially
available products. The 50% focus reduction neutral‑
ization test (FRNT50) titer levels were determined by
performing a focus reduction neutralization test in
Vero E6 cells engineered to express transmembrane
serine protease 2 (TMPRSS2) and human angiotensin-
converting enzyme 2 (ACE2). The data shown are the
mean values for triplicate experiments. Panel B shows
the inhibitory activity of antiviral drugs against omicron
subvariants. The drugs used were purchased from
MedChemExpress. The in vitro 50% inhibitory con‑
centration (IC50) values were determined by perform‑
ing a focus reduction assay in Vero E6 cells engineered
to express TMPRSS2 and ACE2. The data shown are
the mean values for triplicate experiments. GS-441524
(the main metabolite of remdesivir) and EIDD-1931
(the active form of molnupiravir) are RNA-dependent
RNA polymerase inhibitors. PF-07321332 (nirmatrelvir)
is a main protease inhibitor.
that remdesivir, molnupiravir, and nirmatrelvir
are efficacious against both BQ.1.1 and XBB in
vitro.
Our data suggest that the omicron sublineages
BQ.1.1 and XBB have immune-evasion capabilities
that are greater than those of earlier omicron
variants, including BA.5 and BA.2. The continued
evolution of omicron variants reinforces the need
for new therapeutic monoclonal antibodies for
Covid-19.
Masaki Imai, D.V.M., Ph.D.
Mutsumi Ito, D.V.M.
Maki Kiso, D.V.M., Ph.D.
Seiya Yamayoshi, D.V.M., Ph.D.
Ryuta Uraki, Ph.D.
University of Tokyo
Tokyo, Japan
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Shuetsu Fukushi, Ph.D.
Shinji Watanabe, D.V.M., Ph.D.
Tadaki Suzuki, M.D., Ph.D.
Ken Maeda, D.V.M., Ph.D.
National Institute of Infectious Diseases
Tokyo, Japan
Yuko Sakai‑Tagawa, Ph.D.
Kiyoko Iwatsuki‑Horimoto, D.V.M., Ph.D.
University of Tokyo
Tokyo, Japan
Peter J. Halfmann, Ph.D.
University of Wisconsin–Madison
Madison, WI
Yoshihiro Kawaoka, D.V.M., Ph.D.
University of Tokyo
Tokyo, Japan
yoshihiro​.­kawaoka@​­wisc​.­edu
Drs. Imai and Ito and Drs. Kiso and Yamayoshi contributed
equally to this letter.
Supported by grants from the Center for Research on Influ-
enza Pathogenesis and Transmission (75N93021C00014, to Dr.
Kawaoka), funded by the National Institute of Allergy and Infec-
tious Diseases; a Research Program on Emerging and Reemerg-
ing Infectious Diseases (JP21fk0108552 and JP21fk0108615, to
Dr. Kawaoka); a Project Promoting Support for Drug Discovery
(JP21nf0101632, to Dr. Kawaoka); the Japan Program for Infec-
tious Diseases Research and Infrastructure (JP22wm0125002,
to Dr. Kawaoka); and the Japan Agency for Medical Research
and Development (JP223fa627001, to Dr. Kawaoka).
Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
This letter was published on December 7, 2022, at NEJM.org.
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DOI: 10.1056/NEJMc2214302
Correspondence Copyright © 2022 Massachusetts Medical Society.
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