Defining the pediatric response to SARS-CoV-2 variants.

The global population has been severely affected by the coronavirus disease 2019 (COVID-19) pandemic, however, with older age identified as a risk factor, children have been underprioritized. This article discusses the factors contributing to the less severe response observed in children following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including, differing viral entry receptor expression and immune responses. It also discusses how emerging and future variants could present a higher risk to children, including those with underlying comorbidities, in developing severe disease. Furthermore, this perspective discusses the differential inflammatory markers between critical and non-critical cases, as well as discussing the types of variants that may be more pathogenic to children. Importantly, this article highlights where more research is urgently required, in order to protect the most vulnerable of our children.

A SARS-CoV-2 Vaccine Designed for Manufacturability Results in Unexpected Potency and Non-Waning Humoral Response.

The rapid development of several highly efficacious SARS-CoV-2 vaccines was an unprecedented scientific achievement that saved millions of lives. However, now that SARS-CoV-2 is transitioning to the endemic stage, there exists an unmet need for new vaccines that provide durable immunity and protection against variants and can be more easily manufactured and distributed. Here, we describe a novel protein component vaccine candidate, MT-001, based on a fragment of the SARS-CoV-2 spike protein that encompasses the receptor binding domain (RBD). Mice and hamsters immunized with a prime-boost regimen of MT-001 demonstrated extremely high anti-spike IgG titers, and remarkably this humoral response did not appreciably wane for up to 12 months following vaccination. Further, virus neutralization titers, including titers against variants such as Delta and Omicron BA.1, remained high without the requirement for subsequent boosting. MT-001 was designed for manufacturability and ease of distribution, and we demonstrate that these attributes are not inconsistent with a highly immunogenic vaccine that confers durable and broad immunity to SARS-CoV-2 and its emerging variants. These properties suggest MT-001 could be a valuable new addition to the toolbox of SARS-CoV-2 vaccines and other interventions to prevent infection and curtail additional morbidity and mortality from the ongoing worldwide pandemic.

Genomic surveillance identifies SARS-CoV-2 transmission patterns in local university populations, Wisconsin, USA, 2020-2022.

Novel variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge as the coronavirus disease 2019 (COVID-19) pandemic extends into its fourth year. Understanding SARS-CoV-2 circulation in university populations is vital for effective interventions in higher education settings and will inform public health policy during pandemics. In this study, we performed whole-genome sequencing of 537 of 1717 SARS-CoV-2-positive nasopharyngeal/nasal swab samples collected over a nearly 20-month period from two university populations in Wisconsin, USA. We observed that the viral sequences were distributed into 57 lineages/sub-lineages belonging to 15 clades, of which the majority were from 21K (omicron, 36.13 %) and 21J (delta, 30.91 %). Nearly 40 % (213) of the sequences were omicron, of which BA.1 and its eight descendent lineages accounted for 91 %, while the remaining belonged to BA.2 and its six descendent lineages. Independent analysis of the sequences from these two universities revealed significant differences in the circulating SARS-CoV-2 variants. Phylogenetic analysis of university sequences with a global sub-dataset demonstrated that the sequences of the same lineages from the university populations were more closely related. Genome-based analysis of closely related strains, along with phylogenetic clusters and mutational differences, identified that potential virus transmission occurred within and between universities, as well as between the university and the local community. Although this study improves our understanding of the distinct transmission patterns of circulating variants in local universities, expanding genomic surveillance capacity will aid local jurisdictions not only in identifying emerging SARS-CoV-2 variants, but also in improving data-driven public health mitigation and policy efforts.

Global landscape of SARS-CoV-2 mutations and conserved regions.

BACKGROUND: At the end of December 2019, a novel strain of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) disease (COVID-19) has been identified in Wuhan, a central city in China, and then spread to every corner of the globe. As of October 8, 2022, the total number of COVID-19 cases had reached over 621 million worldwide, with more than 6.56 million confirmed deaths. Since SARS-CoV-2 genome sequences change due to mutation and recombination, it is pivotal to surveil emerging variants and monitor changes for improving pandemic management. METHODS: 10,287,271 SARS-CoV-2 genome sequence samples were downloaded in FASTA format from the GISAID databases from February 24, 2020, to April 2022. Python programming language (version 3.8.0) software was utilized to process FASTA files to identify variants and sequence conservation. The NCBI RefSeq SARS-CoV-2 genome (accession no. NC_045512.2) was considered as the reference sequence. RESULTS: Six mutations had more than 50% frequency in global SARS-CoV-2. These mutations include the P323L (99.3%) in NSP12, D614G (97.6) in S, the T492I (70.4) in NSP4, R203M (62.8%) in N, T60A (61.4%) in Orf9b, and P1228L (50.0%) in NSP3. In the SARS-CoV-2 genome, no mutation was observed in more than 90% of nsp11, nsp7, nsp10, nsp9, nsp8, and nsp16 regions. On the other hand, N, nsp3, S, nsp4, nsp12, and M had the maximum rate of mutations. In the S protein, the highest mutation frequency was observed in aa 508-635(0.77%) and aa 381-508 (0.43%). The highest frequency of mutation was observed in aa 66-88 (2.19%), aa 7-14, and aa 164-246 (2.92%) in M, E, and N proteins, respectively. CONCLUSION: Therefore, monitoring SARS-CoV-2 proteomic changes and detecting hot spots mutations and conserved regions could be applied to improve the SARS-CoV-2 diagnostic efficiency and design safe and effective vaccines against emerging variants.

Boosting with Multiple Doses of mRNA Vaccine after Priming with Two Doses of Protein Subunit Vaccine MVC-COV1901 Elicited Robust Humoral and Cellular Immune Responses against Emerging SARS-CoV-2 Variants.

Confronted with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, such as Delta and Omicron, with high infectivity and immune evasion capacity, vaccination remains the most effective tool to prevent infection and severe illness. However, heterologous vaccination of mRNA vaccines primed with protein subunit vaccines had not been evaluated before the current study. Since subunit vaccine MVC-COV1901 (MVC) has been granted emergency use authorization in Taiwan, in this study, we explored the humoral and cellular immune responses to additional third (2× MVC/Mod) and fourth (2× MVC/2× Mod) doses of mRNA-1273 (Mod) after priming with two doses of subunit vaccine MVC against the emerging variants. We found a 12.3- to 16.1-fold increase in antibodies targeting the receptor binding domain (RBD) of the Delta variant with 2× MVC/Mod compared to two doses of MVC (2× MVC) or AZD1222 (2× AZ) regimens and a 26- to 32.2-fold improvement in neutralizing potency against the Omicron variant (BA.1). Besides, the numbers of gamma interferon (IFN-γ)-secreting T cells induced by 2× MVC/Mod were also elevated 3.5-fold and 3.7- to 4.3-fold for the wild type and Delta variant. However, boosting with a fourth dose of Mod (2× MVC/2× Mod) after the 2× MVC/Mod regimen failed to significantly improve the immune responses. Moreover, all vaccination schedules showed reduced neutralizing activity against the Omicron variant. Collectively, our results suggested that the third or fourth dose booster vaccination with mRNA vaccine after priming with two doses of protein subunit vaccine could elicit stronger humoral and cellular immune responses. These findings could provide a future global heterologous boosting strategy against COVID-19. IMPORTANCE Vaccination is the most important strategy to combat the COVID-19 outbreak; however, it remains to be determined whether heterologous prime-boost regimens could induce equal or even stronger immune responses against SARS-CoV-2. Here, we showed that boosting the additional doses of mRNA-1273 (Mod) priming with two doses of MVC-COV1901 (MVC) (2× MVC/Mod) improved humoral and cellular immunity compared to two doses of AZD1222 (2× AZ) or MVC (2× MVC) against SARS-CoV-2 variants. However, the Omicron variant showed strong immune evasion ability for all vaccination schedules. Our findings provided evidence supporting that heterologous vaccination by boosting with mRNA vaccine after priming with two doses of protein subunit vaccine could strongly promote humoral and cellular immune responses against the emerging SARS-CoV-2 variants.

B.1.1.7 (Alpha) variant is the most antigenic compared to Wuhan strain, B.1.351, B.1.1.28/triple mutant and B.1.429 variants.

The rapid spread of the SARS-CoV-2 virus and its variants has created a catastrophic impact worldwide. Several variants have emerged, including B.1.351 (Beta), B.1.1.28/triple mutant (P.1), B.1.1.7 (Alpha), and B.1.429 (Epsilon). We performed comparative and comprehensive antigenicity mapping of the total S-glycoprotein using the Wuhan strain and the other variants and identified 9-mer, 15-mer, and 20-mer CTL epitopes through in silico analysis. The study found that 9-mer CTL epitope regions in the B.1.1.7 variant had the highest antigenicity and an average of the three epitope types. Cluster analysis of the 9-mer CTL epitopes depicted one significant cluster at the 70% level with two nodes (KGFNCYFPL and EGFNCYFPL). The phage-displayed peptides showed mimic 9-mer CTL epitopes with three clusters. CD spectra analysis showed the same band pattern of S-glycoprotein of Wuhan strain and all variants other than B.1.429. The developed 3D model of the superantigen (SAg)-like regions found an interaction pattern with the human TCR, indicating that the SAg-like component might interact with the TCR beta chain. The present study identified another partial SAg-like region (ANQFNSAIGKI) from the S-glycoprotein. Future research should examine the molecular mechanism of antigen processing for CD8+ T cells, especially all the variants' antigens of S-glycoprotein.

SARS-CoV-2 Omicron variant (B.1.1.529): A concern with immune escape.

Omicron, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant that is now spreading across the world, is the most altered version to emerge so far, with mutations comparable to changes reported in earlier variants of concern linked with increased transmissibility and partial resistance to vaccine-induced immunity. This article provides an overview of the SARS-CoV-2 variant Omicron (B.1.1.529) by reviewing the literature from major scientific databases. Although clear immunological and clinical data are not yet available, we extrapolated from what is known about mutations present in the Omicron variant of SARS-CoV-2 and offer preliminary indications on transmissibility, severity, and immune escape through existing research and databases.

An intranasal lentiviral booster reinforces the waning mRNA vaccine-induced SARS-CoV-2 immunity that it targets to lung mucosa.

As the coronavirus disease 2019 (COVID-19) pandemic continues and new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern emerge, the adaptive immunity initially induced by the first-generation COVID-19 vaccines starts waning and needs to be strengthened and broadened in specificity. Vaccination by the nasal route induces mucosal, humoral, and cellular immunity at the entry point of SARS-CoV-2 into the host organism and has been shown to be the most effective for reducing viral transmission. The lentiviral vaccination vector (LV) is particularly suitable for this route of immunization owing to its non-cytopathic, non-replicative, and scarcely inflammatory properties. Here, to set up an optimized cross-protective intranasal booster against COVID-19, we generated an LV encoding stabilized spike of SARS-CoV-2 Beta variant (LV::SBeta-2P). mRNA vaccine-primed and -boosted mice, with waning primary humoral immunity at 4 months after vaccination, were boosted intranasally with LV::SBeta-2P. A strong boost effect was detected on cross-sero-neutralizing activity and systemic T cell immunity. In addition, mucosal anti-spike IgG and IgA, lung-resident B cells, and effector memory and resident T cells were efficiently induced, correlating with complete pulmonary protection against the SARS-CoV-2 Delta variant, demonstrating the suitability of the LV::SBeta-2P vaccine candidate as an intranasal booster against COVID-19. LV::SBeta-2P vaccination was also fully protective against Omicron infection of the lungs and central nervous system, in the highly susceptible B6.K18-hACE2IP-THV transgenic mice.

Detecting SARS-CoV-2 Omicron B.1.1.529 Variant in Wastewater Samples by Using Nanopore Sequencing.

We report wastewater surveillance for SARS-CoV-2 variants of concern by using mutation-specific, real-time PCR and rapid nanopore sequencing. This surveillance might be useful for an early warning in a scenario in which a new variant is emerging, even in areas that have low virus incidences.

Update on SARS-CoV-2 Omicron Variant of Concern and Its Peculiar Mutational Profile.

The process of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genetic diversification is still ongoing and has very recently led to the emergence of a new variant of concern (VOC), defined as Omicron or B.1.1.529. Omicron VOC is the most divergent variant identified so far and has generated immediate concern for its potential capability to increase SARS-CoV-2 transmissibility and, more worryingly, to escape therapeutic and vaccine-induced antibodies. Nevertheless, a clear definition of the Omicron VOC mutational spectrum is still missing. Herein, we provide a comprehensive definition and functional characterization (in terms of infectivity and/or antigenicity) of mutations characterizing the Omicron VOC. In particular, 887,475 SARS-CoV-2 Omicron VOC whole-genome sequences were retrieved from the GISAID database and used to precisely define its specific patterns of mutations across the different viral proteins. In addition, the functional characterization of Omicron VOC spike mutations was finely discussed according to published manuscripts. Lastly, residues characterizing the Omicron VOC and the previous four VOCs (Alpha, Beta, Gamma, and Delta) were mapped on the three-dimensional structure of the SARS-CoV-2 spike protein to assess their localization in the different spike domains. Overall, our study will assist with deciphering the Omicron VOC mutational profile and will shed more light on its clinical implications. This is critical considering that Omicron VOC is currently the predominant variant worldwide. IMPORTANCE The Omicron variant of concern (VOC) has a peculiar spectrum of mutations characterized by the acquisition of mutations or deletions rarely detected in previously identified variants, particularly in the spike glycoprotein. Such mutations, mostly residing in the receptor-binding domain, could play a pivotal role in enhancing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectivity (by increasing binding affinity for ACE2), jeopardizing spike recognition by therapeutic and vaccine-induced antibodies and causing diagnostic assay failure. To our knowledge, this is one of the first exhaustive descriptions of newly emerged mutations underlying the Omicron VOC and its biological and clinical implications.

Molecular and Epidemiological Characterization of Emerging Immune-Escape Variants of SARS-CoV-2.

The successive emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has presented a major challenge in the management of the coronavirus disease (COVID-19) pandemic. There are growing concerns regarding the emerging variants escaping vaccines or therapeutic neutralizing antibodies. In this study, we conducted an epidemiological survey to identify SARS-CoV-2 variants that are sporadically proliferating in vaccine-advanced countries. Subsequently, we created HiBiT-tagged virus-like particles displaying spike proteins derived from the variants to analyze the neutralizing efficacy of the BNT162b2 mRNA vaccine and several therapeutic antibodies. We found that the Mu variant and a derivative of the Delta strain with E484K and N501Y mutations significantly evaded vaccine-elicited neutralizing antibodies. This trend was also observed in the Beta and Gamma variants, although they are currently not prevalent. Although 95.2% of the vaccinees exhibited prominent neutralizing activity against the prototype strain, only 73.8 and 78.6% of the vaccinees exhibited neutralizing activity against the Mu and the Delta derivative variants, respectively. A long-term analysis showed that 88.8% of the vaccinees initially exhibited strong neutralizing activity against the currently circulating Delta strain; the number decreased to 31.6% for the individuals at 6 months after vaccination. Notably, these variants were shown to be resistant to several therapeutic antibodies. Our findings demonstrate the differential neutralization efficacy of the COVID-19 vaccine and monoclonal antibodies against circulating variants, suggesting the need for pandemic alerts and booster vaccinations against the currently prevalent variants.

Viral Load in COVID-19 Patients: Implications for Prognosis and Vaccine Efficacy in the Context of Emerging SARS-CoV-2 Variants.

The worldwide spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an unprecedented public health crisis in the 21st century. As the pandemic evolves, the emergence of SARS-CoV-2 has been characterized by the emergence of new variants of concern (VOCs), which resulted in a catastrophic impact on SARS-CoV-2 infection. In light of this, research groups around the world are unraveling key aspects of the associated illness, coronavirus disease 2019 (COVID-19). A cumulative body of data has indicated that the SARS-CoV-2 viral load may be a determinant of the COVID-19 severity. Here we summarize the main characteristics of the emerging variants of SARS-CoV-2, discussing their impact on viral transmissibility, viral load, disease severity, vaccine breakthrough, and lethality among COVID-19 patients. We also provide a rundown of the rapidly expanding scientific evidence from clinical studies and animal models that indicate how viral load could be linked to COVID-19 prognosis and vaccine efficacy among vaccinated individuals, highlighting the differences compared to unvaccinated individuals.

Discovery of ultrapotent broadly neutralizing antibodies from SARS-CoV-2 elite neutralizers.

A fraction of COVID-19 convalescent individuals mount a potent antibody response to SARS-CoV-2 with cross-reactivity to SARS-CoV-1. To uncover their humoral response in detail, we performed single B cell analysis from 10 SARS-CoV-2 elite neutralizers. We isolated and analyzed 126 monoclonal antibodies, many of which were sarbecovirus cross-reactive, with some displaying merbecovirus- and embecovirus-reactivity. Several isolated broadly neutralizing antibodies were effective against B.1.1.7, B.1.351, B.1.429, B.1.617, and B.1.617.2 variants and 19 prominent potential escape sites. Furthermore, assembly of 716,806 SARS-CoV-2 sequences predicted emerging escape variants, which were also effectively neutralized. One of these broadly neutralizing potent antibodies, R40-1G8, is a IGHV3-53 RBD-class-1 antibody. Remarkably, cryo-EM analysis revealed that R40-1G8 has a flexible binding mode, targeting both "up" and "down" conformations of the RBD. Given the threat of emerging SARS-CoV-2 variants, we demonstrate that elite neutralizers are a valuable source for isolating ultrapotent antibody candidates to prevent and treat SARS-CoV-2 infection.

Computational design of a neutralizing antibody with picomolar binding affinity for all concerning SARS-CoV-2 variants.

Coronavirus disease 2019, caused by SARS-CoV-2, remains an on-going pandemic, partly due to the emergence of variant viruses that can "break-through" the protection of the current vaccines and neutralizing antibodies (nAbs), highlighting the needs for broadly nAbs and next-generation vaccines. We report an antibody that exhibits breadth and potency in binding the receptor-binding domain (RBD) of the virus spike glycoprotein across SARS coronaviruses. Initially, a lead antibody was computationally discovered and crystallographically validated that binds to a highly conserved surface of the RBD of wild-type SARS-CoV-2. Subsequently, through experimental affinity enhancement and computational affinity maturation, it was further developed to bind the RBD of all concerning SARS-CoV-2 variants, SARS-CoV-1 and pangolin coronavirus with pico-molar binding affinities, consistently exhibited strong neutralization activity against wild-type SARS-CoV-2 and the Alpha and Delta variants. These results identify a vulnerable target site on coronaviruses for development of pan-sarbecovirus nAbs and vaccines.

Computational modelling of potentially emerging SARS-CoV-2 spike protein RBDs mutations with higher binding affinity towards ACE2: A structural modelling study.

The spike protein of SARS-CoV-2 and the host ACE2 receptor plays a vital role in the entry to the cell. Among which the hotspot residue 501 is continuously subjected to positive selection pressure and induces unusual virulence. Keeping in view the importance of the hot spot residue 501, we predicted the potentially emerging structural variants of 501 residue. We analyzed the binding pattern of wild type and mutants (Spike RBD) to the ACE2 receptor by deciphering variations in the amino acids' interaction networks by graph kernels along with evolutionary, network metrics, and energetic information. Our analysis revealed that N501I, N501T, and N501V increase the binding affinity and alter the intra and inter-residue bonding networks. The N501T has shown strong positive selection and fitness in other animals. Docking results and repeated simulations (three times) confirmed the structural stability and tighter binding of these three variants, correlated with the previous results following the global stability trend. Consequently, we reported three variants N501I, N501T, and N501V could worsen the situation further if they emerged. The relations between the viral fitness and binding affinity is a complicated game thus the emergence of high affinity mutations in the SARS-CoV-2 RBD brings up the question of whether or not positive selection favours these mutations or not?

Structural basis and mode of action for two broadly neutralizing antibodies against SARS-CoV-2 emerging variants of concern.

Emerging variants of concern for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit more efficiently and partially evade protective immune responses, thus necessitating continued refinement of antibody therapies and immunogen design. Here, we elucidate the structural basis and mode of action for two potent SARS-CoV-2 spike (S)-neutralizing monoclonal antibodies, CV3-1 and CV3-25, which remain effective against emerging variants of concern in vitro and in vivo. CV3-1 binds to the (485-GFN-487) loop within the receptor-binding domain (RBD) in the "RBD-up" position and triggers potent shedding of the S1 subunit. In contrast, CV3-25 inhibits membrane fusion by binding to an epitope in the stem helix region of the S2 subunit that is highly conserved among ß-coronaviruses. Thus, vaccine immunogen designs that incorporate the conserved regions in the RBD and stem helix region are candidates to elicit pan-coronavirus protective immune responses.

SARS-CoV-2: Current trends in emerging variants, pathogenesis, immune responses, potential therapeutic, and vaccine development strategies.

More than a year after the SARS-CoV-2 pandemic, the Coronavirus disease 19 (COVID-19) is still a major global challenge for scientists to understand the different dimensions of infection and find ways to prevent, treat, and develop a vaccine. On January 30, 2020, the world health organization (WHO) officially announced this new virus as an international health emergency. While many biological and mechanisms of pathogenicity of this virus are still unclear, it seems that cytokine storm resulting from an immune response against the virus is considered the main culprit of the severity of the disease. Despite many global efforts to control the SARS-CoV-2, several problems and challenges have been posed in controlling the COVID-19 infection. These problems include the various mutations, the emergence of variants with high transmissibility, the short period of immunity against the virus, the possibility of reinfection in people improved, lack of specific drugs, and problems in the development of highly sensitive and specific vaccines. In this review, we summarized the results of the current trend and the latest research studies on the characteristics of the structure and genome of the SARS-CoV- 2, new mutations and variants of SARS-CoV-2, pathogenicity, immune response, virus diagnostic tests, potential treatment, and vaccine candidate.

SARS-CoV-2 Variants and Their Relevant Mutational Profiles: Update Summer 2021.

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic caused by it, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been undergoing a genetic diversification leading to the emergence of new variants. Nevertheless, a clear definition of the genetic signatures underlying the circulating variants is still missing. Here, we provide a comprehensive insight into mutational profiles characterizing each SARS-CoV-2 variant, focusing on spike mutations known to modulate viral infectivity and/or antigenicity. We focused on variants and on specific relevant mutations reported by GISAID, Nextstrain, Outbreak.info, Pango, and Stanford database websites that were associated with any clinical/diagnostic impact, according to published manuscripts. Furthermore, 1,223,338 full-length high-quality SARS-CoV-2 genome sequences were retrieved from GISAID and used to accurately define the specific mutational patterns in each variant. Finally, mutations were mapped on the three-dimensional structure of the SARS-CoV-2 spike protein to assess their localization in the different spike domains. Overall, this review sheds light and assists in defining the genetic signatures characterizing the currently circulating variants and their clinical relevance. IMPORTANCE Since the emergence of SARS-CoV-2, several recurrent mutations, particularly in the spike protein, arose during human-to-human transmission or spillover events between humans and animals, generating distinct worrisome variants of concern (VOCs) or of interest (VOIs), designated as such due to their clinical and diagnostic impacts. Characterizing these variants and their related mutations is important in tracking SAR-CoV-2 evolution and understanding the efficacy of vaccines and therapeutics based on monoclonal antibodies, convalescent-phase sera, and direct antivirals. Our study provides a comprehensive survey of the mutational profiles characterizing the important SARS-CoV-2 variants, focusing on spike mutations and highlighting other protein mutations.

Host Response to SARS-CoV2 and Emerging Variants in Pre-Existing Liver and Gastrointestinal Diseases.

Background: Novel coronavirus SARS-CoV2 is evolving continuously with emergence of several variants of increasing transmission capabilities and pandemic potential. Generation of variants occurs through accumulation of mutations due to the RNA nature of viral genome, which is further enhanced by variable selection pressures of this ongoing pandemic. COVID-19 presentations of SARS-CoV2 are mainly pulmonary manifestations with or without mild gastrointestinal (GI) and hepatic symptoms. However, the virus has evolved beyond pulmonary manifestations to multisystem disorder due to systemic inflammation and cytokine storm. Definitive cause of acute or late onset of inflammation, infection in various organs, and host response to emerging variants lacks clarity and needs elucidation. Several studies have reported underlying diseases including diabetes, hypertension, obesity, cardio- and cerebrovascular disorders, and immunocompromised conditions as significant risk factors for severe form of COVID-19. Pre-existing liver and GI diseases are also highly predominant in the population, which can alter COVID-19 outcome due to altered immune status and host response. We aim to review the emerging variants of SARS-CoV2 and host response in patients with pre-existing liver and GI diseases. Methods: In this review, we have elucidated the emergence and characteristic features of new SARS-CoV2 variants, mechanisms of infection and host immune response, GI and hepatic manifestation with radiologic features of COVID-19, and outcomes in pre-existing liver and GI diseases. Key Findings: Emerging variants of concern (VOC) have shown increased transmissibility and virulence with severe COVID-19 presentation and mortality. There is a drastic swift of variants from the first wave to the next wave of infections with predominated major VOC including alpha (B.1.1.7, UK), beta (B.1.351, South Africa), gamma (B.1.1.28.1, Brazil), and delta (B1.1.617, India) variants. The mutations in the spike protein of VOC are implicated for increased receptor binding (N501Y, P681R) and immune escape (L452R, E484K/Q, T478K/R) to host response. Pre-existing liver and GI diseases not only have altered tissue expression and distribution of viral entry ACE2 receptor but also host protease TMPRSS2, which is required for both spike protein binding and cleavage to initiate infection. Altered immune status due to pre-existing conditions results in delayed virus clearance or prolonged viremia. Even though GI and hepatic manifestations of SARS-CoV2 are less severe, the detection of virus in patient's stool indicates GI tropism, replication, and shedding from the GI tract. COVID-19-induced liver injury, acute hepatic decompensation, and incidences of acute-on-chronic liver failure may change the disease outcomes. Conclusions: The changes in the spike protein of emerging variants, immunomodulation by viral proteins, and altered expression of host viral entry receptor in pre-existing diseases are the key determinants of host response to SARS-CoV2 and its disease outcome.