Variants of SARS-CoV-2 | Encyclopedia MDPI

The immune response elicited by the current COVID-19 vaccinations declines with time, especially among the immunocompromised population. Furthermore, the emergence of novel SARS-CoV-2 variants, particularly the Omicron variant, has raised serious concerns about the efficacy of currently available vaccines in protecting the most vulnerable people.

SARS-CoV-2
COVID-19
breakthrough infections
neutralizing antibodies (NAbs)

1. Introduction

Safe and effective vaccination has been critical in the ongoing battle against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The development of precise vaccine platforms in such a short period is a testament to global scientific prowess, and, as of 9 June, 2021, more than 2,156,550,767 doses of the COVID-19 vaccine have been given across the five continents [1]. Unfortunately, reports on variants of SARS-CoV-2 brought about by mutations with enhanced virulence, pathogenicity, and the ability to detrimentally affect host immune systems, especially the antibodies produced after COVID-19 vaccination, is a matter of concern and scientific deliberation.

However, the available published data divulge that the current vaccines could still be effective in preventing severe infection and death in people infected with the recent variants of SARS-CoV-2, such as Omicron and Delta [2,3,4,5,6]. Multiple studies have shown several advantages of the numerous mutations of the Omicron variant of the SARS-CoV-2 virus [7,8,9]. The Omicron variant and its subvariants evolved by evolutionary processes that may lead to a number of significant modifications in the virus’s characteristics, such as immunological escape from the nAbs produced by the administration of the vaccines [10,11,12]. The high frequency of mutations has also been linked to improved proteolytic priming with transmembrane serine protease 2 (TMPRSS2) and the increased binding capacities of S Protein to the angiotensin converting enzyme 2 (ACE2) receptor [9,10,13,14,15]. The higher number of mutations in the Omicron variant have also been associated with improved resistance to endosomal restriction factors, specifically IFITM proteins, which enables the variant’s more effective cellular invasion via the endocytic route [16]. Additionally, the modifications may make it more likely for spike protomers to adopt an up configuration to interact with ACE2, and may increase the stability of a down configuration to prevent contact with nAbs [12,17,18].

A variant can be defined as an isolate whose genome sequence differs from that of the reference virus. Thus, the variants share an identical inherited set of distinct mutations and are classified based on a lineage, i.e., the type of mutations that resulted in the origination of a new lineage of SARS-CoV-2. From this perspective, it is crucial to understand the mutational dynamics of SARS-CoV-2 and its effects on the vaccines that are currently available [19]. Studies have deciphered that a typical SARS-CoV-2 virus accrues, on average, one or two single-nucleotide genomic mutations in a period of 30 days [3,4]. This is just 50% of the rate of the mutational dynamics of influenza and 25% of the AIDS human immunodeficiency virus (HIV). The retarded mutational dynamics of SARS-CoV-2 could perhaps be credited to the specific exoribonuclease (ExoN) present in the genome of coronaviruses (CoVs), since inactivation of this ExoN has demonstrated a twenty-fold increase in the mutation rates [4,5].

2. Classification of Variants of SARS-CoV-2

SARS-CoV-2 variants could be classified into four different groups, i.e., variants of interest (VOIs), variants of high consequence (VOHCs), variants under monitoring (VUMs), and variants of concern (VOCs) by the US Department of Health and Human Services [17,18,19], and all five VOCs have been further categorized as α, β, γ, δ, and Omicron variants by the World Health Organization (WHO). The Omicron variant has quickly competed with other VOCs and spread across the world [10] [Table 1].

Table 1. Showing the various categories of the variants of SARS-CoV-2 with their clades and origin information.

Categories	WHO Label	Pango Lineage	GISAID Clade	Nextstrain Clade	Area of Documentation	Time of Documentation
	Epsilon	B.1.427/B.1.429	GH/452R.V1	20C/S.452R	United states of America	March-2020
	Zeta	P.2	GR	20B/S.484K	Brazil	April-2020
Variants of Interest (VOIs)	Eta	B.1.525	G/484K.V3	20A/S484K	Not defined	December-2020
	Theta	P.3	GR	20B/S:265C	Philippines	January-2021
	Iota	B.1.526	GH	20C/S:484K	United states of America	November-2020
	Kappa	B.1.617.1	G/452R.V3	21A/S:154K	India	October-2020
	Alpha	B.1.1.7	GRY	20I (V1)	United Kingdom	September-2020
	Beta	B.1.351	GH/501Y.V2	20H (V2)	South Africa	May-2020
Variants of Concern (VOCs)	Gamma	P.1	GR/501Y.V3	20J (V3)	Brazil	November-2020
	Delta	B.1.617.2	G/478K.V1	21A, 21I, 21J	India,	October-2020
	Omicron	B.1.1.529	GR/484A	21K, 21L, 21M, 22A, 22B, 22C, 22D	First lineage reported in South Africa	November-2021
Variants of High Consequence (VOHCs)	None of variant of high consequence has been recorded

2.1. Variants of Interest (VOIs)

VOI is a variant that has genetic markers specifically linked with changes to host receptor binding, exhibiting reduced antibody neutralization production versus a previous infection by the reference virus or vaccination, and showing a reduced response to hitherto effective treatments, causing a potential diagnostic impediment, and carrying on it a label of predictive upsurge in infection. These include the B.1.525 lineage brought about by the spike protein (S protein) substitutions 69del, 144del, 70del, A67V, D614G, E484K, F888L, andQ677H, which was first detected in the United Kingdom and Nigeria in December 2020; the B.1.526 lineage brought about by spike protein substitutions A701V, D253G, D614G, E484K, L5F, T95I, and S477N, which was first detected in the United States in November 2020; the B.1.526.1 lineage brought about by spike protein (S protein) substitutions D80G, D614G, D950H, 144del, F157S, L452R, T791I, and T859N, which was first detected in the United States in October 2020; the B.1.617 lineage, brought about by spike protein (S protein) substitutions D614G, L452R, and E484Q, which was first noticed in India in February 2021; the B.1.617.1 lineage, brought about by spike protein (S protein) substitutions, i.e., D614G, E484Q, E154K, G142D, L452R, P681R, Q1071H, and T95I, which was first identified in India in December 2020; B.1.617.3 lineage, brought about by spike protein (S protein) substitutions D614G, D950N, E484Q, G142D, L452R, P681R, and T19R, which was first spotted in India in October 2020; and the P.2 lineage, brought about by spike protein (S protein) substitutions D614G, E484K, F565L, andV1176F, which was first identified in Brazil in April 2020 [45,46,47,48,49,50,51].

2.2. Variants of Concern (VOCs)

A variant for concern (VOC) is a variant that has strong evidence of an intensified transmissibility; severity of the disease symptoms, including a higher number of hospitalizations and deaths; shows a significant decrease in neutralization by post-vaccination and convalescent sera; displays the significant reduction in the efficacy of existing treatments and vaccines; and poses notable diagnostic challenges, which lead to insufficiency in the diagnosis of the variant. Up to this point, the WHO has identified five VOC variants, including α, β, γ, δ, and Omicron. The Omicron variant has quickly spread around the globe and fought against all the VOCs. According to the most recent information [10], the Omicron variant (B.1.1.529) contains >30 mutations in the S Protein compared to other VOCs such as α (B.1.1.7), β (B.1.351) and δ (B.1.617.2). Significant changes to the N-terminal domain (NTD) and receptor-binding domain (RBD) of the S Protein have been linked to greater resistance to nAbs and transmission [10]. Interestingly, these VOCs could necessitate serious emergency public health engagements, including immediate notification of the detected variant to the World Health Organisation (WHO) under the regulation of International Health to CDC, and the regional and governmental authorities to control and end the spread.

These variants could also compel improved testing and investigation of the efficacy of pre-existing vaccines and treatments as well as force the deployment of newer diagnostics and the modification or production of suitable vaccines/therapeutics. These include the B.1.1.7 lineage, brought about by S Protein substitutions deletion at 69, 70, 144, N501Y, E484K, A570D, P681H, S982A, K1191N, S494P, D1118H, D614G, and T716I, which was first detected in the United Kingdom [52,53]; the B.1.351 lineage, brought about by spike protein substitutions D2, 241del, 243del, D614G, D80A, E484K, 15G, 242del, K417N, N501Y, and A701V, which was first found in South Africa [52,53,54]; the B.1.427 lineage, brought about by spike protein substitutions L452R and D614G, and observed for the first time in California, USA; the B.1.429 lineage, first observed in California, USA, due to substitutions such as L452R, S13I, W152C, and D614G in the spike protein [54,55,56]; the B.1.617.2 lineage (Delta), brought about by spike protein substitutions T19R, P681R, G142D, D614G, R158G, L452R, T478K, 156del, 157del, and D950N, which was first detected in India in December 2020 [41]; and the P.1 lineage, due to substitution in spike protein (L18F, D138Y, T20N, E484K, D614G, P26S, R190S, T1027I, K417T, N501Y, H655Y), which was first detected in Japan and Brazil [57,58,59,60,61,62,63,64,65,66,67].

2.3. Variants of High Consequence (VOHCs)

A variant of high consequence is explained as a variant for which there is absolute evidence that its prevalence has significantly decreased the effectiveness of medical countermeasures (MCMs) and preventive measures compared to the previously circulating variants. A variant of high consequence can also cause the established failure of diagnostic protocols and severe reduction in efficiency of the currently available vaccines and jeopardize the (EUA) Emergency Use Authorization and approved therapeutics, perhaps with harsher clinical manifestations and a higher number of hospitalizations. To this date, none of the variants of high consequence have been recorded [68].

3. Influence of Variants’ Emergence on Vaccine Effectiveness

VOCs, especially the Delta variant, may affect the neutralising activity of vaccine-elicited Abs and MAbs, which might result in a mild-to-significant decrease in efficiency for COVID-19 vaccines and immunotherapeutic treatment [69,70]. The existing vaccination strategies failed to prevent the outbreak of Omicron variants [59,62,66,71,72,73]. NAbs in sera from those who received a 2-dose Ad26.COV2.S (Johnson & Johnson) vaccine were considerably less efficient against the Omicron variant than the primary strain of SARS-CoV-2. A luciferase-based pseudo virus neutralisation experiment revealed a dramatic decline in the antibody-mediated immune response, 20 × 102, when compared to the original strain, which was 184 × 103 on the eighth day following vaccination [46]. Similar researchers, however, have shown that cellular immunity produced by existing vaccines against SARS-CoV-2 is largely conserved to the SARS-CoV-2 Omicron spike protein [46]. Vaccination with Ad26.COV2.S or BNT162b2 resulted in substantial spike-specific CD8+ and CD4+ T cell responses as well as significant cross-reactivity against both the Delta and Omicron variants in both the central and effector memory cell subpopulations [46].The serum neutralizing ability of individuals receiving BNT162b2 (Pfizer/BioNTech) was diminished 35-fold against BA.1 compared to D614G variant [62,66,74]. Additionally, it was not effective against BA.2 and BA.3 [75]. However, the booster doses of vaccines proved beneficial in increasing the efficacy of serum-neutralizing titers against Omicron [62,71,76].

A Phase III trial of Covaxin (BBV152), an inactivated SARS-CoV-2 vaccine, established by Bharat Biotech, India, confirmed its potential effectiveness against symptomatic cases (77.8%) and the Delta variant (68.2%) [77]. However, the convalescent serum of recipients of BBV152 was not able to neutralise the P.1 lineage [78].

Studies have shown that ChAdOx1 nCoV-19 (AZD1222) is effective against Alpha (74.5%), Delta (67%) [79], and Gamma (77.9%) [80]; however, not against Beta (10.4%) [5]. Further, this vaccine was associated with some cases of thrombosis and thrombocytopenia syndrome (TTS), blood clot events, and deaths, causing the suspension of the use of this vaccine in many European and Asian countries [81].

A renowned mRNA-based vaccine BNT162b2 was created by Pfizer and is often utilized in the immunization programs of nations. Two booster doses of this vaccine give a similar level of protection against Delta, but recent comparative studies have cast doubt on the vaccine’s effectiveness [76,82]. The efficacy of the BNT162b2 and ChAdOx1 nCoV-9 vaccinations was shown to be lower in those who had the Delta variation of the virus than in those who had the other VOCs. It is critical to keep in mind that these outcomes were attained in patients who received only one dose of the vaccine [70].

Further investigation with two doses of the vaccination has demonstrated the apparent efficiency of the primary vaccines against the δ variant. Two doses of the BNT162b2 vaccination were effective in persons with the Alpha version, and 88% in those with the Delta version. Two doses of the ChAdOx1 nCoV-19 vaccine were shown to be 74.5% effective in those with the Alpha form and 67.0% effective among individuals with the δ variant. Upon receiving the two vaccine doses, minor changes in vaccine efficacy were observed between the δ and α variants. Absolute disparities in vaccination effectiveness become more evident after the first dose. This outcome will aid the efforts to increase vaccination uptake among a vulnerable subset of individuals through the administration of two doses [79]. According to several investigations, three doses of BNT162b2 mRNA seem to be necessary to protect against Omicron-driven COVID-19 [83,84,85]. Surprisingly, Gao et al. proposed that pre-existing SARS-CoV-2 spike-specific CD8+ and CD4+ T cell responses are usually intact against Omicron, especially after BNT162b2 vaccination [86].

Additional research revealed that two doses of the BNT162b2 or ChAdOx1 nCoV-19 vaccination only partially protected against the omicron variant. Upon receiving a BNT162b2 or mRNA-1273 vaccine booster shots, the protection from the BNT162b2 or ChAdOx1 nCoV-19 primary vaccination increased but ultimately wore out [87].

However, the serum from individuals administered triple doses of ChAdOx1 (Oxford/AstraZeneca) or BNT162b2 showed a decreased efficacy against BA.4/5, contrary to BA.1 and BA.2 [88]. Recent research by Zou et al. 2022 found that following the complete dosage of the SARS-CoV-2 vaccine, the immune protection diminishes with time against the Omicron variant.

The Omicron form could not be neutralised by more than half of the mRNA-1273 recipients’ plasma, leading to GMTs that were 43 times lower [60]. According to Pajon et al., neutralisation titers against the Omicron version of the mRNA-1273 vaccination were 35 times lower than those against the D614G variant after the first two doses of the vaccine. On the other hand, neutralisation titers against the Omicron variant were 20 times greater following the booster dose of the mRNA-1273 immunisation than following the second dosage, indicating that the risk of relapse is significantly reduced. Six months following the booster injection, neutralisation titers against the Omicron variant decreased [61].

The effectiveness of the serum from people who received an mRNA vaccination against Omicron was evaluated by Edara et al.: using a live viral experiment, they noticed a 30-fold decrease in neutralising activity against the Omicron 2–4 weeks after receiving a primary batch of immunisations, but six months after the first two vaccination doses, no neutralising activity against the Omicron was found, and, in addition, they found that following a booster injection (third dosage), naive individuals’ neutralising activity against Omicron decreased fourteen-fold [62]. This implies that the vaccination’s effectiveness has been compromised by the appearance of variations, which calls for the administration of booster doses of the vaccine at progressively longer intervals.

This entry is adapted from the peer-reviewed paper 10.3390/medicina59030507

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