key: cord-0741980-o2gk8m0v authors: Mishra, Anurag R.; Nayak, Debasis; Byrareddy, Siddappa N. title: Are we moving toward ending SARS‐CoV‐2? date: 2022-03-23 journal: J Med Virol DOI: 10.1002/jmv.27722 sha: 78c42a801b526563d02e0a6f3fa7abf981d4316d doc_id: 741980 cord_uid: o2gk8m0v The SARS-CoV-2 is a highly transmissible pathogen that has caused a global health crisis and a socioeconomic emergency. The emergence of the Omicron variant, with the highest number of mutations in its genome, has raised considerable concern. Currently, there is a crucial gap in our knowledge in understanding how these changes affect the biology of the viruses associated with these mutations so that we can reasonably recognize in which direction the pandemic is headed. This article is protected by copyright. All rights reserved. variants, it has evolved into a dominant variant globally over the past year (2021), potentially increasing the number of infections and deaths globally. 11 Recently the emergence of the novel variant C. 1.2 and Omicron in South Africa have raised concerns as they are shown to potentially escape antibody responses induced by the available vaccines and/or virus-induced immune responses following natural infection. Additionally, this variant is more transmissible than the Alpha and Delta variants. 12 These variants contain multiple mutations in the spike protein, raising concern about the degree of protection by the currently available vaccines and monoclonal antibody therapeutics, designed against the spike protein of the SARS-CoV-2 Wuhan strain or D614G strain circulating during the early phases of a pandemic. Coronaviruses are known to induce innate and virusspecific adaptive immune responses to the infection. 13, 14 These responses are reasoned to provide at least some degree of protection against reinfection. However, protection against the seasonal coronaviruses is limited and diminished with time, concurrent with declining neutralizing antibody titers. 15 A similar trend is also observed in specimens from SARS-CoV-2 infected individuals. They show 50% and 100% seroconversion rates on days 7 and 14 postsymptom onset, with~90% seroconversion by day 10 postsymptom onset that gradually decreases over time. A significant percentage of individuals demonstrate a low or reduced level of neutralizing antibodies after 6 months of infection or vaccination. 16, 17 The only effective protection currently available is the US Food and Drug Administration (FDA)-approved direct-acting smallmolecules antiviral against the SARS-CoV-2, which have been approved or in the advance clinical stage. These drugs do not target the highly mutated spike but rather conserved domain of main viral protease (M pro or 3CL protease) or RNA-dependent RNA polymerase (RdRp). However, recently FDA-approved drugs like remdesivir, molnupiravir, and PAXLOVID remain sensitive toward the Omicron and other VOCs. 18 The mutation in the spike protein and other proteins of the SARS-CoV-2 that occurs as part of this adaptation process is reasoned to increase the fitness of the virus. Although the variants have been shown to have reduced capacity for antibodymediated neutralization, 19 the adjacent arm of the adaptive immunity, T-cell response, is minimally affected and protecting against these variants. Similarly, a mutation in the regulatory region of N such as the Orf9b and Orf6 genes of the SARS-CoV-2 Alpha variant led to the higher expression at both subgenomic RNA and protein levels. Since these proteins are innate immune response antagonists, they delay the host's initial innate immune response and increase viral fitness. 20 in human nasal airway epithelial cells. 21 Omicron vairant has a unprecedented higher mutation rate, specifically with more than 55 mutations compared to the Wuhan strain. It has more than 30 mutations in the spike protein, but it still binds to the ACE2 receptor at a rate that is 44% higher in affinity than the wild-type virus. 22 One of the most striking effects observed in the Omicron is the reduced processing of the S glycoprotein into S1/S2, which has significantly reduced syncytia formation during the cytopathic effect of infection. This property appears to lead to a drastic reduction in cell-to-cell transmission of this variant. 23 Similarly, Omicron variant prefers to use cathepsin-dependent endosomal fusion strategy for cell-surface fusion for viral entry. 21 Similarly, the poor processing of S also results in the reduced incorporation of the spike protein during the derivation of pseudovirus particles. 24 This Omicron pseudovirus F I G U R E 1 Timeline for the emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its evolution and possible end outcome. The SARS-CoV-2 genome is closely related to the bat coronavirus. It crossed the interspecies barrier and was likely transmitted to animals in the live animal market in Wuhan, China. The live-animal market subsequently transmitted the pathogen to humans through direct contact with the virus. Later, the virus acquired the ability of human-to-human transmission through droplets, and local and long-distance travel by infected individuals led to a pandemic shortly thereafter. Chronic infection, colossal transmission, and vaccination, mounted a selection pressure on SARS-CoV2 resulting in continuous viral evolution. This evolution continued until the virus reached maximum transmissibility, immune evasion, and low pathogenicity. Later in the evolution, the virus may act as an attenuated natural vaccine and protect most of the infected individuals, which may potentially lead to an end of the pandemic. The solid black arrow represents the confirmed transfer, whereas the dotted black arrow shows the possibility of viral transfer exhibits a temperature-sensitive decay at a rate similar to those noted for the D614G and Delta pseudoviruses at room temperature and 37°C. Still, it displays a comparatively faster decay rate at 0°C. As the SARS-COV-2 infects the cell types present in the nasal passage and the lower respiratory tract at a cooler temperature and <37°C, respectively, this temperature-dependent S regulation may have implications for pathogenesis. 24 Although the Omicron variant is less virulent with a high transmission rate, it still presents a considerable risk to people with comorbidities, compromised immune response, and older people. The emergence of the Omicron variant with a significantly higher number of mutations than the other SARS-CoV-2 variants during what appears as a single burst has been the subject of considerable concern to scientists. Along these lines, it is essential to note that virus origin is still debated; we do not understand fully how this variant will behave in the long run. Based on phylogenetic analyses, it was found that it diverged from the B. The authors declare no conflict of interest. Data sharing is not applicable to this article as no new data were created or analyzed in this study. Anurag R. Mishra 1 Debasis Nayak 2 Siddappa N. Byrareddy 3,4,5,6 1 The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak A new coronavirus associated with human respiratory disease in China Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan Evolution patterns of SARS-CoV-2: snapshot on its genome variants The 2019-new coronavirus epidemic: evidence for virus evolution Identification of a novel coronavirus causing severe pneumonia in human: a descriptive study A pneumonia outbreak associated with a new coronavirus of probable bat origin The coronavirus is mutating-does it matter? The coronavirus proofreading exoribonuclease mediates extensive viral recombination Tracking changes in SARS-CoV-2 spike: evidence that D614G increases infectivity of the COVID-19 virus Evolutionary analysis of the Delta and Delta Plus variants of the SARS-CoV-2 viruses Omicron SARS-CoV-2 variant: unique features and their impact on pre-existing antibodies The dynamics of humoral immune responses following SARS-CoV-2 infection and the potential for reinfection The time course of the immune response to experimental coronavirus infection of man Dynamics of SARS-CoV-2 neutralising antibody responses and duration of immunity: a longitudinal study Spike-antibody waning after second dose of BNT162b2 or ChAdOx1 Remdesivir, molnupiravir and nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant. bioRxiv Omicron entry route The Omicron variant increases the interactions of SARS-CoV-2 spike glycoprotein with ACE2 The hyper-transmissible SARS-CoV-2 Omicron variant exhibits significant antigenic change, vaccine escape and a switch in cell entry mechanism Functional properties of the spike glycoprotein of the emerging SARS-CoV-2 variant B.1.1.529. bioRxiv Evidence for a mouse origin of the SARS-CoV-2 Omicron variant mRNA-1273 protects against SARS-CoV-2 beta infection in nonhuman primates Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology