Emerging SARS-CoV-2 variants can potentially break set epidemiological barriers in COVID-19.
TL;DR: The new SARS-CoV-2 variants have key mutations that can induce significant changes in the virus-host interactions, such as binding of the receptor-binding domain (RBD) of the viral spike protein with the ACE2 receptor in the host-cells, increase the glycosylation of spike protein at the antigenic sites, and enhance the proteolytic cleavage of the spike protein, thus leading to improved host-cell entry and the replication of the virus as discussed by the authors.
Abstract: Young age, female sex, absence of comorbidities, and prior infection or vaccination are known epidemiological barriers for contracting the new infection and/or increased disease severity. Demographic trends from the recent COVID-19 waves, which are believed to be driven by newer SARS-CoV-2 variants, indicate that the aforementioned epidemiological barriers are being breached and a larger number of younger and healthy individuals are developing severe disease. The new SARS-CoV-2 variants have key mutations that can induce significant changes in the virus-host interactions. Recent studies report that, some of these mutations, singly or in a group, enhance key mechanisms, such as binding of the receptor-binding domain (RBD) of the viral spike protein with the ACE2 receptor in the host-cells, increase the glycosylation of spike protein at the antigenic sites, and enhance the proteolytic cleavage of the spike protein, thus leading to improved host-cell entry and the replication of the virus. The putative changes in the virus-host interactions imparted by the mutations in the RBD sequence can potentially be the reason behind the breach of the observed epidemiological barriers. Susceptibility for contracting SARS-CoV-2 infection and the disease outcomes are known to be influenced by host-cell expressions of ACE2 and other proteases. The new variants can act more efficiently, and even with the lesser availability of the viral entry-receptor and the associated proteases, can have more efficient host-cell entry and greater replication resulting in high viral loads and prolonged viral shedding, widespread tissue-injury, and severe inflammation leading to increased transmissibility and lethality. Furthermore, the accumulating evidence shows that multiple new variants have reduced neutralization by both, natural and vaccine acquired antibodies, indicating that repeated and vaccine breakthrough infections may arise as serious health concerns in the ongoing pandemic. This article is protected by copyright. All rights reserved.
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TL;DR: This retrospective multi-center matched cohort study assessed the risk for severe COVID-19 (combination of severity indicators), intensive care unit (ICU) admission, and in-hospital mortality in hospitalized patients when infected with the Omicron variant compared with the Delta variant to demonstrate the added value of integrated genomic and clinical surveillance to recognize the multifactorial nature of CO VID-19 pathogenesis.
Abstract: This retrospective multi-center matched cohort study assessed the risk for severe COVID-19 (combination of severity indicators), intensive care unit (ICU) admission, and in-hospital mortality in hospitalized patients when infected with the Omicron variant compared to when infected with the Delta variant. The study is based on a causal framework using individually-linked data from national COVID-19 registries. The study population consisted of 954 COVID-19 patients (of which, 445 were infected with Omicron) above 18 years old admitted to a Belgian hospital during the autumn and winter season 2021–2022, and with available viral genomic data. Patients were matched based on the hospital, whereas other possible confounders (demographics, comorbidities, vaccination status, socio-economic status, and ICU occupancy) were adjusted for by using a multivariable logistic regression analysis. The estimated standardized risk for severe COVID-19 and ICU admission in hospitalized patients was significantly lower (RR = 0.63; 95% CI (0.30; 0.97) and RR = 0.56; 95% CI (0.14; 0.99), respectively) when infected with the Omicron variant, whereas in-hospital mortality was not significantly different according to the SARS-CoV-2 variant (RR = 0.78, 95% CI (0.28–1.29)). This study demonstrates the added value of integrated genomic and clinical surveillance to recognize the multifactorial nature of COVID-19 pathogenesis.
29 citations
TL;DR: In this article , the authors examined the SARS-CoV-2 mutant spectra of amplicons from the spike-coding region of 5 nasopharyngeal isolates derived from patients with vaccine breakthrough.
Abstract: Replication of SARS-CoV-2 in the human population is defined by distributions of mutants that are present at different frequencies within the infected host and can be detected by ultra-deep sequencing techniques. In this study, we examined the SARS-CoV-2 mutant spectra of amplicons from the spike-coding (S-coding) region of 5 nasopharyngeal isolates derived from patients with vaccine breakthrough. Interestingly, all patients became infected with the Alpha variant, but amino acid substitutions that correspond to the Delta Plus, Iota, and Omicron variants were present in the mutant spectra of the resident virus. Deep sequencing analysis of SARS-CoV-2 from patients with vaccine breakthrough revealed a rich reservoir of mutant types and may also identify tolerated substitutions that can be represented in epidemiologically dominant variants.
7 citations
TL;DR: In this paper , an in-silico reverse vaccinology approach was applied for multi-epitope vaccine construction against the spike protein of delta variant, which could induce an immune response against COVID-19 infection.
Abstract: The ongoing COVID-19 outbreak, initially identified in Wuhan, China, has impacted people all over the globe and new variants of concern continue to threaten hundreds of thousands of people. The delta variant (first reported in India) is currently classified as one of the most contagious variants of SARS-CoV-2. It is estimated that the transmission rate of delta variant is 225% times faster than the alpha variant, and it is causing havoc worldwide (especially in the USA, UK, and South Asia). The mutations found in the spike protein of delta variant make it more infective than other variants in addition to ruining the global efficacy of available vaccines. In the current study, an in silico reverse vaccinology approach was applied for multi-epitope vaccine construction against the spike protein of delta variant, which could induce an immune response against COVID-19 infection. Non-toxic, highly conserved, non-allergenic and highly antigenic B-cell, HTL, and CTL epitopes were identified to minimize adverse effects and maximize the efficacy of chimeric vaccines that could be developed from these epitopes. Finally, V1 vaccine construct model was shortlisted and 3D modeling was performed by refinement, docking against HLAs and TLR4 protein, simulation and in silico expression. In silico evaluation showed that the designed chimeric vaccine could elicit an immune response (i.e., cell-mediated and humoral) identified through immune simulation. This study could add to the efforts of overcoming global burden of COVID-19 particularly the variants of concern.
6 citations
TL;DR: In this article, the authors performed a demographic characterization of COVID-19 cases in Indian population diagnosed with SARS-CoV-2 genomic sequencing for delta variant, in terms of age and sex, severity of the illness and mortality rate, and post vaccination infections.
Abstract: ImportanceHigher risks of contracting infection, developing severe illness and mortality are known facts in aged and male sex if exposed to the wild type SARS-CoV-2 strains (Wuhan and B.1 strains). Now, accumulating evidence suggests greater involvement of lower age and narrowing the age and sex based differences for the severity of symptoms in infections with emerging SARS-CoV-2 variants. Delta variant (B.1.617.2) is now a globally dominant SARS-CoV-2 strain, however, current evidence on demographic characteristics for this variant are limited. Recently, delta variant caused a devastating second wave of COVID-19 in India. We performed a demographic characterization of COVID-19 cases in Indian population diagnosed with SARS-CoV-2 genomic sequencing for delta variant. ObjectiveTo determine demographic characteristics of delta variant in terms of age and sex, severity of the illness and mortality rate, and post-vaccination infections. DesignA cross sectional study SettingDemographic characteristics, including vaccination status (for two complete doses) and severity of the illness and mortality rate, of COVID-19 cases caused by wild type strain (B.1) and delta variant (B.1.617.2) of SARS-CoV-2 in Indian population were studied. ParticipantsCOVID-19 cases for which SARS-CoV-2 genomic sequencing was performed and complete demographic details (age, sex, and location) were available, were included. ExposuresSARS-CoV-2 infection with Delta (B.1.617.2) variant and wild type (B.1) strain. Main Outcomes and MeasuresThe patient metadata containing details for demographic and vaccination status (two complete doses) of the COVID-19 patients with confirmed delta variant and WT (B.1) infections were analyzed [total number of cases (N) =9500, Ndelta=6238, NWT=3262]. Further, severity of the illness and mortality were assessed in subsets of patients. Final data were tabulated and statistically analyzed to determine age and sex based differences in chances of getting infection and the severity of illness, and post-vaccination infections were compared between wild type and delta variant strains. Graphs were plotted to visualize the trends. ResultsWith delta variant, in comparison to wild type (B.1) strain, higher proportion of lower age groups, particularly <20 year (0-9 year: 4.47% vs. 2.3%, 10-19 year: 9% vs. 7%) were affected. The proportion of women contracting infection were increased (41% vs. 36%). The higher proportion of total young (0-19 year, 10% vs. 4%) (p=.017) population and young (14% vs. 3%) as well as adult (20-59 year, 75% vs. 55%) women developed symptoms/hospitalized with delta variant in comparison to B.1 infection (p< .00001). The mean age of contracting infection [Delta, men=37.9 ({+/-}17.2) year, women=36.6 ({+/-}17.6) year; B.1, men=39.6 ({+/-}16.9) year and women= 40.1 ({+/-}17.4) year (p< .001)] as well as developing symptoms/hospitalization [Delta, men=39.6({+/-} 17.4) year, women=35.6 ({+/-}16.9) year; B.1, men=47({+/-}18) year and women= 49.5({+/-}20.9) year (p< .001)] was considerably lower. The total mortality was about 1.8 times higher (13% vs. 7%). Risk of death increased irrespective of the sex (Odds ratio: 3.034, 95% Confidence Interval: 1.7-5.2, p<0.001), however, increased proportion of women (32% vs. 25%) were died. Further, multiple incidences of delta infections were noted following complete vaccination. Conclusions and RelevanceThe increased involvement of young (0-19 year) and women, lower mean age for contracting infection and symptomatic illness/hospitalization, higher mortality, and frequent incidences of post-vaccination infections with delta variant compared to wild type strain raises significant epidemiological concerns. Key PointsO_ST_ABSQuestionC_ST_ABSDid SARS-CoV-2 B.1.617.2 (Delta) variant infections show varied demographic characteristics in comparison to wild type strains? FindingsIn this cross sectional study viral genomic sequences of 9500 COVID-19 patients were analyzed. As the key findings, increased involvement of young (0-19 year) and women, lower mean age for contracting infection and symptomatic illness/hospitalization, higher mortality, and frequent incidences of post-vaccination infections with delta variant in comparison to wild type (WT) strain (B.1) were observed. MeaningThe findings of this study suggest that delta variant has varied demographic characteristics reflecting increased involvement of the young and women, and increased lethality in comparison to wild type strains.
6 citations
TL;DR: In this paper , a peptide-based chimeric vaccine that may potentially battle SARS-CoV-2 Omicron variant B.1.529 was proposed, which is a Variant of Concern (VOC) announced by the World Health Organization (WHO).
5 citations
References
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TL;DR: It is demonstrated that SARS-CoV-2 uses the SARS -CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming, and it is shown that the sera from convalescent SARS patients cross-neutralized Sars-2-S-driven entry.
15,362 citations
TL;DR: It is demonstrating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination, and it is shown that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of Sars- coV- 2 S and SARS S bind with similar affinities to human ACE2, correlating with the efficient spread of SATS among humans.
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TL;DR: Cryo–electron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter B0AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein of SARS-CoV-2 are presented, providing important insights into the molecular basis for coronavirus recognition and infection.
Abstract: Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome-coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious coronavirus disease 2019 (COVID-19) epidemic. Here, we present cryo-electron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter B0AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resolution of 2.9 angstroms, with a local resolution of 3.5 angstroms at the ACE2-RBD interface. The ACE2-B0AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues. These findings provide important insights into the molecular basis for coronavirus recognition and infection.
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TL;DR: A SARS-CoV-2 variant carrying the Spike protein amino acid change D614G has become the most prevalent form in the global pandemic, and it is found that the G614 variant grows to higher titer as pseudotyped virions.
3,302 citations
TL;DR: A review of the literature on mutations of the SARS-CoV-2 spike protein, the primary antigen, focusing on their impacts on antigenicity and contextualizing them in the protein structure is presented in this article.
Abstract: Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively neutral, a small proportion will affect functional properties and may alter infectivity, disease severity or interactions with host immunity. The emergence of SARS-CoV-2 in late 2019 was followed by a period of relative evolutionary stasis lasting about 11 months. Since late 2020, however, SARS-CoV-2 evolution has been characterized by the emergence of sets of mutations, in the context of ‘variants of concern’, that impact virus characteristics, including transmissibility and antigenicity, probably in response to the changing immune profile of the human population. There is emerging evidence of reduced neutralization of some SARS-CoV-2 variants by postvaccination serum; however, a greater understanding of correlates of protection is required to evaluate how this may impact vaccine effectiveness. Nonetheless, manufacturers are preparing platforms for a possible update of vaccine sequences, and it is crucial that surveillance of genetic and antigenic changes in the global virus population is done alongside experiments to elucidate the phenotypic impacts of mutations. In this Review, we summarize the literature on mutations of the SARS-CoV-2 spike protein, the primary antigen, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets. The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been characterized by the emergence of mutations and so-called variants of concern that impact virus characteristics, including transmissibility and antigenicity. In this Review, members of the COVID-19 Genomics UK (COG-UK) Consortium and colleagues summarize mutations of the SARS-CoV-2 spike protein, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets.
2,047 citations