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RESEARCH HIGHLIGHT OPEN
SARS-CoV-2 variant Omicron: currently the most complete
“escapee”from neutralization by antibodies and vaccines
Maochen Li
1
, Fuxing Lou
1
and Huahao Fan
1
✉
Signal Transduction and Targeted Therapy (2022) 7:28 ; https://doi.org/10.1038/s41392-022-00880-9
On December 23, 2021, five groups published their research results
of clinical-approved monoclonal antibodies, convalescent serum,
and vaccine serum against B.1.1.529 (Omicron) on Nature.
1–5
As a
SARS-CoV-2 variant of concern (VOC), variant Omicron named by
World Health Organization (WHO) with more mutations possesses
the increased immune escape ability than all previous reported
circulating variants, which has attracted extensive attention all over
the world (Fig. 1a).
As of 29 December 2021, COVID-19 has caused at least 282.9
million infections and 5,417,752 deaths (https://coronavirus.jhu.
edu/). Antibody therapies and vaccination are undoubtedly
effective means to alleviate medical pressure and control the
epidemic. At present, U.S. Food and Drug Administration (FDA)
has approved at least seven spike protein-targeted monoclonal
antibodies including Tixagevimab (COV2-2196), Cilgavimab
(COV2-2130), Sotrovimab (S309), Bamlanivimab (LY-CoV555),
Etesevimab (CB6), Casirivimab (REGN10933) and Imdevimab
(REGN10987) for clinical use (https://www.fda.gov/). However,
the emergence of Omicron variant with high infectivity and
immune escape ability brought indelible challenges to the
antibody therapy and vaccines. The number of Omicron
sequences detected worldwide has expanded at least 10-fold in
only 10 days, indicating the strong possibility of Omicron variant
becoming the new dominant variant.
2,3,6
Cao, Y et al.
1
established a magnetic-activated cell sorting based
on yeast display platform and characterized the receptor-binding
domain (RBD) escaping mutation profile for 247 neutralizing
antibodies (NAbs) obtained from convalescent serum and vaccine
recipient serum, and these NAbs were classified into 6 epitope
groups from A to F. Group A to D antibodies overlap with class 1-2
antibodies defined by Planas et al.,
2
and group E-F antibodies are
similar to class 3–4 antibodies. Group A antibodies usually cover
the ACE2-binding motif and are affected by amino acid(aa)
mutations of 417/420/456/475 and 455 sites. Group B antibodies
target the left shoulder of RBD and are very sensitive to the aa486/
487 and 476 mutations. Group C antibodies can bind to both “up”
and “down”RBD with the highest neutralizing activity, while they
are very sensitive to aa484 mutation. Group D antibodies
depended on the ring structure formed by 440-449 residues will
rotate spatially and act on S309 site. Compared with above four
common groups, groups E and F antibodies are relatively rare, the
typical members of them were isolated from SARS-CoV-1
convalescent, and they do not interact directly with ACE2. Group
E antibodies recognize complex protein/carbohydrate structures,
including N-linked glycan on N343. These antibodies will be
affected by aa339, 345 and 346 mutations. Group F antibodies
binding to hidden epitopes of RBD are sensitive to aa374, 376 and
378 mutations. All above six groups of antibodies could be
affected by different mutations in Omicron, respectively, as shown
in Fig. 1b.
The neutralization efficacy of seven FDA-approved antibodies
and eight antibodies in development (Brii-196, Brii-198, VIR-7832,
CT-P59, ADG-2, 910-30, DH1047, S2X259) in alone or combination
use against Omicron variant were estimated.
2,3,5
Among them,
Bamlanivimab, Etesevimab, Casirivimab, Imdevimab, CT-P59
(Regdanvimab) and 910-30 retained no neutralizing activity to
Omicron variant.
1–3,5
The mutation Q493R can induce the
disappearance of hydrogen bonds or the collision of antibody
CDRH3 region by causing the change of amino acid spatial
structure, which may explain the neutralization failure of
Etesevimab (class 1/group A) and Bamlanivimab (class 2/group
C). Other two mutations N440K, G446S reduce the neutralization
activity of class 3/group D antibody Imdevimab by forming steric
hindrance. Sotrovimab, Brii-196, Brii-198, ADG-20, DH1047, and
S2X259 retained neutralizing activity against Omicron variant, and
they all belong to class 3–4/group E-F except for Brii-196.
However, no antiviral activity was detected in Brii-198 and
DH1047 against B.1.1.529 +R346K pseudovirus, supporting that
group E antibodies are sensitive to aa346 mutation.
1,3
Surprisingly,
S371L may affect partial antibodies in all classes by changing the
conformation of mixed protein/carbohydrate epitope involving
N343-N-linked glycan.
1,2
Both Bamlanivimab/Etesevimab cocktail
and Casirivimab/Imdevimab cocktails lost the neutralizing activity,
while Tixagevimab/Cilgavimab cocktail was still effective for
neutralizing Omicron variant.
3,5
All above results indicated that
currently clinically available class 1-2 antibodies were difficult to
neutralize Omicron variant, and the use of class 3–4 antibodies
could be under consideration for further COVID-19 patients’
treatment.
Moreover, the efficacy of vaccines was also severely affected by
Omicron variant. The serum obtained from Ad26.COV2.S (single
dose), Sputnik V (double dose) and BBIBP-CorV (double dose)
recipients all showed negligible neutralization against Omicron
variant,
5
and the neutralizing antibodies against Omicron variant
were not detected in BNT162b2 and AZD1222 vaccine recipients
in the 5th month after the 2nd dose.
2
After the booster dose,
neutralizing activities against Omicron variant of all BNT162b2
vaccine serum significantly increased, but still decreased at least
4-fold compared with the efficiency against Wuhan-Hu-1 strain
2–5
(Fig. 1c). It is worth noting that the serum neutralizing antibodies
Received: 29 December 2021 Revised: 5 January 2022 Accepted: 6 January 2022
1
College of Life Science and Technology, Beijing University of Chemical Technology, 100029, Beijing, China
Correspondence: Huahao Fan (fanhuahao@mail.buct.edu.cn)
These authors contributed equally: Maochen Li, Fuxing Lou
www.nature.com/sigtrans
Signal Transduction and Targeted Therapy
©The Author(s) 2022
1234567890();,:
level from previous-infected recipients with booster dose is higher
than naive-uninfected counterparts,
3,5
which further suggested
that positive vaccination should be encouraged whether infected
by SARS-CoV-2 or not, and the booster dose should be taken in
time to maintain the efficiency.
In conclusion, these recent studies evaluated the neutralization
activity of currently authorized or approved antibodies and
approved vaccines against Omicron variant, and provided
significant guidance for the future individualized antibody
therapy and mass vaccination: (1) For Omicron variant-infected
SARS-CoV-2 variant Omicron: currently the most complete. . .
Li et al.
2
Signal Transduction and Targeted Therapy (2022) 7:28
patients, the treatment with group E/F antibodies should be
taken as priority, and isolation measures are necessary to avoid
the emergence and transmission of immune escape strains
against E/F epitopes antibodies during treatment; (2) For the
SARS-CoV-2 vaccine design, the sequence of seed strain should
be updated according to Omicron variant, and mixed vaccination
to avoid immune escape deserves clinical trials; (3) Positive
vaccination is indispensable regardless of a history of SARS-COV-2
infection or not, and the booster dose should be given in a timely
manner to maintain the efficiency;
6
(4) Continuous mutations of
spike protein could undermine the effect of current vaccination,
while widespread vaccination in combination with the highly
effective oral anti-COVID-19 drugs targeting conservative regions
(e.g., 3CL, RdRp), will greatly contribute to the end of the
epidemic.
7
ACKNOWLEDGEMENTS
We thank Prof. Yigang Tong and Lihua Song (Beijing University of Chemical
Technology, China) for helpful discussions and valuable suggestions. This research
was supported by National Key Research and Development Program of China (grant
no. 2019YFC1200502, 2020YFA0712102, BWS21J025, 20SWAQK22), National Natural
Science Foundation of China (grant no. 82151224), Fundamental Research Funds for
Central Universities (grant no. BUCTZY2022), and H&H Global Research and
Technology Center (grant no. H2021028).
AUTHOR CONTRIBUTIONS
H.F. designed the research; H.F., M.L., and F.L. read the papers and analyzed the data;
H.F. wrote and revised the manuscript.
ADDITIONAL INFORMATION
Competing interests: The authors declare no competing interests.
REFERENCES
1. Cao, Y. et al. Omicron escapes the majority of existing SARS-CoV-2 neutralizing
antibodies. Nature https://doi.org/10.1038/d41586-021-03796-6 (2021).
2. Planas, D. et al. Considerable escape of SARS-CoV-2 Omicron to antibody neu-
tralization. Nature https://doi.org/10.1038/d41586-02103827-2 (2021).
3. Liu, L. et al. Striking antibody evasion manifested by the Omicron variant of SARS-
CoV-2. Nature https://doi.org/10.1038/d41586-02103826-3 (2021).
4. Cele, S. et al. Omicron extensively but incompletely escapes Pfizer BNT162b2
neutralization. Nature https://doi.org/10.1038/d41586-021-03824-5 (2021).
5. Cameroni, E. et al. Broadly neutralizing antibodies overcome SARS-C oV-2 Omicron
antigenic shift. Nature https://doi.org/10.1038/d41586-02103825-4 (2021).
6. He, X. et al. SARS-CoV-2 Omicron variant: Characteristics and prevention. Med-
Comm 2, 838–845 (2020).
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vaccine era. Lancet Microbe https://doi.org/10.1016/S2666-5247(21)00278-0 (2021).
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© The Author(s) 2022
Fig. 1 A schematic illustration of the variant Omicron escaping approved antibodies and vaccines. aFDA has approved several S protein-
targeted monoclonal antibodies, in which Bamlanivimab, Etesevimab, Casirivimab, Imdevimab and CT-P59 (Regdanvimab) as well as the
serum of all kinds of 2nd vaccine dose, fail to neutralize Omicron variant, while Sotrovimab and convalescent plus vaccinated plasma maintain
the efficacy of Omicron variant. bAmino acid substitutions of Omicron variant in the spike protein, some of these mutations in RBD may affect
the neutralization activity of group A–F antibodies, respectively. cThe neutralizations of seven approved antibodies ( Tixagevimab, Cilgavimab,
Sotrovimab, Bamlanivimab, Etesevimab, Casirivimab, and Imdevimab) and six vaccines (BNT162b2, mRNA-1273, AZD1222, Sputnik V, BBIBP-
CorV, Ad26.COV2.S) against Omicron are displayed, among which Bamlanivimab, Etesevimab, Casirivimab, and Imdevimab completely lose the
neutralization while Sotrovimab still can neutralize Omicron variant effectively. All the 1st and 2nd dose vaccine serum fail to neutralize
Omicron variant, and both the serum from convalescent patient with vaccination and booster dose of BNT162b2 retain neutralization activity
against Omicron variant
SARS-CoV-2 variant Omicron: currently the most complete. . .
Li et al.
3
Signal Transduction and Targeted Therapy (2022) 7:28
