key: cord-0686216-1gv2z401 authors: Rajpal, Vijay Rani; Sharma, Shashi; Kumar, Avinash; Chand, Shweta; Joshi, Lata; Chandra, Atika; Babbar, Sadhna; Goel, Shailendra; Raina, Soom Nath; Shiran, Behrouz title: “Is Omicron mild”? Testing this narrative with the mutational landscape of its three lineages and response to existing vaccines and therapeutic antibodies date: 2022-04-27 journal: J Med Virol DOI: 10.1002/jmv.27749 sha: bf889336c409193007dbc891b926d7bc2b8d1241 doc_id: 686216 cord_uid: 1gv2z401 SARS‐CoV‐2 Omicron with its lineages BA.1, BA.2, and BA.3 has triggered a fresh wave of Covid‐19 infections. Though, Omicron has, so far, produced mild symptoms, its genome contains 60 mutations including 37 in the spike protein and 15 in the receptor‐binding domain. Thirteen sites conserved in previous SARS‐CoV‐2 variants carry mutations in Omicron. Many mutations have shown evolution under positive selection. Omicron's giant mutational leap has raised concerns as there are signs of higher virus infectivity rate, pathogenesis, reinfection, and immune evasion. Preliminary studies have reported waning of immunity after two‐dose primary vaccine regime, need for the boosters, folds reduction in vaccine effectiveness and neutralizing antibodies even after boosting and significant neutralization resistance with the therapeutic monoclonal, polyclonal, and convalescent antibodies against Omicron. The narrative that “Omicron is mild,” therefore, needs time to be tested with a deeper, scientific dwelling into the facts. BA1.1 has been identified as a sub-lineage under BA.1. Next strain nomenclature has assigned "clade 21M" to Omicron; "21K to BA.1; "21L" to BA.2, while clade "GRA" has been assigned to Omicron by GISAID. 1 Although, Omicron has emerged at a time when vaccine immunity is increasing in the world, still, it has raised concerns by triggering a fresh wave of Covid-19 infections even among people who had previously received two doses and even boosters of Covid-19 vaccines. Preliminary evidences suggest an increased risk of reinfection associated with this variant. 1 It is even gripping regions where the Delta variant is still prevalent. Due to a short doubling time of 2-3 days, and many unique mutations that may confer it higher transmissibility and immune escape potential than its predecessors, 5 the likelihood of global spread of Omicron is high. At present, Omicron has been detected in 149 countries with an exponential increase in the cases. 1 Although, symptoms produced by Omicron are apparently milder than Delta variant, 6 the ongoing research on the durability of immunogenicity acquired by vaccinations or previous infections and the efficacy of therapeutic antibodies approved for clinical use against SARS-CoV-2 virus will shed light to better understand the long-term effects of this novel variant. It is common for viruses to mutate during their replication. Overall, coronaviruses' replication is highly fidel and shows a low mutational frequency due to 3′-5′ exonuclease activity of their NSP 14 protein. 7 SARS-CoV-2 diversity and mutation rate is half of the influenza virus, 8 but several genes including ORF1a, ORF1b, ORF3a, ORF8, N and S with a high mutational rate [2] [3] [4] 9 have resulted in new mutations that offer survival or selective advantage by improving the "viral fitness." This has led to the emergence of new SARS-CoV-2 variants by modulation of receptor binding efficiency, transmission, severity of disease, reinfection, immune evasion, and resistance to neutralizing and therapeutic antibodies among others. 10 The reported modes of evolution of SARS-CoV-2 variants explained in detail in Section 3 include recombination, epistasis, pervasive, episodic, and directional selection. 4, [11] [12] [13] [14] [15] The latest SARS-CoV-2 variant "Omicron" is heavily mutated 13, 16 and has accumulated an unprecedented high number of mutations. Omicron shares some of its mutations with other SARS-CoV-2 variants but carries a large number of unique mutations (detailed in Section 2.2), some of which have been shown to be linked to higher transmissibility and immune escape, suggesting a significant shift in the evolutionary trajectory of the SARS-CoV-2 virus. In addition, 13 sites previously observed to be conserved in SARS-CoV-2 variants have been found to harbor mutations in Omicron. These sites have been divided into 3 clusters. 4 Cluster 1 (sites 339, 371, 373, 375), cluster 2 (sites 493, 496, 498, 505) and cluster 3 (764, 856, 954, 969, and 981) mutations have shown a decrease in the neutralization of target classes 4, 1, and 2 antibodies and increased interactions between S1 and S2 subunits and reduced S1 shedding, respectively. 4 It is interesting to note that the emergence of various VOIs and VOCs of SARS-CoV-2 including the current Omicron variant has largely been supported by induction of substitution, deletion, and sparingly insertion mutations and ins214EPE mutation has been seen for the first time in Omicron. (Figures 1 and 2) . Sub-lineage BA1.1 with a total of 61 mutations differs from BA.1 in possessing an additional "R346K" lineage, two unique mutations listed were ORF1a-S153R and A3657V mutations (Figure 3 ). Omicron lineage BA.1 has been found to be more pathogenic than ancestral Wuhan virus and Delta VOC. 18 On the other hand, BA.2 shows a 1.4 times higher effective reproduction number than BA.1 and its furogenicity and pathogenicity have also been reported to be higher than BA.1. 19 F I G U R E 1 Schematic representation of distribution and sharing of mutations across genomes of Omicron lineages BA.1 with sub-lineage BA1.1, BA. strain, 20 indicating that the evolution of spike in the novel variants is accompanied with loss of sequences. The Omicron variant shares many spike mutations with other VOCs, VOIs, and VUMs of SARS-CoV-2 ( Figure 2 and The characteristics properties of each of the SARS-CoV-2 variants are due to the specific set of mutations contained in their genome. For instance, due to their characteristic mutations, VOCs Alpha and Delta showed higher transmission rates and spread globally and VOCs Alpha and Beta were discovered to be resistant to neutralizing antibodies, thereby, affecting the effectiveness of vaccines. 21, 22 Many of Omicron spike mutations that overlap with other VOCs have been previously characterized to confer increased transmissibility and higher antibody escape. 23 Mutations K417N, T478K, N501Y, D614G, and others have been found to be associated with reinfection, partial resistance to vaccines and increased transmissibility. 5 35 The origin of the Omicron has been highly contested in the scientific community. 6, 11, 12, 37, 38 The likely modes of origin that have been This mechanism though seems unlikely as the virus prefers to switch hosts rather than continue adapting to extensive changes in one host. diagnosis. 46 The above diagnostic methods can be used to detect all the circulating VOCs of SARS-CoV-2. Like the other SARS-CoV-2 variants, Omicron also uses the same ACE2 receptor in alliance with the host's transmembrane serine protease 2 surface protein used as a primer for entry into the human host. 47 Africa. 78 Waning of immunity against Omicron within a few weeks of two-dose mRNA vaccination was observed in all age groups in Israel, 79 and with either of CoronaVac/mRNA vaccines in Hongkong. 20 21, 58, [60] [61] [62] 64, 66, [80] [81] [82] [83] [84] [85] Therefore, a pressing need was felt for a third booster. 86 or the all the other tested Mabs (casirivimab, imdevimab, bamlanivimab, cilgavimab, and tixagevimab), 26 and only sotrovimab was observed to neutralize the virus. 26, 64 In a study by Imbrechts et al., 97 after testing various mAbs against all the five VOCs of SARS-Cov-2, however, it was concluded that three mAbs including mAb 3B8 at very low doses resulted in complete neutralization of Omicron variant. Identification of more such mAbs can give confidence to handle the continuously evolving novel variants in SARS-CoV-2. In totality, the above initial reports of massive failure of the existing repertoire of therapeutic antibody molecules raise high concern present a vexing situation to perplex the policy makers and scientific community who must now develop alternate strategies to counter this virus. Omicron with an expanded mutational landscape has emerged as a highly transmissible SARS-CoV-2 variant that harbors many muta- The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon request. 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