The Emergence of SARS-CoV-2 Variants

The Emergence of SARS-CoV-2 Variants: Comparison

Please note this is a comparison between Version 1 by Ananda Tiwari and Version 2 by Conner Chen.

The emergence of new variants of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associated with varying infectivity, pathogenicity, diagnosis, and effectiveness against treatments challenged the overall management of the coronavirus disease 2019 (COVID-19) pandemic.

COVID-19
SARS-CoV-2 variants
Alpha (B.1.1.7)

1. Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), continuously underwent mutations leading to the emergence of new variants [1]. These variants are of great concern ^[2][3][4][2,3,4], as they might be associated with increased infectivity ^[1][5][1,5], severity ^[1][6][7][1,6,7], could have higher shedding rates [8], the potential to escape natural or vaccine-induced immunity ^[9][10][9,10], and can also affect the performance of diagnostic methodologies ^[11][12][11,12]. Such changes in virus characteristics affected the overall management plan for the COVID-19 pandemic. For example, it led to travel restrictions both locally and internationally for people from infected areas ^[1][7][1,7], and many more consequences on the daily lives of individuals. Therefore, the emergence of SARS-CoV-2 variants increased the need for genomic surveillance and other innovative tools to protect public health.

Whole-genome sequencing (WGS) of clinical specimens is a primary approach for identifying new emerging variants [13], by comparing the sample genome with the reference genome [14]. However, using WGS for monitoring each clinical specimen is time-consuming, labor-intensive, and expensive, and is usually conducted for individuals with clinical symptoms. Many of the COVID-19-infected individuals can be asymptomatic, so only relying on a clinical monitoring approach in the surveillance can miss the mutant variants carried by asymptomatic individuals.

Wastewater surveillance (WWS), also known as wastewater-based epidemiology (WBE), of infectious diseases through analyzing municipal sewage proved to be a cost-effective approach for monitoring the circulation of SARS-CoV-2 at a population level, covering both symptomatic and asymptomatic individuals ^{[15][16][17][18][19][20]}[15,16,17,18,19,20]. In contrast to the clinical approach, WWS is a comprehensive, rapid technique for regular monitoring and tracking of the possible emergence of new variants at a population level ^{[19][20][21][22][23]}[19,20,21,22,23]. From a surveillance point of view, municipal raw sewage can be a good material for SARS-CoV-2 monitoring, as it comprises the entire population of a community, both healthy and infected individuals (symptomatic, asymptomatic, pre-symptomatic, and post-symptomatic), contributing through feces, nasal mucus, and sputum to sewage from households, hospitals, and nursing homes ^[16][17][24][16,17,24]. Globally, many studies reported monitoring different variants of SARS-CoV-2 in wastewater ^{[11][15][16][17][20][24][25][26][27][28]}[11,15,16,17,20,24,25,26,27,28], thereby highlighting WWS as an alternative tool for detecting different variants in communities. However, a comprehensive evaluation of the state-of-art use of WWS for monitoring SARS-CoV-2 variants is lacking. Such data can help evaluate and optimize WWS for monitoring SARS-CoV-2 variants. Such information can also be useful in managing future infectious outbreaks, such as how the wild and mutated variants differ among geological locations.

2. The Emergence of SARS-CoV-2 Variants

SARS-CoV-2 is an enveloped single-strand RNA (ssRNA) virus belonging to the Coronaviridae family and genus Betacoronavirus ^[9][29][9,29]. As with other ssRNA viruses, SARS-CoV-2 contains RNA-dependent RNA polymerase (RdRP), which is responsible for sub-genomic mRNA synthesis for producing viral proteins, including the virus envelope and spike proteins [30]. RNA viruses are relatively prone to adapt more rapidly to a changed environment by changing their genome structure. SARS-CoV-2 continuously evolves into new variants due to genetic mutation and viral recombination ^{[1][2][13][31]}[1,2,13,31]. Mutation refers to at least a single change in a virus’s genetic code. Genetic modifications can change the virus’s characteristics [1]. A SARS-CoV-2 variant can have one or more mutations that differentiate its features from other variants. SARS-CoV-2 has a similar mutation mechanism to other ssRNA viruses that lack proofreading capability, giving rise to new variants [25]. Uncorrected mutations occur during genome replication, recombination, and RNA editing by the deaminase of the infected host [13]. A recombinant variant is created due to a combination of genetic material from two different variants, and a mutant variant is created due to a mutation in RNA. A lineage is a group of closely related viruses with a common ancestor [32]. The ancestral SARS-CoV-2 (wild variant) genome evolved into several lineages (https://cov-lineages.org/lineage_list.html, accessed on 28 November 2022), such as the Alpha (B.1.1.7), Delta (B. 1.617.2), and Omicron (B.1.1.529) ^{[2][3][7][11][28][32][33][34][35][36][37]}[2,3,7,11,28,32,33,34,35,36,37], due to exposure to some selective pressure [38]. Most of these new variants were developed due to viral spike protein (S-protein) mutation [39].

2.1. Alpha (B.1.1.7 and Q Lineages)

The Alpha variant was first isolated in the United Kingdom in September 2020 and was followed by an upsurge in infection in December 2020 [40]. Soon after, it became the dominant variant until August 2021 in many countries, including the US, India, Sweden, and globally in at least 189 countries (Table 1). The World Health Organization (WHO) classified the Alpha variant as a variant of concern (VOC) on 29 December 2020 [10], after rising hospitalization cases and creating a strain on the public health system and facilities across countries [41]. The Alpha variant was reported to be about 100-fold more lethal than the original SARS-CoV-2 strain [6]. Further, mRNA vaccines were reported to be about 68% less effective against this variant [6]. On 21 September 2021, the WHO designated the Alpha variant as the “variant being monitored” ^[1][7][1,7]. After 2022, this variant’s circulation drastically reduced worldwide, following the emergence of Delta variants, probably due to the impact on vaccine-induced immunity (Table 1).

Table 1. SARS-CoV-2 variants and lineages ^[1][7][33].

SARS-CoV-2 variants and lineages [1,7,33].

WHO Label/Pango Lineage	Country First Detected	Spike Mutations of Interest	Outbreak Countries	Major Outbreak Peaks	Classification (WHO) during November 2022	Outbreak Condition during November 2022
Alpha/B.1.1.7	United Kingdom, September 2020	N501Y, D614G, P681H	At least 189 countries, predominant in the US, India, Sweden, France, Spain, Australia, Nigeria, and so on (1.2 million cases globally reported).	November 2020 to August 2021	VOC: 29 December 2020 VBM: 21 September 2021 PVOC: 9 March 2022	Drastically reduced circulation globally, with almost no reporting at the time of writing the manuscript.
Delta/B.1.617.2	India, October 2020	L452R, T478K, D614G, P681R	At least 208 countries, predominant in the US, UK, Japan, Italy, India, Germany, Canada, Denmark, France, and so on (4.4 million cases globally).	May 2021–January 2022	VOC: 15 June 2021 VBM: 14 April 2022, PVOC: 7 June 2022	Abundance is very low at the time of writing the manuscript.
Beta/B.1.351	South Africa, May 2020	K417N, E484K, N501Y, D614G, A701V	At least 127 countries, predominant in South Africa, the US, India, Sweden, France, Spain, Australia, Nigeria, Iran, and so on (43,000 cases globally).	November 2020 to August 2021	VOC: 29 December 2020 VBM: 21 September 2021, PVOC: 9 March 2022	Drastically reduced circulation globally, with almost no reporting at the time of writing the manuscript.
Gamma/P.1	Brazil, November 2020	K417T, E484K, N501Y, D614G, H655Y	At least 93 countries, predominant in the US, Canada, Brazil, Argentina, Chile, Italy, Peru, Mexico, Sweden, South Korea, Venezuela, and so on (74,300 cases globally).	Feb 2021–November 2021	VOC: 29 December 2020 VBM: 21 September 2021 PVOC: 9 March 2022	No longer detected or detected at extremely low levels globally.
Epsilon/B.1.427, B.1429	California USA, July 2020	I4205V and D1183Y in the ORF1ab gene, and S13I, W152C, L452R in the spike protein’s S-gene	At least 45 countries.	November 2020–March 2021	VOC, March 2021. VBM-September 2021. Previously circulating VOI: March 2022 (WHO),	After an initial increase, its prevalence rapidly decreased from February 2021 and was outcompeted by the more transmissible Alpha variant.
Lambda/C.37	Peru, August 2020	Virus’s spike protein code: G75V, T76I, Δ246–252, L452Q, F490S, D614G and T859N	At least 45 countries (predominant in Peru, Chile, US). Total global cases of less than 10,000.	November 2020–November 2021	VOI June 2021	No longer reported.
Omicron/BA.2, BA.4, BA.5, BA.2.75, BQ.1, XBB	South Africa and Botswana November, 2021	BA.2 (y), BA.4 (L452R, F486V, R493Q), BA.5 (L452R, F486V, R493Q). BA.2.75 (z*), BQ.1 (K444T, N460K), XBB (N460K, F490S)	At least 208 countries, predominant in the US, UK, Denmark, Canada, India, Japan, Germany, France, and so on (6.2 million cases globally, 14 December 2022).	November 2021-Currently circulating lineages: BA.2, BA.4, BA.5, and their recombinants and sub-lineages	BA.2, BA.4, and BA.5 are VOC, and BA.2.75, BQ.1, XBB are current VOI at the time of drafting the manuscript, December 2022.	Many lineages are currently going around the world (83,046 in the last four weeks of 14 December 2022).

Notes: Other variants monitored earlier: Eta/B.1.525 (VOI on 02/29/21, but VBM since 09/21/21), IOTA/B.1.526 (VOI on 02/29/21, but VBM since 09/21/21), Kappa/B.1.617.1 (VOI on 05/07/21 but VBM since 09/21/21), B.1.617.3 (VOI on 05/07/21, but VBM since 09/21/21), Zeta/P.2 (VOI on 02/26/21, but VBM since 09/21/21), and Mu/B.1.621 and B.1.621.1 (VBM on 09/21/21but VBM since 09/21/21) Key: VOI—Variant of interest; VOC—Variants of concern; VBM—Variant being monitored; PVOC-Previous variant of concern. y*: G142D, N211I, Δ212, V213G, G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, N969K, z**: W152R, F157L, I210V, G257S, D339H, G446S, N460K, and Q493 (reversion).

2.2. Delta (B.1.617.2 and AY Lineages)

The Delta variant was first detected in India in October 2020 ^[10][42][10,42], and it swept rapidly through India and then the United Kingdom by mid-April 2021 before spreading to the US and the rest of the world [42]. The Delta variant was reported to be 60% more infectious and lethal than the Alpha variant [1]. It was reported that a single and double dose of AstraZeneca vaccine was 33% and 60% effective in reducing the Delta lineage infection, respectively, compared to 60% and 66% on the Alpha lineage ^[43][44][43,44]. Similar results (i.e., less effective vaccine than with Alpha lineage) were observed in a study when Pfizer vaccines were administered [42]. The emergence of this variant caused a delay in the United Kingdom’s reopening plans after several months of lockdown beyond June 2021 [9]. It became a VOC in the US on 15 June 2021 [1], after it became evident that people infected with the Delta variant were twice as likely to become hospitalized than those with the Alpha variant [41]. This implied that the Delta variant exhibited more infectivity than earlier variants [42]. Until October 2021, Delta was the most dominant variant in the world, with about 90% sequences in the Global Initiative on Sharing Avian Influenza Data (GISAID).

2.3. Omicron (B.1.1.529 and BA Lineages)

The Omicron variant was declared a VOC immediately after it was reported in South Africa in November 2021 [1]. The Omicron variant has the highest number of mutations, compared to the reference wild SARS-CoV-2 genome, with 37 mutations in the spike (S) protein, three mutations in the nucleocapsid (N) protein, one mutation in the envelope (E) protein, three mutations in the membrane (M) protein, and 10 synonymous mutations [45]. This variant is more contagious than the earlier variants, with a reported rise of cases from hundreds per day to thousands per day in South Africa over two weeks [9]. It soon began to spread to several other countries and became one of the most dominant variants after December 2021 ^[25][46][47][25,46,47]. A subvariant known as BA.2 was also discovered and monitored as it accounted for 23% of cases in the US as of March 2022 [48]. The Omicron BA.2 sub-variant has a mutation on the spike protein, which is responsible for infecting host cells, thereby increasing infectability and having the capacity to evade immunity [49], most especially those who recovered from previous COVID-19 variants infection but were yet to be vaccinated [50]. The Omicron variant and its sub-lineages were the most dominant variants circulating globally in 2022, for more than 98% of sequences shared on GISAID between February 2022 and November 2022 belonging to Omicron. Omicron is a complex variant that continues to evolve, leading to descendent lineages with different genetic constellations of mutations [7]. Despite its high transmissibility, it has lower severity than previous Delta and Alpha variants. In December 2022, the world was still passing through the pandemic of the Omicron variant. A total of 83,046 cases were reported in GISAID within four weeks (https://gisaid.org/hcov19-variants/, accessed on: 7 December 2022) (Table 1).

2.4. Other Variants

Aside from the variants mentioned above, many other variants were first declared as VOC but were later re-designated as variants of interest (VOI) ^[1][33][1,33] or declared as variants being monitored (VBM), previously circulating VOCs or VOIs or formerly monitored variants (FMVs). The designation of VOC, VOI, VBM, and FMVs are working definitions periodically updated by WHO and CDC (US and EU) (Table S1). Among the emergence of different variants, the Beta (B.1.351) variant was detected in South Africa [51], and the Gamma (P1) variant was identified in Brazil in November 2020 ^[34][46][34,46]. Both lineages of Epsilon (B.1.427 and B.1.429) were identified in California [35] and were reported to have higher transmissibility, infectibality, and severity than the preceding variants and lineages [41]. The Lambda variant (lineage C.37) was first reported in Peru in August 2020 and was designated as VOI by WHO on 14 June 2021 [36]. This variant was reported to be more resistant to neutralizing antibodies than other variants [36]. The Lambda variant was suspected to be more resistant to vaccines than the Alpha and Gamma variants [37]. Table 1 shows details of SARS-CoV-2 variants and their WHO designation at the time of review. This highlights the importance of genetic surveillance of SARS-CoV-2 variants worldwide.