During the current pandemic, SARS-CoV-2 has considerably diversified. The omicron
variant (B.1.1.529) was identified at the end of November, 2021, and rapidly spread
worldwide. As of May, 2022, the omicron BA.2 subvariant is the most dominant variant
in the world. Other omicron subvariants have since emerged and some of them have begun
to outcompete BA.2 in multiple countries. For instance, omicron BA.2.11 subvariant
is spreading in France, and the BA.2.12.1 and BA.4/5 subvariants are becoming dominant
in the USA and South Africa, respectively (appendix pp 4–5).
Newly emerging SARS-CoV-2 variants need to be carefully monitored for a potential
increase in transmission rate, pathogenicity, and resistance to immune responses.
The resistance of variants to vaccines and therapeutic antibodies can be attributed
to a variety of mutations in the viral spike protein. Although the spike proteins
of new omicron subvariants (BA.2.11, BA.2.12.1, and BA.4/5) are derived from the BA.2
spike protein, the majority of them additionally bear the following mutations in the
spike: BA.2.11, L452R; BA.2.12.1, L452Q and S704L; and BA.4/5, L452R, HV69-70del,
F486V, and R493Q (appendix pp 4–5). In particular, the L452R and L452Q substitutions
were detected in the delta (B.1.617.2) and lambda (C.37) variants, respectively, and
we demonstrated that the L452R/Q substitution affects sensitivity to vaccine-induced
neutralising antibodies.1, 2 Therefore, it is reasonable to assume that these new
omicron subvariants have reduced sensitivity to therapeutic monoclonal antibodies.
To address this possibility, we generated pseudoviruses harbouring the spike proteins
of these omicron subvariants and derivatives and prepared eight therapeutic monoclonal
antibodies (appendix pp 2–3). Consistent with previous studies,3, 4, 5 bamlanivimab,
casirivimab, etesevimab, imdevimab, and tixagevimab were less functional against BA.2
than the parental virus (table
). These five antibodies were also less functional against new omicron subvariants,
whereas the BA.2 spike bearing the R493Q substitution was partially sensitive to casirivimab
and tixagevimab (table; appendix pp 4–5). Bebtelovimab was approximately 2-fold more
effective against BA.2 and all omicron subvariants tested than the parental virus
(table). Although sotrovimab was roughly 20-fold less effective against BA.2 than
the parental virus, the omicron subvariants bearing the L452R substitution, including
BA.2.11 and BA.4/5, were more sensitive to sotrovimab than BA.2 (table). Evusheld
(cilgavimab and tixagevimab), particularly cilgavimab, was effective against BA.2,
whereas the L452R/Q substitution rendered approximately 2–5-fold resistance. Notably,
BA.4/5 exhibited about 20-fold more resistance to cilgavimab and Evusheld than BA.2
(table). Recently, Cao and colleagues showed that the neutralising activity of cilgavimab
against BA.4/5 is approximately 4-fold lower than that against BA.2.
6
Here, we used lentivirus-based pseudoviruses, whereas Cao and colleagues used vesicular
stomatitis virus-based pseudoviruses.
6
Therefore, the disparity between our results and those of Cao and colleagues might
be due to the difference in the type of pseudoviruses used in the neutralisation assay.
Table
50% neutralisation concentration (ng/mL)
Bamlanivimab
Bebtelovimab
Casirivimab
Cilgavimab
Etesevimab
Imdevimab
Sotrovimab
Tixagevimab
Casirivimab plus imdevimab (Ronapreve)
Etesevimab plus bamlanivimab
Cilgavimab plus tixagevimab (Evusheld)
B.1.1 (parental)
12·8
8·1
9·9
21
12
79
94
6·7
6·2
6·7
4·1
BA.2
>3700
3·8
>50 417
19
>6050
>50 000
2190
>2750
>2400
>3700
33
BA.2.11
>3700
2·3
>50 417
71
>6050
>50 000
540
>2750
>2400
>3700
154
BA.2.12.1
>3700
5·5
>50 417
75
>6050
>50 000
629
>2750
>2400
>3700
135
BA.4/5
>3700
6·3
>50 417
443
>6050
>50 000
1261
>2750
>2400
>3700
609
BA.2 L452Q
>3700
5·0
>50 417
26
>6050
>50 000
2443
>2750
>2400
>3700
82
BA.2 S704L
>3700
1·1
>50 417
28
>6050
>50 000
1213
>2750
>2400
>3700
27
BA.2 HV69-70del
>3700
2·2
>50 417
19
>6050
>50 000
774
>2750
>2400
>3700
34
BA.2 F486V
>3700
1·1
>50 417
18
>6050
>50 000
1575
>2750
>2400
>3700
23
BA.2 R493Q
>3700
4·2
3697
22
>6050
>50 000
1791
101
431
>3700
31
Representative neutralisation curves are shown in appendix pp 4–5.
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.
We declare no competing interests. DY, YK, and IK contributed equally. This work was
supported in part by the Japan Agency for Medical Research and Development (AMED)
Research Program on Emerging and Re-emerging Infectious Diseases (JP22fk0108146 to
KS, JP20fk0108413 to KS, and JP20fk0108451 to G2P-Japan Consortium and KS), the AMED
Research Program on HIV/AIDS (JP22fk0410039 to KS), the Japan Science and Technology
Agency CREST programme (JPMJCR20H4 to KS), the Japan Society for the Promotion of
Science (JSPS) Fund for the Promotion of Joint International Research (Fostering Joint
International Research; 18KK0447 to KS), the JSPS Core-to-Core Program JPJSCCA20190008
(A. Advanced Research Networks; to KS), the JSPS Research Fellow DC2 22J11578 (to
KU), and The Tokyo Biochemical Research Foundation (to KS).