key: cord-0936476-ith5vl79 authors: Tian, Dandan; Sun, YanHong; Zhou, JianMing; Ye, Qing title: The global epidemic of SARS‐CoV‐2 variants and their mutational immune escape date: 2021-10-13 journal: J Med Virol DOI: 10.1002/jmv.27376 sha: 2c019084ca5c8cc6d3740773117f95f28d235bd8 doc_id: 936476 cord_uid: ith5vl79 During the COVID‐19 pandemic, genetic variants of SARS‐CoV‐2 have been emerging and spreading around the world. Several SARS‐CoV‐2 endemic variants were found in United Kingdom, South Africa, Japan, and India between 2020 and April 2021. Studies have shown that many SARS‐CoV‐2 variants are more infectious than early wild strain and produce immune escape. These SARS‐CoV‐2 variants have brought new challenges to the prevention and control of COVID‐19. This review summarizes and analyzes the biological characteristics of different amino acid mutations and the epidemic characteristics and immune escape of different SARS‐CoV‐2 variants. We hope to provide scientific reference for the monitoring, prevention, and control measures of new SARS‐CoV‐2 variants and the development strategy of the second‐generation vaccine. D614G mutation is present in all VOC. In vivo and ex vivo studies found that in the early stages of virus infection, the D614G viruses exhibited significantly faster droplet transmission between hamsters, and the virus with D614G mutation resulted in a 0.5 to twofold higher gene expression than wild strain. 26 The infection efficiency of D614G pseudovirus was reported to be 8-10 fold higher than wild strain. D614G is hypothesized to "shift the RBD to an 'up' conformation, promoting binding with the ACE2 receptor, leading to enhanced virion infectivity." 27 Moreover, clinical samples infected with D614G mutant had a high titer of SARS-CoV-2 RNA. 28 N501Y mutation located in the RBD region and appeared in B.1.17, B.1.351, P1. Structural modeling data showed that RBD with N501Y mutation could form a potential aromatic ring-ring interaction and an additional hydrogen bond with ACE2, and these interactions made the binding tightness of N501Y-RBD to ACE2 was 10-fold than wild strain. 29 In addition, N501Y mutation can decrease the polarity of critical residues in RBD, increasing the affinity between RBD and cellular surface ACE2. 30, 31 Interestingly, the binding affinity of N501Y-RBD to ACE2 was much higher than K417N/T-E484K-N501Y-RBD. 32 Therefore, N501Y mutation can enhance the binding affinity and tightness of RBD to ACE2, increasing the chance of the virus infecting host cells. Using combined structural modeling and biophysical approach, researchers revealed that B.1.167 variants with L452R-E484Q double mutations possess a stronger binding affinity to the host-cell receptor ACE2, and has a ability to evade humoral immunity. 33 There were multiple amino acid mutations in the NTD of VOC. By analyzing the S gene sequence from December 1, 2019, to October 24, 2020 in the GISAID database, 90% deletions were found in the NTD region in 1108 sequences of the S gene with deletion mutation. 34 with HV69-70del induces more rapid cell-cell fusion and the formation of multi-nucleated cells. Whereas, repairing these two amino acids can lead to reduced the infectivity of B.1.1.7 and reduced cellcell fusion kinetics back to wild strain level. 36 Furthermore, an experiment in vitro indicated that D796H mutation produces immune escape but reduces infectivity. When D796H and HV69-70del appeared in SARS-CoV-2 variants simultaneously, HV69-70del can compensate for the reduction of infectivity caused by D796H mutation. 37 The above study demonstrated that HV69•70del is responsible for increasing the infectivity of B. The furin protease cleavage sites located between S1 and S2 subunits of S protein of SARS-CoV-2, which contain amino acid site: 681-685. The cleavage of this region is key to the entry of the virus into human host cells. P681H is present in the Alpha VOC and the Theta VOI, and P681R is found in the Delta VOC and the Kappa VOI, respectively. Previous studies have noted that P681H and P681R may increase S1/S2 cleavage by furin-like proteases and enhance virus-host cell membrane fusion. 39 Altogether, these results indicated that multiple amino acid mutations (D614G, N501Y, L452R, P681H/R, T478K, HV69-70del) which can enhance the infectivity of the virus appeared in the RBD and NTD of S protein of VOC. By increasing the expression of Spike and the interaction forces (aromatic ring-ring interaction, hydrogen bond) bond between spike and host cell ACE2 or increasing the rate of S1/S2 cleavage, these mutations can increase the binding affinity and binding tightness of SARS-CoV-2 spike to hACE2 receptor, and leading to enhance the infectivity of VOC variants, as shown in Figures 1 and 2 Resistance to partial monoclonal antibodies (mAbs) ++: Resistance to partial mAbs, convalescent plasma and partial vaccine. Resistance even immune escape to many mAbs, convalescent plasma and many vaccine. Among the accessory proteins, ORF3a is the largest one containing 274 amino acids in SARS-CoV. 51 Cell surface localization of ORF3a in SARS-CoV potentiates viral entry within the host, and ORF3a is also implicated in ion channel formation and modulates the release of virus from the host cell. 51, 52 ORF1ab and ORF3a mutations The deletion in the NTD Despite the RBD is the dominant neutralization targeted by mAbs. Evidence indicated that the NTD of the SARS-CoV-2 Spike has a substantial role in antigenicity. 71 These mutations occur in VOC variants and generate resistance to mAbs, convalescent plasma, and vaccine, as shown in Figures 1 and 2, and All authors declare that there are no conflict of interests. 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