The genomic and clinical features of the COVID-19 Omicron variant: a narrative review

Decsa Medika Hertanto; Henry Sutanto; Maria Inge Lusida; Kuntaman Kuntaman; Djoko Santoso

doi:10.12688/f1000research.110647.1

Home Browse The genomic and clinical features of the COVID-19 Omicron variant:...

ALL Metrics

Views

Downloads

Get PDF

Get XML

Export

▬

✚

Review

The genomic and clinical features of the COVID-19 Omicron variant: a narrative review

[version 1; peer review: 1 not approved]

Decsa Medika Hertanto¹, Henry Sutanto², Maria Inge Lusida^3,4, Kuntaman Kuntaman³, Djoko Santoso ¹

Decsa Medika Hertanto¹, Henry Sutanto², [...] Maria Inge Lusida^3,4, Kuntaman Kuntaman³, Djoko Santoso ¹

PUBLISHED 23 Mar 2022

Author details Author details

¹ Department of Internal Medicine, Faculty of Medicine, Airlangga University, Dr. Soetomo Teaching Hospital, Surabaya, 60286, Indonesia
² Department of Physiology and Pharmacology, SUNY Downstate Medical Center, Brooklyn, New York, 11203, USA
³ Department of Clinical Microbiology, Faculty of Medicine, Airlangga University, Surabaya, 60132, Indonesia
⁴ Institute of Tropical Disease, Airlangga University, Surabaya, 60115, Indonesia

Decsa Medika Hertanto
Roles: Conceptualization, Investigation, Writing – Original Draft Preparation, Writing – Review & Editing

Henry Sutanto
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Maria Inge Lusida
Roles: Formal Analysis, Writing – Review & Editing

Kuntaman Kuntaman
Roles: Formal Analysis, Writing – Review & Editing

Djoko Santoso
Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

This article is included in the Emerging Diseases and Outbreaks gateway.

This article is included in the Pathogens gateway.

This article is included in the Coronavirus (COVID-19) collection.

Abstract

Coronavirus disease 2019 (COVID-19) is a major cause of morbidity and mortality worldwide. Since late November 2021, the Omicron variant has emerged as the primary cause of COVID-19 and caused a huge increase in the reported incidence around the world. To date, 32-34 spike mutations have been reported to be present in the Omicron variant, 15 of which were located in the receptor-binding domain that interacts with the cell surface of the host cells, while the rest were located in the N-terminal domain and around the furin cleavage site. Recent studies have suggested that those mutations could have a major role in the transmissibility and pathogenicity of the Omicron variant. Additionally, some mutations might contribute to the change of viral tropism of this novel variant. Here, we aim to discuss the recent reports on the transmissibility and severity of the Omicron variant from both the genetic and clinical perspectives. Afterward, we also take the chance to deliver our personal view on the topic.

Keywords

COVID-19, pandemic, SARS-CoV-2, Omicron variant, emerging disease, global health, virus, genome, mutation

Corresponding author: Djoko Santoso

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2022 Hertanto DM et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Hertanto DM, Sutanto H, Lusida MI et al. The genomic and clinical features of the COVID-19 Omicron variant: a narrative review [version 1; peer review: 1 not approved]. F1000Research 2022, 11:353 (https://doi.org/10.12688/f1000research.110647.1) First published: 23 Mar 2022, 11:353 (https://doi.org/10.12688/f1000research.110647.1) Latest published: 28 Jul 2022, 11:353 (https://doi.org/10.12688/f1000research.110647.2)

Introduction

Coronavirus disease 2019 (COVID-19) has been a major cause of morbidity and mortality worldwide since December 2019. Up to February 2022, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 400 million people and contributed to the death of more than 5.5 million individuals around the world. Intriguingly, after more than 2 years of its existence, the infection rate remains high, and the pandemic has not been resolved. Following the devastating impacts of the B.1.617.2 (Delta) variant, predominantly in health and socioeconomic sectors, there was a high expectation that the viral disease could be tamed by the rapid, collaborative and evolutionary development of COVID-19 vaccines. Indeed, the massive vaccination program in several countries has successfully reduced the fatality of the disease and together with the implementation of strict public health and social control measures (PHSCM), the infection rate could also be lowered.¹^–⁴ For example, in the United States (US), COVID-19 vaccines reduced the overall attack rate (i.e., number of new cases during specified time interval divided by the total population at start of time interval) in vaccinated individuals by 4.4% on day 300 from the start of vaccination (9% in the unvaccinated group vs. 4.6% in the vaccinated group), as well as the rate of hospitalization, intensive care unit (ICU) occupancy, incidence of major adverse events and mortality.¹ Despite the reported effectivity decline of BNT162b2 and ChAdOx1 vaccines against the Delta variant (10–13% and 16% lower than B.1.1.7 (Alpha) variant, respectively),⁵ vaccination was proven to remain effective in reducing infection and accelerating viral clearance,² as well as lowering mortality caused by the Delta variant.⁴

However, a glimpse of hope to end the pandemic was once again challenged by the presence of the new COVID-19 B.1.1.529 (a.k.a. Omicron) variant. Since its first reported appearance in South Africa in November 2021, it has rapidly taken the attention of experts around the world. A few days after its appearance, the World Health Organization (WHO) immediately classified Omicron as a Variant of Concern (VoC). Since then, it has vastly spread from Africa to Europe, then Asia, Australia and America (Figure 1). Since early January 2022, the Omicron variant has become the major COVID-19 variant in most countries (Table 1)⁶^,⁷ and contributed to the rise of COVID-19 incidence from ~600,000 new cases in late November 2021 to ~3.5 million cases in late January 2022.

Figure 1. World map depicting the total number of coronavirus disease 2019 (COVID-19) cases for the given period.

Table 1. Confirmed coronavirus disease 2019 (COVID-19) cases from December 1^st, 2021 to February 23^rd, 2022 and shares of the Omicron variant.

20 countries with highest confirmed cases during observed period	Total cases within observed period (in million)	Relative change compared with data on December 1^st, 2021	Shares of Omicron variant per November 29^th, 2022	Shares of Omicron variant per February 21^st, 2022
World	165.85	+63%	-	-
United States	30.01	+62%	0.06%	99.77%
France	14.75	+190%	0.16%	99.14%
United Kingdom	8.49	+82%	0.17%	99.75%
India	8.27	+24%	0.35%	95.88%
Germany	8.25	+138%	0.21%	99.51%
Italy	7.56	+150%	0.11%	89.91%
Brazil	6.38	+29%	0.14%	99.75%
Russia	6.07	+64%	0.00%	(Jan 24, 2022) 69.23%
Spain	5.74	+111%	0.22%	99.03%
Turkey	4.94	+56%	0.00%	97.90%
Argentina	3.54	+66%	0.00%	(Feb 7, 2022) 100.00%
Netherlands	3.50	+131%	1.72%	100.00%
Japan	2.97	+172%	1.61%	(Feb 7, 2022) 99.44%
Australia	2.91	+1,364%	0.44%	99.73%
Israel	2.25	+167%	0.30%	99.78%
Denmark	2.17	+441%	0.04%	99.92%
Portugal	2.07	+179%	1.55%	99.72%
South Korea	2.04	+446%	0.15%	(Feb 7, 2022) 89.86%
Poland	2.03	+57%	0.00%	98.88%
Belgium	1.74	+98%	0.20%	99.74%

The genomic basis of the Omicron variant and the predicted effects of its mutations

The consequences of reported mutations on transmissibility and pathogenicity of the Omicron variant

A study conducted based upon the genome sequencing data of 108 samples collected from patients infected with the Omicron variant⁸ revealed that this variant possessed 61-64 mutations, 54 of which were single nucleotide polymorphisms (SNPs). Of those, 34 mutations were positioned at the spike (S) proteins and 32 of those spike mutations were non-synonymous, which means that the mutations alter the amino acid sequences.⁸ Importantly, the mutations in the Omicron variant were reported to be present in all three key regions in the spike of SARS-CoV-2: The receptor binding domain (RBD), N-terminal domain (NTD) and furin cleavage site (FCS). Overall, 15 of the spike mutations were located in the RBD, a region that is responsible for the viral attachment to the cell surface (Table 2).

Table 2. Reported mutations in S-proteins of the Omicron variant.

NTD	RBD	FCS & adjacent
A67V^a^,^b^,#	G339D^a^,^b^,#	T547K^a^,^b^,#
IHV68I^a	S371L^a^,^b	D614G^a^,^b
del69-70^b^,#	S373P^a^,^b	H655Y^a^,^b^,#
T95I^a^,^b	S375F^a^,^b	N679K^a^,^b^,#
GVYY142D^a	K417N^a^,^b	P681H^a^,^b^,#
del142-144^b	N440K^a^,^b	N764K^a^,^b
Y145D^b	G446S^a^,^b	D796Y^a^,^b^,#
NL211I^a	S477N^a^,^b	N856K^a^,^b^,#
del211^b	T478K^a^,^b	Q954H^a^,^b^,#
L212I^b	E484A^a^,^b	N969K^a^,^b^,#
Ins214EPE^b	Q493R^a^,^b	L981F^a^,^b^,#
	G496S^a^,^b
	Q498R^a^,^b
	N501Y^a^,^b
	Y505H^a^,^b

a was reported by Ma et al.⁸ and

b was reported by the United States Centers for Disease Control and Prevention (CDC). The mutations that are potentially suitable for Omicron screening are marked by (#). This was assessed based on the exclusivity of these mutations for Omicron variant (present in >95% of Omicron (and sub-lineage) sequences and present in <1% of recent non-Omicron sequences) according to the Communicable Diseases Genomics Network (CDGN) per 20 December 2021 (FCS = furin cleavage site; NTD = N-terminal domain; RBD = receptor binding domain).

Mutations in RBD

As displayed in Table 2, the N501Y mutation that converts amino acid asparagine to tyrosine at position 501 was identified in the Omicron variant. This particular mutation enhanced the binding affinity of the RBD to angiotensin converting enzyme type-2 (ACE2) receptor in the surface of the host cell.⁹ As a consequence, the Omicron variant could have a stronger attachment to the host cells than some of the other COVID-19 variants, fostering its transmissibility. Meanwhile, the mutation Q498R (converting glutamine to arginine at position 498) of the RBD alone negatively affected the protein stability and binding. However, due to its known epistatic effect with N501Y, the combination of both mutations was shown to increase the affinity of the RBD to ACE2 receptor by 4-fold.¹⁰ Of note, the N501Y mutation was also identified in other COVID-19 variants (e.g., C.1.2, Alpha, Beta and Gamma), but not Q498R. In addition to their effect on the binding affinity to ACE2 receptor, Omicron-associated mutations in the RBD could also promote the escape from existing neutralizing antibodies. In the study done by Cao et al.,¹¹ the effect of Omicron-associated mutations in the RBD region on neutralizing antibodies was assessed using a high throughput yeast display screening. As the result, K417N, G446S, E484A and Q493R mutations assisted the virus to evade neutralizing antibodies, especially the ones which epitope overlapped with the ACE2 binding motif (epitope group A-D). Also, there was evidence that G339D, S371L and N440K mutations of the RBD could facilitate the virus evasion from other neutralizing antibodies (epitope group E-F). Overall, of the 247 antibodies tested, 85% were evaded by Omicron, suggesting the potentially low efficacy of preexisting neutralizing antibodies against the Omicron variant.¹¹

Mutations in NTD

Several mutations in the NTD region were shown to have significant effect on viral infectivity and the modulation of immune evasion. For example, the del69-70 boosted the infectivity of the Alpha variant through the elevation of cleaved spike incorporation into virions.¹² Conversely, T95I mutation that was previously identified in the B.1.617.1 variant seems not to be substantially involved in immune evasion due to its location outside of the antigenic supersite.¹³ Interestingly, two cases of BNT162b2 and mRNA-1273 vaccines breakthrough infection were reported in COVID-19 patients harboring T95I mutation of the NTD, as well as the del142-144 mutation of the NTD and D614G mutation of the FCS, indicating the possible contribution of those mutations on viral immune escape.¹⁴ Meanwhile, evidence of a marked (4-16-fold) reduction of neutralizing capacity of COVID-19 convalescent sera against a recombinant vesicular stomatitis virus carrying SARS-CoV-2 spike protein with Y145D mutation was also reported.¹⁵

Mutations in FCS

The FCS region has been shown to be a key part of SARS-CoV-2 pathogenesis and severity. For instance, a mutant lacking FCS (ΔPRRA) displayed a reduced replication rate in a human respiratory cell line.¹⁶ Meanwhile, in regard to Omicron-associated mutations, the H655Y and N679K mutations which are located proximal to the FCS, and the P681H mutation of the FCS could enhance the SARS-CoV-2 spike cleavage and increase the transmissibility of the Omicron variant. Moreover, the P681H mutation, which was previously identified in the B.1.1.7 (Alpha) variant, was demonstrated to facilitate the viral resistance against innate immunity (i.e., interferon-β) in lung epithelial cells.¹⁷ Yet, another study on this particular mutation did not find any notable change on the spike cleavage, viral entry or intercellular spreading.¹⁸ Next, the D614G mutation, a common mutation found in existing COVID-19 variants, increased viral replication in human lung epithelia and respiratory tract by fostering the virion stability and infectivity. Moreover, it increased the viral load in the upper respiratory tract, thereby promoting viral transmission.¹⁹ However, it is important to note that the effect of such mutations on Omicron pathogenicity may differ from what was reported in previous COVID-19 variants due to distinct interactions among variant-associated mutations.

The viral tropism of the Omicron variant

The change of viral tropism in the Omicron variant is also important to scrutinize. A recent UK-based study showed that the Omicron variant was strongly associated with symptoms from upper respiratory tract more than the lower respiratory tract.²⁰ This could be explained by the presence of two Omicron-specific mutations: N764K and N856K. Those mutations were shown to produce cleavage sites for subtilisin-kexin isozyme-1/site-1 protease (SKI-1/S1P) serine protease predominantly situated in the upper airway. Such cleavage sites are important to cleave viral envelope glycoproteins, which modulate SARS-CoV-2 replication and pathogenesis.²¹ Indeed, the Omicron variant was shown to replicate faster in the bronchus than in the lung parenchyma.²² Another study also highlighted that despite the similar viral replication in human nasal epithelial cultures, the Omicron variant demonstrated lower replication in lower respiratory and pulmonary cells than the Delta variant.²³ Additionally, Omicron spike protein has a lower S1/S2 cleavage efficiency than the Delta variant and Omicron tends to avoid cells expressing a high level of transmembrane protease, serine 2 (TMPRSS2). This was due to Omicron’s failure in exploiting the TMPRSS2 that promotes cell entry via plasma membrane fusion. As a consequence, the cell entry of the Omicron variant was largely mediated through the endocytic pathway.²³^,²⁴ The fact that SKI-1/S1P was also present in pulmonary macrophages²¹ could suggest the potential consequences of N764K and N856K mutations on the host innate immunity. Nevertheless, more studies are needed to confirm this notion.

What can we tell from the Ct value of patients with the Omicron variant?

Real-time reverse transcription polymerase chain reaction (rtRT-PCR) or quantitative RT-PCR (qRT-PCR) is a gold-standard diagnostic tool for identifying SARS-CoV-2, the causative agent of COVID-19. This method usually detects ≥ 2 genes of SARS-CoV-2, including ORF1ab/RdRp, N and E.²⁵ At present, due to the increasing incidence of Omicron variant infection, S gene with S gene target failure (SGTF) is frequently used as an indicator for screening of the Omicron variant. Most reported Omicron variant sequences include a deletion in the S gene, which can cause an SGTF in some PCR assays.

Cycle threshold (Ct) is the thermal cycle number at which the amplified DNA that shows as a fluorescent signal exceeds and thus passes the threshold for positivity. A higher Ct value means that the tool requires more copy numbers to reach the positivity threshold, indicating a lower viral concentration in the specimens. Conversely, the lower the Ct level the greater the amount of identified target ribonucleic acid (RNA) in the sample. A recent study assessing the real-time (RT) qPCR data from 10,324 specimens and comparing 97 Omicron against 107 Delta variant infections reported that the Ct values was higher for Omicron infections than for Delta infections (Omicron: Ct 23.3 vs. Delta: Ct 20.5), suggesting a lower peak viral RNA of the Omicron variant. Moreover, the clearance phase for Omicron was shorter while the clearance rate was similar with the Delta variant.²⁶ Similarly, studies conducted in France also reported a significantly higher Ct value for Omicron infection than the non-Omicron variants.²⁷^,²⁸ These findings suggest that the high transmissibility of the Omicron variant might not be due to a high viral load in the upper respiratory tract, despite the presence of D614G mutation which was known to increase viral replication in the upper respiratory tissue.¹⁹ Thus, at present, the cause of a higher Ct value in Omicron variant infection than other variants, including Delta, remains unclear.

Clinical features of the Omicron variant

A recent observational study conducted in Texas, US, from late December 2021 to early January 2022 reported that the Omicron variant displayed some different clinical patterns than its predecessors.²⁹ Compared to patients infected by Alpha and Delta variants, these patients were younger and predominantly female. The number of patients requiring hospitalization was significantly lower in Omicron than in Alpha and Delta variant infections (19.8% vs. 54.6% and 43.1%, respectively). Of those who were hospitalized, the average length of stay was significantly shorter in Omicron than Alpha and Delta (3.2 days vs. 5.1 days and 5.4 days, respectively). Moderate to severe cases (e.g., number of patients requiring extracorporeal membrane oxygenation [ECMO], mechanical ventilation and high-flow oxygenation) and mortality were also lower in Omicron infection. As expected, while Alpha and Delta variants affected mostly the unvaccinated individuals, the Omicron variant proportionally infected both the unvaccinated (44.1%) and vaccinated people (55.9%).²⁹ These findings and comparable results from other studies³⁰^,³¹ confirm the hypothesis that the Omicron variant causes less severe disease, resulted in a lower hospitalization rate. Importantly, the fact that Omicron caused an increased mRNA vaccine (i.e., BNT162b2 and mRNA-1273) breakthrough incidence²⁹ needs to be swiftly responded to by speeding up the vaccination booster campaign. The third vaccine (booster) dose has been shown to rescue and broaden the viral neutralization.³²^–³⁵ A study comparing the mRNA vaccines effectiveness on 16,087 Omicron versus 4,261 Delta cases revealed that the second dose vaccine effectiveness against the Delta variant reduced from 89% to 80% after 240 days. Interestingly, against the Omicron variant, the second dose vaccine effectiveness was only 36% at day 7-59 and completely diminished after 180 days. However, the third dose (booster) vaccination recovered the vaccine effectiveness against the Delta and Omicron variants to 97% and 61% after day 7, respectively.³⁵ Therefore, booster vaccination is expected to be beneficial to tackle this emerging COVID-19 variant.

Table 3 lists the reported clinical symptoms associated with Omicron variant infection.³⁶^–⁴¹ In most studies, upper respiratory symptoms (e.g., runny or stuffy nose, sneezing, cough and sore throat) dominated, while the lower respiratory complaint (e.g., shortness of breath) was identified in less than 20% of patients infected by the Omicron variant. Non-respiratory symptoms, such as fatigue, headache, muscle pain and fever, were also seen in some patients, although the number varies between studies. Importantly, COVID-19-pathognomonic symptoms, such as anosmia and ageusia, were only observed in a limited number of patients across studies (less than 25%). Overall, this observation is consistent with the abovementioned viral tropism of the Omicron variant.

Table 3. Reported clinical symptoms of the Omicron variant.

Symptoms	Brandal et al.³⁶ N = 81	Young et al.³⁷ N = 87	CDC Team³⁸ N = 43	Maisa et al.³⁹ N = 277	Menni et al.⁴⁰ N = 4,990	Hajjo et al.⁴¹ N = 500
Symptoms	Norway	Singapore	USA	France	UK	Jordan
Sneezing	35 (43%)	-	-	-	3,143 (63%)	-
Runny or stuffy nose	63 (78%)	30 (35%)	22 (59%)	74 (27%)	3,818 (77%)	33%
Loss of smell/anosmia	10 (12%)	3 (3%)	3 (8%)	23 (8%)	~17%	1%
Loss of taste/ageusia	19 (23%)	-	3 (8%)	25 (9%)	-	1%
Cough	67 (83%)	39 (45%)	33 (89%)	143 (52%)	2,486 (50%)	47%
Hoarseness	-	-	-	-	2,145 (43%)	9%
Sore throat	58 (72%)	40 (46%)	-	88 (32%)	3,517 (71%)	45%
Shortness of breath	10 (12%)	-	6 (16%)	31 (11%)	~5%	-
Reduced appetite	27 (33%)	-	-	-	~25%	-
Nausea or vomiting	-	-	8 (22%)	20 (7%)	~18%	-
Abdominal pain	5 (6%)	-	-	-	~18%	-
Diarrhea	-	5 (6%)	4 (11%)	17 (6%)	~19%	-
Fatigue/lethargy	60 (74%)	-	24 (65%)	158 (57%)	-	32%
Headache	55 (68%)	-	-	121 (44%)	3,729 (75%)	13%
Muscle pain	47 (58%)	-	-	107 (39%)	~30%	29%
Fever	44 (54%)	24 (28%)	14 (38%)	169 (61%)	~35%	48%
Asymptomatic	-	20 (23%)	3 (7%)	-	-	31%

* Multiple symptoms could be reported by one person (UK = United Kingdom; USA = United States of America).

Nevertheless, it is also crucial to acknowledge that although studies have shown compelling evidence of a less severe disease and a lower hospitalization due to Omicron infection, the high transmissibility of this variant might still impact the healthcare system readiness and increase the absolute number of hospitalization.⁴² These conditions would cause a severe delay on the non-COVID-19 patient care and might result in bigger indirect consequences than we expected. Also, the effect of the Omicron variant in immunocompromised individuals, and patients with concomitant diseases and comorbidities (e.g., diabetes mellitus) is still unknown. In general, these individuals have an impaired immune response against infections, a condition that favors Omicron and other COVID-19 variants. Nonetheless, the effect of Omicron on this special population is yet to be explored.

Highlights

Overall, the genomic profile of the Omicron variant hinted a high affinity to ACE2 receptor, a high transmissibility and a likelihood to evade neutralizing antibodies,²³ either from the previous vaccination³²^,⁴³ or prior infection(s).⁴⁴ This evidence suggests the need for Omicron-specific vaccines, which could provide a better protection against the disease than the currently available COVID-19 vaccines. Indeed, an Omicron-based vaccine is currently being studied in a clinical trial to evaluate the safety, tolerability and immunogenicity in healthy adults. In addition, the fact that the Omicron variant had a lower predisposition to damage lower respiratory tract and pulmonary tissue could indicate its potentially lower severity than its predecessors (e.g., Delta variant). Indeed, the less severe feature of Omicron has been seen in several observational studies. Nonetheless, the consequences of this variant on special populations (e.g., individuals with altered immune response, diabetes mellitus or advanced age) remain to be elucidated.

Also, it is important to highlight that in a recent statement, WHO’s Technical Advisory Group on SARS-CoV-2 Virus Evolution (TAG-VE) has raised a concern regarding Omicron sublineage BA.2. To date, several Omicron sublineages have been identified (e.g., BA.1, BA.1.1., BA.2 and BA.3) and each of them exhibits different mutations than the others. For the past few weeks, globally, the proportion of BA.2 sublineage has been increasing relative to BA.1. Initial data regarding this subvariant suggested that Omicron sublineage BA.2 was more transmissible than BA.1, with a reproduction rate of 1.4 times higher than BA.1.⁴⁵ It was also more replicative in human nasal epithelial cells. Moreover, the pathogenicity and the ability to evade neutralizing antibodies were reported to be higher in BA.2 Omicron sublineage.⁴⁵ In addition, the absence of del69-70 mutation of NTD in BA.2 could significantly lower the identifiability of this subvariant in some PCR assays.

Regardless, implementing an effective PHSCM could still be beneficial to limit person-to-person transmission of Omicron variant. The application of well-fitting mask, imposing strict physical distancing, cough etiquette and hand hygiene, as well as avoiding crowds remain vital. The WHO has already advised to enhance surveillance with rapid testing, cluster investigations, contact tracing and quarantine, as well as case isolation to cut the chain of transmission. Only by a collaborative effort, the COVID-19 pandemic could be brought to an end.

Data availability

No data are associated with this article.

Acknowledgements

An earlier version of this article can be found on https://www.preprints.org/ (doi: 10.20944/preprints202202.0224.v1).

References

1. Moghadas SM, Vilches TN, Zhang K, et al.: The Impact of Vaccination on Coronavirus Disease 2019 (COVID-19) Outbreaks in the United States. Clin. Infect. Dis. 2021; 73(12): 2257–2264. PubMed Abstract | Publisher Full Text
2. Singanayagam A, Hakki S, Dunning J, et al.: Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study. Lancet Infect. Dis. 2022; 22(2): 183–195. PubMed Abstract | Publisher Full Text
3. Ng OT, Koh V, Chiew CJ, et al.: Impact of Delta Variant and Vaccination on SARS-CoV-2 Secondary Attack Rate Among Household Close Contacts. Lancet Reg. Health West Pac. 2021; 17: 100299. PubMed Abstract | Publisher Full Text
4. Sheikh A, Robertson C, Taylor B: BNT162b2 and ChAdOx1 nCoV-19 Vaccine Effectiveness against Death from the Delta Variant. N. Engl. J. Med. 2021; 385(23): 2195–2197. PubMed Abstract | Publisher Full Text
5. Pouwels KB, Pritchard E, Matthews PC, et al.: Effect of Delta variant on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK. Nat. Med. 2021; 27(12): 2127–2135. PubMed Abstract | Publisher Full Text
6. Dong E, Du H, Gardner L: An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect. Dis. 2020; 20(5): 533–534. PubMed Abstract | Publisher Full Text
7. Khare S, Gurry C, Freitas L, et al.: GISAID's Role in Pandemic Response. China CDC Wkly. 2021; 3(49): 1049–1051. PubMed Abstract | Publisher Full Text
8. Ma W, Yang J, Fu H, et al.: Genomic perspectives on the emerging SARS-CoV-2 omicron variant. Genomics Proteomics Bioinformatics. 2022. Publisher Full Text
9. Liu Y, Liu J, Plante KS, et al.: The N501Y spike substitution enhances SARS-CoV-2 infection and transmission. Nature. 2022; 602(7896): 294–299. PubMed Abstract | Publisher Full Text
10. Zahradnik J, Marciano S, Shemesh M, et al.: SARS-CoV-2 variant prediction and antiviral drug design are enabled by RBD in vitro evolution. Nat. Microbiol. 2021; 6(9): 1188–1198. PubMed Abstract | Publisher Full Text
11. Cao Y, Wang J, Jian F, et al.: Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies. Nature. 2021; 602: 657–663. PubMed Abstract | Publisher Full Text
12. Meng B, Kemp SA, Papa G, et al.: Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7. Cell Rep. 2021; 35(13): 109292. PubMed Abstract | Publisher Full Text
13. McCallum M, Walls AC, Sprouse KR, et al.: Molecular basis of immune evasion by the Delta and Kappa SARS-CoV-2 variants. Science. 2021; 374(6575): 1621–1626. PubMed Abstract | Publisher Full Text
14. Hacisuleyman E, Hale C, Saito Y, et al.: Vaccine Breakthrough Infections with SARS-CoV-2 Variants. N. Engl. J. Med. 2021; 384(23): 2212–2218. PubMed Abstract | Publisher Full Text
15. Haslwanter D, Dieterle ME, Wec AZ, et al.: A Combination of Receptor-Binding Domain and N-Terminal Domain Neutralizing Antibodies Limits the Generation of SARS-CoV-2 Spike Neutralization-Escape Mutants. MBio. 2021; 12(5): e0247321. PubMed Abstract | Publisher Full Text
16. Johnson BA, Xie X, Bailey AL, et al.: Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis. Nature. 2021; 591(7849): 293–299. PubMed Abstract | Publisher Full Text
17. Lista MJ, Winstone H, Wilson HD, et al.: The P681H mutation in the Spike glycoprotein confers Type I interferon resistance in the SARS-CoV-2 alpha (B.1.1.7) variant. bioRxiv 2021:2021.11.09.467693.
18. Lubinski B, Fernandes MHV, Frazier L, et al.: Functional evaluation of the P681H mutation on the proteolytic activation of the SARS-CoV-2 variant B.1.1.7 (Alpha) spike. iScience. 2022; 25(1): 103589. PubMed Abstract | Publisher Full Text
19. Plante JA, Liu Y, Liu J, et al.: Spike mutation D614G alters SARS-CoV-2 fitness. Nature. 2021; 592(7852): 116–121. PubMed Abstract | Publisher Full Text
20. Vihta K-D, Pouwels KB, Peto TE, et al.: Omicron-associated changes in SARS-CoV-2 symptoms in the United Kingdom. medRxiv 2022:2022.01.18.22269082.
21. Maaroufi H: The N764K and N856K mutations in SARS-CoV-2 Omicron S protein generate potential cleavage sites for SKI-1/S1P protease. bioRxiv 2022:2022.01.21.477298.
22. Hui KPY, Ho JCW, Cheung MC, et al.: SARS-CoV-2 Omicron variant replication in human bronchus and lung ex vivo. Nature. 2022. PubMed Abstract | Publisher Full Text
23. Meng B, Abdullahi A, Ferreira I, et al.: Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts tropism and fusogenicity. Nature. 2022. Publisher Full Text
24. Zhao H, Lu L, Peng Z, et al.: SARS-CoV-2 Omicron variant shows less efficient replication and fusion activity when compared with Delta variant in TMPRSS2-expressed cells. Emerg Microbes Infect. 2022; 11(1): 277–283. PubMed Abstract | Publisher Full Text
25. van Kasteren PB , van der Veer B , van den Brink S , et al.: Comparison of seven commercial RT-PCR diagnostic kits for COVID-19. J. Clin. Virol. 2020; 128: 104412. PubMed Abstract | Publisher Full Text
26. Hay JA, Kissler SM, Fauver JR, et al.: Viral dynamics and duration of PCR positivity of the SARS-CoV-2 Omicron variant. medRxiv 2022:2022.01.13.22269257.
27. Sofonea MT, Roquebert B, Foulongne V, et al.: From Delta to Omicron: analysing the SARS-CoV-2 epidemic in France using variant-specific screening tests (September 1 to December 18, 2021). medRxiv 2022:2021.12.31.21268583.
28. Sentis C, Billaud G, Bal A, et al.: SARS-CoV-2 Omicron variant, lineage BA.1, is associated with lower viral load in nasopharyngeal samples compared to Delta variant. medRxiv 2022:2022.02.02.22269653.
29. Christensen PA, Olsen RJ, Long SW, et al.: Signals of Significantly Increased Vaccine Breakthrough, Decreased Hospitalization Rates, and Less Severe Disease in Patients with Coronavirus Disease 2019 Caused by the Omicron Variant of Severe Acute Respiratory Syndrome Coronavirus 2 in Houston, Texas. Am. J. Pathol. 2022. PubMed Abstract | Publisher Full Text
30. Maslo C, Friedland R, Toubkin M, et al.: Characteristics and Outcomes of Hospitalized Patients in South Africa During the COVID-19 Omicron Wave Compared With Previous Waves. JAMA. 2022; 327(6): 583–584. PubMed Abstract | Publisher Full Text
31. Espenhain L, Funk T, Overvad M, et al.: Epidemiological characterisation of the first 785 SARS-CoV-2 Omicron variant cases in Denmark, December 2021. Euro Surveill. 2021; 26(50) PubMed Abstract | Publisher Full Text
32. Accorsi EK, Britton A, Fleming-Dutra KE, et al.: Association Between 3 Doses of mRNA COVID-19 Vaccine and Symptomatic Infection Caused by the SARS-CoV-2 Omicron and Delta Variants. JAMA. 2022; 327: 639–651. PubMed Abstract | Publisher Full Text
33. Perez-Then E, Lucas C, Monteiro VS, et al.: Neutralizing antibodies against the SARS-CoV-2 Delta and Omicron variants following heterologous CoronaVac plus BNT162b2 booster vaccination. Nat. Med. 2022. PubMed Abstract | Publisher Full Text
34. Schmidt F, Muecksch F, Weisblum Y, et al.: Plasma Neutralization of the SARS-CoV-2 Omicron Variant. N. Engl. J. Med. 2022; 386(6): 599–601. PubMed Abstract | Publisher Full Text
35. Buchan SA, Chung H, Brown KA, et al.: Effectiveness of COVID-19 vaccines against Omicron or Delta symptomatic infection and severe outcomes. medRxiv 2022:2021.12.30.21268565.
36. Brandal LT, MacDonald E, Veneti L, et al.: Outbreak caused by the SARS-CoV-2 Omicron variant in Norway, November to December 2021. Euro Surveill. 2021; 26(50). PubMed Abstract | Publisher Full Text
37. Young B, Fong S-W, Chang ZW, et al.: Comparison of the clinical features, viral shedding and immune response in vaccine breakthrough infection by the Omicron and Delta variants. Research Square. 2022.
38. Team CC-R: SARS-CoV-2 B.1.1.529 (Omicron) Variant - United States, December 1-8, 2021. MMWR Morb. Mortal. Wkly Rep. 2021; 70(50): 1731–1734. Publisher Full Text
39. Maisa A, Spaccaferri G, Fournier L, et al.: First cases of Omicron in France are exhibiting mild symptoms, November 2021-January 2022. Infect. Dis. Now. 2022. PubMed Abstract | Publisher Full Text
40. Menni C, Valdes A, Polidori L, et al.: A Comparison of Symptom Prevalence, Severity and Duration in the SARS-CoV-2 Omicron Versus Delta Variants Among Vaccinated Individuals from the ZOE COVID Study. SSRN. 2022. Publisher Full Text
41. Hajjo R, AbuAlSamen MM, Alzoubi HM, et al.: The Epidemiology of Hundreds of Individuals Infected with Omicron BA.1 in Middle-Eastern Jordan. medRxiv 2022:2022.01.23.22269442.
42. Ulloa AC, Buchan SA, Daneman N, et al.: Early estimates of SARS-CoV-2 Omicron variant severity based on a matched cohort study, Ontario, Canada. medRxiv 2022:2021.12.24.21268382.
43. Collie S, Champion J, Moultrie H, et al.: Effectiveness of BNT162b2 Vaccine against Omicron Variant in South Africa. N. Engl. J. Med. 2022; 386(5): 494–496. PubMed Abstract | Publisher Full Text
44. Altarawneh HN, Chemaitelly H, Hasan MR, et al.: Protection against the Omicron Variant from Previous SARS-CoV-2 Infection. N. Engl. J. Med. 2022. PubMed Abstract | Publisher Full Text
45. Yamasoba D, Kimura I, Nasser H, et al.: Virological characteristics of SARS-CoV-2 BA.2 variant. bioRxiv 2022:2022.02.14.480335.

Comments on this article Comments (0)

Version 2

VERSION 2 PUBLISHED 23 Mar 2022

Author details Author details

Decsa Medika Hertanto
Roles: Conceptualization, Investigation, Writing – Original Draft Preparation, Writing – Review & Editing

Henry Sutanto
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Maria Inge Lusida
Roles: Formal Analysis, Writing – Review & Editing

Kuntaman Kuntaman
Roles: Formal Analysis, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

Article Versions (2)

version 2

Revised

Published: 28 Jul 2022, 11:353

https://doi.org/10.12688/f1000research.110647.2

version 1

Published: 23 Mar 2022, 11:353

https://doi.org/10.12688/f1000research.110647.1

© 2022 Hertanto DM et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Download

Export To

metrics

	Views	Downloads
F1000Research	-	-
PubMed Central Data from PMC are received and updated monthly.	-	-

Citations

SEE MORE DETAILS

CITE

how to cite this article

Hertanto DM, Sutanto H, Lusida MI et al. The genomic and clinical features of the COVID-19 Omicron variant: a narrative review [version 1; peer review: 1 not approved]. F1000Research 2022, 11:353 (https://doi.org/10.12688/f1000research.110647.1)

NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.

track

receive updates on this article

Track an article to receive email alerts on any updates to this article.

Open Peer Review

Version 1

VERSION 1

PUBLISHED 23 Mar 2022

Views

Reviewer Report 18 Jul 2022

Leyi Wang, Veterinary Diagnostic Laboratory and Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA

Vanessa Revindran-Stam, Veterinary Diagnostic Laboratory , College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA

Not Approved

https://doi.org/10.5256/f1000research.122274.r141228

The genomic and clinical features of the COVID-19 Omicron variant: a narrative review. (Hertanto et al.)

Summary:

The ongoing COVID-19 pandemic is a major cause of worldwide mortality and morbidity. The review manuscript by Hertanto et al. looks at the Omicron variant that first emerged in South Africa in November of 2021 and how it became a Variant of Concern relatively quickly. This review paper is split into two parts, the first covers the genomic basis of the Omicron variant and the second part looks at the clinical features of the same variant.

Major comments:

What we find lacking in this review is that authors fail to introduce the readers to any basic background of Omicron. There are phylogenetic studies that point to the suggestion that the Omicron variant likely diverged early on from other SARS-CoV-2 strains. Examination of the whole genome has indicated that the Omicron variant can be classified into two different lineages, BA.1 and BA.2. Maybe more could have been presented on this earlier rather than at the end in the highlights section of the paper. If this is a narrative review, the hope is that an overall picture of the subject is presented. We find that this is lacking in this narrative.

The major focus of the section on the genomic bases of the Omicron variant is on the mutations that are present in the 3 key regions of the spike of SARS-CoV-2: the receptor binding domain, the N-terminal domain and the furin cleavage site. There are more than just the mutations found in these three regions that account for the mutations present in the Omicron variant. The authors do not cover these mutations or their effect.

The first sentence in Mutations in RBD section: "As displayed in Table 2, the N501Y mutation that converts amino acid asparagine to tyrosine at position 501 was identified in the Omicron variant", is slightly misleading. On first read, it implies that this mutation was identified first in the Omicron variant. This mutation has been identified in other variants, and this is represented five sentences later in the same paragraph.

On the section titled: What can we tell from the Ct value of patients with the Omicron variant? : While the authors present that Omicron variant samples had a higher Ct value compared to other variant samples, there is nothing notable to take away from this section. The authors do not highlight any key point as to what having a higher Ct value means for the Omicron variant.

Minor Comments:

Table 2: Reported mutations in S-protein of the Omicron variant. This table was not helpful and did not contribute anything to the review. All the mutations identified in the Omicron variant should have been presented, not just the ones in the RBD, NTD and Furin Cleavage site. Legend for Table 2 mentions the mutations that are potentially suitable for Omicron screening but no where in the body of the text is there mention of using the mutations for screening purposes.

Clinical features of the Omicron variant:

For this section of the paper, the authors highlight the different clinical patterns observed in the Omicron variant compared to its predecessors. This section is written and presented very well. Being able to read some comparisons between the Omicron, Alpha and Delta variant was a plus and helped accomplish the author’s goal. With the presentation of the Omicron came asymptomatic and symptomatic variant infection. It would be a nice touch if the authors mentioned something notable about this occurrence.

The data presented in Table 3 might have been better served if presented in graph/chart form. It would have had a better impact if that data was presented differently.

Summary:

Overall, this review is missing in many areas. There is no new scientific information that is presented. There are other reviews, (1: Omicron genetic and clinical peculiarities that may overturn SARS-CoV-2 pandemic: a literature review; 2: Literature review of Omicron: A grim reality amidst COVID-19) that give a good understanding of the Omicron variant and the impact on the COVID-19 pandemic.

References:

Arora, S.; Grover, V.; Saluja, P.; Algarni, Y.A.; Saquib, S.A.; Asif, S.M.; Batra, K.; Alshahrani, M.Y.; Das, G.; Jain, R.; et al. Literature Review of Omicron: A Grim Reality Amidst COVID-19. Microorganisms 2022, 10, 451. https://doi.org/10.3390/microorganisms10020451

Kupperschmidt, K. Where did ‘weird’ Omicron come from? Science, Vol 374, Issue 6572, Dec 2021. https://doi.org/10.1126/science.acx9754

Sujan Poudel, Angela Ishak, Javier Perez-Fernandez, Efrain Garcia, Darwin A. León-Figueroa, Luccio Romaní, D. Katterine Bonilla-Aldana, Alfonso J. Rodriguez-Morales. Highly mutated SARS-CoV-2 Omicron variant sparks significant concern among global experts – What is known so far? Travel Medicine and Infectious Disease,Volume 45, 2022, 102234, ISSN 1477-8939, https://doi.org/10.1016/j.tmaid.2021.102234.

Tiecco, G.; Storti, S.; Degli Antoni, M.; Focà, E.; Castelli, F.; Quiros-Roldan, E. Omicron Genetic and Clinical Peculiarities That May Overturn SARS-CoV-2 Pandemic: A Literature Review. Int. J. Mol. Sci. 2022, 23, 1987. https://doi.org/10.3390/ijms23041987

Is the topic of the review discussed comprehensively in the context of the current literature?

Partly
Are all factual statements correct and adequately supported by citations?

Partly
Is the review written in accessible language?

Yes
Are the conclusions drawn appropriate in the context of the current research literature?

Partly

References

1. Arora S, Grover V, Saluja P, Algarni YA, et al.: Literature Review of Omicron: A Grim Reality Amidst COVID-19.Microorganisms. 2022; 10 (2). PubMed Abstract | Publisher Full Text
2. Kupferschmidt K: Where did ‘weird’ Omicron come from?. Science. 2021; 374 (6572). Publisher Full Text
3. Poudel S, Ishak A, Perez-Fernandez J, Garcia E, et al.: Highly mutated SARS-CoV-2 Omicron variant sparks significant concern among global experts – What is known so far?. Travel Medicine and Infectious Disease. 2022; 45. Publisher Full Text
4. Tiecco G, Storti S, Degli Antoni M, Focà E, et al.: Omicron Genetic and Clinical Peculiarities That May Overturn SARS-CoV-2 Pandemic: A Literature Review.Int J Mol Sci. 2022; 23 (4). PubMed Abstract | Publisher Full Text

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Virology, Molecular Diagnostics, SARS-CoV-2

We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above.

CITE

Report a concern

Author Response 28 Jul 2022

Djoko Santoso, Department of Internal Medicine, Faculty of Medicine, Airlangga University, Dr. Soetomo Teaching Hospital, Surabaya, 60286, Indonesia

28 Jul 2022

Author Response

The ongoing COVID-19 pandemic is a major cause of worldwide mortality and morbidity. The review manuscript by Hertanto et al. looks at the Omicron variant that first emerged in South ... Continue reading The ongoing COVID-19 pandemic is a major cause of worldwide mortality and morbidity. The review manuscript by Hertanto et al. looks at the Omicron variant that first emerged in South Africa in November of 2021 and how it became a Variant of Concern relatively quickly. This review paper is split into two parts, the first covers the genomic basis of the Omicron variant and the second part looks at the clinical features of the same variant.

First, we would like to thank the Referee(s) for the time and willingness to review our manuscript, as well as for the critical assessment, which we believe has improved our manuscript significantly. Here, we address the comments and concerns raised by the Referee(s) point-by-point:

Major comments:
What we find lacking in this review is that authors fail to introduce the readers to any basic background of Omicron. There are phylogenetic studies that point to the suggestion that the Omicron variant likely diverged early on from other SARS-CoV-2 strains. Examination of the whole genome has indicated that the Omicron variant can be classified into two different lineages, BA.1 and BA.2. Maybe more could have been presented on this earlier rather than at the end in the highlights section of the paper. If this is a narrative review, the hope is that an overall picture of the subject is presented. We find that this is lacking in this narrative.

We thank the Referee(s) for these excellent and useful suggestions. Previously, we did not include the phylogenetics of the Omicron variant because at the time of writing, it was not yet clear whether it had its own clade or shared some connections with the preexisting COVID-19 variants. In this revised version, we added a paragraph discussing the phylogenetics of the Omicron variant reported by previous studies.

Similarly, regarding the BA.1 and BA.2 classifications, at the time of the writing (January 2022), BA.1 was the dominating subvariant, whereas BA.2 just began to rise. As the consequence, we provided a warning at the end of the original manuscript to highlight the potential hazard of this BA.2 subvariant. At present (6 months later), we clearly see that BA.2 took over the domination from BA.1 and as suggested, we have now added some discussion about the existing Omicron subvariants / sublineages (not only BA.1 and BA.2, but also BA.3, BA.4, BA.5 and XE subvariants).

In general, we fully agree that ideally, in our narrative review, we should be able to capture the overall picture of the subject of interest, which is Omicron variant in our case. However, the rapid development and progression of the disease, as well as the rapid changing information about this variant make it difficult to cover everything simultaneously. Employing the unique feature of F1000 Research (which allow us to submit updated versions of our manuscript), we hope to be able to keep this review live and updated, should we find new information regarding the Omicron variant in the future.

The major focus of the section on the genomic bases of the Omicron variant is on the mutations that are present in the 3 key regions of the spike of SARS-CoV-2: the receptor binding domain, the N-terminal domain and the furin cleavage site. There are more than just the mutations found in these three regions that account for the mutations present in the Omicron variant. The authors do not cover these mutations or their effect.

Again, thank you for this meticulous observation. Indeed, we originally focused only on the spike protein mutations because the spike region was the most studied part of the virus (due to its importance in the binding to ACE2 receptor and cell invasion) and the S-protein mutations were the ones that were heavily linked with the clinical features of the SARS-CoV-2 variants, including the Omicron variant. As reported by early papers about this variant, the mutations in RBD, NTD and FCS could be associated with the transmission, pathogenicity and immune response of the virus. However, we agree with the Referee(s) that several other mutations are now discovered outside of this region, including the ones in the NSP and ORF regions. Therefore, we have added a paragraph discussing this aspect as well in our revised manuscript.

The first sentence in Mutations in RBD section: "As displayed in Table 2, the N501Y mutation that converts amino acid asparagine to tyrosine at position 501 was identified in the Omicron variant", is slightly misleading. On first read, it implies that this mutation was identified first in the Omicron variant. This mutation has been identified in other variants, and this is represented five sentences later in the same paragraph.

Thanks for this correction regarding the semantics of “identify”. Since the Referee(s) feel that the word “identified” could be misleading, we want to avoid similar misunderstanding in the future. Therefore, we have replaced “identified” with “detected” in the revised manuscript and introduce the associated information “Of note, the N501Y mutation was also identified in other COVID-19 variants (e.g., C.1.2, Alpha, Beta and Gamma)” right after the sentence.

On the section titled: What can we tell from the Ct value of patients with the Omicron variant? : While the authors present that Omicron variant samples had a higher Ct value compared to other variant samples, there is nothing notable to take away from this section. The authors do not highlight any key point as to what having a higher Ct value means for the Omicron variant.

Thank you for the critics regarding this Ct section. With all due respect, allow us to disagree with the Referee(s) on this particular point. We believe that there are some important insights can be obtained from this section that the Ct value of the Omicron variant was higher than Delta, despite the higher transmissibility of the Omicron variant. A higher Ct value indicates lower viral loads in the sample taken (normally from the upper respiratory tract) and this was contradictory with the rapid spreading of the Omicron variant. Taking into account the results of previous studies, we suggest that the Omicron variant might be using another way to increase its transmissibility, rather than increasing the viral loads in the upper airways. This was also confirmed by a recent study by Laitman and colleagues which concluded that the rapid dissemination of the Omicron variant was not attributed to higher nasal viral loads as compared to prior variants.

Minor Comments:
Table 2: Reported mutations in S-protein of the Omicron variant. This table was not helpful and did not contribute anything to the review. All the mutations identified in the Omicron variant should have been presented, not just the ones in the RBD, NTD and Furin Cleavage site. Legend for Table 2 mentions the mutations that are potentially suitable for Omicron screening but no where in the body of the text is there mention of using the mutations for screening purposes.

As mentioned above, we previously focused on the S-protein mutations because they were more heavily studied than other mutations outside of the spike region. In response to the Referee(s) comment, we now added new figures displaying the site of the mutations outside and inside of the spike region that we obtained from The Stanford University Coronavirus Antiviral and Resistance Database. We hope that these figures are informative and suffice. We believe that research is still ongoing, thus it could be that some newly discovered mutations associated with the Omicron variant will be subsequently reported in the future.

Regarding the legend for Table 2, we have now removed the text regarding “…potentially suitable for Omicron screening” since it is not relevant anymore to be included.

Clinical features of the Omicron variant:
For this section of the paper, the authors highlight the different clinical patterns observed in the Omicron variant compared to its predecessors. This section is written and presented very well. Being able to read some comparisons between the Omicron, Alpha and Delta variant was a plus and helped accomplish the author’s goal. With the presentation of the Omicron came asymptomatic and symptomatic variant infection. It would be a nice touch if the authors mentioned something notable about this occurrence.

This is a very interesting and useful comment. We have now added a new paragraph comparing the reported clinical characteristics of the Omicron vs. Delta vs. Alpha vs. Gamma variants. Of note, COVID-19 symptoms are heterogeneous and could be influenced by gender, race, ethnic, environmental factors, comorbidities etc., so head-to-head comparisons between two or more distinct studies have to be carefully interpreted.

Regarding the asymptomatic vs. symptomatic, as per the definition, there is no symptom reported in the “asymptomatic” individuals, therefore we could not compare it with the clinical characteristics of the symptomatic patients. However, the study by Laitman and colleagues for example, revealed that the Ct value in the symptomatic individuals were lower than the asymptomatic ones (which we believe might not be too surprising that higher viral loads may induce overt disease). Additionally, the fact that some patients were asymptomatic or mildly affected by the virus could be associated with an increasing herd immunity in the population. Nevertheless, a quantitative calculation of herd immunity is needed to confirm the notion.

The data presented in Table 3 might have been better served if presented in graph/chart form. It would have had a better impact if that data was presented differently.

We sincerely thank the Referee(s) for this suggestion. However, we believe that a table is more appropriate to display the exact number and percentage, as done by the original studies. To provide a clearer overall data regarding the most reported symptoms of the Omicron variant, we now calculated and added the approximate mean percentage from 6 studies that we included in this manuscript.

Summary:
Overall, this review is missing in many areas. There is no new scientific information that is presented. There are other reviews, (1: Omicron genetic and clinical peculiarities that may overturn SARS-CoV-2 pandemic: a literature review; 2: Literature review of Omicron: A grim reality amidst COVID-19) that give a good understanding of the Omicron variant and the impact on the COVID-19 pandemic.

We wholeheartedly appreciate the efforts made by the Referee(s) and we fully agree that our narrative review is still far from perfection. We are confident that following the revision, our manuscript has improved significantly and we hope that it can be approved by the Referee(s).

Indeed, the nature of a narrative review does not allow us to add new scientific information. Per definition (https://libguides.csu.edu.au/review/Traditional), a narrative or traditional literature review is a comprehensive, critical and objective analysis of the current knowledge on a topic. Therefore, most journals prohibit adding original data into a narrative review. This is clearly different than a meta-analysis that uses a more quantitative approach on a more specific and focused topic of interest.

The abovementioned reviews about the Omicron variants are nice examples and we believe that our revised manuscript can complement those reviews.
The ongoing COVID-19 pandemic is a major cause of worldwide mortality and morbidity. The review manuscript by Hertanto et al. looks at the Omicron variant that first emerged in South Africa in November of 2021 and how it became a Variant of Concern relatively quickly. This review paper is split into two parts, the first covers the genomic basis of the Omicron variant and the second part looks at the clinical features of the same variant.

First, we would like to thank the Referee(s) for the time and willingness to review our manuscript, as well as for the critical assessment, which we believe has improved our manuscript significantly. Here, we address the comments and concerns raised by the Referee(s) point-by-point:

Major comments:
What we find lacking in this review is that authors fail to introduce the readers to any basic background of Omicron. There are phylogenetic studies that point to the suggestion that the Omicron variant likely diverged early on from other SARS-CoV-2 strains. Examination of the whole genome has indicated that the Omicron variant can be classified into two different lineages, BA.1 and BA.2. Maybe more could have been presented on this earlier rather than at the end in the highlights section of the paper. If this is a narrative review, the hope is that an overall picture of the subject is presented. We find that this is lacking in this narrative.

We thank the Referee(s) for these excellent and useful suggestions. Previously, we did not include the phylogenetics of the Omicron variant because at the time of writing, it was not yet clear whether it had its own clade or shared some connections with the preexisting COVID-19 variants. In this revised version, we added a paragraph discussing the phylogenetics of the Omicron variant reported by previous studies.

Similarly, regarding the BA.1 and BA.2 classifications, at the time of the writing (January 2022), BA.1 was the dominating subvariant, whereas BA.2 just began to rise. As the consequence, we provided a warning at the end of the original manuscript to highlight the potential hazard of this BA.2 subvariant. At present (6 months later), we clearly see that BA.2 took over the domination from BA.1 and as suggested, we have now added some discussion about the existing Omicron subvariants / sublineages (not only BA.1 and BA.2, but also BA.3, BA.4, BA.5 and XE subvariants).

In general, we fully agree that ideally, in our narrative review, we should be able to capture the overall picture of the subject of interest, which is Omicron variant in our case. However, the rapid development and progression of the disease, as well as the rapid changing information about this variant make it difficult to cover everything simultaneously. Employing the unique feature of F1000 Research (which allow us to submit updated versions of our manuscript), we hope to be able to keep this review live and updated, should we find new information regarding the Omicron variant in the future.

The major focus of the section on the genomic bases of the Omicron variant is on the mutations that are present in the 3 key regions of the spike of SARS-CoV-2: the receptor binding domain, the N-terminal domain and the furin cleavage site. There are more than just the mutations found in these three regions that account for the mutations present in the Omicron variant. The authors do not cover these mutations or their effect.

Again, thank you for this meticulous observation. Indeed, we originally focused only on the spike protein mutations because the spike region was the most studied part of the virus (due to its importance in the binding to ACE2 receptor and cell invasion) and the S-protein mutations were the ones that were heavily linked with the clinical features of the SARS-CoV-2 variants, including the Omicron variant. As reported by early papers about this variant, the mutations in RBD, NTD and FCS could be associated with the transmission, pathogenicity and immune response of the virus. However, we agree with the Referee(s) that several other mutations are now discovered outside of this region, including the ones in the NSP and ORF regions. Therefore, we have added a paragraph discussing this aspect as well in our revised manuscript.

The first sentence in Mutations in RBD section: "As displayed in Table 2, the N501Y mutation that converts amino acid asparagine to tyrosine at position 501 was identified in the Omicron variant", is slightly misleading. On first read, it implies that this mutation was identified first in the Omicron variant. This mutation has been identified in other variants, and this is represented five sentences later in the same paragraph.

Thanks for this correction regarding the semantics of “identify”. Since the Referee(s) feel that the word “identified” could be misleading, we want to avoid similar misunderstanding in the future. Therefore, we have replaced “identified” with “detected” in the revised manuscript and introduce the associated information “Of note, the N501Y mutation was also identified in other COVID-19 variants (e.g., C.1.2, Alpha, Beta and Gamma)” right after the sentence.

On the section titled: What can we tell from the Ct value of patients with the Omicron variant? : While the authors present that Omicron variant samples had a higher Ct value compared to other variant samples, there is nothing notable to take away from this section. The authors do not highlight any key point as to what having a higher Ct value means for the Omicron variant.

Thank you for the critics regarding this Ct section. With all due respect, allow us to disagree with the Referee(s) on this particular point. We believe that there are some important insights can be obtained from this section that the Ct value of the Omicron variant was higher than Delta, despite the higher transmissibility of the Omicron variant. A higher Ct value indicates lower viral loads in the sample taken (normally from the upper respiratory tract) and this was contradictory with the rapid spreading of the Omicron variant. Taking into account the results of previous studies, we suggest that the Omicron variant might be using another way to increase its transmissibility, rather than increasing the viral loads in the upper airways. This was also confirmed by a recent study by Laitman and colleagues which concluded that the rapid dissemination of the Omicron variant was not attributed to higher nasal viral loads as compared to prior variants.

Minor Comments:
Table 2: Reported mutations in S-protein of the Omicron variant. This table was not helpful and did not contribute anything to the review. All the mutations identified in the Omicron variant should have been presented, not just the ones in the RBD, NTD and Furin Cleavage site. Legend for Table 2 mentions the mutations that are potentially suitable for Omicron screening but no where in the body of the text is there mention of using the mutations for screening purposes.

As mentioned above, we previously focused on the S-protein mutations because they were more heavily studied than other mutations outside of the spike region. In response to the Referee(s) comment, we now added new figures displaying the site of the mutations outside and inside of the spike region that we obtained from The Stanford University Coronavirus Antiviral and Resistance Database. We hope that these figures are informative and suffice. We believe that research is still ongoing, thus it could be that some newly discovered mutations associated with the Omicron variant will be subsequently reported in the future.

Regarding the legend for Table 2, we have now removed the text regarding “…potentially suitable for Omicron screening” since it is not relevant anymore to be included.

Clinical features of the Omicron variant:
For this section of the paper, the authors highlight the different clinical patterns observed in the Omicron variant compared to its predecessors. This section is written and presented very well. Being able to read some comparisons between the Omicron, Alpha and Delta variant was a plus and helped accomplish the author’s goal. With the presentation of the Omicron came asymptomatic and symptomatic variant infection. It would be a nice touch if the authors mentioned something notable about this occurrence.

This is a very interesting and useful comment. We have now added a new paragraph comparing the reported clinical characteristics of the Omicron vs. Delta vs. Alpha vs. Gamma variants. Of note, COVID-19 symptoms are heterogeneous and could be influenced by gender, race, ethnic, environmental factors, comorbidities etc., so head-to-head comparisons between two or more distinct studies have to be carefully interpreted.

Regarding the asymptomatic vs. symptomatic, as per the definition, there is no symptom reported in the “asymptomatic” individuals, therefore we could not compare it with the clinical characteristics of the symptomatic patients. However, the study by Laitman and colleagues for example, revealed that the Ct value in the symptomatic individuals were lower than the asymptomatic ones (which we believe might not be too surprising that higher viral loads may induce overt disease). Additionally, the fact that some patients were asymptomatic or mildly affected by the virus could be associated with an increasing herd immunity in the population. Nevertheless, a quantitative calculation of herd immunity is needed to confirm the notion.

The data presented in Table 3 might have been better served if presented in graph/chart form. It would have had a better impact if that data was presented differently.

We sincerely thank the Referee(s) for this suggestion. However, we believe that a table is more appropriate to display the exact number and percentage, as done by the original studies. To provide a clearer overall data regarding the most reported symptoms of the Omicron variant, we now calculated and added the approximate mean percentage from 6 studies that we included in this manuscript.

Summary:
Overall, this review is missing in many areas. There is no new scientific information that is presented. There are other reviews, (1: Omicron genetic and clinical peculiarities that may overturn SARS-CoV-2 pandemic: a literature review; 2: Literature review of Omicron: A grim reality amidst COVID-19) that give a good understanding of the Omicron variant and the impact on the COVID-19 pandemic.

We wholeheartedly appreciate the efforts made by the Referee(s) and we fully agree that our narrative review is still far from perfection. We are confident that following the revision, our manuscript has improved significantly and we hope that it can be approved by the Referee(s).

Indeed, the nature of a narrative review does not allow us to add new scientific information. Per definition (https://libguides.csu.edu.au/review/Traditional), a narrative or traditional literature review is a comprehensive, critical and objective analysis of the current knowledge on a topic. Therefore, most journals prohibit adding original data into a narrative review. This is clearly different than a meta-analysis that uses a more quantitative approach on a more specific and focused topic of interest.

The abovementioned reviews about the Omicron variants are nice examples and we believe that our revised manuscript can complement those reviews.
Competing Interests: None Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 28 Jul 2022

Djoko Santoso, Department of Internal Medicine, Faculty of Medicine, Airlangga University, Dr. Soetomo Teaching Hospital, Surabaya, 60286, Indonesia

28 Jul 2022

Author Response

The ongoing COVID-19 pandemic is a major cause of worldwide mortality and morbidity. The review manuscript by Hertanto et al. looks at the Omicron variant that first emerged in South ... Continue reading The ongoing COVID-19 pandemic is a major cause of worldwide mortality and morbidity. The review manuscript by Hertanto et al. looks at the Omicron variant that first emerged in South Africa in November of 2021 and how it became a Variant of Concern relatively quickly. This review paper is split into two parts, the first covers the genomic basis of the Omicron variant and the second part looks at the clinical features of the same variant.

First, we would like to thank the Referee(s) for the time and willingness to review our manuscript, as well as for the critical assessment, which we believe has improved our manuscript significantly. Here, we address the comments and concerns raised by the Referee(s) point-by-point:

Major comments:
What we find lacking in this review is that authors fail to introduce the readers to any basic background of Omicron. There are phylogenetic studies that point to the suggestion that the Omicron variant likely diverged early on from other SARS-CoV-2 strains. Examination of the whole genome has indicated that the Omicron variant can be classified into two different lineages, BA.1 and BA.2. Maybe more could have been presented on this earlier rather than at the end in the highlights section of the paper. If this is a narrative review, the hope is that an overall picture of the subject is presented. We find that this is lacking in this narrative.

We thank the Referee(s) for these excellent and useful suggestions. Previously, we did not include the phylogenetics of the Omicron variant because at the time of writing, it was not yet clear whether it had its own clade or shared some connections with the preexisting COVID-19 variants. In this revised version, we added a paragraph discussing the phylogenetics of the Omicron variant reported by previous studies.

Similarly, regarding the BA.1 and BA.2 classifications, at the time of the writing (January 2022), BA.1 was the dominating subvariant, whereas BA.2 just began to rise. As the consequence, we provided a warning at the end of the original manuscript to highlight the potential hazard of this BA.2 subvariant. At present (6 months later), we clearly see that BA.2 took over the domination from BA.1 and as suggested, we have now added some discussion about the existing Omicron subvariants / sublineages (not only BA.1 and BA.2, but also BA.3, BA.4, BA.5 and XE subvariants).

In general, we fully agree that ideally, in our narrative review, we should be able to capture the overall picture of the subject of interest, which is Omicron variant in our case. However, the rapid development and progression of the disease, as well as the rapid changing information about this variant make it difficult to cover everything simultaneously. Employing the unique feature of F1000 Research (which allow us to submit updated versions of our manuscript), we hope to be able to keep this review live and updated, should we find new information regarding the Omicron variant in the future.

The major focus of the section on the genomic bases of the Omicron variant is on the mutations that are present in the 3 key regions of the spike of SARS-CoV-2: the receptor binding domain, the N-terminal domain and the furin cleavage site. There are more than just the mutations found in these three regions that account for the mutations present in the Omicron variant. The authors do not cover these mutations or their effect.

Again, thank you for this meticulous observation. Indeed, we originally focused only on the spike protein mutations because the spike region was the most studied part of the virus (due to its importance in the binding to ACE2 receptor and cell invasion) and the S-protein mutations were the ones that were heavily linked with the clinical features of the SARS-CoV-2 variants, including the Omicron variant. As reported by early papers about this variant, the mutations in RBD, NTD and FCS could be associated with the transmission, pathogenicity and immune response of the virus. However, we agree with the Referee(s) that several other mutations are now discovered outside of this region, including the ones in the NSP and ORF regions. Therefore, we have added a paragraph discussing this aspect as well in our revised manuscript.

The first sentence in Mutations in RBD section: "As displayed in Table 2, the N501Y mutation that converts amino acid asparagine to tyrosine at position 501 was identified in the Omicron variant", is slightly misleading. On first read, it implies that this mutation was identified first in the Omicron variant. This mutation has been identified in other variants, and this is represented five sentences later in the same paragraph.

Thanks for this correction regarding the semantics of “identify”. Since the Referee(s) feel that the word “identified” could be misleading, we want to avoid similar misunderstanding in the future. Therefore, we have replaced “identified” with “detected” in the revised manuscript and introduce the associated information “Of note, the N501Y mutation was also identified in other COVID-19 variants (e.g., C.1.2, Alpha, Beta and Gamma)” right after the sentence.

On the section titled: What can we tell from the Ct value of patients with the Omicron variant? : While the authors present that Omicron variant samples had a higher Ct value compared to other variant samples, there is nothing notable to take away from this section. The authors do not highlight any key point as to what having a higher Ct value means for the Omicron variant.

Thank you for the critics regarding this Ct section. With all due respect, allow us to disagree with the Referee(s) on this particular point. We believe that there are some important insights can be obtained from this section that the Ct value of the Omicron variant was higher than Delta, despite the higher transmissibility of the Omicron variant. A higher Ct value indicates lower viral loads in the sample taken (normally from the upper respiratory tract) and this was contradictory with the rapid spreading of the Omicron variant. Taking into account the results of previous studies, we suggest that the Omicron variant might be using another way to increase its transmissibility, rather than increasing the viral loads in the upper airways. This was also confirmed by a recent study by Laitman and colleagues which concluded that the rapid dissemination of the Omicron variant was not attributed to higher nasal viral loads as compared to prior variants.

Minor Comments:
Table 2: Reported mutations in S-protein of the Omicron variant. This table was not helpful and did not contribute anything to the review. All the mutations identified in the Omicron variant should have been presented, not just the ones in the RBD, NTD and Furin Cleavage site. Legend for Table 2 mentions the mutations that are potentially suitable for Omicron screening but no where in the body of the text is there mention of using the mutations for screening purposes.

As mentioned above, we previously focused on the S-protein mutations because they were more heavily studied than other mutations outside of the spike region. In response to the Referee(s) comment, we now added new figures displaying the site of the mutations outside and inside of the spike region that we obtained from The Stanford University Coronavirus Antiviral and Resistance Database. We hope that these figures are informative and suffice. We believe that research is still ongoing, thus it could be that some newly discovered mutations associated with the Omicron variant will be subsequently reported in the future.

Regarding the legend for Table 2, we have now removed the text regarding “…potentially suitable for Omicron screening” since it is not relevant anymore to be included.

Clinical features of the Omicron variant:
For this section of the paper, the authors highlight the different clinical patterns observed in the Omicron variant compared to its predecessors. This section is written and presented very well. Being able to read some comparisons between the Omicron, Alpha and Delta variant was a plus and helped accomplish the author’s goal. With the presentation of the Omicron came asymptomatic and symptomatic variant infection. It would be a nice touch if the authors mentioned something notable about this occurrence.

This is a very interesting and useful comment. We have now added a new paragraph comparing the reported clinical characteristics of the Omicron vs. Delta vs. Alpha vs. Gamma variants. Of note, COVID-19 symptoms are heterogeneous and could be influenced by gender, race, ethnic, environmental factors, comorbidities etc., so head-to-head comparisons between two or more distinct studies have to be carefully interpreted.

Regarding the asymptomatic vs. symptomatic, as per the definition, there is no symptom reported in the “asymptomatic” individuals, therefore we could not compare it with the clinical characteristics of the symptomatic patients. However, the study by Laitman and colleagues for example, revealed that the Ct value in the symptomatic individuals were lower than the asymptomatic ones (which we believe might not be too surprising that higher viral loads may induce overt disease). Additionally, the fact that some patients were asymptomatic or mildly affected by the virus could be associated with an increasing herd immunity in the population. Nevertheless, a quantitative calculation of herd immunity is needed to confirm the notion.

The data presented in Table 3 might have been better served if presented in graph/chart form. It would have had a better impact if that data was presented differently.

We sincerely thank the Referee(s) for this suggestion. However, we believe that a table is more appropriate to display the exact number and percentage, as done by the original studies. To provide a clearer overall data regarding the most reported symptoms of the Omicron variant, we now calculated and added the approximate mean percentage from 6 studies that we included in this manuscript.

Summary:
Overall, this review is missing in many areas. There is no new scientific information that is presented. There are other reviews, (1: Omicron genetic and clinical peculiarities that may overturn SARS-CoV-2 pandemic: a literature review; 2: Literature review of Omicron: A grim reality amidst COVID-19) that give a good understanding of the Omicron variant and the impact on the COVID-19 pandemic.

We wholeheartedly appreciate the efforts made by the Referee(s) and we fully agree that our narrative review is still far from perfection. We are confident that following the revision, our manuscript has improved significantly and we hope that it can be approved by the Referee(s).

Indeed, the nature of a narrative review does not allow us to add new scientific information. Per definition (https://libguides.csu.edu.au/review/Traditional), a narrative or traditional literature review is a comprehensive, critical and objective analysis of the current knowledge on a topic. Therefore, most journals prohibit adding original data into a narrative review. This is clearly different than a meta-analysis that uses a more quantitative approach on a more specific and focused topic of interest.

The abovementioned reviews about the Omicron variants are nice examples and we believe that our revised manuscript can complement those reviews.
The ongoing COVID-19 pandemic is a major cause of worldwide mortality and morbidity. The review manuscript by Hertanto et al. looks at the Omicron variant that first emerged in South Africa in November of 2021 and how it became a Variant of Concern relatively quickly. This review paper is split into two parts, the first covers the genomic basis of the Omicron variant and the second part looks at the clinical features of the same variant.

First, we would like to thank the Referee(s) for the time and willingness to review our manuscript, as well as for the critical assessment, which we believe has improved our manuscript significantly. Here, we address the comments and concerns raised by the Referee(s) point-by-point:

Major comments:
What we find lacking in this review is that authors fail to introduce the readers to any basic background of Omicron. There are phylogenetic studies that point to the suggestion that the Omicron variant likely diverged early on from other SARS-CoV-2 strains. Examination of the whole genome has indicated that the Omicron variant can be classified into two different lineages, BA.1 and BA.2. Maybe more could have been presented on this earlier rather than at the end in the highlights section of the paper. If this is a narrative review, the hope is that an overall picture of the subject is presented. We find that this is lacking in this narrative.

We thank the Referee(s) for these excellent and useful suggestions. Previously, we did not include the phylogenetics of the Omicron variant because at the time of writing, it was not yet clear whether it had its own clade or shared some connections with the preexisting COVID-19 variants. In this revised version, we added a paragraph discussing the phylogenetics of the Omicron variant reported by previous studies.

Similarly, regarding the BA.1 and BA.2 classifications, at the time of the writing (January 2022), BA.1 was the dominating subvariant, whereas BA.2 just began to rise. As the consequence, we provided a warning at the end of the original manuscript to highlight the potential hazard of this BA.2 subvariant. At present (6 months later), we clearly see that BA.2 took over the domination from BA.1 and as suggested, we have now added some discussion about the existing Omicron subvariants / sublineages (not only BA.1 and BA.2, but also BA.3, BA.4, BA.5 and XE subvariants).

In general, we fully agree that ideally, in our narrative review, we should be able to capture the overall picture of the subject of interest, which is Omicron variant in our case. However, the rapid development and progression of the disease, as well as the rapid changing information about this variant make it difficult to cover everything simultaneously. Employing the unique feature of F1000 Research (which allow us to submit updated versions of our manuscript), we hope to be able to keep this review live and updated, should we find new information regarding the Omicron variant in the future.

The major focus of the section on the genomic bases of the Omicron variant is on the mutations that are present in the 3 key regions of the spike of SARS-CoV-2: the receptor binding domain, the N-terminal domain and the furin cleavage site. There are more than just the mutations found in these three regions that account for the mutations present in the Omicron variant. The authors do not cover these mutations or their effect.

Again, thank you for this meticulous observation. Indeed, we originally focused only on the spike protein mutations because the spike region was the most studied part of the virus (due to its importance in the binding to ACE2 receptor and cell invasion) and the S-protein mutations were the ones that were heavily linked with the clinical features of the SARS-CoV-2 variants, including the Omicron variant. As reported by early papers about this variant, the mutations in RBD, NTD and FCS could be associated with the transmission, pathogenicity and immune response of the virus. However, we agree with the Referee(s) that several other mutations are now discovered outside of this region, including the ones in the NSP and ORF regions. Therefore, we have added a paragraph discussing this aspect as well in our revised manuscript.

The first sentence in Mutations in RBD section: "As displayed in Table 2, the N501Y mutation that converts amino acid asparagine to tyrosine at position 501 was identified in the Omicron variant", is slightly misleading. On first read, it implies that this mutation was identified first in the Omicron variant. This mutation has been identified in other variants, and this is represented five sentences later in the same paragraph.

Thanks for this correction regarding the semantics of “identify”. Since the Referee(s) feel that the word “identified” could be misleading, we want to avoid similar misunderstanding in the future. Therefore, we have replaced “identified” with “detected” in the revised manuscript and introduce the associated information “Of note, the N501Y mutation was also identified in other COVID-19 variants (e.g., C.1.2, Alpha, Beta and Gamma)” right after the sentence.

On the section titled: What can we tell from the Ct value of patients with the Omicron variant? : While the authors present that Omicron variant samples had a higher Ct value compared to other variant samples, there is nothing notable to take away from this section. The authors do not highlight any key point as to what having a higher Ct value means for the Omicron variant.

Thank you for the critics regarding this Ct section. With all due respect, allow us to disagree with the Referee(s) on this particular point. We believe that there are some important insights can be obtained from this section that the Ct value of the Omicron variant was higher than Delta, despite the higher transmissibility of the Omicron variant. A higher Ct value indicates lower viral loads in the sample taken (normally from the upper respiratory tract) and this was contradictory with the rapid spreading of the Omicron variant. Taking into account the results of previous studies, we suggest that the Omicron variant might be using another way to increase its transmissibility, rather than increasing the viral loads in the upper airways. This was also confirmed by a recent study by Laitman and colleagues which concluded that the rapid dissemination of the Omicron variant was not attributed to higher nasal viral loads as compared to prior variants.

Minor Comments:
Table 2: Reported mutations in S-protein of the Omicron variant. This table was not helpful and did not contribute anything to the review. All the mutations identified in the Omicron variant should have been presented, not just the ones in the RBD, NTD and Furin Cleavage site. Legend for Table 2 mentions the mutations that are potentially suitable for Omicron screening but no where in the body of the text is there mention of using the mutations for screening purposes.

As mentioned above, we previously focused on the S-protein mutations because they were more heavily studied than other mutations outside of the spike region. In response to the Referee(s) comment, we now added new figures displaying the site of the mutations outside and inside of the spike region that we obtained from The Stanford University Coronavirus Antiviral and Resistance Database. We hope that these figures are informative and suffice. We believe that research is still ongoing, thus it could be that some newly discovered mutations associated with the Omicron variant will be subsequently reported in the future.

Regarding the legend for Table 2, we have now removed the text regarding “…potentially suitable for Omicron screening” since it is not relevant anymore to be included.

Clinical features of the Omicron variant:
For this section of the paper, the authors highlight the different clinical patterns observed in the Omicron variant compared to its predecessors. This section is written and presented very well. Being able to read some comparisons between the Omicron, Alpha and Delta variant was a plus and helped accomplish the author’s goal. With the presentation of the Omicron came asymptomatic and symptomatic variant infection. It would be a nice touch if the authors mentioned something notable about this occurrence.

This is a very interesting and useful comment. We have now added a new paragraph comparing the reported clinical characteristics of the Omicron vs. Delta vs. Alpha vs. Gamma variants. Of note, COVID-19 symptoms are heterogeneous and could be influenced by gender, race, ethnic, environmental factors, comorbidities etc., so head-to-head comparisons between two or more distinct studies have to be carefully interpreted.

Regarding the asymptomatic vs. symptomatic, as per the definition, there is no symptom reported in the “asymptomatic” individuals, therefore we could not compare it with the clinical characteristics of the symptomatic patients. However, the study by Laitman and colleagues for example, revealed that the Ct value in the symptomatic individuals were lower than the asymptomatic ones (which we believe might not be too surprising that higher viral loads may induce overt disease). Additionally, the fact that some patients were asymptomatic or mildly affected by the virus could be associated with an increasing herd immunity in the population. Nevertheless, a quantitative calculation of herd immunity is needed to confirm the notion.

The data presented in Table 3 might have been better served if presented in graph/chart form. It would have had a better impact if that data was presented differently.

We sincerely thank the Referee(s) for this suggestion. However, we believe that a table is more appropriate to display the exact number and percentage, as done by the original studies. To provide a clearer overall data regarding the most reported symptoms of the Omicron variant, we now calculated and added the approximate mean percentage from 6 studies that we included in this manuscript.

Summary:
Overall, this review is missing in many areas. There is no new scientific information that is presented. There are other reviews, (1: Omicron genetic and clinical peculiarities that may overturn SARS-CoV-2 pandemic: a literature review; 2: Literature review of Omicron: A grim reality amidst COVID-19) that give a good understanding of the Omicron variant and the impact on the COVID-19 pandemic.

We wholeheartedly appreciate the efforts made by the Referee(s) and we fully agree that our narrative review is still far from perfection. We are confident that following the revision, our manuscript has improved significantly and we hope that it can be approved by the Referee(s).

Indeed, the nature of a narrative review does not allow us to add new scientific information. Per definition (https://libguides.csu.edu.au/review/Traditional), a narrative or traditional literature review is a comprehensive, critical and objective analysis of the current knowledge on a topic. Therefore, most journals prohibit adding original data into a narrative review. This is clearly different than a meta-analysis that uses a more quantitative approach on a more specific and focused topic of interest.

The abovementioned reviews about the Omicron variants are nice examples and we believe that our revised manuscript can complement those reviews.
Competing Interests: None Close
Report a concern

Comments on this article Comments (0)

Version 2

VERSION 2 PUBLISHED 23 Mar 2022

Open Peer Review

Reviewer Status

Reviewer Reports

	Invited Reviewers
	1	2
Version 2 (revision) 28 Jul 22		read
Version 1 23 Mar 22	read

Leyi Wang, University of Illinois at Urbana-Champaign, Urbana, USA

Vanessa Revindran-Stam, University of Illinois at Urbana-Champaign, Urbana, USA
Nicolas de Prost, Hôpitaux Universitaires Henri Mondor, Créteil, France

Comments on this article

All Comments(0)

Add a comment

Browse by related subjects

Back to all reports

Reviewer Report

10 Views

13 Dec 2022 | for Version 2

Nicolas de Prost, Service de Médecine Intensive Réanimation, Hôpitaux Universitaires Henri Mondor, Créteil, France

10 Views Cite this report Responses(0)

Not Approved

Hertanto and colleagues wrote a comprehensive review on the genomic and clinical features of the SARS-CoV-2 Omicron variant. While they performed a nice literature review, this is a moving topic and there are some important new data which I believe should be added to the revised version of the manuscript.

In the "existing Omicron subvariants" section, the authors should discuss the characteristics of the BQ.1.1 subvariant, particularly regarding its resistance to monoclonal antibodies.

Some changes should be Added to the "Clinical features of the Omicron variant" section, where important references were not cited:

Vieillard-Baron et al. (AJRCCM 2022) showed that there were more immunocompromised patients among ICU Omicron-infected patients than among Delta-infected patients.
Bouzid (Ann Internal Med 2022) showed that Omicron patients presenting to the emergency room had better in-hospital outcomes than those with Delta
de Prost et al. (Nat Commun 2022) showed that ICU Omicron-infected patients who were immunosuppressed had a two times higher mortality than immunocompetent and that they had a poor humoral response to vaccination.

In the highlights section: a larger perspective should be provided regarding the problem of monoclonal antibody resistance of current circulating variants.

Is the topic of the review discussed comprehensively in the context of the current literature?

Partly
Are all factual statements correct and adequately supported by citations?

Yes
Is the review written in accessible language?

Yes
Are the conclusions drawn appropriate in the context of the current research literature?

Partly

References

1. Vieillard-Baron A, Flicoteaux R, Salmona M, Chariot A, et al.: Omicron Variant in the Critical Care Units of the Paris Metropolitan Area: The Reality Research Group. American Journal of Respiratory and Critical Care Medicine. 2022; 206 (3): 349-363 Publisher Full Text
2. Bouzid D, Visseaux B, Kassasseya C, Daoud A, et al.: Comparison of Patients Infected With Delta Versus Omicron COVID-19 Variants Presenting to Paris Emergency Departments : A Retrospective Cohort Study.Ann Intern Med. 2022; 175 (6): 831-837 PubMed Abstract | Publisher Full Text
3. de Prost N, Audureau E, Heming N, Gault E, et al.: Clinical phenotypes and outcomes associated with SARS-CoV-2 variant Omicron in critically ill French patients with COVID-19.Nat Commun. 2022; 13 (1): 6025 PubMed Abstract | Publisher Full Text

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Medical Intensivist with an area of expertise in pulmonary viral infections an ARDS

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

Respond to this report

Responses (0)

Back to all reports

Reviewer Report

67 Views

18 Jul 2022 | for Version 1

Leyi Wang, Veterinary Diagnostic Laboratory and Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA

Vanessa Revindran-Stam, Veterinary Diagnostic Laboratory , College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA

67 Views Cite this report Responses(1)

Not Approved

Is the topic of the review discussed comprehensively in the context of the current literature?

Partly
Are all factual statements correct and adequately supported by citations?

Partly
Is the review written in accessible language?

Yes
Are the conclusions drawn appropriate in the context of the current research literature?

Partly

References

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Virology, Molecular Diagnostics, SARS-CoV-2

Respond to this report

Responses (1)

Author Response

28 Jul 2022

Djoko Santoso, Department of Internal Medicine, Faculty of Medicine, Airlangga University, Dr. Soetomo Teaching Hospital, Surabaya, 60286, Indonesia

The ongoing COVID-19 pandemic is a major cause of worldwide mortality and morbidity. The review manuscript by Hertanto et al. looks at the Omicron variant that first emerged in South Africa in November of 2021 and how it became a Variant of Concern relatively quickly. This review paper is split into two parts, the first covers the genomic basis of the Omicron variant and the second part looks at the clinical features of the same variant.

First, we would like to thank the Referee(s) for the time and willingness to review our manuscript, as well as for the critical assessment, which we believe has improved our manuscript significantly. Here, we address the comments and concerns raised by the Referee(s) point-by-point:

Major comments:
What we find lacking in this review is that authors fail to introduce the readers to any basic background of Omicron. There are phylogenetic studies that point to the suggestion that the Omicron variant likely diverged early on from other SARS-CoV-2 strains. Examination of the whole genome has indicated that the Omicron variant can be classified into two different lineages, BA.1 and BA.2. Maybe more could have been presented on this earlier rather than at the end in the highlights section of the paper. If this is a narrative review, the hope is that an overall picture of the subject is presented. We find that this is lacking in this narrative.

We thank the Referee(s) for these excellent and useful suggestions. Previously, we did not include the phylogenetics of the Omicron variant because at the time of writing, it was not yet clear whether it had its own clade or shared some connections with the preexisting COVID-19 variants. In this revised version, we added a paragraph discussing the phylogenetics of the Omicron variant reported by previous studies.

Similarly, regarding the BA.1 and BA.2 classifications, at the time of the writing (January 2022), BA.1 was the dominating subvariant, whereas BA.2 just began to rise. As the consequence, we provided a warning at the end of the original manuscript to highlight the potential hazard of this BA.2 subvariant. At present (6 months later), we clearly see that BA.2 took over the domination from BA.1 and as suggested, we have now added some discussion about the existing Omicron subvariants / sublineages (not only BA.1 and BA.2, but also BA.3, BA.4, BA.5 and XE subvariants).

In general, we fully agree that ideally, in our narrative review, we should be able to capture the overall picture of the subject of interest, which is Omicron variant in our case. However, the rapid development and progression of the disease, as well as the rapid changing information about this variant make it difficult to cover everything simultaneously. Employing the unique feature of F1000 Research (which allow us to submit updated versions of our manuscript), we hope to be able to keep this review live and updated, should we find new information regarding the Omicron variant in the future.

The major focus of the section on the genomic bases of the Omicron variant is on the mutations that are present in the 3 key regions of the spike of SARS-CoV-2: the receptor binding domain, the N-terminal domain and the furin cleavage site. There are more than just the mutations found in these three regions that account for the mutations present in the Omicron variant. The authors do not cover these mutations or their effect.

Again, thank you for this meticulous observation. Indeed, we originally focused only on the spike protein mutations because the spike region was the most studied part of the virus (due to its importance in the binding to ACE2 receptor and cell invasion) and the S-protein mutations were the ones that were heavily linked with the clinical features of the SARS-CoV-2 variants, including the Omicron variant. As reported by early papers about this variant, the mutations in RBD, NTD and FCS could be associated with the transmission, pathogenicity and immune response of the virus. However, we agree with the Referee(s) that several other mutations are now discovered outside of this region, including the ones in the NSP and ORF regions. Therefore, we have added a paragraph discussing this aspect as well in our revised manuscript.

The first sentence in Mutations in RBD section: "As displayed in Table 2, the N501Y mutation that converts amino acid asparagine to tyrosine at position 501 was identified in the Omicron variant", is slightly misleading. On first read, it implies that this mutation was identified first in the Omicron variant. This mutation has been identified in other variants, and this is represented five sentences later in the same paragraph.

Thanks for this correction regarding the semantics of “identify”. Since the Referee(s) feel that the word “identified” could be misleading, we want to avoid similar misunderstanding in the future. Therefore, we have replaced “identified” with “detected” in the revised manuscript and introduce the associated information “Of note, the N501Y mutation was also identified in other COVID-19 variants (e.g., C.1.2, Alpha, Beta and Gamma)” right after the sentence.

On the section titled: What can we tell from the Ct value of patients with the Omicron variant? : While the authors present that Omicron variant samples had a higher Ct value compared to other variant samples, there is nothing notable to take away from this section. The authors do not highlight any key point as to what having a higher Ct value means for the Omicron variant.

Thank you for the critics regarding this Ct section. With all due respect, allow us to disagree with the Referee(s) on this particular point. We believe that there are some important insights can be obtained from this section that the Ct value of the Omicron variant was higher than Delta, despite the higher transmissibility of the Omicron variant. A higher Ct value indicates lower viral loads in the sample taken (normally from the upper respiratory tract) and this was contradictory with the rapid spreading of the Omicron variant. Taking into account the results of previous studies, we suggest that the Omicron variant might be using another way to increase its transmissibility, rather than increasing the viral loads in the upper airways. This was also confirmed by a recent study by Laitman and colleagues which concluded that the rapid dissemination of the Omicron variant was not attributed to higher nasal viral loads as compared to prior variants.

Minor Comments:
Table 2: Reported mutations in S-protein of the Omicron variant. This table was not helpful and did not contribute anything to the review. All the mutations identified in the Omicron variant should have been presented, not just the ones in the RBD, NTD and Furin Cleavage site. Legend for Table 2 mentions the mutations that are potentially suitable for Omicron screening but no where in the body of the text is there mention of using the mutations for screening purposes.

As mentioned above, we previously focused on the S-protein mutations because they were more heavily studied than other mutations outside of the spike region. In response to the Referee(s) comment, we now added new figures displaying the site of the mutations outside and inside of the spike region that we obtained from The Stanford University Coronavirus Antiviral and Resistance Database. We hope that these figures are informative and suffice. We believe that research is still ongoing, thus it could be that some newly discovered mutations associated with the Omicron variant will be subsequently reported in the future.

Regarding the legend for Table 2, we have now removed the text regarding “…potentially suitable for Omicron screening” since it is not relevant anymore to be included.

Clinical features of the Omicron variant:
For this section of the paper, the authors highlight the different clinical patterns observed in the Omicron variant compared to its predecessors. This section is written and presented very well. Being able to read some comparisons between the Omicron, Alpha and Delta variant was a plus and helped accomplish the author’s goal. With the presentation of the Omicron came asymptomatic and symptomatic variant infection. It would be a nice touch if the authors mentioned something notable about this occurrence.

This is a very interesting and useful comment. We have now added a new paragraph comparing the reported clinical characteristics of the Omicron vs. Delta vs. Alpha vs. Gamma variants. Of note, COVID-19 symptoms are heterogeneous and could be influenced by gender, race, ethnic, environmental factors, comorbidities etc., so head-to-head comparisons between two or more distinct studies have to be carefully interpreted.

Regarding the asymptomatic vs. symptomatic, as per the definition, there is no symptom reported in the “asymptomatic” individuals, therefore we could not compare it with the clinical characteristics of the symptomatic patients. However, the study by Laitman and colleagues for example, revealed that the Ct value in the symptomatic individuals were lower than the asymptomatic ones (which we believe might not be too surprising that higher viral loads may induce overt disease). Additionally, the fact that some patients were asymptomatic or mildly affected by the virus could be associated with an increasing herd immunity in the population. Nevertheless, a quantitative calculation of herd immunity is needed to confirm the notion.

The data presented in Table 3 might have been better served if presented in graph/chart form. It would have had a better impact if that data was presented differently.

We sincerely thank the Referee(s) for this suggestion. However, we believe that a table is more appropriate to display the exact number and percentage, as done by the original studies. To provide a clearer overall data regarding the most reported symptoms of the Omicron variant, we now calculated and added the approximate mean percentage from 6 studies that we included in this manuscript.

Summary:
Overall, this review is missing in many areas. There is no new scientific information that is presented. There are other reviews, (1: Omicron genetic and clinical peculiarities that may overturn SARS-CoV-2 pandemic: a literature review; 2: Literature review of Omicron: A grim reality amidst COVID-19) that give a good understanding of the Omicron variant and the impact on the COVID-19 pandemic.

We wholeheartedly appreciate the efforts made by the Referee(s) and we fully agree that our narrative review is still far from perfection. We are confident that following the revision, our manuscript has improved significantly and we hope that it can be approved by the Referee(s).

Indeed, the nature of a narrative review does not allow us to add new scientific information. Per definition (https://libguides.csu.edu.au/review/Traditional), a narrative or traditional literature review is a comprehensive, critical and objective analysis of the current knowledge on a topic. Therefore, most journals prohibit adding original data into a narrative review. This is clearly different than a meta-analysis that uses a more quantitative approach on a more specific and focused topic of interest.

The abovementioned reviews about the Omicron variants are nice examples and we believe that our revised manuscript can complement those reviews.

View more View less

Competing Interests

None

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

[1] 1. Moghadas SM, Vilches TN, Zhang K, et al.: The Impact of Vaccination on Coronavirus Disease 2019 (COVID-19) Outbreaks in the United States. Clin. Infect. Dis. 2021; 73(12): 2257–2264. PubMed Abstract | Publisher Full Text

[2] 2. Singanayagam A, Hakki S, Dunning J, et al.: Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study. Lancet Infect. Dis. 2022; 22(2): 183–195. PubMed Abstract | Publisher Full Text

[3] 3. Ng OT, Koh V, Chiew CJ, et al.: Impact of Delta Variant and Vaccination on SARS-CoV-2 Secondary Attack Rate Among Household Close Contacts. Lancet Reg. Health West Pac. 2021; 17: 100299. PubMed Abstract | Publisher Full Text

[4] 4. Sheikh A, Robertson C, Taylor B: BNT162b2 and ChAdOx1 nCoV-19 Vaccine Effectiveness against Death from the Delta Variant. N. Engl. J. Med. 2021; 385(23): 2195–2197. PubMed Abstract | Publisher Full Text

[5] 5. Pouwels KB, Pritchard E, Matthews PC, et al.: Effect of Delta variant on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK. Nat. Med. 2021; 27(12): 2127–2135. PubMed Abstract | Publisher Full Text

[6] 6. Dong E, Du H, Gardner L: An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect. Dis. 2020; 20(5): 533–534. PubMed Abstract | Publisher Full Text

[7] 7. Khare S, Gurry C, Freitas L, et al.: GISAID's Role in Pandemic Response. China CDC Wkly. 2021; 3(49): 1049–1051. PubMed Abstract | Publisher Full Text

[8] 8. Ma W, Yang J, Fu H, et al.: Genomic perspectives on the emerging SARS-CoV-2 omicron variant. Genomics Proteomics Bioinformatics. 2022. Publisher Full Text

[9] 9. Liu Y, Liu J, Plante KS, et al.: The N501Y spike substitution enhances SARS-CoV-2 infection and transmission. Nature. 2022; 602(7896): 294–299. PubMed Abstract | Publisher Full Text

[10] 10. Zahradnik J, Marciano S, Shemesh M, et al.: SARS-CoV-2 variant prediction and antiviral drug design are enabled by RBD in vitro evolution. Nat. Microbiol. 2021; 6(9): 1188–1198. PubMed Abstract | Publisher Full Text

[11] 11. Cao Y, Wang J, Jian F, et al.: Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies. Nature. 2021; 602: 657–663. PubMed Abstract | Publisher Full Text

[12] 12. Meng B, Kemp SA, Papa G, et al.: Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7. Cell Rep. 2021; 35(13): 109292. PubMed Abstract | Publisher Full Text

[13] 13. McCallum M, Walls AC, Sprouse KR, et al.: Molecular basis of immune evasion by the Delta and Kappa SARS-CoV-2 variants. Science. 2021; 374(6575): 1621–1626. PubMed Abstract | Publisher Full Text

[14] 14. Hacisuleyman E, Hale C, Saito Y, et al.: Vaccine Breakthrough Infections with SARS-CoV-2 Variants. N. Engl. J. Med. 2021; 384(23): 2212–2218. PubMed Abstract | Publisher Full Text

[15] 15. Haslwanter D, Dieterle ME, Wec AZ, et al.: A Combination of Receptor-Binding Domain and N-Terminal Domain Neutralizing Antibodies Limits the Generation of SARS-CoV-2 Spike Neutralization-Escape Mutants. MBio. 2021; 12(5): e0247321. PubMed Abstract | Publisher Full Text

[16] 16. Johnson BA, Xie X, Bailey AL, et al.: Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis. Nature. 2021; 591(7849): 293–299. PubMed Abstract | Publisher Full Text

[17] 17. Lista MJ, Winstone H, Wilson HD, et al.: The P681H mutation in the Spike glycoprotein confers Type I interferon resistance in the SARS-CoV-2 alpha (B.1.1.7) variant. bioRxiv 2021:2021.11.09.467693.

[18] 18. Lubinski B, Fernandes MHV, Frazier L, et al.: Functional evaluation of the P681H mutation on the proteolytic activation of the SARS-CoV-2 variant B.1.1.7 (Alpha) spike. iScience. 2022; 25(1): 103589. PubMed Abstract | Publisher Full Text

[19] 19. Plante JA, Liu Y, Liu J, et al.: Spike mutation D614G alters SARS-CoV-2 fitness. Nature. 2021; 592(7852): 116–121. PubMed Abstract | Publisher Full Text

[20] 20. Vihta K-D, Pouwels KB, Peto TE, et al.: Omicron-associated changes in SARS-CoV-2 symptoms in the United Kingdom. medRxiv 2022:2022.01.18.22269082.

[21] 21. Maaroufi H: The N764K and N856K mutations in SARS-CoV-2 Omicron S protein generate potential cleavage sites for SKI-1/S1P protease. bioRxiv 2022:2022.01.21.477298.

[22] 22. Hui KPY, Ho JCW, Cheung MC, et al.: SARS-CoV-2 Omicron variant replication in human bronchus and lung ex vivo. Nature. 2022. PubMed Abstract | Publisher Full Text

[23] 23. Meng B, Abdullahi A, Ferreira I, et al.: Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts tropism and fusogenicity. Nature. 2022. Publisher Full Text

[24] 24. Zhao H, Lu L, Peng Z, et al.: SARS-CoV-2 Omicron variant shows less efficient replication and fusion activity when compared with Delta variant in TMPRSS2-expressed cells. Emerg Microbes Infect. 2022; 11(1): 277–283. PubMed Abstract | Publisher Full Text

[25] 25. van Kasteren PB , van der Veer B , van den Brink S , et al.: Comparison of seven commercial RT-PCR diagnostic kits for COVID-19. J. Clin. Virol. 2020; 128: 104412. PubMed Abstract | Publisher Full Text

[26] 26. Hay JA, Kissler SM, Fauver JR, et al.: Viral dynamics and duration of PCR positivity of the SARS-CoV-2 Omicron variant. medRxiv 2022:2022.01.13.22269257.

[27] 27. Sofonea MT, Roquebert B, Foulongne V, et al.: From Delta to Omicron: analysing the SARS-CoV-2 epidemic in France using variant-specific screening tests (September 1 to December 18, 2021). medRxiv 2022:2021.12.31.21268583.

[28] 28. Sentis C, Billaud G, Bal A, et al.: SARS-CoV-2 Omicron variant, lineage BA.1, is associated with lower viral load in nasopharyngeal samples compared to Delta variant. medRxiv 2022:2022.02.02.22269653.

[29] 29. Christensen PA, Olsen RJ, Long SW, et al.: Signals of Significantly Increased Vaccine Breakthrough, Decreased Hospitalization Rates, and Less Severe Disease in Patients with Coronavirus Disease 2019 Caused by the Omicron Variant of Severe Acute Respiratory Syndrome Coronavirus 2 in Houston, Texas. Am. J. Pathol. 2022. PubMed Abstract | Publisher Full Text

[30] 30. Maslo C, Friedland R, Toubkin M, et al.: Characteristics and Outcomes of Hospitalized Patients in South Africa During the COVID-19 Omicron Wave Compared With Previous Waves. JAMA. 2022; 327(6): 583–584. PubMed Abstract | Publisher Full Text

[31] 31. Espenhain L, Funk T, Overvad M, et al.: Epidemiological characterisation of the first 785 SARS-CoV-2 Omicron variant cases in Denmark, December 2021. Euro Surveill. 2021; 26(50) PubMed Abstract | Publisher Full Text

[32] 32. Accorsi EK, Britton A, Fleming-Dutra KE, et al.: Association Between 3 Doses of mRNA COVID-19 Vaccine and Symptomatic Infection Caused by the SARS-CoV-2 Omicron and Delta Variants. JAMA. 2022; 327: 639–651. PubMed Abstract | Publisher Full Text

[33] 33. Perez-Then E, Lucas C, Monteiro VS, et al.: Neutralizing antibodies against the SARS-CoV-2 Delta and Omicron variants following heterologous CoronaVac plus BNT162b2 booster vaccination. Nat. Med. 2022. PubMed Abstract | Publisher Full Text

[34] 34. Schmidt F, Muecksch F, Weisblum Y, et al.: Plasma Neutralization of the SARS-CoV-2 Omicron Variant. N. Engl. J. Med. 2022; 386(6): 599–601. PubMed Abstract | Publisher Full Text

[35] 35. Buchan SA, Chung H, Brown KA, et al.: Effectiveness of COVID-19 vaccines against Omicron or Delta symptomatic infection and severe outcomes. medRxiv 2022:2021.12.30.21268565.

[36] 36. Brandal LT, MacDonald E, Veneti L, et al.: Outbreak caused by the SARS-CoV-2 Omicron variant in Norway, November to December 2021. Euro Surveill. 2021; 26(50). PubMed Abstract | Publisher Full Text

[37] 37. Young B, Fong S-W, Chang ZW, et al.: Comparison of the clinical features, viral shedding and immune response in vaccine breakthrough infection by the Omicron and Delta variants. Research Square. 2022.

[38] 38. Team CC-R: SARS-CoV-2 B.1.1.529 (Omicron) Variant - United States, December 1-8, 2021. MMWR Morb. Mortal. Wkly Rep. 2021; 70(50): 1731–1734. Publisher Full Text

[39] 39. Maisa A, Spaccaferri G, Fournier L, et al.: First cases of Omicron in France are exhibiting mild symptoms, November 2021-January 2022. Infect. Dis. Now. 2022. PubMed Abstract | Publisher Full Text

[40] 40. Menni C, Valdes A, Polidori L, et al.: A Comparison of Symptom Prevalence, Severity and Duration in the SARS-CoV-2 Omicron Versus Delta Variants Among Vaccinated Individuals from the ZOE COVID Study. SSRN. 2022. Publisher Full Text

[41] 41. Hajjo R, AbuAlSamen MM, Alzoubi HM, et al.: The Epidemiology of Hundreds of Individuals Infected with Omicron BA.1 in Middle-Eastern Jordan. medRxiv 2022:2022.01.23.22269442.

[42] 42. Ulloa AC, Buchan SA, Daneman N, et al.: Early estimates of SARS-CoV-2 Omicron variant severity based on a matched cohort study, Ontario, Canada. medRxiv 2022:2021.12.24.21268382.

[43] 43. Collie S, Champion J, Moultrie H, et al.: Effectiveness of BNT162b2 Vaccine against Omicron Variant in South Africa. N. Engl. J. Med. 2022; 386(5): 494–496. PubMed Abstract | Publisher Full Text

[44] 44. Altarawneh HN, Chemaitelly H, Hasan MR, et al.: Protection against the Omicron Variant from Previous SARS-CoV-2 Infection. N. Engl. J. Med. 2022. PubMed Abstract | Publisher Full Text

[45] 45. Yamasoba D, Kimura I, Nasser H, et al.: Virological characteristics of SARS-CoV-2 BA.2 variant. bioRxiv 2022:2022.02.14.480335.

The genomic and clinical features of the COVID-19 Omicron variant: a narrative review

Abstract

Keywords

Introduction

Figure 1. World map depicting the total number of coronavirus disease 2019 (COVID-19) cases for the given period.

Table 1. Confirmed coronavirus disease 2019 (COVID-19) cases from December 1st, 2021 to February 23rd, 2022 and shares of the Omicron variant.

The genomic basis of the Omicron variant and the predicted effects of its mutations

The consequences of reported mutations on transmissibility and pathogenicity of the Omicron variant

Table 2. Reported mutations in S-proteins of the Omicron variant.

The viral tropism of the Omicron variant

What can we tell from the Ct value of patients with the Omicron variant?

Clinical features of the Omicron variant

Table 3. Reported clinical symptoms of the Omicron variant.

Highlights

Data availability

Acknowledgements

References

Comments on this article Comments (0)

Open Peer Review

Comments on this article Comments (0)

Open Peer Review

Reviewer Status

Reviewer Reports

Comments on this article

Browse by related subjects

Competing Interests Policy

Stay Updated

Table 1. Confirmed coronavirus disease 2019 (COVID-19) cases from December 1^st, 2021 to February 23^rd, 2022 and shares of the Omicron variant.