**2.5 Impact of the omicron (B.1.1.529) variant on the severity and spread of the disease**

The omicron (B.1.1.529) variant was first reported in a sample of Botswana on November 11, 2021 and in South Africa on November 24, 2021 (WHO, CDCC). On November 26th, 2021, the WHO classified them as lineage B.1.1.529 and declared them a variant of concern. It contains a large number of variations in the SARS-CoV-2 genome, as more than 60 variations (substitutions/deletions/insertions) in the omicron variant have been reported, some of which are concerning [76]. The spike protein in the Omicron variant has 32–35 mutations, 15 of which are located in the receptor binding domain, which is critical for viral-cell interaction mediated by the ACE-2 receptor. The high variations in spike protein of omicron could be a potential reason for the immune escape and vaccine neutralisation. Few variations shared by earlier SARS-CoV-2 variants have already been reported in immune invasion. The E484 mutation, which is known to be involved in immune escape, has been reported in beta and gamma variants, but the substituted amino acid was lysine in beta and gamma variants, and alanine in omicron variants [63, 77]. The E484A mutation in the Omicron may have been a significant mutation that was also present as E484K in other VOCs. Omicron also shares the most common mutations in spike protein of other variants, including K417N, E484A, N501Y, D614G, and T478K. The K417N mutation, which has previously been reported in beta variants, disrupts the effect of known antibodies. Chen et al. demonstrated that the E484A mutation has a massively disruptive effect on many known antibodies. The combination of K417N and E484A mutations in omicron increases its effectiveness in vaccine neutralisation. Y505H is the third disruptive mutation. It can also disrupt many known antibodies to bind

*Perspective Chapter: Emerging SARS-CoV-2 Variants of Concern (VOCs) and Their Impact… DOI: http://dx.doi.org/10.5772/intechopen.107844*

RBD complexes [78]. Recent genetic research revealed that the omicron continued to evolve, giving rise to a variety of lineages, including BA.1, BA.2, BA.3, BA.4, and BA.5. A few of these sub-lineages have replaced other circulating strains and have emerged as the globally dominant variants, each demonstrating a different pattern of immune escape and transmission rate [28, 79]. Most spike mutations are the same across all sub-lineages. BA.2 shares 12 mutations with BA.1 and has four unique mutations in the receptor binding domain. Apart from, a new NSP6 (A88V) mutation, BA.3 shares the majority of its mutations with BA.1 and BA.2 [80]. The L452R and F486V mutations unique to BA.4/5 or the L452Q mutation specific to BA.2.12.1 play significant roles in immune evasion, resulting in numerous infections and re-infections following vaccine breakthroughs [81]. BA.4 and BA.5 share the same mutant profile in their S proteins, despite showing different spreading trends [28]. The F486V mutation found in BA.4/5 promote immune invasion by evading neutralising antibodies but reduces spike affinities for the viral receptor. The R493Q reversion mutation, on the other hand, restores receptor affinity and, as a result, BA.4/5 fitness [80]. BA.4 differs from BA.5 in that it has several rare mutations, including del 141–143 in NSP1, L11F in ORF7b, and P151S in nucleocapsid protein. A considerable humoral immunity escape could be caused by BA.2.12.1, BA.4 and BA.5 carrying the lineage-specific L452Q/R mutation [82].

#### *2.5.1 Transmission and hospitalisation*

Karim and Karim demonstrated that the omicron variant is more infectious than the other variants of concern. As reported, the doubling time of infection rates is comparatively faster than for previously reported VOCs. Omicron infection doubled in 1.2 days, which is faster than the 1.7 and 1.5 days for beta and delta variants, respectively [83]. Mutations in spike's RBD domains (N440K, T478K, and N501Y) may make omicron 10 times more contagious than the original virus and twice as contagious as the delta variant [78, 83]. However, a 2022 study by Nyberg et al. found that the risk of hospitalisation and mortality in omicron was significantly lower than in delta [26]. Like omicron, their sub-lineages appear to be more transmissible. The BA.2 variant is more transmissible and can infect people who have previously been infected with BA.1 [84, 85]. As a result, BA.2 has quickly replaced BA.1 and other circulating strains in many countries, including South Africa, the United Kingdom (UK), and India, and has become the most prevalent strain. However, BA.3 has shown lower fitness and is reported with limited frequency among other variants. During the global pandemic of the BA.2 strain, two new variants emerged, BA.4 and BA.5, which were first reported in South Africa and then detected in many other countries. The BA.4 and BA.5 variants are more transmissible and pathogenic, and they can reinfect previously infected BA.1 and BA.2 patients [79, 86]. According to the Centers for Disease Control and Prevention (CDC), July 2022, Omicron subvariants BA.5 and BA.4 are the predominant strains of SARS-CoV-2 in the United States, accounting for more than 80% of cases, according to the CDC.

#### *2.5.2 Vaccine response/breakthrough infections*

Many re-infections and breakthrough infections have been caused by the Omicron variation and its sublineages, which demonstrate enhanced transmissibility and immune invasion from neutralising antibodies produced by prior infection or vaccination [28]. The RBD domain mutations K417N, E484A, and Y505H provide

omicron with a strong vaccine breakthrough capability, causing disrupted binding of spike protein with the majority of 132 antibodies [22]. Omicron has been linked to an increased risk of reinfection and breakthrough infection as studies found that the few vaccines did not produce neutralising antibodies against the omicron virus in recipients. The Omicron variant reduced the efficacy of Pfizer-COVID-19 BioNTech's vaccine, but the vaccine still reduced the risk of hospitalisation. A study published in 2021 by Lu et al. revealed that the neutralising ability of BNT162b2 and Coronavac vaccines is much less effective against the Omicron variant than the Beta variant [27]. Hoffmann et al. discovered that the omicron spike conferred 12-to 44-fold lower neutralising antibodies in convalescent patients or BioNTech-Pfizer vaccine (BNT162b2) vaccinated individuals, in comparison to the Delta variant spike [87]. A preliminary laboratory report showed a 25-fold increase in antibody titers against the omicron after the third dose of BNT162b2 administration (https://www.businesswire. com/news/home/20211208005542/en/). Kurhade et al. demonstrated the efficacy of BNT162b2 vaccine against omicron sub-lineages after 1 month of 3 dosages, and found that the vaccine's neutralisation efficacy was 3.6, 4.0, and 6.4-fold lower for the BA.1-, BA.2, and BA.3-spike SARS-CoV-2 s than it was for USA-WA1/2020 (a strain isolated in Jan. 2020), respectively [88]. Xi et al. studies showed that BA.5 had the lowest neutralisation after four dosages of BNT162b2 vaccination, but the efficacy



*Perspective Chapter: Emerging SARS-CoV-2 Variants of Concern (VOCs) and Their Impact… DOI: http://dx.doi.org/10.5772/intechopen.107844*
