key: cord-0872755-rc8hohw8 authors: Khan, Abbas; Khan, Taimoor; Ali, Shughla; Aftab, Summiya; Wang, Yanjing; Qiankun, Wang; Khan, Mazhar; Suleman, Muhammad; Ali, Shahid; Heng, Wang; Ali, Syed Shujait; Wei, Dong-Qing; Mohammad, Anwar title: SARS-CoV-2 New Variants: Characteristic Features and impact on the Efficacy of Different Vaccines date: 2021-09-11 journal: Biomed Pharmacother DOI: 10.1016/j.biopha.2021.112176 sha: 3a597888cb4507acc1f94d240ba44b832607f3b7 doc_id: 872755 cord_uid: rc8hohw8 The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its new variants reported in different countries have posed a serious threat to human health and social fabrics worldwide. In addition, these new variants hindered the efforts of vaccines and other therapeutic developments. In this review article, we explained the emergence of new variants of SARS-CoV-2, their transmission risk, mortality rate, and, more importantly, the impact of each new variant on the efficacy of the developed vaccines reported in different literature and findings. The literature reported that with the emergence of new variants, the efficacy of different vaccines is declined, hospitalization is increased while the risk of reinfection also increased. The reports concluded that the emergence of a variant that entirely evades the immune response triggered by the vaccine is improbable. The emergence of new variants and reports of re-infections are creating a more distressing situation and therefore demands further investigation to formulate an effective therapeutic strategy. : Graphical representation of SARS-CoV-2 structure. Interspersed genomic regions are also shown in the right panel (created with biorender.com). SARS-CoV-2, like other coronaviruses, also uses the same S protein for attachment to ACE2 and ingress to the host cell (Figure 2) [17]. The NTD domain of the S1 subunit (comprised of the NTD and CTD domains) of the S protein helps the virus to attach, while the S2 subunit mediates the viral membrane integration at the CTD [18] . A basic amino acid-enriched furin cleavage site (S2′) is obtained upon the cleavage of the S1 and S2 subunits. During viral endocytosis, the S2′ site acts as a fusion peptide after the S2 subunit is cleaved. The presence of the S2′ site is a distinguishable feature of SARS-CoV-2, which makes it unique in origin from the others. This S2′ site via various irreversible conformations stimulates the protein for the fusion of the viral and host membranes, rendering the penetration of SARS-CoV-2 into the prone cells [19, 20] . Due to the significant likeness with SARS at the receptorbinding site (RBD), both viruses exhibit a similar binding mechanism to the ACE2 [21] [22] [23] . However, the distinguished feature, the S2′ site, makes SARS-CoV-2 have enhanced pathogenicity and transmissibility [24, 25] . Structural data have indicated that the availability of key hotspots (i.e., Glu31 and Lys353) facilitates binding in a claw-like structure of ACE2 [26] . Residues such as Glu31 and Lys353 possess greater compatibility for Leu455, Phe486, Glu493, Ser494, and Asp501, ultimately enhancing the binding with the host receptor [27] . The super affinity and super efficiency of the entry are associated with tissue tropism and the host range [26, 28] . Upon the binding of the S1 subunit, the fusion is further assisted by the S2 subunit by decreasing the distance between the host cell and viral spike protein [29] . Next, the fusion peptide starts acting and completes the other necessary steps, such as deformation and membrane attachment [30] . Either the endosomal or non-endosomal pathway, or both, could be selected for entry into the host cell [31] . Alternative approaches may be used based on the pH of the cell. In the case of low pH inside the cell, the endosomal pathway is utilized, assisted by cysteine protease cathepsin [32] . At the same time, for the non-endosomal pathway, TMPRSS2 and TMPTESS11D facilitate the S1/S2 cleavage to stimulate the S protein for induction. In this regard, the host membrane fluidity is stimulated by the IFITM3 to halt the SARS-CoV-2 invasion into the cell [33, 34] . The life cycle of SARS-CoV-2 inside the human cell mainly relies on the nonstructural proteins (NSPs), which are necessary for entry to the cell glycoprotein (spike glycoprotein) [35] . SARS-CoV-2 shares a similar genomic arrangement with related betacoronaviruses. The positive-sense, single-stranded, ~30 kb RNA genome codes six J o u r n a l P r e -p r o o f functionally unique open reading frames (ORFs) in 5′ to 3′ sequence: ORF1a/ORF1b (replicase), envelope (E) protein, spike protein, nucleocapsid (N), and membrane (M). Additionally, the accessory proteins are encoded by seven ORFs, which are sprinkled among the structural genes ( Figure 3 ) [36] . The attachment of spike protein to the ACE2 of human cells for infection. The S1, S2 and cleavage site of S protein is depicted to clearly show the early stage of infection (created with biorender.com). The preliminary route for SARS-CoV-2 transmission is close contact with an infected person [37, 38] . Secondary events such as small tiny droplets or aerosols cleared by an infected person either by sneezing, speaking, or coughing helps the virus to spread to another person [39] [40] [41] . The eyes and nose are alternate routes of transmission for the virus [42] . In addition, contaminated surfaces may also enable the spread of the virus. However, further investigations are required to confirm the fast transmission routes of SARS-CoV-2 [43] . Variable symptoms such as loss of smell, fatigue, fever, breathing hitches, cough, and loss of taste and asymptomatic cases have been reported [44, 45] . These symptoms take approximately 1-14 days after exposure to develop [46] . Among patients with noticeable symptoms, approximately 81% of them developed mild pneumonia[47]; 14% developed severe symptoms such as severe hypoxia and dyspnea [48] ; and 5% developed fatal symptoms such as respiratory disruption, shock, and multi-organ defects. One-third of the infected people showed no noticeable symptoms [49] . On the contrary, some patients reportedly experienced symptoms for weeks or months after their initial recovery from COVID-19 infection, referred to as -Long COVID.‖ These patients are more sensitive to organ impairment [50] . Nonetheless, the long-term impact of COVID-19 infection needs further investigation [51] . COVID-19 primarily and rapidly affects the upper respiratory (nose, sinuses, and throat) and lower respiratory (lungs and windpipe) tracts [52, 53] . The abundant expression of angiotensin-converting enzyme 2 (ACE2) on the surface of type II alveolar cells enables the virus to damage the lungs significantly [54] . Moreover, the severity of organ damage is directly correlated with ACE2 density [55, 56] . Therefore, most deaths in SARS-CoV-2 infection could be attributed to densely infected lungs [57] . Furthermore, although no association between the central nervous system (CNS) involvement and COVID-19 has been reported, low levels of SARS-CoV-2 have been detected in the brains of patients who died due to COVID-19 [58] . It has been speculated that the virus may have entered the bloodstream, evading the blood-brain barrier to pass into the CNS, although the exact mechanism needs further research [59, 60] . In addition, ACE2 expression in the gastrointestinal organs may affect different tissues [61] . Acute myocardial injury, cardiovascular complications, thrombosis, venous thromboembolism, pulmonary embolism, ischemic events, vasoconstrictive responses, and injury to the olfactory bulbs have been reported in patients who died from COVID-19 [62] [63] [64] [65] . Lymphocyte-containing inflammatory infiltrates and diffused alveolar damage also contribute to death risk in COVID-19 [66, 67] . Conclusively, the pathophysiology of COVID-19 is haphazard and may need further research to reveal the diversity in affected organs [68] . The whole pathogenesis cascade of SARS-CoV-2 is illustrated in [70] . This vaccine, however, is still under the Phase-II clinical stage and reported that it works in a dose-dependent manner. A lipid nanoparticle-encoated mRNA-based vaccine known as mRNA-1273, comanufactured by Moderna and NIAID, also triggered a robust immune response against the SARS-CoV-2 [71] . Increased antibodies production was observed after the injection of the second dose. Furthermore, inactivated and whole vaccines are under investigation and 320 participants developed effective neutralizing antibodies [72] . Approximately 4.74 billion doses as of August 17, 2021, have been administered worldwide [73] . A list of approved vaccine are given in Table 1 . The natural selection process is liable for the selection of mutations and the fate of emerging variants. Mutations that facilitated the survival, replication, and fitness of an organism were maintained in the population and the deleterious ones were purged. A strong correlation between the selection process and chance events played a significant role in the evolution of the new variants. Variations in the genomics sequences were referred to as new variants, while those that induced changes in the characteristic properties, i.e., virulence or transmissibility, were tagged as new strains. Understanding the viral nomenclature helps in controlling the infection and better surveillance. Classification of viruses into large groups known as clades and the species of SARS-CoV-2 were further classified into many groups based on the genetic variability when compared to the reference sequence. Many variants after the reference strain were reported and their potential features were explored to understand their role in the transmissibility and vaccine effectiveness. The following sections will discuss the notable variants reported during this pandemic. The replacement of a polar charged amino acid-aspartic acid by a nonpolar aliphatic amino acid glycine at position 614 reported in early 2020 played an essential role in the J o u r n a l P r e -p r o o f conformational changes in the S1 and S2 domains of the spike protein. This mutation made it easier for the viral spike protein to connect to the ACE2 receptor, consequently enhancing the risk of infection [74] . Spike D614G variation became universally prevalent a few months after perception of the parental strain, probably due to better ability to interact with human ACE2 receptor [75] . In both human and animal models, the D614G mutation resulted in increased replication capacity and susceptibility. The disease severity of the patients infected with the D614G variant was comparable with the wild type; however, viral load in the nasopharyngeal was reported to be comparatively high. In addition, loss of smell was more dominant in infections with this strain due to its robust interaction with host ACE2 in the olfactory epithelium [76] . Furthermore, an investigation of animal models infected with this strain reported a higher level of neutralizing antibodies than the zero strain. Structural modeling study of furin binding to the wild type and D614G revealed that the binding of furin was enhanced by the mutation and thus potentially increases the infectivity [77] . Consequently, this showed that strain had no significant impact on the vaccine efficacy or any other therapeutics agents [78] . The D614G in the furin binding was a notable frequent mutation reported in almost all the new variants [79] . The evolution of the SARS-CoV-2 new variant, B. [84] . The N501Y mutation, which is a replacement of asparagine by tyrosine in the receptor-binding motif is of major concern [85] . Structural modeling analysis revealed that the orientation of aromatic ring and establishment of additional hydrogen bonds with the ACE2 receptor increases the binding affinity and consequently the infection. Moreover, increasing specificity towards the ACE2 receptor by this mutation was also observed. The hospitalization and mortality rates were reported to increase by 52% and 59%, respectively [86] . Minimal reduction in the efficacy of natural and vaccination-triggered antibodies was observed [80] . Computational analysis of the binding of the N501Y variant of RBD to the host receptor ACE2 revealed enhanced binding and variations in the inter-hydrogen bonding network [87] . They also revealed the structural basis for B. The beta variant from South Africa, which was reported in December 2020, carries E484K mutations amongst others. A total of 12 variations and one deletion were reported in this lineage [95] . Young individuals with comorbidities are more likely to be infected by this variant, and it causes serious disease more frequently than other variants in similar situations. The new variants from both UK and South Africa appear to be more contagious; however, mutations in the UK variants are unlikely to impede the effectiveness of the developed vaccines, though the South African variants (501.V2) may interfere with it to some extent, J o u r n a l P r e -p r o o f particularly because of K417N and E484K mutations [96] . In this regard, the lack of empirical data is the major challenge to predict which one of the recently emerged strains of SARS-CoV-2 is more lethal [97] . The transmissibility of this variant has been reported to increase up to 52%, while the hospitalization of patients remains under investigation. Moreover, the mortality rate due to the infection of this variant is increased. The risk of reinfection with this variation has reportedly reduced because the T cell response provoked by the D614G variant remains effective against it. More importantly, the efficacy of the developed vaccine is reduced for many. Furthermore, conformational changes in the flexible loop site of S RBD induced by the E484K mutation confers a critical role in immune evasion, viral receptor binding affinity, and infectivity. In Denmark, ΔFVI-spike, characterized as cluster 5 strain and identified in minks, This variant is placed within the clade B. increases the transmissibility and hospitalization by +64% and +85%, respectively [110] . Moreover, the reinfection probability is decreased, while the vaccine efficacy is also compromised [111] . With mutations E484K and D618G and two amino acid deletions, Tyr145 and His146, in the spike protein, this variant was reported in West Bengal, India. It was reported as the key immune evading variant due to its ability to escape from multiple monoclonal antibodies and convalescent plasma [109] . Besides the aforementioned variants, other variants have been reported in different countries. are two more noteworthy variants [121] [122] [123] . In October 2020, lineage B. [126] . Although lineage B.1.1.317 is not a variant of concern, it is notable; the Queensland Health ordered two individuals undergoing hotel quarantine in Brisbane, Australia, to spend an additional 5 days in quarantine on top of the statutory 14 days when it was proven they were infected with the variant. The rapid availability of vaccinations has altered the natural interaction between SARS-CoV-2 and its human hosts [127] . The emergence of SARS-CoV-2 variants that are partly or completely resistant to the antibody response induced by COVID-19 vaccinations needs further evaluation [128] . According to a study, several vaccines produced for the initial strain had lesser efficacy against the newly emerged variants [129] . However, the US Food and [144, 145] . Scientists also believed that new variants completely evading the immune responses triggered by vaccines are very unlikely. Furthermore, it is believed that the E484K variant may compromise the effectiveness of the current vaccine. The emergence of new variants and reports of reinfection are creating a more distressing situation and therefore demands further investigation to formulate an effective therapeutic strategy. Researchers, private firms, educational institutes, ministries, and people from all walks of life are focusing on eliminating COVID-19, which has posed a serious health risk to human life. 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