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The worldwide battle against the SARS-CoV-2 virus rages on, with millions infected and many innocent lives lost. The causative organism, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a beta coronavirus that belongs to the Coronaviridae family. Many clinically significant variants have emerged, as the virus’s genome is prone to various mutations, leading to antigenic drift and resulting in evasion of host immune recognition. The current variants of concern (VOCs) include B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617/B.1.617.2 (Delta), and P.1 (Gamma). The emerging variants contain various important mutations on the spike protein, leading to deleterious consequences, such as immune invasion and vaccine escape. These adverse effects result in increased transmissibility, morbidity, and mortality and the evasion of detection by existing or currently available diagnostic tests, potentially delaying diagnosis and treatment. This review discusses the key mutations present in the VOC strains and provides insights into how these mutations allow for greater transmissibility and immune evasion than the progenitor strain. Continuous monitoring and surveillance of VOC strains play a vital role in preventing and controlling the virus’s spread.
B.1.1.7 | B.1.351 | B.1.617.2 | P.1 | |
---|---|---|---|---|
WHO Label | Alpha [30] | Beta [13] | Delta [62] | Gamma [65] |
Country First Detected | England [30] | South Africa [13] | India [56] | Brazil [65] |
First Detected | September 2020 | October 2020 | December 2020 | December 2020 |
Spike mutations | 69–70HV and 144Y deletions, N501Y, D614G, A570D, P681H, T716I, S982A, D1118H [33] E484K, S494P, and K1191N (found in some sequences) [35] |
L242–244 deletions, A701V, D215G, D80A, D614G, E484K, K417N, N501Y, R246I, L18F [50] | 156–157 deletions, D614G, D950N, L452R, T19R, T478K, P681R, R158GG142D (Found in some) [62] | K417T, E484K, N501Y, L18F, T20N, P26S, D138Y, R190S, D614G, H655Y, V1176F, T1027I [67] |
Transmissibility | 43–82% more transmissible [30] | 50% more transmissible [53] | 60% more transmissible [61] | Some studies reported 1.7–2.5 times more transmissible [65][74][75] |
Viral Load | High [23][36] No difference [38] |
High [49] | N/A | High in reinfection case [15] |
Duration of Infection | Long [26] | N/A | N/A | N/A |
Hospitalization | High [32][39] | High [32] | High [61] | High [32][74] |
Mortality | Increase [25][40] | Increase [52] | N/A | Increase [65] |
Severity | No change [38][42][43] | N/A | N/A | N/A |
Risk of reinfection | Not higher [42] | High [51][76] | N/A | 6.4% [74] |
Resistant to antibody neutralization | Resistant to most a mAbs directed against b NTD and slightly resistant to some mAbs directed against the c RBD [44] | Resistant to most mAbs directed against NTD and many mAbs directed against the RBD [44] | N/A | Resistant to some mAbs directed against RBD [69] |
Resistance against convalescent plasma and sera | Less resistant [11][44] | More resistant [11][44][77] | N/A | Less resistant than B.1.351 [44][78] |
Vaccine efficacy | Minimal impact [21][22] | Decrease for Pfizer [33], Moderna [79], Novavax, Johnson & Johnson [80][81][82], AstraZeneca [82][83] | 2 doses of Pfizer [84][85][86] or AstraZeneca [84] is still protective | Decrease for CoronaVac [87] |
Key Mutations | Implications | References |
---|---|---|
D614G | Increases human host infectivity and transmission efficiency. | [6][95] |
Strengthens cleavage efficiency by substituting spike conformational diversity. | [101][124][125] | |
Δ69–70 deletion | Modifies loop 2 (69–76aa), pulling it nearer to the a NTD. | [29] |
Increases infectivity by 2-fold over a single round of infection. | [109] | |
ΔY144 deletion | Loss of binding ability with neutralizing antibodies. | [28][44] |
ΔL242–Δ244 | Loss of binding ability with neutralizing antibodies. | [28][44] |
A570D, D614G and S982A | Possibly enhances dynamic viral fusion mechanism via the reduction in intermolecular stability of spike protein subunits. | [34] |
However, contradicts Hoffman et al., who found that B.1.1.7, B.1.351, and P.1 had no significant difference in spike protein stability and entry kinetics compared with the progenitor isolate with D614G exchange. | [116] | |
N501Y | Increases binding affinity to b ACE2 due to solid aromatic interactions of π stacking between Y41 (Tyr41) and Y501 (Tyr501), and forming two hydrogen bonds with K353 (Lys353) and D38 (Asp38). | [54][99][105][106][108] |
Could be the cause for increased transmissibility of B.1.1.7 and B.1.351. | [52][92][109] | |
Contributes to the escape of some class 1 neutralizing antibodies. | [117][142][143][148] | |
Antigenic effects limited to a small number of c mAbs, with no significant impact on the neutralizing activity of convalescent plasma or sera from vaccinated individuals. | [44][46][79][149] | |
Does not drastically affect the overall function of polyclonal T cell responsiveness. | [34] | |
E484K/Q | Mutation E484K and E484Q have neutral to mildly advantageous effects on the affinity of d RBD for ACE2. | [54] |
E484K: Favor RBD-up confirmation due to S1 movements opposite of normal E484, which stabilizes the RBD-down confirmation. | [107][111] | |
In progenitor and B.1.1.7+E484K strains, it disrupts the electrostatic bond, increasing the binding affinity of RBD to ACE2 moderately. | [13][54][112] | |
In P.1, it forms a strong hydrogen bond with residue E75 (Glu75) on human ACE2, near enough to form a salt bridge, strengthening the binding affinity. | [108] | |
Results in partial resistance to neutralization. | [44][46][51][78][150][151] | |
Causes resistance to neutralizing antibodies in class 2 and convalescent sera. | [117][142][143][148] | |
A few studies found no significant effect on the binding affinity between SARS-CoV- 2 RBD and ACE2. | [108][114] | |
E484Q: Associated with lower convalescent serum neutralization, neutralization of antibodies, and the ability to reinfect individuals who had not been infected by these mutated variants. | [142][143] | |
K417N/T | Unfavorable for RBD–ACE2 complex formation. | [108][121] |
Moderate impact on the binding affinity of RBD–ACE2. | [108] | |
Escapes neutralization by mAbs. | [71][143][145] | |
K417N: Destabilizes the RBD-down conformation; increases the tendency for open configuration. | [107] | |
Stops crucial interactions with class 1 neutralizing antibodies and possibly has a role in immune evasion. | [117][142][143][148] | |
P681H/R | Causes structural rearrangement and host cell fusion, allowing cell entry. | [34] |
Contributes to SARS-CoV-2 transmission and infection. | [126][127] | |
Causes slight ↑ in S1/S2 cleavage, but does not significantly affect viral fitness. | [129] | |
L452R | Increases infectivity by stabilizing the e S glycoprotein and ACE2 interaction. | [130][131][132] |
Causes huge increase in free energy at the RBD and ACE2 binding complex, resulting in stronger cell–virus attachment and increased infectivity. | [131][133] | |
Could evade the human leukocyte antigen (HLA)-24 limited cellular immunity, boost viral infectivity, and possibly stimulate viral replication. | [134] | |
Can decrease the sensitivity to a few antibodies and human convalescent sera. | [139][158] | |
N501Y + E484K + K417N | More significant decrease in neutralization compared with any of these mutations alone. | [51][70][71] |