**4. Variant of concern**

### **4.1 Delta**

Viruses constantly undergo mutations resulting in new variants [23]. **Table 2** shows the Delta variant of COVID-19, formally known as B.1.617.2 [4, 19]. Part of the AY lineage, this variant appeared in late 2020 from India and had spread to over 179 countries by late 2021 [4, 24]. By late 2021, the Delta variant was the most transmissible, spreading more easily than the first identified Alpha variant - roughly two times more contagious than the original virus [24]. Mutations of the S protein in the Delta variant have not been analyzed in detail, though the following substitutions identified are T19R, (V70F\*), T95I, G142D, E156-, F157-, R158G, (A222V\*), (W258L\*), (K417N\*), L452R, T478K, D614G, P681R, and D950N [4]. The Delta variant is thought to have a distinct receptor-binding interface than the other forms [24]. The replication capacity of the Delta variant has been noted to be more efficient, leading to increased rates of transmission, infectivity, and viral load in comparison to other strains [24].

Antiviral medication has been developed to minimize symptoms and lessen the duration of viral infection. There are no less than 13 vaccines against SARS-CoV-2 being used [25]. Each vaccine has been developed with the aim of the immune system recognizing the immunodominant S protein [26]. Although the development of vaccines has proven successful in decreasing fatalities, reports suggest that mutations continue to increase - proposing that the administration of these vaccines does not eradicate disease spread [24]. Therefore, the attributes for the Delta variant suggest that monoclonal antibody therapies with Emergency Use Authorization (EUA) are effective against nearly all Delta lineages [4]. The AY.1 and AY.2 lineages are resistant to several monoclonal antibody treatments [4]. In addition, research has shown a decrease in post-vaccination sera neutralization [4].

#### **4.2 Omicron**

The Omicron variant (B.1.1.529, BA lineages, and other recombinant lineages, respectively depicted in **Table 2**) of SARS-CoV-2 was initially reported to the WHO in late November 2021, by South Africa [4, 7, 27, 28]. By December 2021, the United States reported its first case of COVID-19 connected to the Omicron variant [4, 27, 28]. Numerous mutations not previously seen in the original SARS-CoV-2 strain have


**Table 2.** *Circulating variants of concern.* been recognized in Omicron [29]. Omicron possesses greater than 30 mutations on its surface within the S protein, one insertion, and three deletions which allows the virus to infect cells, rendering elusive characteristics [27, 29].

A substantial number of amino acid substitutions are in the receptor-binding domain (RBD) with several alternative changes in other genomic regions [27]. Mutations to the S protein of the Omicron variant increase the affinity of binding to receptors, allowing the virus to circumvent antibodies against previous variants and remain infectious [30]. Factors influencing the transmissibility and infectivity of the Omicron variant are dependent on genetic variability and the location of the mutation [31].

Monoclonal antibody treatments aid the immune system in recognizing and responding more effectively to the virus [32]. The attributes for the Omicron variant suggest that some monoclonal antibody treatments with EUA may reduce neutralization [4]. In addition, post-vaccination sera may also reduce neutralization [4]. A comprehensive list of the lineages can be cross-referenced from **Table 1** [4, 7].

### **5. Discussion**

Viruses regularly undergo mutations, sometimes creating a lineage of virus progeny known as variants. SARS-CoV-2 has mutated several times since its discovery. Using the original Wuhan-Hu-1 protein as a reference, researchers discovered that the genes encoding the pathogenic S protein had mutated to the point that just 3.5% of the original coding sequence remains [9]. The SIG was founded by the United States Department of Health and Human Services (HHS). SIG and the CDC collaborated on a report that accounted for these variants and their classification [33]. In terms of population impact, the VBM are quite a minimal risk. Alpha, Beta, Gamma, Epsilon, Eta, Iota, Kappa, Mu, and Zeta are the varieties under the VBM class as of December 2021, with B.1.617.3's structure being unique when comparing other progenies: B.1617.1 and B.1.617.2 [2]. As per the CDC, the VBM class poses no significant and imminent risk to public health in the United States; in addition, there are no VOI or VOHC for SARS-CoV-2 [4].

Countries such as the United Kingdom, South Africa, Brazil, and India have growing variants of concern [23]. These mutations have a pedigree that includes N501Y (i.e., B.1.1.7 and several lineages), D614G (i.e., B.1 lineage and the initial dominant variant of 2020), N439K (i.e., arising from the B.1 lineage of the mutated D614G), Y453F (i.e., Cluster 5 and mink variant), and additional mutations that are dominated by clades [23]. Clades are classified according to the year they first appeared and are given a new alphabetical letter depending on their discovery: 19A (first emerging in 2019), 19B (appearing after 19A), 20A (new appearance at the start of 2020), 20B, and 20C, so on and so forth [23]. Delta (i.e., of clades 21A, 21I, and 21 J) and Omicron (i.e., of clades 21 K and 21 L) were designated as VOCs by the CDC and SIG in late 2021 [7]. The Delta variant was discovered to be the most infectious version, with an estimated transmission rate double that of the original virus. Its evolved receptorbinding interface may be the reason for its success when compared to the other variants [24]. Where Delta may have been the fastest transmissible variant, Omicron was the most clandestine [27, 29, 34]. First seen in late November of 2021, researchers found over 30 mutations within the S protein. These mutations increased the affinity of receptor binding, allowing the virus to circumvent antibodies against previous variants and remain infectious [30]. It was also reported that monoclonal antibody treatments were found to be effective against Omicron [34].

#### *Perspective Chapter: SARS-CoV-2 Variants – Two Years Post-Onset of the Pandemic DOI: http://dx.doi.org/10.5772/intechopen.105913*

The S protein is found on the external surface of the virus and is categorized into two subunits, S1 and S2 [24]. The S protein is the main virulence factor that moderates host infection by binding to the ACE2 receptors prominent on type II alveolar epithelial cells found in the respiratory epithelium [24]. Once the S protein binds to the host cell, it undergoes a conformational change in its structure from the inactive "down" state into an active "up" state, which signals a cascade of cleavages to the S1/ S2 subunits by the host enzymes and other proteases [24]. This change further alters the S protein into an amino N-terminal S1 subunit containing an RBD and a carboxyl (C)-terminal S2 subunit for virus and host cell membrane fusion [24]. Much of the SARS-CoV-2 genome is made of ORF1ab (one large open reading frame), and when the virus penetrates the host cell, it gets translated into polypeptides pp1a or pp1ab [24]. These polypeptides primarily make non-structural proteins nsp1-nsp16 that mediate ssRNA replication [24]. Approximately one-third of the SARS-CoV-2 genome is responsible for synthesizing structural proteins such as the S (spike) protein, E (envelope) protein, M (membrane) protein, and N (nucleocapsid) protein, as well as accessory proteins ORF3a, ORF6, ORF7a, ORF7b, ORF8, and ORF10 [24].

During viral replication, mutations in the ssRNA genome can be classified as synonymous with no changes to the amino acid being synthesized or non-synonymous with modifications to the amino acid [24]. The S protein has two regions that are susceptible to mutation, the N-terminal domain, and the receptor-binding domain, which directly interacts with host ACE2 and is a region that contains a heightened number of amino acid substitutions [24].

#### **5.1 +S: K417N (Delta)**

The mutation K417N has lysine (K) being substituted with asparagine (N) [35]. This mutation is found close to the RBD and has displayed the capability of impairing the RBD inactive "down" state [24]. Recent data also indicates that multiple combination mutations are possible and can generate an even more significant decline in neutralization attempts, such as mutation K417N in conjunction with mutations E484K and N501Y [24].

#### **5.2 +S: E484K (Delta)**

The mutation E484K has arisen from multiple lineages, such as Beta and Gamma [24]. This variant indicates an amino acid substitution in position 484 with glutamic acid (E) substituting for lysine (K) [35]. In addition, this mutation is close to the tip of the spike [24]. This substitution alters the shape of the S protein and grants resistance to several antibodies and the ability to evade the immune response [24].

#### **5.3 +S: R346K (Omicron)**

A recent study conducted by Lu et al., which used transmembrane protease serine 2 (TMPRSS2) to isolate variant Omicron strains HKU691, and HKU344-R346K from patients indicated that the Omicron variant has an extra spike R346K mutation that is seen in 8.5% of strains reported in the GISAID database [36]. The study also indicated that both strains were less susceptible to neutralization, and many patients did not demonstrate neutralizing antibodies to Omicron variant isolates [36]. The R346K mutation is also found in the receptor-binding domain and the mu variant [36].

Coronaviruses often recombine; therefore, a single phylogenetic tree will not necessarily depict SARS-CoV-2's evolutionary history accurately [10]. While this complicates the phylogenetic analysis, recombination is made possible with the approach of lineage nomenclature and assignment [10]. Conversely, the co-infection of both Delta and Omicron, although rare, happens [34, 36]. If a different recombination event initiates continuous transmission, it will result in the formation of a new viral lineage with a distinct common ancestor. Because this new lineage lacks a specific or clear ancestor, it will be given the next available alphabetical prefix [10]. For example, XE, a cross between two Omicron strains that are now well-known: BA.1 (the original Omicron strain) and BA.2 (the more contagious strain that is now prominent in the United States and other countries) [4, 7, 10].
