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Received: April Revised: July Accepted: July
DOI: ./mco.
REVIEW
Sub-lineages of the SARS-CoV-2 Omicron
variants: Characteristics and prevention
Ailan Xu1,2,#Bixia Hong1,#Fuxing Lou1,#Shuqi Wang1,#Wenye Li1
Amna Shafqat1Xiaoping An1Yunwei Zhao2,∗Lihua Song1,∗
Yigang Tong1,∗Huahao Fan1,∗
College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
The First Affiliated Hospital of Jiamusi University, Jiamusi, China
∗Correspondence
Yunwei Zhao, The First Affiliated
Hospital of Jiamusi University, Jiamusi
, China.
Email: @qq.com
Lihua Song, Yigang Tong and Huahao
Fan, College of Life Science and
Technology, Beijing University of
Chemical Technology, Beijing ,
China.
Email: songlihua@mail.buct.edu.cn,
tongyigang@mail.buct.edu.cn,
fanhuahao@mail.buct.edu.cn
Funding information
National Key Research and Development
Program of China, Grant/Award
Numbers: YFC,
YFC, YFA,
BWSJ, SWAQK; National
Natural Science Foundation of China,
Grant/Award Number: ;
Fundamental Research Funds for Central
Universities, Grant/Award Number:
BUCTZY; H&H Global Research and
Technology Center, Grant/Award
Number: H; Key Project of Beijing
University of Chemical Technology,
Grant/Award Numbers: XK-,
XK-
Abstract
Since the start of the coronavirus disease (COVID-) pandemic, new vari-
ants of severe acute respiratory syndrome coronavirus (SARSCoV) have
emerged, accelerating the spread of the virus. Omicron was defined by the World
Health Organization in November as the fifth “variant of concern” after
Alpha, Beta, Gamma, and Delta. In recent months, Omicron has become the
main epidemic strain. Studies have shown that Omicron carries more muta-
tions than Alpha, Beta, Gamma, Delta, and wild-type, facilitating immune escape
and accelerating its transmission. This review focuses on the Omicron variant’s
origin, transmission, main biological features, subvariants, mutations, immune
escape, vaccination, and detection methods. We also discuss the appropriate
preventive and therapeutic measures that should be taken to address the new
challenges posed by the Omicron variant. This review is valuable to guide the
surveillance, prevention, and development of vaccines and other therapies for
Omicron variants. It is desirable to develop a more efficient vaccine against the
Omicron variant and take more effective measures to constrain the spread of the
epidemic and promote public health.
KEYWORDS
immune escape, neutralizing antibodies, Omicron variant, SARS-CoV-, vaccination
#Ailan Xu, Bixia Hong, Fuxing Lou and Shuqi Wang contributed equally.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the
original work is properly cited.
© The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.
MedComm. ;:e. wileyonlinelibrary.com/journal/mco 1of24
https://doi.org/./mco.
2of24 XU .
1 INTRODUCTION
Since December , severe acute respiratory syndrome
coronavirus (SARS-CoV-) has swept the world in var-
ious forms, with different mutations. As of July , ,
there were ,, cases of coronavirus disease
(COVID-) and ,, deaths (https://covid.who.int/
[July , ]). Under the wall of vaccines, antibodies, and
drugs, variants continue to arise, including five variants of
concern (VOCs) (Alpha, Beta, Gamma, Delta, and Omi-
cron) with increased transmissibility, virulence, or reduced
diagnostic, therapeutic, and vaccine potency, which pose a
potential threat to public health.
The Delta wave, which occupied a dominant position in
most countries worldwide, gradually faded in South Africa
and was replaced with the looming of a new variant—
Omicron, and it has become the fourth peak driving the
epidemic in South Africa (first peak: Alpha; second peak:
Beta; third peak: Delta). Omicron was a newly emerged
VOC, which possessed seven subvariants, including BA.,
BA.., BA., BA., BA..., BA., and BA.. Currently,
Omicron BA. is the main variant causing SARS-CoV-
infections worldwide. However, the SARS-CoV- Omicron
BA..., BA., and BA. subvariants are phylogeneti-
cally independent of the BA. evolutionary branch. The
Omicron BA. and BA. subvariants are currently at low
endemic levels globally. The rapid spread of new subvari-
ants of Omicron has led to a rapid increase in prevalence
in the USA and South Africa, implying its potential for fur-
ther global pandemics. The new subvariants of Omicron
have unique mutational sites, which facilitate accelerating
virus transmission. BA. and BA. were found in South
Africa in December and January , respectively.
LQ and SL mutation sites were found in the spike
protein of Omicron BA.... Del-, LR, FV, and
RQ mutation sites were found in the spike protein of
BA. and BA., which accelerated the spread of the virus
and enhanced pathogenicity.Current BA./BA. is replac-
ing BA.... Relevant studies have shown that BA. and
BA. Omicron subvariants propagate faster compared with
the other variants.A recent study published in Science
found that people infected with Omicron produce insuf-
ficient titers of neutralizing antibodies against Omicron
itself, and thus the idea of “Omicron infection as a natural
vaccine” is unrealistic.
The emergence of Omicron, especially the new subvari-
ants, may reduce the effectiveness of current drugs and
COVID- vaccines. Omicron variants have attracted much
attention worldwide and pose a serious threat to public
health. This review aims to introduce Omicron variants
in a more comprehensive, detailed, and timely manner,
the characteristics of Omicron, mutation sites of known
subvariants, and new subvariants. Meanwhile, the protec-
Red: infected with Omicron
Blue: uninfected with Omicron
N
S
WE
FIGURE 1 Main areas ravaged by Omicron. As of July ,
, the Omicron variant has been detected in at least countries
and US states. (https://outbreak.info/situation-reports/omicron?
loc =ZAF&loc =GBR&loc =USA&selected =Worldwide&
overlay =false [July , ])
tive efficacy of existing drugs, antibodies, and COVID-
vaccines to Omicron will be summarized and may help
to block the Omicron transmission and provide relevant
theories and countermeasures for COVID- therapy and
ending epidemics.
2 CHARACTERISTICS OF THE
OMICRON VARIANT
2.1 The outbreak and transmission of
Omicron
Omicron (B...) was initially sequenced in South
Africa. It was first reported by the World Health
Organization (WHO) on the November , , and
then designated as a VOC by WHO on November
, (https://www.who.int/news/item/---
classification-of-omicron-(b...)-sars-cov--variant-
of-concern [November , ]). Until July , ,
Omicron spreads to at least countries all over the
world (Figure ). Seven subvariants of Omicron (BA.,
BA.., BA., BA., BA..., BA., and BA.) with unique
mutations have been identified. The first lineage officially
designated as Omicron VOC is BA.. The case of BA. with
no / deletion in the spike protein region is growing in
several countries such as India, South Africa, Denmark,
and the United Kingdom. BA.. carries an additional
RK mutation that is absent in other Omicron lineages,
spike protein of the BA. contains fewer mutations, and
current sequence monitoring data on BA. are limited.
It should be noted that BA. tended to out-
perform BA.. Israeli news indicated that BA.
was approximately % more infectious than BA.
XU . 3of24
(https://www.haaretz.com/israel-news/more-infectious-
variant-of-omicron-likely-to-become-israel-s-dominant-
covid-strain-. [March , ]). According to
statistics from Denmark as of February, Omicron BA.
was responsible for % of all SARS-CoV- cases, and
BA. may even evade BA.-induced natural immunity.
Omicron BA.-BA. reinfections were found in of
the (%) reinfected samples. However, most of
these cases were from individuals without a com-
plete vaccination. BA. may trigger another wave of
infection in areas that experienced BA., which was
noteworthy.The Centers for Disease Control and Pre-
vention (CDC) of America estimates that new cases of
BA. leaped from one-tenth of emerging COVID- cases
in the United States to nearly one-quarter in week
(https://www.cdc.gov/coronavirus/-ncov/index.html
[July , ]). In addition, compared with BA., BA.
could cause more severe diseases in hamsters.All the
evidence suggests that the threat posed by BA. should
not be underestimated.
The first diagnosis of Omicron was collected on Novem-
ber , , and rapidly progressed from a -day moving
average of </, to more than /, in less
than days. In the early stages of the Omicron epi-
demic, Viana et al.estimated that it had a daily growth
advantage of .-fold higher than Delta. South Africa
suffered recurrent VOC assault and harbored around a
quarter of vaccine-elicited herd immunity. The frightening
growth of Omicron in South Africa suggests a risk of break-
through infection. According to a real-world reinfection
risk assessment in Qatar, previous infections conferred
% protection against Alpha, Beta, and Delta but only %
protection against Omicron.Ratio of the hazard for rein-
fections to the hazard for primary infections can indicate
the risk of variant reinfection. The estimated relative haz-
ard ratio of Omicron versus Alpha was ., much higher
than that of Delta (.) and Beta (.), which strongly
hints the breakthrough infection ability of Omicron.
Epidemic surveillance in several African countries has
revealed that the Omicron possesses a faster and larger
transmission rate than VOCs preceding it. Another study
found that Omicron had a .% higher transmissibility
than Delta. Danish epidemic assessment revealed that
the instantaneous reproduction number (R) of Omicron
is .-fold more elevated than that of Delta (R of Delta is
.–, with an average of .). Martin Hibberd, a profes-
sor of emerging infectious diseases at the London School
of Hygiene and Tropical Medicine, estimates that the R
of Omicron could be as high as . Two new subvariants
BA. and BA. emerged in South Africa and were discov-
ered in mid-December and January , respectively.
The BA. and BA. Omicron subvariants also appeared in
Europe in the following months. BA. and BA. Omicron
subvariants have become new epidemic strains in many
countries and spread more rapidly than other subtypes.
Two reasons may account for their faster transmission.
The first is that they have a stronger intrinsic transmission
capacity versus the previous Omicron subvariants; the sec-
ond is that BA. and BA. carry some key mutations that
are more conducive to escaping the immune response.
The key mutations FV and LR in the spike protein of
BA./ facilitate their immune escape at a faster rate and
accelerate virus transmission., BA./ developed more
significant escape responses to sera from those vaccinated
with three doses COVID- vaccine.
2.2 The origin of Omicron
There are two main hypotheses regarding the source of
Omicron; one is from the host with low immune func-
tion, and the other is from reverse zoonosis. Dr. Del
Rio a distinguished professor of medicine in the Divi-
sion of Infectious Diseases at Emory University School
of Medicine believes that all these mutations occur in
the same host and do not accumulate throughout the
transmission. Molecular spectral analysis speculated that
pre-outbreak Omicron mutations are consistent with an
evolutionary history in mice, not humans, suggesting the
possibility of an early host jump in the origin of Omicron.
InsEPE vanishing in previous mutations is presumably
due to template switching caused by two or more coro-
naviruses coinfection in one host. Regardless of origin,
adaptive mutations in the virus are evident. Thorne et al.
hypothesized that mutations other than the spike protein
might contribute to viral adaptation, which is supported by
the significantly enhanced expression of natural immune
antagonists (nucleocapsid protein (N), Orfb, and Orf)
in Alpha. Simultaneously, comparable changes in the N
and Orfb regulatory regions from Omicron (A>T,
–GGG>AAC) suggested an adaptive viral trans-
mission tendency and the importance of mutations outside
the spike.
2.3 The severity of the disease caused by
Omicron infection
Preliminary data from South Africa, and England
(https://spiral.imperial.ac.uk/handle///
[December , ]) showed that people infected with
Omicron are –% less likely to require hospitalization
than Delta. A survey by a hospital in South Africa showed
that only one-third of patients infected with Omicron
developed pneumonia symptoms, % of pneumonia
patients had mild to moderate disease, and % of patients
4of24 XU .
needed oxygen supplementation. Clinical symptoms
caused by Omicron appear to be diminishing compared
with the Alpha. In Canada, Omicron has a % lower
risk of hospitalization or death than Delta and an %
lower risk of intensive care unit admission or death.
Investigation in Norseland yielded similar results regard-
ing the probability of hospitalization due to Omicron
infection, which was decreased by %. It is worth noting
that the reduction in risk of hospitalization for Omicron
cases after two (Omicron: % vs. Delta: %) or three
(Omicron: % vs. Delta: %) vaccinations was less than
that of Delta., These data suggest that Omicron was
related to evading the vaccine protection and that the
booster dose may be a stalling tactic during the pan-
demic. Compared with Delta, hospitalization duration for
patients infected with Omicron was likewise declining.
Studies find that people infected with Omicron tend to be
younger.,, The Scottish report also mentioned that
.% of Omicron cases were between and years old
(https://www.research.ed.ac.uk/en/publications/severity-
of-omicron-variant-of-concern-and-vaccine-effectiveness
[July , ]). In addition, children may be more sus-
ceptible to Omicron than variants preceding it. In the
United States, children account for approximately % of
all COVID- hospitalization cases caused by Omicron,
which is fourfold higher than the previous wave (Alpha,
Beta, Delta), similar to South Africa. And this may
be related to low vaccination rates among children.
A study in England confirmed that vaccinated adults
and children (– years old) have significantly lower
Omicron infection rates than unvaccinated children
(– years old). Fortunately, milder disease severity
than predecessors were present in Omicron-infected
children, adults, and the elderly. An increase in asymp-
tomatic rates of COVID- may be caused by Omicron
(https://www.who.int/publications/m/item/enhancing-
readiness-for-omicron-(b...)-technical-brief-and-
priority-actions-for-member-states [January , ]). It
is worth nothing that in areas ravaged by Omicron, most
people have a history of SARS-CoV- infection and have
received at least one dose of the COVID- vaccine; there-
fore, milder disease severity does not indicate reduced
virulence of Omicron, considering previous immunization
could protect against serious diseases.
The clinical symptoms of Omicron vary owing to
plentiful mutations. To study Omicron replication, Meng
et al. revealed that although both Omicron and Delta
could infect epithelial cells, Omicron viral replication
was substantially lower in lower airway organs than
Delta. Omicron presents an early infection advantage over
Delta in human nasal epithelial cells. Compared with
interferon-active cells (caco- and calu-), Omicron was
more likely to infect the interferon-deficient cells (Vero),
implying a higher sensitivity of Omicron to interferon. In
the hamster model, Omicron-infected mice showed lower
pulmonary infectivity and more serious pathogenicity
than Delta and wild-type (WT)-infected mice, which
was also confirmed in K-ACE mice. Preliminary
research from the University of Hong Kong has shown
that the infection and replication of the Omicron variant
in the human bronchus are -fold faster than that of
its predecessor (https://www.the-scientist.com/news-
opinion/omicron-propagates--times-faster-than-delta-
in-bronchi-study- [December , ]). Differences
in the pattern of Omicron infection generated by abun-
dant mutations were strongly associated with changes
in the transmission rate and clinical severity. Omicron
can enter cells effectively through the endosomal path-
way independent of TMPRSS and is weak in inducing
syncytial formation.,– Variants preceding Omicron
tended to adopt the TMPRSS-mediated membrane fusion
route to infect host cells, but only a low proportion of
upper respiratory tract cells expressed both ACE and
TMPRSS. This explains why Omicron infects the upper
respiratory tract more frequently than its predecessors.
It is worth mentioning that the change in the infective
route broadens the range of cells that may be infected by
Omicron and expands the damage caused by Omicron. In
addition, a preference for the upper respiratory tract of
Omicron makes it easier virus excretion through the nose
and mouth, resulting in rapid transmission.
2.4 Mutations in spike protein of
Omicron
Omicron carried a large number of mutations. The essen-
tial amino acid substitutions in spike protein are high-
lighted in red: AV, del-, TI, del-, YD,
del, LI, insEPE, GD, SL, SP, SF,
KN, NK, GS, SN, TK, EA, QR,
GS, QR, NY, YH, TK, DG, HY,
NK, PH, NK, DY, NK, QH, NK,
and LF. Fifteen of these were located in the receptor-
bindingdomain(RBD):GD,SL,SP,SF,KN,
NK, GS, SN, TK, EA, QR, GS,
QR, NY, and YH (Figure ).
The combination of QR and NY at the RBD/ACE
interface (QR, NY, QR, QR, EA, TK,
and SN) has been shown to enhance binding affinity.
QR is speculated to be responsible for the enhanced
binding of Omicron RBD to mouse ACE. This raises the
alarm that Omicron can infect rodents and that the exten-
sion of the host range is harmful to human health in the
long term. Deep mutation scan results of the remaining
mutations in the RBD/ACE interface revealed no effect or
XU . 5of24
FIGURE 2 Mutations in Spike protein of seven Omicron subvariants. Schematic shows the locations of amino acid substitutions of
seven Omicron subvariants (BA., BA., BA.., BA., BA..., BA., and BA.) in spike protein. The RBD and RBM region is shown in
shallow violet red and deep violet red respectively, and the N-terminal domain (NTD) region is demonstrated in bluish violet. (The figure was
drawn on “Adobe illustrator” tool)
6of24 XU .
negative consequence.– The overall structure of Omi-
cron spike protein may be more convincing for evaluating
the binding relationship of the receptor. John et al. found
that the binding affinity of Omicron RBD to human-ACE
was .-fold higher than that of WT by surface plasmon res-
onance. Cryo-electron microscopic structural analysis of
the Omicron variant spike protein complexed with hACE
revealed that QR, GS, and QR mutations could
compensate for the weakened affinity caused by KN.
A peculiar RBD–RBD interaction induced by a ring con-
sisting of SL, SP, GD, and SF mutations was
identified in the Omicron S trimer structure but not in
WT. It is expected to stabilize the upward conformation of
RBD and facilitate its binding to ACE. Han et al. ana-
lyzed the crystal structure of the RBD-hACE complex and
revealed that the affinity between the Omicron RBD and
hACE was comparable to that of WT. Overall, the binding
affinity between Omicron RBD and ACE was not superior
to other VOCs (Delta, Beta). In addition to ACE, the pri-
mary receptor, GRP, a SARS-CoV- coreceptor, appears
to have a stronger affinity for the Omicron spike protein
than WT. Omicron pseudoviruses were found to infect
HEKT-ACE cells easier than Beta,Delta, and DG.
Mutations in RBD are also responsible for viral eva-
sion by clinical monoclonal antibodies. Of the five
currently United States Food and Drug Administration
(US FDA)-approved emergency use authorization mono-
clonal antibody therapies (REGEN-COV; a combination of
Bamlanivimab and Etesevimab; Sotrovimab; Tocilizumab;
Bebtelovimab), REGEN-COV and the combination of
Bamlanivimab and Etesevimab were eliminated as a treat-
ment or postexposure prophylaxis for COVID- due to
the advent of Omicron (https://www.cms.gov/monoclonal
[July , ]). Sotrovimab appears to be minimally
affected by mutations in Omicron with a twofold to
threefold neutralizing ability reduction, while the rest of
the therapies are remarkably affected. Omicron gener-
ated tremendous leaps in resistance to all four classes of
antibodies targeting the RBD (class , , , and ) and anti-
bodies targeting the N-terminal domain (NTD) (Figure ).
EA and QR influence the neutralizing activity of the
class antibodies, including LY-CoV and – remark-
ably, leading to a loss of activity about -fold. The
effect of NK and GS on the neutralizing activity of
REGN belonged to class ; the newly emerged SL
in Omicron can even cause a decrease in the neutraliz-
ing activity of three classes of antibodies including class ,
class , and class . However, individual mutations do not
always result in loss of binding or neutralization ability. Liu
et al. used a pseudovirus neutralization model to assess
the effect of five VOCs on antibodies. They confirmed that
Omicron enables immune escape against more antibod-
ies, developing resistance only against NTD antibodies and
class and , to almost complete resistance against class
and RBD antibodies, and essential resistance against
class and RBD antibodies.
The proximity of HY, NK, PH, and DY to
the furin cleavage site in the spike protein has been hypoth-
esized to be associated with increased infectivity; how-
ever, cellular-level experiments have demonstrated these
mutations may contribute to a weakening in facilitating
S/S cleavage.,–
The NTD contains four mutations, three deletions and
one insertions: AV, del/, TI, GD, del/,
NI, del, and insEPE. Del/ also existed in
Alpha and can be recognized by a useful detection method
called s-gene target failure (SGTF). BA. contains no /
deletions and therefore cannot be detected by SGTF.
The numerous mutations resulting in altered local con-
formation, charge, and hydrophobic microenvironment of
Omicron spike render them unrecognized by most NTD
and RBD antibodies, leading to viral immune escape.,
Interestingly, the accumulated mutations in Omicron
included multiple essential amino acids (polar positively
charged), increasing the total charge of the spike protein.
This change may make spike protein more sensitive to
low-pH-induced conformational changes.
3 DETECTION OF OMICRON VARIANT
Due to the large number of variants in Omicron, appro-
priate detection methods are urgently needed. The main
detection methods for Omicron are standard polymerase
chain reaction (PCR) assays, reverse transcription-PCR
(RT-PCR) assays, multiplex qRT-PCR assays, and viral
genome sequencing.
Kozlov collected nasopharyngeal swabs from infected
patients, and the viral load of different VOCs was mea-
sured by PCR technique. The results showed that patients
infected with Delta had a higher peak viral load than those
infected with Omicron. RT-PCR is required for patients
with positive samples of the Omicron variant. In addition,
RT-PCR testing is necessary for potentially infected indi-
viduals with Omicron, such as a history of recent travel
to the epidemic area and close contact with confirmed
patients., For VOCs, including the Omicron variant,
two-tube multiplex qRT-PCR can detect five copies of viral
RNA. Next-generation sequencing has become the gold
standard for identifying Omicron. Scott et al. have shown
that viral genome sequencing can be used for detecting
apparent deletions of the S gene (S-). Omicron mutation
screening is another effective method for preventing the
spread of the Omicron variant. Two single nucleotide
polymorphism genotyping methods were used to screen
the Omicron variant for the GD or TK mutation,
XU . 7of24
A67V
Del69-70
T95I
G142D
Del143-145
N211I
Del212
ins214EPE
Fold change in
IC50 compared
with WT
NTD
RBD
RBM
HR1
G339D
S371L
S373P
S375F
K417N
N440K
G446S
S477N
T478K
E484A
Q493R
G496S
Q498R
N501Y
Y505H
T547K
D614G
H655Y
N679K
P681H
N764K
N856K
Q954H
N969K
L981F
class 1
class 2 class 3 class 4
Strong → Weak
NTD mAbs
→→→
FIGURE 3 Resistance of individual mutations from Omicron spike protein to five types of antibodies (class , class , class , class , and
NTD mAbs). The degree of resistance is represented by different colors. Resistance from strong to weak is indicated by red, orange, and
yellow, respectively, while those favorable to antibody binding were blue. If the resistance strength is not marked, it indicates that there is
little change in resistance to the antibody after the individual mutation. Mutations with strong resistance to NTD mAbs are GD,
Del-, NI, SN, and NY; mutations with robust impedance to class antibody are EA and QR; LF showed well binding
ability to class and class antibodies. (The figure was drawn on “Adobe illustrator” tool)
which can also distinguish the Omicron variant from other
VOCs. Furthermore, high-resolution melting analysis
methods can be used for screening Omicron and Delta
variants. Besides, some antigen detection kits are help-
ful for rapid detection of Omicron in vitro. In addition,
Omicron variants are also found in the wastewater of epi-
demic areas. An Omicron-positive passenger was found on
a flight from Johannesburg to Darwin, Australia, and the
presence of Omicron variants in aircraft wastewater was
confirmed, suggesting that aircraft wastewater may serve
as an independent and invasive monitoring point. Coin-
cidentally, the presence of Omicron variant was also found
in outlet water at Frankfurt Airport in November ,
even before the first clinical report of Omicron positivity in
GermanyonNovember,.
Similarly, Omicron was
found in US community sewage samples from November
to December . Simultaneously, a novel SARS-CoV-
lineage with multiple monoclonal resistances sharing
8of24 XU .
TABLE 1 Neutralization activity against Omicron of sera from different vaccinated individuals
Name
Reduced neutralization activity
(compared with WT) Positive proportion
BNTb (two does) .–,,– .–%–,,
mRNA (two does) .–,,, not mentioned
ChAdOx-S (two does) No neutralizing activity, .% (/) ( days)
Ad.COV.S (two does) No neutralizing activity, .% (/) ( days)
CoronaVac (two does) . or no neutralizing activity,, Not mentioned
BBIBP-CorV (two does) .–.– .–.%–
ChAdOx- S-BNTb No neutralizing activity or %
BNTb (three does) .–.,,,,, .–%,
mRNA- (three does) –., Not mentioned
Inactivated vaccine (three does) .–.,, .–%,
ADZ (three does) . Not mentioned
ZF (three does) . .%
The table summarizes the proportion with detectable Omicron neutralization activity of serum from different vaccinated individuals and reduced neutralization
activity against Omicron in serum samples from different vaccinated individuals compared with WT SARS-CoV-.
many mutations with the Omicron variant was detected in
sewage in New York City.
4 OMICRON’S IMMUNE ESCAPE
Several studies have shown that the Omicron variant has
significantly more immune evasion properties than its
predecessor., According to computational prediction,
the Omicron variant can escape % of distinct epitopes
from convalescent plasma and vaccine-induced serum.
Live virus neutralization experiments identified no neu-
tralizing activity of Omicron in .% of serum samples
from recovering patients and vaccine recipients and a .-
fold reduction in neutralizing titers compared with the WT
in additional serum samples. Omicron’s immune eva-
sion ability contributed to its rapid spread globally, and
universal vaccine boosters can restore the protection to
Omicron in a certain extent., We systematically sum-
marize the effects of Omicron on the immune responses
induced by infection and vaccination (Table ).
4.1 Neutralization of Omicron in serum
of convalescent patients
As expected, convalescent sera from COVID- patients
were resistant to various variants, with Omicron con-
ferring the strongest immune escape. Analysis of the
clinical data also revealed that the risk of reinfection with
Omicron was higher than Delta in previous SARS-CoV-
-infected patients. In vitro neutralization experiments
found that patients infected with D virus had the most
elevated antibody neutralization titers in serum approxi-
mately one month after infection. Then, the neutralization
activity decreased over time., Schmidtetal.
found
that the % neutralization titer (NT ) value of Omicron
was -fold, -fold, and -fold lower than that of Wuhan-
hu- after month, months, and year of WT infection.
In contrast, neutralizing activity against the Omicron vari-
ant was largely absent at day or months post-WT
infection.,
Several independent teams have also successively
demonstrated that only –% of the convalescent serum
samples from WT infected patients have neutralizing
activity against Omicron.,,,,, Moreover, Liu
et al. found that only serum from .% (two out
of nine) ICU and .% (one out of nine) hospitalized
patients have detectable Omicron neutralization antibody
in DG-wave. At the same time, the antibody activity
against Omicron showed a significant decrease compared
with the WT, with .– times,,,,, decrease in
DG convalescent serum and a .-fold reduction in
the serum of patients infected with Victoria strain. Com-
pared with the USA/WA strain, the Omicron-neutralizing
antibody titers were reduced by . and . folds in the
serum collected from non-Omicron-infected patients after
and months of WT infection, respectively. Similar
results were obtained in enzyme-linked immunosorbent
assay (ELISA) experiments. The binding of Omicron spike
protein to serum from WT infected patients was decreased
by .–. times compared with that of WT spike protein,
but this serum retained the binding to Omicron NTD, and
the binding ability was reduced by . times compared
with the WT.
Whether SARS-CoV- variants can cause cross-
protection after infection is also an issue of widespread
XU . 9of24
concern. Studies have found that the neutralizing activity
of serum against Omicron is still limited after infection
with most variants. The proportion of Omicron neutraliz-
ing activity from B... (Alpha) infected patients ranges
from to %,, and the neutralizing antibody titers
against Omicron are reduced .-fold compared with
that of Alpha variants (n=). Although Kimpel et al.
found there was no neutralizing activity against Omicron
in serum samples from patients with B.. (Beta) infec-
tion, Weiss et al. found that two samples infected with
Beta variants had neutralizing activity against Omicron
above the threshold.
Sera from patients infected with the B... (Delta)
variant appear to provide broader cross-neutralization of
Omicron; –.% of samples had detectable Omicron
neutralization titers above the threshold.,,,, How-
ever, neutralization titers against the Omicron variants
remained variably decreased in serum from Delta infected
people, with a >-fold decrease compared with WT
or .–.-fold lower than the Delta strain., Even
samples collected from people who recovered from to
weeks after Delta infection only had good neutraliza-
tion ability for USA/WA and Delta. However, some
ICU patient samples collected during the Delta wave
had neutralizing ability against Omicron comparable with
those who received booster vaccines. A few studies
have been conducted on individuals infected with the
AY (AY././././././.) variant, and one report
stated that % (nine out of ) of the individuals infected
with an AY variant had antibody titers above the threshold
against Omicron.
In addition, and somewhat unexpected, the cross-
neutralizing response induced by infection with the Omi-
cron variants appeared to be limited. Ott et al. found
that serum from mice infected with Omicron could only
neutralize the Omicron variant itself, showing limited neu-
tralization against the remaining variants, whereas sera
from mice infected with the Delta showed good neutral-
izing activity against various variants, including Omicron
(except the Beta variant).
4.2 Neutralization of Omicron by serum
from two doses mRNA vaccine recipients
It is generally accepted that mRNA vaccination produces
higher antibody-neutralizing titers that peak around
days and decline significantly after months, but also gen-
erate remarkably lower or even no neutralizing activity
against Omicron. Vaccine efficacy against Omicron was
.% – weeks after the second dose of BNTb and
decreased to . and .% after – and weeks, respec-
tively. The neutralizing activity against Omicron after two
doses of mRNA- also reduced from .% after to
weeks to .% after or more weeks.
Pfizer and BioNTech reported that the neutralization
titer against the Omicron variant in the serum of indi-
viduals receiving two doses of their COVID- vaccine
decreased by more than times. Taken together, the
neutralizing antibody titers against Omicron in serum fol-
lowing two doses of mRNA vaccine (BNTb or mRNA-
) were reduced about .–-fold compared with the
WT,,,, and –.% of these sera showed Omi-
cron neutralization resistance.,, Some studies also
showed that the neutralization activity from mRNA vac-
cinee’s serum to Omicron decreased more in a short time
after the second dose of mRNA vaccine, and the NT to
Omicron of samples collected in . months after vaccina-
tion decreased times than that of Wuhan-hu-, while
samples collected within – days after vaccination had
little neutralization ability to Omicron variants.
Studies have shown that the serum from mRNA-
vaccine recipients appears to have slightly better neutral-
izing activity than that from Pfizer/BioNTech BNTb
vaccine recipients among healthcare workers (HCWs).
Therefore, the effects of Omicron on mRNA- and
BNTb vaccines were compared and analyzed. Vac-
cinated versus unvaccinated participants were tested for
neutralizing activity against BA. and BA. clinical iso-
lates. In unvaccinated participants, FRNT against BA.
and BA. decreased .-fold and .-fold compared with
that of BA., respectively. In the vaccinated participants,
FRNT against BA. and BA. decreased .-fold and .-
fold compared with that of BA., respectively.The results
indicated that the vaccinated people were more resistant
to BA. and BA. than the unvaccinated people.Infection
with BA. and BA. in vaccinated persons do not cause
more severe clinical symptoms.
The neutralization activity of serum to Omicron in
patients vaccinated with two doses of BNTb vaccine
decreased about .-. times compared with that of
WT.,,– Surprisingly, Balazs et al. demonstrated
that the neutralizing antibody activity against Omicron
of the serum from BNTb recipients had a -fold
decrease compared with WT after three months of
vaccination by pseudovirus neutralization experiment.
Meanwhile, only .–% of the samples vaccinated with
two doses of BNTb vaccine had detectable Omicron
neutralizing activity,–,, and the proportions of
positive sera were only % and % against the HKU
and HKU-RK strains, respectively. Interestingly,
the fold decrease in neutralizing activity of BNTb
vaccinees’ sera against Omicron over the WT appeared
to diminish over time. Vaccine efficacy against Omicron
decreased -fold compared with the WT . weeks after
the second dose of BNTb and decreased .- or
10 of 24 XU .
.-fold after or months of the second dose of
BNTb, respectively. A review of clinical data found
that the severity of unvaccinated persons was five times
when they were infected by Omicron than those who
received two doses of Pfizer BNTb mRNA vaccine.
Comparable Omicron immune escape capacity was
also observed in samples from recipients of two doses
of mRNA- vaccine, with an average decrease in
neutralization titers of approximately .–-fold.,,,
In conclusion, there seems to be no significant difference
in the neutralization effect against Omicron between the
serum from people who received two doses of mRNA-
and BNTb vaccinees. In addition, WT and Omicron
variant RBD binding did not differ significantly between
the two doses of mRNA- or BNTb vaccinated sera
in the ELISA experimental group. The binding ability
between Omicron RBD and the sera vaccinated with two
doses of mRNA- or BNTb vaccine was . times
and . times lower than that of WT RBD and these sera,
respectively.
4.3 Neutralization of Omicron by two
doses adenovirus vaccine recipients
Relevant studies have shown that the adenovirus vec-
tor vaccine ChAdOx-S/nCoV- and Ad.COV.S had
significantly less neutralizing activity than the mRNA vac-
cine at and days postvaccination. However, the
neutralizing antibody in serum from people vaccinated
with a two doses adenovirus vaccine seems to be more
stable and not easily decrease over time. Meanwhile,
the protective effect against Omicron in the serum of
adenovirus vector vaccine recipients is minimal or even
no neutralization effect has been found in most stud-
ies. No neutralizing activity against Omicron was found
in serum month or – days after receiving two
doses of the ChAdOx-S/nCoV- vaccine,,, or only
one of samples ( days after vaccination) had neu-
tralization activity against Omicron. A similar situation
occurred with two doses of the Ad.COV.S vaccine, with
no neutralizing activity against Omicron in samples –
days after vaccination,, or only .% of samples
had Omicron variant neutralization activity days after
vaccination.
4.4 Neutralization of Omicron by serum
from recipients receiving two doses of
inactivated virus vaccine
Inactivated vaccines are currently the most widely used
COVID- vaccines, but they may have minor protection
against Omicron infection. For the CoronaVac vaccine,
almost no detectable neutralizing antibody titers against
Omicron in recipient sera or very low antibody titers can
be detected.,, However, Wang et al. found detectable
neutralizing activity against Omicron in samples collected
days after two doses of Corona Vac vaccine, with a .-
fold decrease in neutralization activity compared with the
WT. The proportion of Omicron positive serum in recip-
ients of the BBIBP-CorV vaccine from Sinopharm is only
.–.%.– And the neutralization titer against Omi-
cron of serum vaccinated two doses of BBIBP-CorV vac-
cine decreased by approximately .–. times compared
with the WT.– Neutralizing activity against Omicron
decreased by only .-fold at – months after two doses of
inactivated vaccine, but this appeared to correlate with a
large decrease in neutralizing titers of WT. On the th day
after two doses of inactivated vaccination, the neutraliz-
ing activity decreased by approximately .– times.,
On the th day after vaccination, it fell by . times
compared with the WT.
4.5 Heterologous inoculation
Heterologous vaccination is uncommon in two doses
vaccinated populations, and some studies showed that
heterologous vaccination seem to enhance neutraliz-
ing activity against Omicron. Sera collected within one
month after vaccination with heterologous ChAdOx-
S/BNTb showed higher neutralizing activity than
sera collected within three months after vaccination
with BNTb/BNTb. The inhibition efficiency
against Omicron of the sera from ChAdOx-S/BNTb-
vaccinated individuals was times lower than that of
DG, and the positive rate against Omicron in these
serum samples was out of . However, it was also
reported that the serum from heterologous ChAdOx-
S/BNTb vaccine recipients displayed no neutralizing
response to Omicron.
4.6 Neutralization of Omicron after
vaccination in convalescent patients
Studies have shown that the revaccination of patients
infected with SARS-CoV- can significantly increase the
neutralizing activity against Omicron. Nine out of ten
samples that received a single dose of vaccine following
infection had Omicron neutralizing activity. Meanwhile,
the neutralization capacity against the Omicron variant of
individuals who received two doses of BNTb vaccine
after SARS-CoV- infection is comparable to that against
the DG. Although the sera of postinfection and
XU . 11 of 24
completion of three doses of mRNA vaccination popu-
lations had considerable neutralization activity against
Omicron, it is undeniable that its neutralizing activ-
ity against Omicron had decreased to varying degrees
compared with the WT. A single dose of BNTb
induced a substantial increase in neutralizing activity
against Omicron of convalescent individuals’ serum, with
a GeoMean ID was , and . times lower than that
of WT. Two additional doses of BNTb or mRNA-
increased the neutralizing activity against Omicron of con-
valescent individuals’ serum, by –. times.,, The
neutralizing activity against Omicron of serum from con-
valescent individuals vaccinated with Ad.COV.S was
-fold lower than the WT. The three doses vaccination
further improved the neutralizing activity against Omi-
cron, with an average increase of two to three times the
neutralizing titer, which was only . times lower than
the WT.
4.7 The neutralizing effect against
Omicron after the booster injection
Based on current evidence, it is widely believed that a
booster dose against COVID- provides further protection
to vaccinated individuals and that booster doses are critical
regardless of the circulating variant. Arashiro et al.,
believe that strengthening vaccination is still the best
option against Omicron in Japan. Moreover, additional
doses of the vaccine significantly increased the number of
neutralizing antibodies in the serum from the vaccinated
population, but further clinical data are still needed
to determine the efficacy of boosters. Booster doses
of both mRNA- and CoronaVac/PiCoVacc, and other
mRNA-based vaccines, were potent and effective in caus-
ing sustained enhancement of Omicron neutralization
months after the second vaccination, which increased
the neutralization ability approximately between three-
fold and -fold. Although Omicron has a significant
immune evasion ability in almost all sera from recovered
patients or two doses COVID- vaccinees, the reduction
in neutralization ability under the effect of booster is only
four to eight times.
Clinical data have also shown that the booster dose
reduces the infection risk and morbidity ratio of Omi-
cron to a certain extent. The CDC stated that on January
, , the third dose of the mRNA vaccine prevented
% of patients infected with Omicron from entering the
emergency room or urgent care and % from being
hospitalized. Without a booster shot, unvaccinated cases
were % more likely to infect other family members
than fully vaccinated cases. In October–November
period, the incidence rate ratio (IRR) of the booster vac-
cinated group was ., and the IRR of group without a
booster was . in the United States, and the booster sig-
nificantly affected Omicron infection and death caused by
SARS-CoV- in people aged – years. However, data
from the UK showed that weeks after the third injec-
tion, the effectiveness of the booster against hospitalization
dropped from to %, and the protection provided by
the booster appeared to be waning. Thus, an ongoing
comprehensive assessment of the effects of boosters is
needed.
.. Effects of homologous reinforcement
The neutralizing antibodies against Omicron had a signif-
icant (–-fold) increase a few months later with a third
dose of the same vaccine boost, but only a modest (onefold
to fourfold) increase against the WT.
mRNA vaccine homologous boost
Overall, the mRNA vaccine booster substantially boosted
the neutralizing activity of the recipients’ sera, and the
neutralizing activity was still largely retained over time.
However, the neutralizing antibody titers against Omi-
cron were still lower than the WT. Vaccine effectiveness
increased to .% – weeks after the third BNTb
booster dose, with .% remaining after weeks or
longer. And after the mRNA- homologous boost
for – weeks, vaccine effectiveness reached .%.
The neutralizing antibody titers of serum from mRNA
homologous booster-vaccinated individuals against
Omicron pseudovirus or live virus improved approxi-
mately .- to more than fold.,,,,,,, Three
doses of BNTb increased infection protection by
-fold, with an average of >.-fold increase in neutral-
izing activity against Omicron – days after booster
vaccination.
Approximately month after mRNA booster vaccina-
tion, the neutralizing activity against the Omicron live
virus of serum was .-fold higher than that of the two
doses of mRNA vaccinees’ serum. And the neutralizing
activity of serum from mRNA booster vaccinees against
the Omicron pseudovirus increased by .-fold compared
with that against the WT from the second dose of mRNA
vaccinees. Similarly, the mRNA homologous booster
improved the neutralizing activity against Omicron about
– times over – days after the boosting.,,
In addition, the breadth of protection induced after the
booster was also greatly increased, essentially with the
proportion against Omicron positive serum samples
above % and even %.,,, However, at the
same time, compared with the WT, the neutralization
activity against Omicron still had a slight decrease, with
12 of 24 XU .
an average reduction of about .– times.,,,
Three doses of BNTb resulted in the neutralization
activity of the serum against Omicron was .-fold lower
than that against Victoria. Some even reported that
serum neutralizing activity against the Omicron variant
after the BNTb vaccine booster is greater than that
against Wu-. The neutralizing activity against Omi-
cron was slightly different in the serum from BNTb
or mRNA- homologous booster vaccinated people.
The neutralizing activity against Omicron was . or
. times and four or six times lower than that against
the WT in the BNTb booster or mRNA- booster,
respectively., All together, BNTb booster may
show slightly higher neutralizing antibody titers against
Omicron than the mRNA- vaccine booster, and the
same finding was also found in HCWs. Statistical
analysis yielded similar results, the adjusted odds ratio
(ORs) for Omicron were . for three doses of BNTb
versus unvaccinated and . for three doses of mRNA-
versus unvaccinated. And the adjusted ORs for
Omicron were . for three doses of BNTb versus two
doses and . for three doses of mRNA- versus two
doses.
Adenovirus vaccine homologous boost
The three doses of ADZ vaccine increased .-fold
than the second dose in the serum neutralization activ-
ity against Omicron days after vaccination, although
the neutralization activity against Omicron was . times
lower than the Victoria. While the AdCOV.S booster
resulted in the neutralizing activity of the serum against
Omicron was approximately times lower than that
against WT.
Inactivated vaccine homologous boost
Similarly, the inactivated vaccine homologous booster pro-
vided more protection to Omicron to a certain extent, and
three doses of inactivated vaccine significantly improved
the neutralization effect against Omicron, with .% effec-
tiveness against Omicron at – weeks after inactivated
booster vaccination and an average seroconversion rate
of .–%.,,, In a study with a seroconversion
rate of % ( out of ), the seroconversion rate of inac-
tivated homologous booster vaccination was .% higher
than that of two doses vaccination. However, only %
of patients were seropositive for Omicron days after the
CoronaVac booster. At the same time, three doses of inac-
tivated vaccine will increase the neutralization titer against
Omicron about .–. times than that of two doses of
inactivated vaccine,,,– and the titer was almost equal
to or even higher than that observed days after the second
dose. The neutralization antibody titers against Omi-
cron of serum from inactivated boosters were still lower
than against other variants and .–. times lower than
against the WT.,,
Subunit virus vaccine boost
In individuals vaccinated with the RBD-based protein sub-
unit vaccine ZF, .% (seven out of ) of sera sampled
– days after the third dose could not neutralize Omi-
cron. And the geometric mean titers (GMT, % inhibitory
dose [ID ]) of these sera against Omicron were .-fold
lower than those against DG.
.. Effects of heterologous boosting
Previous studies have found that heterologous booster
seem to induce a stronger, longer-lasting immune
response. However, for the Omicron variant, heterol-
ogous boosting did not appear to have a significantly
enhanced effect over homologous boosting. Two doses
of BBIBP-CorV vaccination followed by subunit vaccine
ZF boosters increased neutralizing titers by more than
-fold for WT and approximately fourfold for Omicron.
The neutralization activity against Omicron increased .-
fold in the serum vaccinated with the BNTb vaccine
as a booster following two doses of CoronaVac vaccine,
although it was still reduced .-fold compared with the
WT; the BBIBP-CorV/ZF heterologous booster
increased the neutralization activity by . times of the
serum collected days after vaccination and . times
days after vaccination compared with that before the
booster. Similar to the homologous boost, the neutraliz-
ing activity against Omicron after the heterologous boost
was still lower than that of the WT. The neutralization
titer of the serum vaccinated with BBIBP-CorV/ZF
was . times lower than that of the WT days after
the heterologous boost, and . times lower than that of
the WT days after the heterologous boost;BNTb
booster vaccine partially restored neutralization against
the Omicron variant after two doses of mRNA- or
Ad.COV., and the neutralization activity against Omi-
cron of serum from individuals vaccinated with BNTb
booster had a -fold reduction compared with WT;
serum neutralization capacity against Omicron from
individuals vaccinated with BNTb as a booster after
two doses of mRNA- vaccine increased to .%, but
also and . times lower than the WT at months or
. months after vaccination; whereas mRNA- booster
vaccination increased vaccine efficacy to .% after a two
doses BNTb, then decreased to .% after – weeks;
ChAdOx-S/nCoV- inoculated as the first two doses,
BNTb and mRNA- booster doses increased their
neutralizing activity against Omicron to . and .%
XU . 13 of 24
after – weeks, respectively, and then dropped to .
and .%., Serum neutralization capacity against
Omicron in BNTb-enhanced mice after two doses
of mRNA- vaccination has also increased and was
.-fold lower than that against the WT. IgG antibody
concentrations increased significantly, and % of samples
were sensitive to Omicron in all groups days after
the heterologous booster dose following two previous
doses of the CoronaVac inactivated virus vaccine. And
the seropositivity ratios of Ad.CoV.S, BNTb, and
ChAdOx-S/nCoV- as heterologous booster vaccination
reached %.
4.8 Effect of breakthrough infection on
Omicron neutralization after vaccination
Omicron breakthrough infection after vaccination also
further increased the level of neutralizing antibodies in
serum, with binding antibody titers of samples from Omi-
cron breakthrough individuals (three doses of BNTb
vaccine (n=), two doses of BNTb vaccine followed by
a booster shot of CX- or ChAdOx-S-BNTB vac-
cine) were comparable to that four weeks after the second
dose of vaccine. The Omicron breakthrough infection
(OP) occurred days after the second dose of BNTb
and induced the neutralizing activity of serum from <:
to an average IC value of :, with .-fold higher
than in those who received only two doses of BNTb;
While the mean IC value against Omicron in the serum
of patients with confirmed Omicron infection (OP)
days after vaccination with mRNA- was :.. And
sera from vaccinated individuals with confirmed Omicron
breakthrough infection showed the highest level of protec-
tion (>%) against most variants, including WA, Delta,
Alpha, Beta, and Omicron. Breakthrough infection with
other variants can also significantly increase the protec-
tive activity of Omicron. The serum from individuals with
breakthrough infection of the Delta variant has a neutral-
izing effect against many variants, including Omicron, but
the NT of Omicron is relatively low. The GMT against
the Omicron variant and WT in serum from patients with
Delta breakthrough infection after two doses of inacti-
vated vaccine (CoronaVac) were . and ., and
the neutralizing activity against Omicron was an .-fold
reduction compared with the WT. Neutralizing antibody
activity against Omicron could be detected in nine of ten
serum samples from the individuals with two doses vacci-
nation followed by breakthrough infection or convalescent
participants followed by two doses vaccination, although
the neutralizing activity was lower than that of the Delta
variant.
4.9 The effect of Omicron infection on
cellular immunity
T-cell immune responses elicited by infection with SARS-
CoV- or vaccines are still effective against Omicron,
and SARS-CoV- has not yet evolved extensive T-cell
escape mutations. Eight months after two doses of
Ad.COV.S vaccination, the spike protein-specific CD+
T cell responses in serum against WA, Delta, and Omi-
cron strains were ., ., and .%, respectively,
and the specific CD+T cell responses were ., .,
and .%, respectively. And the serum from individ-
uals vaccinated with two doses of BNTb had .
and .% CD+T cell responses against WA and
Omicron, and . and .% CD+T cell responses,
respectively. Cellular immunity induced after vaccination
remained highly cross-reactive to Omicron variants.
The capacity of T cells to respond to Omicron spike pro-
tein was maintained at –% in participants vaccinated
with Ad.CoV.S, BNTb, or unvaccinated convales-
cent COVID- patients (n=), and T cell responses
induced by vaccination or infection could still recognize
the Omicron variant.,
4.10 Antibody activity against Omicron
in special populations
The neutralization activity of serum from lung cancer
patients vaccinated with mRNA vaccine showed lower
than that from healthy adults vaccinated with the same
type of vaccine according to live virus neutralization
experiments. At the same time, there was no significant
difference in the antibody response to SARS-CoV- vacci-
nation in patients receiving either PD- monotherapy or a
combination of chemotherapy and PD- targeted therapy
compared with patients receiving no cancer therapy at
the time of vaccination. Similarly, the neutralizing activity
against Omicron in the serum of lung cancer patients after
receiving the mRNA vaccine was -fold lower than that of
the WT. Pseudovirus neutralization experiments found
that weeks after the second dose of mRNA- ( μg),
the GMT against Omicron of serum was .-fold lower
than that against DG in adults over years; .-fold
lower than that against DG in adolescents (– years),
and the GMTs against DG and Omicron variants in
adolescents were .-fold and .-fold higher than that in
adults, respectively. Similarly, the GMTs against Omicron
were .-fold lower than those against DG in chil-
dren (– years old), and the GMTs against DG and
Omicron in children were . and . times higher than
those that in adults, respectively. Among those who
14 of 24 XU .
received two doses of the BNTb vaccine with a mean
age of years, only .% ( out of ) had detectable
Omicron neutralizing titers, and their GMT was ., which
was -fold lower than that of the WT (GMT =.).
In a population of COVID- recovered patients with an
average age of . years, .% (four out of ) of the serum
samples were able to neutralize the Omicron variant,
and its GMT value was only ., which was times
lower than that of the WT (GMT =). Compared
with DG, the neutralization titer against the Omicron
variant was only .-fold lower in the sera of cancer
patients following the mRNA vaccine booster, and .%
( out of ) of the patients had Omicron neutralization
activity.
Vaccination remains significantly associated with a sub-
stantial reduction in the risk of symptomatic COVID-,
both during and before the Omicron wave. Moderna,
Pfizer, and their partner BioNTech announced that
boosters tailored for Omicron may offer better protection
and they could supply Omicron-tailored vaccines as
early as March , although moving to a new vaccine
would reduce current vaccine production. John Moore,
an immunologist at Weill Cornell Medical College,
said that the Omicron wave might be over when these
vaccines are scaled up. The development of a universal
vaccine effective for all SARS-CoV- variants instead
of frequently updating the vaccines for the emerging
variant is promising and expected., Humans repeat-
edly exposed to the SARS-CoV- spike protein through
infection or booster doses are likely to have neutralizing
antibody activity against Omicron. Moreover, studies
have also shown that even booster doses are insuffi-
cient to prevent symptomatic disease and emphasize
the need to maintain additional non-pharmacological
interventions.
5 PROPHYLAXIS AND TREATMENT
OF OMICRON VARIANT
5.1 Drug treatment of Omicron variants
The emergence of various variants during the COVID-
pandemic has created a great challenge for the devel-
opment of vaccines. Antiviral drugs have more stable
chemical structures compared with vaccines. The sensitiv-
ities of the Omicron to antiviral drugs are summarized in
Table . Effective drugs are always important for treating
COVID- and helping to end global epidemics.
Remdesivir, a viral RNA-dependent RNA polymerase
(RdRp) inhibitor, has been approved by the US FDA
for the emergency treatment of COVID-, which
inhibits the replication of several RNA viruses, includ-
ing coronaviruses. Molnupiravir, a derivative of the
antiviral drug ribavirin, the active ingredient of which
is EIDD-, was first approved in the United Kingdom
for the treatment of SARS-CoV--infected patients.,
Several studies have confirmed the effectiveness of
remdesivir and molnupiravir against Omicron BA..,
Remdesivir, molnupiravir, and the viral protease inhibitor
nirmatrelvir are highly conserved in their target proteins,
which have the same antiviral activity against the original
strains and VOCs (Alpha, Beta, Gamma, Delta, and
Omicron). Li et al. used clinical isolates cultured
from infected patients to assess whether molnupiravir
had inhibitory effects on Omicron variants. Viral repli-
cation was significantly inhibited by molnupiravir in
SARS-CoV--infected cells. Omicron replication could
also be inhibited by nirmatrelvir in Calu- cells, and
combined treatment with molnupiravir and nirmatrelvir
showed synergistic antiviral activity against both WT
and Omicron. The oral novel COVID- therapeutic
drug PF- (Pfizer) is a ritonavir-boosted protease
inhibitor. Drożdżal et al. studied COVID- patients
(non-hospitalized adults) in a randomized double-blind
controlled study, patients received PF- treatment
within days of symptom onset, and the results showed
that the risk of hospitalization and death associated with
SARS-CoV- was reduced by %. PF-, ritonavir,
and paxlovid effectively reduced the hospitalization
duration of COVID- infected patients in clinical trials.
Potent oral antiviral drugs, such as molnupiravir and
PF, could avoid side effects such as phlebitis
caused by intravenous medications and have shown better
clinical outcomes.,
Corticosteroids, such as dexamethasone, were used in
critically ill patients infected with the Omicron variant,
especially in patients on high-flow oxygen therapy, nonin-
vasive ventilation, and mechanical ventilation. However,
dexamethasone should not be recommended for mild to
moderate COVID- patients (in patients not receiving
oxygen therapy). In addition, hydrocortisone, methyl-
prednisolone, and prednisone were equally effective in
patients infected with Omicron variants. Corticosteroids
have been shown to have satisfactory anti-inflammatory
and immunomodulatory effects on Omicron infection.
Targeted anti-inflammatory drugs, such as IL-
and JAK inhibitors, can inhibit the Omicron variants.
Tocilizumab effectively reduces inflammation and mortal-
ity in patients. Whether sarilumab is effective against
Omicron variants still needs further studies in the future.
Tocilizumab and baricitinib were probably effective in
severe cases of Omicron infection.
Both WHO and related studies have indicated that
JAK and IL- inhibitors in combination with dexametha-
sone contribute to remission in patients with Omicron
XU . 15 of 24
TABLE 2 Sensitivities of the Omicron (B...) to different antiviral drugs
Antiviral Viral lineage Viral type
Full/partial
variant
Fold
change
Reference
strain
Camostat B... Live virus Full variant . B...
Molnupiravir B... Live virus Full variant . Wuhan-Hu-
Remdesivir B... Live virus Full variant . A
Ensovibep B...(BA.) Pseudovirus Full variant . Wuhan-Hu-
GS- B... Live virus Full variant . USA-WA/
Nirmatrelvir B... Live virus Full variant . B...
S- B... Live virus Full variant . A
“Fold change” is an indicator of susceptivity of Omicron to potential antiviral drugs.
infection., Bafilomycin A and chloroquine effectively
suppressed Omicron variants. Eight drugs (PF-,
EIDD-, ribavirin, nafamostat, favipiravir, remdesivir,
aprotinin, and camostat) from the antiviral assay were used
on the Omicron and Delta isolates, which were found to be
similarly susceptible to both variants, with the Omicron
remaining sensitive to broad-spectrum anti-SARS-CoV-
drugs. Adequate protection of the respiratory tract from
Omicron infection (B.. and B...) was achieved
by nasal administration of interferon-λin mice. Some
studies have demonstrated that hydroxychloroquine, con-
valescent plasma, and camostat were ineffective in treating
patients infected with SARS-CoV- Omicron variants.
However, amantadine, the effects of ivermectin and cloni-
dine on Omicron infection were uncertain, and further
studies are needed in the future.,
5.2 Neutralizing antibody
.. Protective effects of monoclonal
antibodies against Omicron variant
The Omicron variant contains a wide range of mutations
that can escape neutralizing antibodies produced from vac-
cination. Nevertheless, monoclonal antibodies have the
merits of high biotransformation efficiency, high speci-
ficity, high immunogenicity, and transparent mechanism
of action.
Compared with previous seasonal coronaviruses and
influenza A, SARS-CoV- has faster evolutionary and
propagation rates. Most monoclonal antibodies induced
by the receptor-binding domain (RBM) have lost neutral-
izing antibody activity against Omicron, whereas some
monoclonal antibodies recognize Omicron by antigenic
binding sites outside the RBM. The neutralizing antibody
recognizes the conserved RBD epitope of VOCs, which
is beneficial for constraining VOCs infection. Hence,
the sensitivities of the Omicron to different neutralizing
antibodies are indicated by “fold change” in Table .
Kovacech et al. showed that AX and AX
have a nanoscale affinity to the RBD of the viral
spike protein. Sotrovimab binds conserved epitopes of
the RBD, which were used as a cocktail therapy for
Omicron infection. GlaxoSmithKline’s VIR- (sotro-
vimab) and Regeneron monoclonal antibody cocktail have
shown better efficacy., VIR- (sotrovimab) and
VIR- are dual-acting monoclonal antibodies against
spike-in glycoproteins with neutralizing activity against
Omicron variants. Moreover, sotrovimab is more neu-
tralizing against Omicron variants. It has been shown
that Hu has a higher neutralizing effect against Omi-
cron pseudovirus than S. It has been suggested that
camel-derived nanosomes, along with bovine-derived anti-
bodies, can effectively reduce the chances of immune
escape caused by Omicron infection.
RBD mutations in Omicron variants lead to escape
against some monoclonal antibodies. For example, QR
could lead to immune escape of Omicron from LY-
CoV/CT-P, QR/SN results in the immune
escape from LY-CoV/ COV-/REGN, GD
contributes to the immune escape from S, GS gives
rise to the immune evasion from COV-/ REGN,
and so on. The failure of the Omicron variant rec-
ognized by many NTD and RBD antibodies is proba-
bly related to its stable structure, local conformation,
hydrophobic microenvironment, and so on. Single muta-
tions analysis of the Omicron variant suggests that Bam-
lanivimab/Etesevimab is ineffective against the Omicron
variants. Meanwhile, various US FDA-approved mon-
oclonal antibodies are ineffective against the Omicron
variant, including REGN, REGN, LY-CoV,
LY-CoV, and CT-P. A related study confirmed that
approximately % of human RBD mAbs failed to bind
with the Omicron variant.
Omicron RBD has a solid binding capacity to ACE.
The neutralization of the Omicron variant by antibodies
from vaccination was evaluated with VSV (pseudo-
typed recombinant vesicular stomatitis virus) based
pseudovirus. Monoclonal antibodies are effective
16 of 24 XU .
TABLE 3 Sensibilities of the Omicron (B...) to diverse neutralizing antibodies
neutralizing
antibody
(NAB) Viral lineage Viral type Full/partial variant
Fold
change Reference strain
Amubarvimab B... Pseudovirus Partial variant . Wuhan-Hu-
B... Pseudovirus Partial variant . Wuhan-Hu-
B...(BA./) Pseudovirus Full variant . Wuhan-Hu- DG
Bamlanivimab B... Pseudovirus Partial variant Wuhan-Hu- DG
Bebtelovimab B... Pseudovirus Partial variant . Wuhan-Hu-
B...(BA./) Pseudovirus Full variant . Wuhan-Hu- DG
Casirivimab B... Pseudovirus Partial variant . B.
B... Pseudovirus Partial variant . Wuhan-Hu-
Cilgavimab B... Pseudovirus Full variant USA-WA/ DG
B... Live virus Full variant . VIC
B...(BA./) Pseudovirus Full variant . B..
Etesevimab B... Pseudovirus Partial variant Wuhan-Hu-
B... Live virus Full variant . USA-WA/
B... Pseudovirus Partial variant Wuhan-Hu-
Evusheld B... Pseudovirus Partial variant . Wuhan-Hu-
B...(BA./) Pseudovirus Pseudovirus . Wuhan-Hu-
DG
Imdevimab B... Pseudovirus Partial variant Wuhan-Hu-
B...(BA./) Pseudovirus Full variant . Wuhan-Hu-
DG
Regdanvimab B... Pseudovirus Full variant >= Wuhan-Hu-
Romlusevimab B... Pseudovirus Full variant . USA-WA/
DG
B...(BA./) Pseudovirus Full variant . Wuhan-Hu- DG
Ronapreve B... Pseudovirus Full variant >= Wuhan-Hu-
B...(BA./) Pseudovirus Full variant . Wuhan-Hu- DG
Sotrovimab B... Live virus Full variant . USA-WA/
B... Pseudovirus Full variant Wuhan-Hu-
B...(BA./) Pseudovirus Full variant . B..
Tixagevimab B... Pseudovirus Full variant . A..
B... Pseudovirus Partial variant >= Wuhan-Hu-
VIR- B... Pseudovirus Full variant Wuhan-Hu-
“Fold change” is an indicator of sensibility of Omicron to dissimilar neutralizing antibodies.
against Omicron variants, although they are expensive
and unevenly distributed globally.
.. Omicron variants along with the
protective effect of vaccines
Cancer patients and children are immunocompromised
and susceptible to Omicron infection. Currently, vacci-
nations, especially the booster vaccination, offer broad
protection against Omicron variants. Mohiuddin and
Kasahara showed that Omicron variants accelerate
cellular senescence in cancer patients, promote oxidative
stress, and aggravate patient complications. Protective
antibodies produced after mRNA- vaccination in
patients with multiple myeloma developed severe break-
through infections weeks after vaccination. After
two doses of mRNA vaccination to Non-small cell lung
cancer (NSCLC) patients and healthy counterparts,
NSCLC patients had lower live virus-neutralizing activity
than healthy counterparts. Cancer patients infected
with the Omicron variant showed strong nAb resistance
XU . 17 of 24
after two doses of the mRNA vaccination. In contrast,
booster vaccination increased nAb titers in cancer
patients, which provided broad protection against cancer
patients.
A related study in South Africa showed that children
infected with the Omicron variant had higher hospital-
ization rates than those infected with other VOCs. In
Berlin, the number of children infected with the Omi-
cron variant drastically increased. It is possible that
mutations, low vaccination rates, previous waves of VOCs
infection, immunodeficiency, and other factors have led
to increased hospitalization rates in children infected
with Omicron variants, In the United States, the
severity of infection in children (under years old) were
significantly lower during the Omicron variant wave than
during the Delta variant wave. For children infected
with the Omicron variant, the number of children’s visits
to the emergency department and hospitalization rates
(under years old) were also significantly lower than
for those infected with the Delta variant. One study
showed different responses in children (– years old)
vaccinated with varying doses of mRNA vaccines. Cross-
VOC antibody responses were observed at and μg
vaccination, and humoral immunity to Omicron was
observed at μg vaccination. Convalescent children
who have been infected with SARS-CoV- and children
vaccinated with two doses of BNTb have reduced
sensitivity to serum antibodies against the Omicron
variants and have been more vulnerable to breakthrough
infection.
A retrospective study conducted live virus and pseu-
dovirus neutralization tests on the Omicron variant
showed that the neutralizing effect of Omicron (B...)
variant decreased in serum from people who were
vaccinated with BNTb vaccine, mRNA- vac-
cine, Sinopharm BBIBP-CorV vaccine, and the neutral-
izing activity against Omicron increased after booster
vaccination. Vaccination with the third dose of mRNA
produced a strong cross-neutralizing effect on the Omi-
cron variant,,, significantly increased serum antibody
titers and reduced the escape of neutralizing antibodies
from the Omicron variant.,, Vaccination with three
doses of the mRNA vaccine BNTb effectively increased
neutralizing antibody levels against Omicron. Vaccina-
tion with two doses of BNTb (> months) showed no
neutralizing activity against the Omicron variant. After
vaccination with booster vaccine, the titer of neutralizing
antibody against Omicron variant was times higher
than that of the second dose. Moreover, after two doses
of mRNA- vaccination followed by an mRNA-
booster immunization, a significant increase in neutral-
izing antibody activity against the Omicron variant was
observed, just fivefold lower than that of DG. After
two doses of BNTb vaccination, antibody neutralizing
titers in serum against the Omicron variant were reduced
more than -fold compared with that of WT, whereas a
third booster dose was also effective in preventing the Omi-
cron variant. Vaccination with the BBIBP-CorV booster
increased the neutralizing activity of the Omicron vari-
ant by approximately .-fold. After two doses of mRNA
vaccine, the neutralizing activity of antibodies against the
Omicron variant was absent or significantly decreased in
vaccinees, who then received a booster dose, and neu-
tralizing antibody activity against Omicron was greatly
enhanced.
Neutralizing activity against the Omicron variant was
detected in convalescent serum. Omicron variants pro-
duce an escape response to neutralizing antibodies initi-
ated by BNTb or CoronaVac. One study has com-
pared sera from COVID- patients one year after the
original DG strain infection, where the former showed
lower neutralizing activity against the Omicron variant
than the latter. Chen et al. conducted a live virus
neutralization test of serum from children who recovered
from SARS-CoV- infection and children who received two
doses of the BNTb vaccine. The results showed that
serum antibodies reached the detectable threshold in only
.% of the recovered children with SARS-CoV- infec-
tion and .% of children who had received two doses of
BNTb vaccine. These results showed that neutralizing
antibody activity against Omicron of sera from children
who recovered from COVID- and received two doses of
BNTb vaccine had remarkably decreased.
All the above studies suggest that vaccination, espe-
cially booster vaccination, enhances neutralizing antibody
activity against Omicron variants. Infection elicits T cell
responses that cross-recognize Omicron variants and
multiple spike-mutated VOCs also increase the breadth of
antibody cross-neutralization.
Rössler et al. showed that cross-neutralizing reac-
tions against the Omicron variants were observed in
homologous BNTb vaccine recipients or heterologous
ChAdOx-S-BNTb vaccine recipients. Heterologous
vaccination with booster doses (recombinant adenovirus
vector vaccine Ad.CoV.S, mRNA vaccine BNTb,
recombinant adenovirus vector ChAdOx nCoV- vac-
cine AZD, CoronaVac vaccine) induced a significant
increase in antibody-neutralizing activity compared
with homologous immunization. The serum from
the convalescent who received two doses of inactivated
virus vaccine had poor neutralizing antibody activity
against the Omicron variant. However, homologous inac-
tivated vaccine booster or heterologous booster protein
subunit vaccine (ZF) could significantly increase
neutralizing antibody activity against the Omicron
variant.
18 of 24 XU .
6 FURTHER STRESS AND RISK
BROUGHT BY OMICRON
Omicron brings a more significant medical burden:In
November , a rapid rise of Omicron cases hap-
penedinGauteng,SouthAfrica.
Since Omicron was
first reported by the WHO on November , , Omi-
cron cases have spread to more than countries in a
month. Omicron variants have increased transmissibil-
ity, extensive immune escape, and a potentially altered host
range., SARS-CoV- transmission dynamics in South
Africa reconstructed by the model inference system indi-
cated that the infection capacity of Omicron was .%
higher than the WT, .% higher than Delta, and Omicron
also eroded .% of population immunity in Gauteng.
Although the clinical symptoms caused by Omicron are
mild, higher infection rates of hospital staff and more hos-
pitalizations have overwhelmed the healthcare systems in
many countries.– The Omicron breakthrough infec-
tions had a significantly higher proportion than other
variants in clinical cases. For example, two travelers vacci-
nated with BNTb were detected positive for Omicron
in Hong Kong, and another case is that a doctor in
Israel receiving three doses of BNTb was also infected
with the Omicron, and he even infected another person.
As of December , , an epidemiological investigation
found that .% ( out of ) of Omicron-positive patients
had no international travel history in South Korea; there-
fore, the omicron case in South Korea may be more than
reported. As of December , , Denmark had con-
firmed cases of the Omicron variant, most of which
were fully vaccinated (%) or boosted (.%), and (.%)
cases had previously been infected with SARS-CoV-.
On December , , the number of new Omicron cases
in India was /day, after which the number surged to
,/day on January , .
Several factors may account for the emergence of Omi-
cron: low vaccination rates in low-income countries, many
immunocompromised individuals, and inadequate health-
related infrastructure to cope with the worsening epi-
demic. At the same time, the management of booster
vaccines exacerbates global vaccine inequalities, so the
international health agencies must take action to provide
more vaccines for countries with the lowest vaccination
rates and the highest susceptibility to SARS-CoV- and its
variants.
Coinfection: There may be simultaneous infections of
Omicron and Delta, resulting in a simple combinatorial
variant of double-spiked spikes called “Delmicron.”
Israel reported a woman infected with both the coro-
navirus and the flu named “flurona.” However, these
require thorough investigation before conclusions can be
drawn.
Investigation of time and space: Computer models play
an important role in predicting Omicron evolution and
transmission trend. The Wills-Riley model, an airborne
disease risk spatiotemporal willingness model, helped to
solve the spatiotemporal problem of SARS-CoV- infection
risk in ventilated indoor environments. The provincial
WKDE model retrospectively analyzed the entire dynamic
process of Omicron transmission in South Africa. It pro-
vided a scientific reference for controlling the SARS-CoV-
variant through a simulation comparison of how to con-
trol the spread of Omicron under different scenarios
with different levels of Omicron protection measures and
vaccination rates.
The mental impact of Omicron on COVID-19 patients:
Several studies have pointed out that the side effects
of SARS-CoV- epidemics include worsening depression,
anxiety, obsessive-compulsive symptoms, and posttrau-
matic stress disorder symptoms; An increasing number
of COVID- patients exhibit extreme burnout and even
suicide.
7PROSPECTS AND PERSPECTIVES
Preventive and control measures during the Omicron wave
especially BA. and BA. should be more positive and
scientific, measures including vaccination, increased ven-
tilation, timely detection and isolation, wearing masks
in indoor public places, washing hands, and keeping
social distance from others should also be taken. Mea-
sures carried out in past influenza pandemics have pro-
vided many valuable suggestions. Vaccination, espe-
cially booster vaccination, is essential to control the spread
of Omicron. Countries are called upon to unite to fight
the Omicron variant and remove restrictions on the import
and export of vaccines to achieve vaccine equity. In addi-
tion to primary two doses vaccination, booster vaccination,
in particular heterologous booster vaccination, would mit-
igate the spread of the Omicron variant. Developed
countries are expected to help countries with inadequate
medical infrastructure, vaccine shortages, low vaccination
rates, and high infection rates.,
Public places such as schools, hospitals, restaurants,
hotels, buses, subways, and movie theaters are high-risk
environments for VOC transmission. The CDC requires
the PCR test results h before arrival and -day self-
isolation after arrival in the United States. Related
studies have shown that N masks can prevent infection
and alleviate Omicron transmission in hospitals after daily
testing. High-performance nanosystems (NS) have been
designed for manufacturing nanoprotective equipment
(masks, gloves, nanoemulsifying disinfectants, etc.) and
intended to delay the infectivity of Omicron variants.
XU . 19 of 24
It is necessary to take strict prevention and control mea-
sures for the residence and community where SARS-CoV-
positive patients were found.
Children and the elderly with weaker immunity are sus-
ceptible to the Omicron variant. The WHO recommends
that the aged, especially those over years old, should
not travel during the Omicron pandemic., It is rec-
ommended that children and seniors receive a booster
vaccination as soon as possible to boost immunity by
expanding the availability of childhood vaccines. Omi-
cron is hoped to help end the pandemic, although the
current situation is still unstable and challenging.
ACKNOWLEDGMENTS
This research was supported by National Key Research
and Development Program of China (Grant Nos.
YFC, YFC, YFA,
BWSJ, and SWAQK), National Natural Science
Foundation of China (Grant No. ), Fundamen-
tal Research Funds for Central Universities (Grant No.
BUCTZY), and H&H Global Research and Technology
Center (Grant No. H).
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
AUTHOR CONTRIBUTION
H. F., Y. T., L. S., and Y. Z. designed the research; A. X.,
B. H., and F. L. read and analyzed the papers; A. S., W. L.,
and X. A. participated in discussion; A. X., B. H., F. L., S.
W., and H. F. wrote and revised the manuscript. All authors
have read and approved the article. A. X., B. H., F. L., and
S. W. contributed equally to this work.
ETHICS STATEMENT
Not applicable.
DATA AVAILABILITY STATEMENT
The data included in this study are available upon request
from the corresponding author.
ORCID
Huahao Fan https://orcid.org/---
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