Perspective Chapter: Emerging SARS-CoV-2 Variants of Concern (VOCs) and Their Impact on Transmission Rate, Disease Severity and Breakthrough Infections

Abstract

SARS-CoV-2, like all RNA viruses, evolves over time, and genetic mutations have been linked to increased replication fitness and evolvability. SARS-CoV-2 spreads quickly between countries, resulting in new mutations. SARS-CoV-2 genome sequencing reveals that variants emerge through point mutations, insertions, and deletions. Concerns have been raised about the ability of currently approved vaccines to protect against emerging variants. Viral spike protein is a component of many approved vaccine candidates, and mutations in the S-protein may affect transmission dynamics and the risk of immune escape, resulting this pandemic last-longer in populations. Understanding the evolution of the SARS-CoV-2 virus, as well as its potential relationship with transmissibility, infectivity, and disease severity, may help us predict the consequences of future pandemics. SARS-CoV-2 genome studies have identified a few mutations that could potentially alter the transmissibility and pathogenicity of the SARS-CoV-2 virus. At the moment, it is worth mentioning that a few variants have increased the transmissibility of SARS-CoV-2. The Alpha, Beta, Gamma, Delta, Delta+, and omicron variants are designated as variants of concern (VOCs) by the World Health Organisation and have been linked with an increased risk to the community in terms of transmission, hospitalisation, and mortality. This chapter thoroughly discusses the impact of SARS-CoV-2 mutations, mainly VOCs, on public health by mining many published articles.

1. Introduction

COVID-19 has been declared a pandemic by the World Health Organisation (WHO) on March 11, 2020. For the short time period, the COVID-19 time has passed in a few countries throughout the past 2 years of the pandemic, but there has been a new infection outbreak recorded in a few continents, and it has spread quickly globally, causing new waves in many countries. According to the WHO, as of today, June 22nd, a total of 6,544,553 new infections have been reported worldwide in just 24 hours. All viruses, including SARS-CoV-2, mutate over time, and high mutation rates have been linked to improved replication fitness and evolvability. These characteristics give RNA viruses a high level of adaptability. As a result, RNA viruses adapt quickly to changing environmental conditions [1, 2]. The genomes of RNA viruses, including coronavirus, are prone to mutation in three different ways. The first is due to the low fidelity and proof-reading activity of RNA polymerase, which results in the erroneous incorporation of mutations during replication. The second is due to a recombinational event between two viral lineages, and the third is due to the host RNA editing system. Mutations may be neutral, beneficial, or deleterious. Although the majority of circulating RNA virus mutations are neutral, some may affect viral replication and infectivity [3, 4, 5]. The COVID-19 pandemic’s longevity could lead to the accumulation of immunologically important mutations in the viral genome that provide the virus an edge in its ability to replicate and survive [6, 7]. In most RNA viruses, RNA polymerase lacks proofreading activity [8, 9]. Mutations in the surface protein can significantly alter viral function and/or interactions with neutralising antibodies. Spike protein receptor-binding domain (RBD) mutations in the SARS-CoV-2 genome are being studied for their potential impact on infectivity and antibody resistance caused by this new variant. This is because the RBD on the S protein of SARS-COV-2 facilitates binding between the S protein and the host angiotensin-converting enzyme 2 (ACE2). S-ACE2 binding allows SARS-CoV-2 to enter the host cell and begin the viral infection process [10, 11]. SARS-CoV-2 infection is only detected in humans, and there have been numerous reports of mutations in the gene that codes for the Spike (S) protein [5, 7, 12, 13]. Since the COVID-19 pandemic disease outbreak, mutations have been reported in 96.5 percent of the SARS-CoV-2 spike protein’s amino acid residues [14]. The use of vaccines is the only method for treating the viral pandemic, and several COVID-19 vaccines have been rolled out globally to stop the spread of sickness. However, like other vaccines, these ones are also not 100% effective, and as a result of the SARS-CoV-2 breakthrough infection, vaccine recipients are now being diagnosed with COVID-19. However, despite breakthrough infection, vaccines are still effective in treating serious illnesses linked with COVID-19 [15, 16, 17]. A number of variants of SARS-CoV-2 have been reported worldwide since the first reports of pandemics. The World Health Organisation classified some of them as variants of concern because they are extremely contagious and frequently lead to breakthrough infections. VOCs have the ability to neutralise the effects of numerous vaccinations. These are the causes of recent waves and breakthrough infections in various countries. Variants of Concern (VOCs) are an emerging topic of research since they can alter the transmissibility, clinical presentation, and severity of the disease, as well as have an effect on treatment options such as medicines and vaccines.

2. Emergence of variants of concern (VOCs) of SARS-CoV-2

Several variations in the SARS-CoV-2 genome have been reported in the last 2 years of the pandemic. Spike proteins, an outward projection of the SARS-surface, CoV-2’s interacted with ACE-2 receptors on host cells, resulting in viral pathogenesis. Since the beginning of the pandemic, the amino acids of spike protein have been mutated, and a large number of variations have emerged. A few variations have been linked to viral replication fitness and survival advantages, which ultimately increases the risk of disease transmission and severity in the human population (Figure 1). Furthermore, a few variants are highly transmissible and less susceptible to vaccine-induced and infection-induced immune responses, causing breakthrough infections. Based on this, the World Health Organisation classified a few SARS-CoV-2 virus variants as Variants of Concern (Table 1). This chapter discussed how VOCs have posed health risks to the human population in the last 2 years.

Figure 1.

Schematic representation of emergence of VOCs of SARS-CoV-2 during last 2 years of pandemic and their impact on COVID-19 risk.

2.1 Impact of the alpha variant (B.1.1.7 & Q lineages) on the severity and spread of the disease

The alpha variant was the first variant of concern for SARS-CoV-2 after the induction of the pandemic in March 2020. The first case of the alpha variant was detected in October 2020 in the United Kingdom and subsequently spread to many countries, causing an outbreak. The WHO labelled the variant as an alpha and in lineage B.1.1.7. The alpha spike protein contains non-synonymous mutations and deletions, including deletions 69–70, 144, N501Y, A570D, D614G, P681H, T716I, S982A, and D1118H, and each mutation has its own biological significance, which increases overall infectivity [29]. The alpha variant spread rapidly in the UK in Oct-Dec 2020 and the most frequently observed mutation was the N501Y mutation in spike protein. The substitution of tyrosine for asparagine at position 501 of spike protein increases its affinity for ACE-2 receptors on host cells. [30], as results increase in transmission rate, which derived the first wave of COVID-19 in many countries. A strain carrying D614G in RBD domains is more infective and resistant to some neutralising antibodies, which has obvious implications for COVID-19 patient recovery [31]. According to studies, the G614 variant has a greater number of functional spikes on its surface than the D614 variant. Furthermore, it has been shown that the D614G mutation stabilises the interaction between the S1 and S2 domains and limits S1 shedding, resulting in increased overall infectivity [32].

2.1.1 Transmission and hospitalisation

It originated in the UK, but the variant was present on all continents within 2 months of its emergence. As of December 2020 [33], B.1.1.7 was the cause of two-thirds of COVID-19 infections in the UK and one-quarter of all cases worldwide as of December 2020 [34]. The emergence of alpha variants resulted in an increase in the transmission rate and hospitalisation of COVID-19 cases, as few studies estimated the infection rate and it was 45–71% higher in the alpha variants than in the original virus [19, 34, 35]. SARS-CoV-2 lineage B.1.1.7 infection was linked to an increased risk of hospitalisation. Bager et al. discovered in 2021 that the hospitalisation rate in alpha variants rises over time. They enrolled 50,958 COVID-19 patients, of whom 30,572 had their SARS-CoV-2 genome sequenced, and followed up with 14 days of hospitalisation data. The Alpha variant infected 34.5 percent of all patients and hospitalised 6.4 percent. 29.4 percent of the hospitalised patients were infected with Alpha, while 70.6 percent were infected with other strains. During the study period, the number of COVID-19 hospitalizations decreased, but the proportion of patients with the Alpha variant increased dramatically, from 3.5 percent in week 1 to 92.1 percent in week 10 [36]. Veneti et al. included 27,753 COVID-19 patients in their study, of whom 23,169 are cases of alpha variant. Study showed that the B.1.1.7 was linked with a 1.9-fold increased risk of hospitalisation and a 1.8-fold increased risk of ICU admission, in comparison to non-alpha strain [37]. Several studies showed that the emergence of the alpha variant was linked to an increase in transmission risk and hospitalisation rate [19, 38].

2.1.2 Vaccine response

According to studies, vaccinated people are less likely to be hospitalised than un-vaccinated people. According to Eyre et al., vaccinated individuals infected with alpha variants had a lower transmission and hospitalisation rate [39]. Study of Lopez et al. in UK population infected with alpha variant showed that the one dose of BNT162b2 and ChAdOx1 nCoV-19 (AstraZeneca) vaccine was found to be effective against 48.7% (95% CI, 45.5–51.7) symptomatic alpha variant infection, whereas effectiveness increased to 93.7% (95% CI, 91.6–95.3) and 74.5% (95% CI, 68.4–79.4), respectively, after second dose of administration BNT162b2 and ChAdOx1 nCoV-19 (AstraZeneca) vaccine [40]. A similar study conducted by Chemaitelly et al. showed that the mRNA-1273 vaccines were effective 88.1% (95% CI, 83.7–91.5) after the first dose, whereas it was found to be 100% (95% CI, 91.8–100) after the second dose of administration [41]. Mahase et al. also evaluated the effectiveness of the Novavax vaccine, and it was found to be 85.6% effective against symptomatic COVID-19 with the alpha variant [42].

2.2 Impact of the beta variant (B.1.351) on the severity and spread of the disease

The beta form was first discovered in South Africa, and primarily infected young people with no disease severity risk. This variant was responsible for more than 90% of all cases and the 2nd wave of COVID-19 in South Africa in the last month of 2020 [43], and spread to other African countries, Asia, Australia, and North and Central America [44]. Among several structural and non-structural mutations in beta spike, K417N, E484K, and N501Y are the three critical changes that could give SARS-CoV-2 viral fitness and survival advantages over the circulating strains in the same region where it was common [44].

2.2.1 Transmission and hospitalisation

Studies showed that the beta variant is comparatively highly transmissible than that of earlier circulating strain of SARS-CoV-2. In 2021, Pearson et al. demonstrated that prior exposure only partially protects against beta variant infection, and it has been accounted for about 40% of new SARS-CoV-2 infections compared to only 20% for Alpha variants in the prevalent area. As estimated 501Y.V2 is 1.50 times as transmissible as previously circulating variants [45]. Studies showed that the person infected with beta variant has higher risk for disease severity than the alpha variant. The study of Veneti et al. showed that the B.1.351 was associated with a 2.4-fold increased risk of hospitalisation and a 2.7-fold increased risk of ICU admission compared to non-VOC [20].

2.2.2 Vaccine response and breakthrough infections

Studies showed that the efficacy of vaccines is greatly reduced when dealing with the beta variants. In a study conducted by Garcia-Beltran et al. in 2021, the B.1.351 variant significantly reduced neutralisation even in fully vaccinated individuals with BNT162b2 and mRNA-1273 vaccines, whereas protection for other circulatory strains remained constant during the same period [21]. Wu et al. showed that the B.1.351 reduced the neutralisation efficiency of the mRNA-1273 vaccine but that it was still effective to neutralise the B.1.351 virus in fully vaccinated individuals [46]. Mahase, stated that the Novavax was 60% effective against the B.1.351 variants and 95.6% effective against the original SARS-CoV-2 virus [42].

2.3 Impact of the gamma (P.1 and descendent lineages) on the severity and spread of the disease

The first case of the gamma variant was detected in Tokyo, Japan in Jan-2021 and patients were relocated from the Brazilian Amazon state. The WHO has classified the variant as a gamma and assigned it to lineage P.1. Ten of the non-synonymous defining mutations in the S gene are present in the gamma lineage, which evolved following a period of rapid genetic diversification. Of these changes, three (N501Y, E484K, and K417T) increased favourable stable interaction with the human ACE-2 receptor. This mutation caused an outbreak in the Manaus region of Brazil in December 2020, with gamma variant cases accounting for 42% of all cases [22].

2.3.1 Transmission and hospitalisation

In a study done in Brazil in the year 2021 by Chen and Lu, it was demonstrated that patients with gamma variations have high viral loads that are 10 times higher than those of patients with other lineages. Transmissibility and infectivity were twice higher than the other circulating strains in all age groups. Studies showed that the gamma variant can overcome the immunity developed from earlier infections, increasing the risk of a breakthrough infection. Additionally, the death rate was 10–80% greater in the group infected with the gamma variant [22]. A study by Funk et al. showed that gamma variant patients had significantly higher adjusted odds ratios for hospitalisation (2.6, 95% CI, 1.4–4.8) and ICU admission (2.2, 95% CI, 1.8–2.9) [47].

2.3.2 Vaccine response and breakthroughs infection

Studies revealed that the Gamma variant also had a decrease in anti-RBD antibody neutralisation, and it has been connected to reinfections and breakthrough infections in those who have received vaccinations [48, 49, 50, 51]. The Gamma variant was found to reduce the antibody neutralising activity of Pfizer or Moderna vaccines, as the report showed the prevalence of breakthrough infections in fully vaccinated recipients. In a 2021 study on fully vaccinated Gold Miners recipients in French Guiana, Vignier et al. showed that 60% of BNT162b2 vaccine recipients experienced breakthrough infection [52]. Wang et al. also demonstrated that gamma variants had a neutralising effect on multiple monoclonal antibodies and were more resistant to neutralisation by convalescent plasma and vaccinee sera. The gamma variant was estimated to be 3.8–4.8 times more resistant to BNT162b2 or mRNA-1273 vaccine recipients [23, 53].

2.4 Impact of the delta and delta+ (B.1.617) variants on the severity and spread of the disease

The first instance of delta variations was discovered in India, and it was one of the most common SARS-CoV-2 variants that affected the majority of the world. Lineage B.1.617 was assigned to these variations. The L452R, T478K, D614G, and P681R are four of the 17 variations in the Delta variation that are of particular concern, due to their involvement in infectivity and transmission. In comparison to alpha, the infection and transmissibility rates were extremely high. Despite immunisation, this variation resulted in a large number of human deaths. L452R and E484Q is not found in the B.1.617.2 lineage [54, 55]. The B.1.617.2 lineage was first associated with infection in India, and the dominant variant in infection in the UK in 2021. It was highly infectious and spread more rapidly than the original version of the virus. A study conducted by Deng et al. showed that the mutation L425R in the California population resulted in an increase in the binding affinity of the spike protein of SARS-CoV-2 with ACE-2 host receptors, which increased the viral load and 20% transmission rate [56]. Few studies have shown that L452 is not directly linked with the host ACE-2 receptor. This mutation located in the RBD’s hydrophobic plaques generates structural alterations that promote binding of spike protein with the ACE-2 receptor [57, 58]. In addition to this, there was 3–6 folds reduction in neutralisation capacity of vaccine elicited sera in experiments with pseudotyped virus (PV) particles [58]. Few studies demonstrated that the D614G mutation in the spike protein promotes viral multiplication in the upper respiratory tract and enhanced transmission rate [59, 60]. The P681R, which is a substitution at position 681, may increase the variant’s cell-level infectivity [61, 62]. During outbreak of delta variants worldwide, a new variant was emerged in United Kingdom that carries a novel point mutation’ K417N’ in delta variant and designated as a delta plus. Lineage AY.1 or B.1.617.2.1 was assigned to this variant. The three most prominent mutation K417N, V70F, and W258L in spike were exclusively present in the Delta Plus variant [63]. Besides this, few other delta variants emerged, Delta-AY.2 in the USA and Delta-∆144 in Vietnam [64].

2.4.1 Transmission and hospitalisation

During the second wave of the pandemic, COVID-19 patients required more ICU time, oxygen, and non-invasive and invasive ventilatory support. According to estimates, hospital mortality in the second wave was double that of the first [65]. Ong et al. calculated the risk linked with the delta variant by observing the need for oxygen, ICU admission time, and death and found that delta was associated with increased disease severity when compared to non-VOCs [66]. Several studies revealed that a large percentage of vaccine recipients reported breakthrough infection during the delta variant wave [67, 68, 69, 70, 71]. Initial studies demonstrated that the delta variant increased the hospitalisation risk in the population, despite the first dosage of vaccination [24, 72, 73]. Non-vaccinated people and those who contacted viruses within 14 days of vaccination were more prone to hospitalisation [74]. A similar study conducted by Twohig et al. showed delta variant infections linked to an increased hospitalisation rate (hazard ratio 226 [95% CI 132–389]) in comparison to alpha variant infections. All age categories experienced an increase in mortality during the Delta wave, with patients under 45 experiencing the most increase in infection (10.5 percent vs. 7.2 percent, p 0.001), compared to pre-Delta wave [24].

2.4.2 Vaccine response and breakthroughs infection

Davis et al. calculated the neutralisation capacity of BNT162b2 (Pfizer/BioNTech) and ChAdOx1 (Oxford/AstraZeneca) vaccines against the SARS-CoV-2 B.1.617.1 and B.1.617.2 lineages. Both B.1.617.1 and B.1.617.2 reduced antibody neutralisation by 4.31 and 5.11-fold in vaccine recipients, respectively. However, the neutralisation response was significantly higher in two doses of BNT162b2 vaccine recipients than in two doses of ChAdOx1 [55]. During a period of high Delta prevalence, Havers et al. found that hospitalisation rates in unvaccinated individuals were more than 10 times higher than in vaccinated recipients [75]. Twohig et al. found that the risk of hospitalisation or emergency care was higher in delta variant patients who were either unvaccinated or received the first dose (dose taken within 21 days) compared to that of alpha variant patients [24]. When compared to unvaccinated individuals, Veneti et al. showed a reduction in hospitalisation risk of 72 percent (95% CI 59–82%) and 76% (95% CI 61–85%) in partially or fully vaccinated individuals after adjusting for gender, age group, country of birth, variant, and underlying comorbidities [37].

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 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 against other lineages was increased after booster dosages [89]. Overall, the emergence of VOCs over time decreases the neutralisation efficacy of vaccines, despite booster immunisation. The first VOC alpha had little effect on antibody neutralisation activity in post-vaccination sera (Table 2). Neutralisation was reduced even further by new emerging variants and waning with time [90, 91, 92, 93, 94, 95, 96, 97, 98, 99], and the newly evolved omicron BA.5 variant has better survival fitness, transmissibility, and neutralisation even after booster immunisation.

Strains	Notable mutations in spike protein	Transmission/Hospitalisation/ICU admission	Breakthrough Infection	First waves in countries	References
Alpha (B.1.1.7 & Q lineages)	N501Y, D614G, P681H	Studies showed that the alpha was linked with a ~ 2 folds increase in hospitalisation and ICU admission risk compared to non-alpha infection	Not reported, a modest anti-CoV-2 antibody neutralisation effect was observed	United Kingdom	[18, 19]
Beta (B.1.351)	K417N, E484K, N501Y, D614G, A701V	Studies showed that ~2.5 folds increased risk of hospitalisation and risk of ICU admission	Prevalence of breakthrough infections increases	South Africa	[20, 21]
Gamma (P.1.)	K417T, E484K, N501Y, D614G, H655Y	1.4 to 2.2. times more transmission rate and 10–80% more lethal compared to other circulating strains in the prevalent area	Prevalence of breakthrough infections increases	Brazil	[22, 23]
Delta/Delta+ (B.1.617)	L452R, T478K, D614G, P681R	Very high infection rate, hospitalisation and ICU admission	High rate of breakthrough infections, neutralisation effect on vaccine response	India	[24, 25]
Omicron (BA.1 or B.1.1.529)	K417N, E484A, N440K, T478K, N501Y,; Y505H	Infection rate is higher than the delta waves, while the hospitalisation and severity risk were comparatively lower.	Very high rate of re-infection or vaccine breakthrough infections	Affected globally	[26, 27, 28]
Descendent lineages
BA.2	T376A, R408S, D405N
BA.3	Carry both BA.1 & BA.2 mutations
BA.4/5	L452R, F486V, and R493Q

Table 1.

Variant of concerns, notable mutations in SARS-CoV-2 spike and their impact on viral replication fitness and survival advantages over original SARS-CoV-2 virus.

Strains	Studies vaccine	Tested Populations (location)	Neutralisation (live /pseudotyped virus)	Efficacy of vaccine post booster doses (2nd doses, otherwise specified)	References
Alpha (B.1.1.7 & Q lineages)	BNT162b2; ChAdOx1 nCoV-19; NVX-CoV2373; mRNA-1273	UK; UK; UK; Qatar	Live	93.7% (95% CI, 91.6–95.3) for BNT162b2, post ≥14 days; 74.5% for ChAdOx1 post ≥14 days; 86.3% (71.3–93.5) for NVX-CoV2373, post ≥7 days; 100% (95% CI: 91.8–100.0%) for mRNA-1273, post ≥14 days	[40, 41, 42, 90, 91]
Beta (B.1.351)	BNT162b2; ChAdOx1 nCoV-19; mRNA-1273; NVX-CoV2373; BNT162b2; BNT162b2	Canada; Qatar; South Africa; Qatar; France	Live	87% (against BNT162b2, ChAdOx1 nCoV-19 and mRNA-1273 vaccines); 96.4% (95% CI 91.9–98.7) for mRNA-1273 post ≥14 days; 60% (19.9 to 80.1) for NVX-CoV2373 post ≥7 days; 75% (95% CI, 70.5 to 78.9) for BNT162b2, post ≥14 days; 49% (14–69) post ≥14 days	[41, 42, 91, 92, 93, 94]
Gamma (P.1.)	BNT162b2; mRNA-1273	Canada	Live	88% for BNT162b2, and mRNA-1273 vaccines, post ≥7 days	[92, 95]
Delta/Delta+ (B.1.617)	BNT162b2; ChAdOx1; mRNA-1273	UK; UK; USA; Canada	Live	88% (85.3–90.1) for BNT162b2, post ≥14 days; 67% (95% CI, 61.3 to 71.8) for ChAdOx1 post ≥14 days; 85% after 2 doses post ≥14 days, 93% after 3 doses for mRNA-1273; 87–95% for BNT162b2, ChAdOx1 and mRNA vaccine	[40]; [90]; [92]
Omicron (B.1.1.529)	BNT162b2; mRNA-1273	Canada; USA; South Africa; Canada	live	32 (24–38) after 3rd doses of BNT162b2 (evaluated on days ≤84 days); 65% for two doses on ≥14 days and 86% for three doses of BNT162b2 in US; 70% (62–76) for BNT162b2, post ≥14 days; 44 (38–49) after 3rd doses; (evaluated on ≤84 days) for mRNA-1273	[90, 96, 97]

Table 2.

Tested efficacy of vaccines against VOCs.

3. Concluding remark

The emergence of SARS-CoV-2 signals an emergency for the global health care system. Emerging recent COVID-19 waves and causalities worldwide are due to breakthrough infection among vaccinated or unvaccinated individuals, which demonstrated a reduction in vaccine response in neutralising virus infection, but the hospitalisation rate is significantly lower among those who completed vaccination dosages. The high transmission rate and vaccine breakthrough capability of VOCs, particularly the delta and omicron variants, are the reasons for the community’s global spread. During the detla and delta plus waves in India, the situation was critical, and many people were hospitalised and died. Recently emerged Omicron or its sub-lineages have shown multiple re-infections and breakthrough infections due to their high transmissibility and immunological escape from neutralising antibodies produced by prior infections or vaccinations. Vaccines respond differently to each variant of concern. The effectiveness of booster vaccinations is decreasing over time, although it has been enhanced with successive booster doses. The vaccinations are very successful in reducing recipients’ risk of developing severe illness due to COVID-19. Overall, despite vaccination efforts, many countries experienced the consequences of omicron variants, and since SARS-CoV-2 tends to mutate and adapt in our community, the emergence of highly transmissible and deadly strains of COVID-19 variants cannot be ruled out. Understanding the origin, transmission, and breakthrough infections of the SARS-CoV-2 variant may allow us to better prepare for future pandemics.

Acknowledgments

Authors dully acknowledge CSIR, New Delhi and Department of Biotechnology, India for providing financial assistance for COVID-19 testing facility [OLP0043].

Conflict of interest

Authors declare no competing interest.

Ethical approval statement

Not applicable.