Coronavirus disease 2019 (COVID-19) first emerged in Wuhan city in December 2019, and became a grave global concern due to its highly infectious nature [1,2,3]. The Severe Acute Respiratory Coronavirus-2, with its predecessors (i.e., MERS-CoV and SARS-CoV) belong to the family of Coronaviridae. Reportedly, COVID-19 has infected 344,710,576 people around the globe and killed nearly 5,598,511 persons in the short span of two years [4]. As with other viruses, coronavirus constantly changes through genetic mutations, which have posed new challenges in the road to recovery. According to the United States (U.S.) government-led SARS-CoV-2 Interagency Group (SIG), SARS-CoV-2 variants can be categorized into four classes: Variant Being Monitored (VBM), Variant of Interest (VOI), Variant of Concern (VOC), and Variant of High Consequence (VOHC) [5]. Among the VOC class, variants such as Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2 and AY lineages) evolved, and recently a new variant, B.1.1.529, was detected in several countries [5]. It quickly became a subject of discussion and exploration among the scientific community. The variant B.1.1.529 was first detected in Botswana, followed by South Africa between 11 November 2021 and 14 November 2021 [6]. It is a VOC due to its high transmissibility and less susceptibility to neutralization by antibodies produced either by previous viral exposure or vaccine administration [5,6]. According to the estimates, the cases of B.1.1.529 in South Africa grew by over fivefold in one week from 16 November to 25 November 2021 [7,8]. These upward trends remained for four weeks, followed by a rapid decline by 48% from 27 December 2021 to 2 January 2022 [7,8]. Other countries to report cases of infection by B.1.1.529 include, but are not limited to, France, The Netherlands, Germany, Portugal, Italy, the United Kingdom (U.K.), Canada, Hong Kong, Australia, and the United States. On 25 November, the B.1.1.529 variant was termed a Variant Under Monitoring by the United Kingdom Health Security Agency, and was considered as the maximally mutated variant amongst the other variants [7,8]. A day after, on 26 November 2021, this variant was designated as an official Variant of Concern by the World Health Organization (WHO) and named Omicron [9]. According to the epidemiological update provided by the European Surveillance System (TESSy), travel-related cases were identified in 13% of the confirmed infections, with nearly 70% of the remaining cases having arisen locally [10]. Omicron created chaos around the world and different studies are being conducted to study its presenting symptoms, transmission, risk of reinfection, severity, and its tendency to evade immune responses [11,12,13,14]. There are concerns related to its rampant transmission, which could hinder containment efforts, such as vaccine effectiveness. The surging trend in Omicron cases is worrisome, because this could cause an overwhelming demand on health care systems which have not yet completely recovered from the health and financial damages caused by the initial virus outbreak [14,15].

2. Structural Characteristics of the Omicron

The Omicron variant, which is a derivative of the Pango lineage B.1.1.529, exhibiting a variation in the 21 amino acid pertaining to the spike protein with the majority residing in the receptor binding domain (RBD) (residues 319–541) compared with the original strain [16,17,18,19,20,21]. SARS-CoV-2 has continuously undergone a series of unprecedented mutations and evolved to exhibit varying characteristics [16,17,18,19,20,21]. These mutations have largely occurred in the spike (S) protein (which is the site for antibody binding), which attribute high infectivity and transmissibility properties to Omicron variant [16,17,18,19,20]. According to the genomic reports, the S protein of Omicron has a total of 30 amino acid substitutions, 3 deletions, and 1 small insertion [21]. About 50% (n = 15) of amino acid substitutions occur exclusively in the receptor binding domain (RBD) [16,17,18,19,20,21]. Among the 15 RBD substitutes, N501Y and Q498R have a stronger affinity towards the angiotensin-converting enzyme (ACE-2 receptors), which explain the high transmissibility of the Omicron variant [16,17,18,19,20,21,22]. The ACE-2 receptors play a significant role in COVID-19 pathogenesis, which may involve serious organ failure [23].

3. Virologic Characteristics Explained (Omicron vs. Delta Variant)

Recent studies have reported that Omicron has a different mechanism for entering the host, and is capable of gaining cell entry independent of the transmembrane serine protease 2 (TMPRSS2) [24]. The entry pathway and viral replication of Omicron is through the endocytic pathway rather than TMPRS22 pathway, unlike Delta variant, which may have contributed to the differences in the disease presentation following exposure to Delta and Omicron variants [24]. TMPRS22 is highly expressed in alveolar cells of the lungs; thus, due to the lesser or no dependence of Omicron on the TMPRS22 pathway for its replication, lung involvement following exposure might be absent or limited [24,25]. In addition, the fusion capabilities to aid syncytia (structure that results following the fusion of multiple cells) formations are reduced in Omicron compared with the Delta variant. The reduced capacity of the syncytia formation translates to the lesser severity of the clinical manifestations and tissue tropism following the Omicron infection [24,25,26].

4. Epidemiology of Omicron and a Tropism Shift

Omicron spreads faster than the original virus; however, data related to its reproductive number remain limited. According to the European Center for Disease Prevention and Control, this variant could be more transmissible than the Delta variant [10]. Early reports from South Africa in November suggested the effective reproductive number (Re) of the variant to be in the range of 1.5–3; however, a recent estimate of Re as low as 0.75 was also reported [27]. These latest estimates should be interpreted with caution, because several factors, including changes in the testing measures or efforts and lag in case reporting, might have contributed to the change in the reproductive number [27]. The collective evidence suggests that Omicron has greater infectivity and potential to cause reinfection as compared with its predecessors [9,27]; however, data are insufficient to quantify its overall impact.

The symptoms of Omicron include a dry cough, scratchy throat, body aches, fatigue, runny nose, fever, and night symptoms [18,19]. According to recent evidence from South Africa, no peculiar symptoms associated with the variant have been reported, and some patients remained asymptomatic or only presented mild symptoms [10,20]. The patients infected with Omicron had fewer or no symptoms related to neurotropism (i.e., loss of taste and smell), which were peculiar with the earlier strains of the virus [18,28,29,30,31,32]. This tropism shift is attributed to the reduced dependence of Omicron on TMPRS22-expressing cells, such as the lower respiratory tract, brain, heart, kidney, and other extrapulmonary organs [33].