Reprogramming viral immune evasion for a rational design of next-generation vaccines for RNA viruses.

Type I interferons (IFNs-α/ß) are antiviral cytokines that constitute the innate immunity of hosts to fight against viral infections. Recent studies, however, have revealed the pleiotropic functions of IFNs, in addition to their antiviral activities, for the priming of activation and maturation of adaptive immunity. In turn, many viruses have developed various strategies to counteract the IFN response and to evade the host immune system for their benefits. The inefficient innate immunity and delayed adaptive response fail to clear of invading viruses and negatively affect the efficacy of vaccines. A better understanding of evasion strategies will provide opportunities to revert the viral IFN antagonism. Furthermore, IFN antagonism-deficient viruses can be generated by reverse genetics technology. Such viruses can potentially serve as next-generation vaccines that can induce effective and broad-spectrum responses for both innate and adaptive immunities for various pathogens. This review describes the recent advances in developing IFN antagonism-deficient viruses, their immune evasion and attenuated phenotypes in natural host animal species, and future potential as veterinary vaccines.

SARS-CoV-2 NSP13 interacts with host IRF3, blocking antiviral immune responses.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses an unprecedented threat to human health since late 2019. Notably, the progression of the disease is associated with impaired antiviral interferon (IFN) responses. Although multiple viral proteins were identified as potential IFN antagonists, the underlying molecular mechanisms remain to be fully elucidated. In this study, we firstly demonstrate that SARS-CoV-2 NSP13 protein robustly antagonizes IFN response induced by the constitutively active form of transcription factor IRF3 (IRF3/5D). This induction of IFN response by IRF3/5D is independent of the upstream kinase, TBK1, a previously reported NSP13 target, thus indicating that NSP13 can act at the level of IRF3 to antagonize IFN production. Consistently, NSP13 exhibits a specific, TBK1-independent interaction with IRF3, which, moreover, is much stronger than that of NSP13 with TBK1. Furthermore, the NSP13-IRF3 interaction was shown to occur between the NSP13 1B domain and IRF3 IRF association domain (IAD). In agreement with the strong targeting of IRF3 by NSP13, we then found that NSP13 blocks IRF3-directed signal transduction and antiviral gene expression, counteracting IRF3-driven anti-SARS-CoV-2 activity. These data suggest that IRF3 is likely to be a major target of NSP13 in antagonizing antiviral IFN responses and provide new insights into the SARS-CoV-2-host interactions that lead to viral immune evasion.

SARS-CoV-2 Evasion of the Interferon System: Can We Restore Its Effectiveness?

Type I and III Interferons (IFNs) are the first lines of defense in microbial infections. They critically block early animal virus infection, replication, spread, and tropism to promote the adaptive immune response. Type I IFNs induce a systemic response that impacts nearly every cell in the host, while type III IFNs' susceptibility is restricted to anatomic barriers and selected immune cells. Both IFN types are critical cytokines for the antiviral response against epithelium-tropic viruses being effectors of innate immunity and regulators of the development of the adaptive immune response. Indeed, the innate antiviral immune response is essential to limit virus replication at the early stages of infection, thus reducing viral spread and pathogenesis. However, many animal viruses have evolved strategies to evade the antiviral immune response. The Coronaviridae are viruses with the largest genome among the RNA viruses. Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) caused the coronavirus disease 2019 (COVID-19) pandemic. The virus has evolved numerous strategies to contrast the IFN system immunity. We intend to describe the virus-mediated evasion of the IFN responses by going through the main phases: First, the molecular mechanisms involved; second, the role of the genetic background of IFN production during SARS-CoV-2 infection; and third, the potential novel approaches to contrast viral pathogenesis by restoring endogenous type I and III IFNs production and sensitivity at the sites of infection.

Long term anti-SARS-CoV-2 antibody kinetics and correlate of protection against Omicron BA.1/BA.2 infection.

Binding antibody levels against SARS-CoV-2 have shown to be correlates of protection against infection with pre-Omicron lineages. This has been challenged by the emergence of immune-evasive variants, notably the Omicron sublineages, in an evolving immune landscape with high levels of cumulative incidence and vaccination coverage. This in turn limits the use of widely available commercial high-throughput methods to quantify binding antibodies as a tool to monitor protection at the population-level. Here we show that anti-Spike RBD antibody levels, as quantified by the immunoassay used in this study, are an indirect correlate of protection against Omicron BA.1/BA.2 for individuals previously infected by SARS-CoV-2. Leveraging repeated serological measurements between April 2020 and December 2021 on 1083 participants of a population-based cohort in Geneva, Switzerland, and using antibody kinetic modeling, we found up to a three-fold reduction in the hazard of having a documented positive SARS-CoV-2 infection during the Omicron BA.1/BA.2 wave for anti-S antibody levels above 800 IU/mL (HR 0.30, 95% CI 0.22-0.41). However, we did not detect a reduction in hazard among uninfected participants. These results provide reassuring insights into the continued interpretation of SARS-CoV-2 binding antibody measurements as an independent marker of protection at both the individual and population levels.

Modeling of ACE2 and antibodies bound to SARS-CoV-2 provides insights into infectivity and immune evasion.

Given the COVID-19 pandemic, there is interest in understanding ligand-receptor features and targeted antibody-binding attributes against emerging SARS-CoV-2 variants. Here, we developed a large-scale structure-based pipeline for analysis of protein-protein interactions regulating SARS-CoV-2 immune evasion. First, we generated computed structural models of the Spike protein of 3 SARS-CoV-2 variants (B.1.1.529, BA.2.12.1, and BA.5) bound either to a native receptor (ACE2) or to a large panel of targeted ligands (n = 282), which included neutralizing or therapeutic monoclonal antibodies. Moreover, by using the Barnes classification, we noted an overall loss of interfacial interactions (with gain of new interactions in certain cases) at the receptor-binding domain (RBD) mediated by substituted residues for neutralizing complexes in classes 1 and 2, whereas less destabilization was observed for classes 3 and 4. Finally, an experimental validation of predicted weakened therapeutic antibody binding was performed in a cell-based assay. Compared with the original Omicron variant (B.1.1.529), derivative variants featured progressive destabilization of antibody-RBD interfaces mediated by a larger set of substituted residues, thereby providing a molecular basis for immune evasion. This approach and findings provide a framework for rapidly and efficiently generating structural models for SARS-CoV-2 variants bound to ligands of mechanistic and therapeutic value.

Wastewater-based modeling, reconstruction, and prediction for COVID-19 outbreaks in Hungary caused by highly immune evasive variants.

(MOTIVATION): Wastewater-based epidemiology (WBE) has emerged as a promising approach for monitoring the COVID-19 pandemic, since the measurement process is cost-effective and is exposed to fewer potential errors compared to other indicators like hospitalization data or the number of detected cases. Consequently, WBE was gradually becoming a key tool for epidemic surveillance and often the most reliable data source, as the intensity of clinical testing for COVID-19 drastically decreased by the third year of the pandemic. Recent results suggests that the model-based fusion of wastewater measurements with clinical data and other indicators is essential in future epidemic surveillance. (METHOD): In this work, we developed a wastewater-based compartmental epidemic model with a two-phase vaccination dynamics and immune evasion. We proposed a multi-step optimization-based data assimilation method for epidemic state reconstruction, parameter estimation, and prediction. The computations make use of the measured viral load in wastewater, the available clinical data (hospital occupancy, delivered vaccine doses, and deaths), the stringency index of the official social distancing rules, and other measures. The current state assessment and the estimation of the current transmission rate and immunity loss allow a plausible prediction of the future progression of the pandemic. (RESULTS): Qualitative and quantitative evaluations revealed that the contribution of wastewater data in our computational epidemiological framework makes predictions more reliable. Predictions suggest that at least half of the Hungarian population has lost immunity during the epidemic outbreak caused by the BA.1 and BA.2 subvariants of Omicron in the first half of 2022. We obtained a similar result for the outbreaks caused by the subvariant BA.5 in the second half of 2022. (APPLICABILITY): The proposed approach has been used to support COVID management in Hungary and could be customized for other countries as well.

SARS-CoV-2 omicron BA.1.1 is highly resistant to antibody neutralization of convalescent serum from the origin strain.

The emergence and rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (BA.1.1) has attracted global attention. The numerous mutations in the spike protein suggest that it may have altered susceptibility to immune protection elicited by the existing coronavirus disease 2019 (COVID-19) infection. We used a live virus neutralization test and SARS-CoV-2 pseudotype vesicular stomatitis virus vector-based neutralization assay to assess the degree of immune escape efficiency of the original, Delta (B1.617.2), and Omicron strains against the serum antibodies from 64 unvaccinated patients who had recovered from COVID-19 and the results were strongly correlated. The convalescent serum neutralization was more markedly reduced against the Omicron variant (9.4-57.9-fold) than the Delta variant (2.0-4.5-fold) as compared with the original strain. Our results demonstrate the reduced fusion and notable immune evasion capabilities of the Omicron variants, highlighting the importance of accelerating the development of vaccines targeting them.

IFI44 is an immune evasion biomarker for SARS-CoV-2 and Staphylococcus aureus infection in patients with RA.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic of severe coronavirus disease 2019 (COVID-19). Staphylococcus aureus is one of the most common pathogenic bacteria in humans, rheumatoid arthritis (RA) is among the most prevalent autoimmune conditions. RA is a significant risk factor for SARS-CoV-2 and S. aureus infections, although the mechanism of RA and SARS-CoV-2 infection in conjunction with S. aureus infection has not been elucidated. The purpose of this study is to investigate the biomarkers and disease targets between RA and SARS-CoV-2 and S. aureus infections using bioinformatics analysis, to search for the molecular mechanisms of SARS-CoV-2 and S. aureus immune escape and potential drug targets in the RA population, and to provide new directions for further analysis and targeted development of clinical treatments. Methods: The RA dataset (GSE93272) and the S. aureus bacteremia (SAB) dataset (GSE33341) were used to obtain differentially expressed gene sets, respectively, and the common differentially expressed genes (DEGs) were determined through the intersection. Functional enrichment analysis utilizing GO, KEGG, and ClueGO methods. The PPI network was created utilizing the STRING database, and the top 10 hub genes were identified and further examined for functional enrichment using Metascape and GeneMANIA. The top 10 hub genes were intersected with the SARS-CoV-2 gene pool to identify five hub genes shared by RA, COVID-19, and SAB, and functional enrichment analysis was conducted using Metascape and GeneMANIA. Using the NetworkAnalyst platform, TF-hub gene and miRNA-hub gene networks were built for these five hub genes. The hub gene was verified utilizing GSE17755, GSE55235, and GSE13670, and its effectiveness was assessed utilizing ROC curves. CIBERSORT was applied to examine immune cell infiltration and the link between the hub gene and immune cells. Results: A total of 199 DEGs were extracted from the GSE93272 and GSE33341 datasets. KEGG analysis of enrichment pathways were NLR signaling pathway, cell membrane DNA sensing pathway, oxidative phosphorylation, and viral infection. Positive/negative regulation of the immune system, regulation of the interferon-I (IFN-I; IFN-α/ß) pathway, and associated pathways of the immunological response to viruses were enriched in GO and ClueGO analyses. PPI network and Cytoscape platform identified the top 10 hub genes: RSAD2, IFIT3, GBP1, RTP4, IFI44, OAS1, IFI44L, ISG15, HERC5, and IFIT5. The pathways are mainly enriched in response to viral and bacterial infection, IFN signaling, and 1,25-dihydroxy vitamin D3. IFI44, OAS1, IFI44L, ISG15, and HERC5 are the five hub genes shared by RA, COVID-19, and SAB. The pathways are primarily enriched for response to viral and bacterial infections. The TF-hub gene network and miRNA-hub gene network identified YY1 as a key TF and hsa-mir-1-3p and hsa-mir-146a-5p as two important miRNAs related to IFI44. IFI44 was identified as a hub gene by validating GSE17755, GSE55235, and GSE13670. Immune cell infiltration analysis showed a strong positive correlation between activated dendritic cells and IFI44 expression. Conclusions: IFI144 was discovered as a shared biomarker and disease target for RA, COVID-19, and SAB by this study. IFI44 negatively regulates the IFN signaling pathway to promote viral replication and bacterial proliferation and is an important molecular target for SARS-CoV-2 and S. aureus immune escape in RA. Dendritic cells play an important role in this process. 1,25-Dihydroxy vitamin D3 may be an important therapeutic agent in treating RA with SARS-CoV-2 and S. aureus infections.

High-throughput screening of mutations affecting SARS-CoV-2 spike functions.

The spike (S) protein of SARS-CoV-2, which is undergoing rapid evolution, plays crucial roles in viral immune escape, infectivity, and transmissibility. To gain clinical insight, Dadonaite et al. developed a novel deep mutational scanning (DMS) platform for mapping the effects of S protein mutations on immune evasion and viral infectivity.

SARS-CoV-2 Omicron XBB subvariants exhibit enhanced fusogenicity and substantial immune evasion in elderly population, but high sensitivity to pan-coronavirus fusion inhibitors.

Numerous emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants have shown significant immune evasion capacity and caused a large number of infections, as well as vaccine-breakthrough infections, especially in elderly populations. Recently emerged Omicron XBB was derived from the BA.2 lineage, but bears a distinct mutant profile in its spike (S) protein. In this study, we found that Omicron XBB S protein drove more efficient membrane-fusion kinetics on human lung-derived cells (Calu-3). Considering the high susceptibility of the elderly to the current Omicron pandemic, we performed a comprehensive neutralization assessment of elderly convalescent or vaccine sera against XBB infection. We found that the sera from elderly convalescent patients who experienced with BA.2 infection or breakthrough infection potently inhibited BA.2 infection, but showed significantly reduced efficacy against XBB. Moreover, recently emerged XBB.1.5 subvariant also showed more significant resistance to the convalescent sera of BA.2- or BA.5-infected elderly. On the other hand, we found that the pan-CoV fusion inhibitors EK1 and EK1C4 can potently block either XBB-S- or XBB.1.5-S-mediated fusion process and viral entry. Moreover, EK1 fusion inhibitor showed potent synergism when combined with convalescent sera of BA.2- or BA.5-infected patients against XBB and XBB.1.5 infection, further indicating that EK1-based pan-CoV fusion inhibitors are promising candidates for development as clinical antiviral agents to combat the Omicron XBB subvariants.

An updated atlas of antibody evasion by SARS-CoV-2 Omicron sub-variants including BQ.1.1 and XBB.

Emerging Omicron sub-variants are causing global concerns, and their immune evasion should be monitored continuously. We previously evaluated the escape of Omicron BA.1, BA.1.1, BA.2, and BA.3 from an atlas of 50 monoclonal antibodies (mAbs), covering seven epitope classes of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD). Here, we update the atlas of totally 77 mAbs against emerging sub-variants including BQ.1.1 and XBB and find that BA.4/5, BQ.1.1, and XBB display further evasion. Besides, investigation into the correlation of binding and neutralization of mAbs reveals the important role of antigenic conformation in mAb functioning. Moreover, the complex structures of BA.2 RBD/BD-604/S304 and BA.4/5 RBD/BD-604/S304/S309 further elucidate the molecular mechanism of antibody evasion by these sub-variants. By focusing on the identified broadly potent mAbs, we find a general hotspot epitope on the RBD, which could guide the design of vaccines and calls for new broad-spectrum countermeasures against COVID-19.

The immune evasion ability of Delta variant is comparable to that of Beta variant in South Africa.

BACKGROUND: The high immune evasion ability of SARS-COV-2 Omicron variant surprised the world and appears to be far stronger than any previous variant. Previous to Omicron it has been difficult to assess and compare immune evasion ability of different variants, including the Beta and Delta variants, because of the relatively small numbers of reinfections and because of the problems in correctly identifying reinfections in the population. This has led to different claims appearing in the literature. Thus we find claims of both high and low immune evasion for the Beta variant. Some findings have suggested that the Beta variant has a higher immune evasion ability than the Delta variant in South Africa, and others that it has a lower ability. METHOD: In this brief report, we re-analyse a unique dataset of variant-specific reinfection data and a simple model to correct for the infection attack rates of different variants. RESULT: We find that a model with the Delta variant having  an equal or higher immune evasion ability than Beta variant is compatible with the data. CONCLUSION: We conclude that the immune evasion ability of Beta variant is not stronger than Delta variant, and indeed, the immune evasion abilities of both variants are weak in South Africa.

Evolution of Immune Evasion and Host Range Expansion by the SARS-CoV-2 B.1.1.529 (Omicron) Variant.

Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant B.1.1.529 (Omicron) has rapidly become the dominant strain, with an unprecedented number of mutations within its spike gene. However, it remains unknown whether these variants have alterations in their entry efficiency, host tropism, and sensitivity to neutralizing antibodies and entry inhibitors. In this study, we found that Omicron spike has evolved to escape neutralization by three-dose inactivated-vaccine-elicited immunity but remains sensitive to an angiotensin-converting enzyme 2 (ACE2) decoy receptor. Moreover, Omicron spike could use human ACE2 with a slightly increased efficiency while gaining a significantly increased binding affinity for a mouse ACE2 ortholog, which exhibits limited binding with wild-type (WT) spike. Furthermore, Omicron could infect wild-type C57BL/6 mice and cause histopathological changes in the lungs. Collectively, our results reveal that evasion of neutralization by vaccine-elicited antibodies and enhanced human and mouse ACE2 receptor engagement may contribute to the expanded host range and rapid spread of the Omicron variant. IMPORTANCE The recently emerged SARS-CoV-2 Omicron variant with numerous mutations in the spike protein has rapidly become the dominant strain, thereby raising concerns about the effectiveness of vaccines. Here, we found that the Omicron variant exhibits a reduced sensitivity to serum neutralizing activity induced by a three-dose inactivated vaccine but remains sensitive to entry inhibitors or an ACE2-Ig decoy receptor. Compared with the ancestor strain isolated in early 2020, the spike protein of Omicron utilizes the human ACE2 receptor with enhanced efficiency while gaining the ability to utilize mouse ACE2 for cell entry. Moreover, Omicron could infect wild-type mice and cause pathological changes in the lungs. These results reveal that antibody evasion, enhanced human ACE2 utilization, and an expanded host range may contribute to its rapid spread.

The evolution of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of deaths and substantial morbidity worldwide. Intense scientific effort to understand the biology of SARS-CoV-2 has resulted in daunting numbers of genomic sequences. We witnessed evolutionary events that could mostly be inferred indirectly before, such as the emergence of variants with distinct phenotypes, for example transmissibility, severity and immune evasion. This Review explores the mechanisms that generate genetic variation in SARS-CoV-2, underlying the within-host and population-level processes that underpin these events. We examine the selective forces that likely drove the evolution of higher transmissibility and, in some cases, higher severity during the first year of the pandemic and the role of antigenic evolution during the second and third years, together with the implications of immune escape and reinfections, and the increasing evidence for and potential relevance of recombination. In order to understand how major lineages, such as variants of concern (VOCs), are generated, we contrast the evidence for the chronic infection model underlying the emergence of VOCs with the possibility of an animal reservoir playing a role in SARS-CoV-2 evolution, and conclude that the former is more likely. We evaluate uncertainties and outline scenarios for the possible future evolutionary trajectories of SARS-CoV-2.

Potent NKT cell ligands overcome SARS-CoV-2 immune evasion to mitigate viral pathogenesis in mouse models.

One of the major pathogenesis mechanisms of SARS-CoV-2 is its potent suppression of innate immunity, including blocking the production of type I interferons. However, it is unknown whether and how the virus interacts with different innate-like T cells, including NKT, MAIT and γδ T cells. Here we reported that upon SARS-CoV-2 infection, invariant NKT (iNKT) cells rapidly trafficked to infected lung tissues from the periphery. We discovered that the envelope (E) protein of SARS-CoV-2 efficiently down-regulated the cell surface expression of the antigen-presenting molecule, CD1d, to suppress the function of iNKT cells. E protein is a small membrane protein and a viroporin that plays important roles in virion packaging and envelopment during viral morphogenesis. We showed that the transmembrane domain of E protein was responsible for suppressing CD1d expression by specifically reducing the level of mature, post-ER forms of CD1d, suggesting that it suppressed the trafficking of CD1d proteins and led to their degradation. Point mutations demonstrated that the putative ion channel function was required for suppression of CD1d expression and inhibition of the ion channel function using small chemicals rescued the CD1d expression. Importantly, we discovered that among seven human coronaviruses, only E proteins from highly pathogenic coronaviruses including SARS-CoV-2, SARS-CoV and MERS suppressed CD1d expression, whereas the E proteins of human common cold coronaviruses, HCoV-OC43, HCoV-229E, HCoV-NL63 and HCoV-HKU1, did not. These results suggested that E protein-mediated evasion of NKT cell function was likely an important pathogenesis factor, enhancing the virulence of these highly pathogenic coronaviruses. Remarkably, activation of iNKT cells with their glycolipid ligands, both prophylactically and therapeutically, overcame the putative viral immune evasion, significantly mitigated viral pathogenesis and improved host survival in mice. Our results suggested a novel NKT cell-based anti-SARS-CoV-2 therapeutic approach.

Immune evasion of neutralizing antibodies by SARS-CoV-2 Omicron.

Since its emergence at the end of 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the infection of more than 600 million people worldwide and has significant damage to global medical, economic, and political structures. Currently, a highly mutated variant of concern, SARS-CoV-2 Omicron, has evolved into many different subvariants mainly including BA.1, BA.2, BA.3, BA.4/5, and the recently emerging BA.2.75.2, BA.2.76, BA.4.6, BA.4.7, BA.5.9, BF.7, BQ.1, BQ.1.1, XBB, XBB.1, etc. Mutations in the N-terminal domain (NTD) of the spike protein, such as A67V, G142D, and N212I, alter the antigenic structure of Omicron, while mutations in the spike receptor binding domain (RBD), such as R346K, Q493R, and N501Y, increase the affinity for angiotensin-converting enzyme 2 (ACE2). Both types of mutations greatly increase the capacity of Omicron to evade immunity from neutralizing antibodies, produced by natural infection and/or vaccination. In this review, we systematically assess the immune evasion capacity of SARS-CoV-2, with an emphasis on the neutralizing antibodies generated by different vaccination regimes. Understanding the host antibody response and the evasion strategies employed by SARS-CoV-2 variants will improve our capacity to combat newly emerging Omicron variants.

Immune evasion of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2); molecular approaches.

In December 2019, a new betacoronavirus, known as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), caused an outbreak at the Wuhan seafood market in China. The disease was further named coronavirus disease 2019 (COVID-19). In March 2020, the World Health Organization (WHO) announced the disease to be a pandemic, as more cases were reported globally. SARS-CoV-2, like many other viruses, employs diverse strategies to elude the host immune response and/or counter immune responses. The infection outcome mainly depends on interactions between the virus and the host immune system. Inhibiting IFN production, blocking IFN signaling, enhancing IFN resistance, and hijacking the host's translation machinery to expedite the production of viral proteins are among the main immune evasion mechanisms of SARS-CoV-2. SARS-CoV-2 also downregulates the expression of MHC-I on infected cells, which is an additional immune-evasion mechanism of this virus. Moreover, antigenic modifications to the spike (S) protein, such as deletions, insertions, and also substitutions are essential for resistance to SARS-CoV-2 neutralizing antibodies. This review assesses the interaction between SARS-CoV-2 and host immune response and cellular and molecular approaches used by SARS-CoV-2 for immune evasion. Understanding the mechanisms of SARS-CoV-2 immune evasion is essential since it can improve the development of novel antiviral treatment options as well as vaccination methods.

A Detailed Overview of SARS-CoV-2 Omicron: Its Sub-Variants, Mutations and Pathophysiology, Clinical Characteristics, Immunological Landscape, Immune Escape, and Therapies.

The COVID-19 pandemic has created significant concern for everyone. Recent data from many worldwide reports suggest that most infections are caused by the Omicron variant and its sub-lineages, dominating all the previously emerged variants. The numerous mutations in Omicron's viral genome and its sub-lineages attribute it a larger amount of viral fitness, owing to the alteration of the transmission and pathophysiology of the virus. With a rapid change to the viral structure, Omicron and its sub-variants, namely BA.1, BA.2, BA.3, BA.4, and BA.5, dominate the community with an ability to escape the neutralization efficiency induced by prior vaccination or infections. Similarly, several recombinant sub-variants of Omicron, namely XBB, XBD, and XBF, etc., have emerged, which a better understanding. This review mainly entails the changes to Omicron and its sub-lineages due to it having a higher number of mutations. The binding affinity, cellular entry, disease severity, infection rates, and most importantly, the immune evading potential of them are discussed in this review. A comparative analysis of the Delta variant and the other dominating variants that evolved before Omicron gives the readers an in-depth understanding of the landscape of Omicron's transmission and infection. Furthermore, this review discusses the range of neutralization abilities possessed by several approved antiviral therapeutic molecules and neutralizing antibodies which are functional against Omicron and its sub-variants. The rapid evolution of the sub-variants is causing infections, but the broader aspect of their transmission and neutralization has not been explored. Thus, the scientific community should adopt an elucidative approach to obtain a clear idea about the recently emerged sub-variants, including the recombinant variants, so that effective neutralization with vaccines and drugs can be achieved. This, in turn, will lead to a drop in the number of cases and, finally, an end to the pandemic.