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2.
Cell Reports Medicine ; : 100634, 2022.
Article in English | ScienceDirect | ID: covidwho-1805326

ABSTRACT

Lipid-nanoparticle (LNP)-mRNA vaccines offer protection against COVID-19. However, multiple variant lineages caused widespread breakthrough infections. Here, we generate LNP-mRNAs specifically encoding wildtype (WT), B.1.351 and B.1.617 SARS-CoV-2 spikes, and systematically study their immune responses. All three LNP-mRNAs induced potent antibody and T cell responses in animal models. However, differences in neutralization activity have been observed between variants. All three vaccines offer potent protection against in vivo challenges of authentic viruses of WA-1, Beta and Delta variant. Single cell transcriptomics of WT- and variant-specific LNP-mRNA vaccinated animals reveal a systematic landscape of immune cell populations and global gene expression. Variant-specific vaccination induces a systemic increase of reactive CD8 T cells and altered gene expression programs in B and T lymphocytes. BCR-seq and TCR-seq unveil repertoire diversity and clonal expansions in vaccinated animals. These data provide assessment of efficacy and direct systems immune profiling of variant-specific LNP-mRNA vaccination in vivo.

3.
Computational and Structural Biotechnology Journal ; 20:1168-1176, 2022.
Article in English | Web of Science | ID: covidwho-1800120

ABSTRACT

SARS-CoV-2, the virus causing the COVID-19 pandemic, changes frequently through the appearance of mutations constantly leading to new variants. However, only few variants evolve as dominating and will be considered as "Variants of Concern " (VOCs) by the world health organization (WHO). At the end of 2020 the alpha (B.1.1.7) variant appeared in the United Kingdom and dominated the pandemic situation until mid of 2021 when it was substituted by the delta variant (B.1.617.2) that first appeared in India as predominant. At the end of 2021, SARS-CoV-2 omicron (B.1.1.529) evolved as the dominating variant. Here, we use in silico modeling and molecular dynamics (MD) simulations of the receptor-binding domain of the viral spike protein and the host cell surface receptor ACE2 to analyze and compare the interaction pattern between the wild type, delta and omicron variants. We identified residue 493 in delta (glutamine) and omicron (arginine) with altered binding properties towards ACE2. (c) 2022 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creative-commons.org/licenses/by-nc-nd/4.0/).

4.
Chin Med ; 17(1): 40, 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1770556

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) causes a global pandemic and has devastating effects around the world, however, there are no specific antiviral drugs and vaccines for the constant mutation of SARS-CoV-2. PURPOSE: In this study, we evaluted the antiviral and anti-inflammatory activities of Liushen Capsules (LS) on different novel coronavirus in vitro, studied its therapeutic effects on novel SARS-CoV-2 infected mice and observed the LS's clinical efficacy and safety in COVID-19. METHODS: The antiviral and aiti-inflammatory effects of LS on the 501Y.V2/B.1.35 and G/478K.V1/ B.1.617.2 strains were determined in vitro. A hACE2 mouse model of novel SARS-CoV-2 pneumonia was established. Survival rates, histological changes, inflammatory markers, lung virus titers and the expression of the key proteins in the NF-κB/MAPK signaling pathway was detected by western blotting and immumohistochemical staining in the lungs were measured. Subsequently, the disease duration, prognosis of disease, time of negative nucleic acid and the cytokines levels in serum were used to assess the efficacy of treatment with LS in patients. RESULTS: The results showed that LS (2, 1, 0.5 µg/mL) could significantly inhibit the replication of the two SARS-CoV-2 variants and the expression of pro-inflammatory cytokines (IL-6, IL-8, IP-10, CCL-5, MIP-1α, IL-1α) induced by the virus in vitro. As for the survival experiment in mice, the survival rate of virus group was 20%, while LS-treatment groups (40, 80, 160 mg/kg) could increase the survival rate to 60, 100 and 100%, respectively. LS (40, 80, 160 mg/kg) could significantly decrease the lung titers in mice and it could improve the pathological changes, inhibit the excessive inflammatory mediators (IFN-α, IFN-γ, IP-10, MCP-1) and the protein expression of p-NF-κB p65 in mice. Moreover, LS could significantly decrease SARS-CoV-2-induced activation of p-NF-κB p65, p-IκBα, and p-p38 MAPK and increase the protein expression of the IκBα. In addition, the patient got complete relief of symptoms after being treated with LS for 6 days and was proven with negative PCR test after being treated for 23 days. Finally, treatment with LS could reduce the release of inflammatory cytokines (IL-6, PDGF-AA/BB, Eotaxin, MCP-1, MIP-1α, MIP-1ß, GRO, CCL-5, MCP-3, IP-10, IL-1α). CONCLUSION: LS effectively alleviated novel SARS-CoV-2 or variants induced pneumonia in vitro and in vivo, and improved the prognosis of COVID-19. In light of the efficacy and safety profiles, LS could be considered for the treatment of COVID-19 with a broad-spectrum antiviral and anti-inflammatory agent.

5.
Int J Biol Sci ; 18(5): 1844-1851, 2022.
Article in English | MEDLINE | ID: covidwho-1753905

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a pandemic. With the continuous evolution of the viral genome, SARS-CoV-2 has evolved many variants. B.1.617.2, also called Delta, is one of the most concerned variants. The Delta variant was first reported in India at the end of 2020 but has spread globally, by now, to 135 countries and is not stand still. Delta shared some mutations with other variants, and owned its special mutations on spike proteins, which may be responsible for its strong transmission and increasing virulence. Under these circumstances, a systematic summary of Delta is necessary. This review will focus on the Delta variant. We will describe all the characteristics of Delta (including biological features and clinical characteristics), analyze potential reasons for its strong transmission, and provide potential protective ways for combating Delta.


Subject(s)
COVID-19 , SARS-CoV-2 , Genome, Viral/genetics , Humans , Pandemics , SARS-CoV-2/genetics
6.
Viruses ; 14(3)2022 03 21.
Article in English | MEDLINE | ID: covidwho-1753692

ABSTRACT

There is a growing interest in using monoclonal antibodies (mAbs) in the early stages of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection to prevent disease progression. Little is known about the efficacy of mAbs against the delta variant of concern and its clinical presentations. We evaluated the effect of casirivimab/imdevimab treatment among five delta vaccine breakthrough patients. Symptomatic non-hospitalized vaccinated patients were submitted to nasopharyngeal swabs for the detection of SARS-CoV-2 and Next-Generation Sequencing (NGS). Blood analysis and chest Computed Tomography were also performed. A cocktail of casirivimab/imdevimab was administrated, and patients were monitored weekly. Clinical evolution was evaluated by the regression of the symptoms, negative results by real-time RT-PCR, and by the need of hospitalization: these aspects were considered as significant outcomes. In four cases, symptom reversion and viral load reduction were observed within 2 days and 7 days after mAbs treatment, respectively. Only one case, suffering from thymoma, was hospitalized 2 days later because of respiratory failure, which reverted within 18 days. mAbs treatment seems to be safe and effective against the delta variant and its clinical manifestations.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , COVID-19/drug therapy , Humans , SARS-CoV-2/genetics
7.
Cell ; 2022 Mar 18.
Article in English | MEDLINE | ID: covidwho-1748150

ABSTRACT

Virus-like particle (VLP) and live virus assays were used to investigate neutralizing immunity against Delta and Omicron SARS-CoV-2 variants in 259 samples from 128 vaccinated individuals. Following Delta breakthrough infection, titers against WT rose 57-fold and 3.1-fold compared with uninfected boosted and unboosted individuals, respectively, versus only a 5.8-fold increase and 3.1-fold decrease for Omicron breakthrough infection. Among immunocompetent, unboosted patients, Delta breakthrough infections induced 10.8-fold higher titers against WT compared with Omicron (p = 0.037). Decreased antibody responses in Omicron breakthrough infections relative to Delta were potentially related to a higher proportion of asymptomatic or mild breakthrough infections (55.0% versus 28.6%, respectively), which exhibited 12.3-fold lower titers against WT compared with moderate to severe infections (p = 0.020). Following either Delta or Omicron breakthrough infection, limited variant-specific cross-neutralizing immunity was observed. These results suggest that Omicron breakthrough infections are less immunogenic than Delta, thus providing reduced protection against reinfection or infection from future variants.

8.
Journal of Microbiology & Infectious Diseases ; 12(1):38-51, 2022.
Article in English | Academic Search Complete | ID: covidwho-1744717

ABSTRACT

The emergence of numerous variants of SARS-CoV-2 has caused massive setbacks and prolonged the COVID-19 pandemic. Some of the variants are still under investigation, while some have become a reason of grave concern. One such variant is B.1.617.2, known as the Delta variant, which was first detected in India. A comprehensive analysis and comparison of this particular variant have been done to the original Wuhan strain, and the possible reasons behind rapid mutation have also been discussed. A comprehensive literature search was done to summarize the information on the variants of SARS-CoV-2 and the reasons behind their mutation, with a significant focus on the B.1.617.2 variant. Data were collected from various online sources such as PubMed, Google Scholar, MEDLINE, Worldometer, WHO, CDC, and GISAID. In addition, 3D structures of spike proteins were obtained from Protein Data Bank (PDB). The data shows that the spike protein of the B.1.617.2 strain is highly mutated and has accumulated eight amino acid changes. Besides spike protein, changes in non-structural proteins (nsP2, nsP3, nsP4, nsP12, and nsP15), other structural proteins (nucleocapsid and membrane protein), and accessory proteins (ns3, ns7a) have been observed as well. Furthermore, in almost all the variants of SARS-CoV-2, D614G mutation occurs, suggesting its role in increased infectivity and transmission. New variants are continuously emerging on which we have no control. Spike mutations are more favored and essential in the evolution of new variants because it increases the transmissibility and infectivity of the virus. Therefore, to maximally protect public health, knowledge of different variants is essential. [ FROM AUTHOR] Copyright of Journal of Microbiology & Infectious Diseases is the property of Journal of Microbiology & Infectious Diseases and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

9.
Front Public Health ; 10: 823043, 2022.
Article in English | MEDLINE | ID: covidwho-1742277

ABSTRACT

An outbreak of the Delta (B.1.617.2) variant of SARS-CoV-2 that began around mid-June 2021 in Sydney, Australia, quickly developed into a nation-wide epidemic. The ongoing epidemic is of major concern as the Delta variant is more infectious than previous variants that circulated in Australia in 2020. Using a re-calibrated agent-based model, we explored a feasible range of non-pharmaceutical interventions, including case isolation, home quarantine, school closures, and stay-at-home restrictions (i.e., "social distancing.") Our modelling indicated that the levels of reduced interactions in workplaces and across communities attained in Sydney and other parts of the nation were inadequate for controlling the outbreak. A counter-factual analysis suggested that if 70% of the population followed tight stay-at-home restrictions, then at least 45 days would have been needed for new daily cases to fall from their peak to below ten per day. Our model predicted that, under a progressive vaccination rollout, if 40-50% of the Australian population follow stay-at-home restrictions, the incidence will peak by mid-October 2021: the peak in incidence across the nation was indeed observed in mid-October. We also quantified an expected burden on the healthcare system and potential fatalities across Australia.


Subject(s)
COVID-19 , SARS-CoV-2 , Australia/epidemiology , COVID-19/epidemiology , Disease Outbreaks , Humans
10.
Microbiol Spectr ; : e0217621, 2022 Mar 14.
Article in English | MEDLINE | ID: covidwho-1741582

ABSTRACT

In this report, we describe the development of a reverse transcription-quantitative PCR (RT-qPCR) assay, termed Alpha-Delta assay, which can detect all severe acute respiratory syndrome coronavirus 2 (SC-2) variants and distinguish between the Alpha (B.1.1.7) and Delta (B.1.617.2) variants. The Alpha- and Delta-specific reactions in the assay target mutations that are strongly linked to the target variant. The Alpha reaction targets the D3L substitution in the N gene, and the Delta reaction targets the spike gene 156 to 158 mutations. Additionally, we describe a second Delta-specific assay that we use as a confirmatory test for the Alpha-Delta assay that targets the 119 to 120 deletion in the Orf8 gene. Both reactions have similar sensitivities of 15 to 25 copies per reaction, similar to the sensitivity of commercial SC-2 detection tests. The Alpha-Delta assay and the Orf8119del assay were successfully used to classify clinical samples that were subsequently analyzed by whole-genome sequencing. Lastly, the capability of the Alpha-Delta assay and Orf8119del assay to identify correctly the presence of Delta RNA in wastewater samples was demonstrated. This study provides a rapid, sensitive, and cost-effective tool for detecting and classifying two worldwide dominant SC-2 variants. It also highlights the importance of a timely diagnostic response to the emergence of new SC-2 variants with significant consequences on global health. IMPORTANCE The new assays described herein enable rapid, straightforward, and cost-effective detection of severe acute respiratory syndrome coronavirus 2 (SC-2) with immediate classification of the examined sample as Alpha, Delta, non-Alpha, or non-Delta variant. This is highly important for two main reasons: (i) it provides the scientific and medical community with a novel diagnostic tool to rapidly detect and classify any SC-2 sample of interest as Alpha, Delta, or none and can be applied to both clinical and environmental samples, and (ii) it demonstrates how to respond to the emergence of new variants of concern by developing a variant-specific assay. Such assays should improve our preparedness and adjust the diagnostic capacity to serve clinical, epidemiological, and research needs.

11.
World J Pediatr ; 2022 Mar 14.
Article in English | MEDLINE | ID: covidwho-1739438

ABSTRACT

BACKGROUND: The aim of this study was to analyze the clinical characteristics of 66 pediatric patients with B.1.617.2 (Delta) variant of coronavirus disease 2019 (COVID-19). METHODS: Sixty-six pediatric patients with B.1.617.2 (Delta) variant of COVID-19 admitted to the hospital from July to August 2021 were classified into mild (n = 41) and moderate groups (n = 25). Clinical characteristics, laboratory data and dynamic trends in different time periods were analyzed retrospectively. RESULTS: There were no statistically significant differences in age, gender ratios and clinical symptoms between the mild group and the moderate group. All the patients in the moderate group had clusters of onsets, and the incubation period was shorter than that of the mild group. Within 24 hours of admission, the levels of erythrocyte sedimentation rate, cardiac troponin I, D-dimer in the moderate group were higher than that in the mild group (P < 0.05). The titers of immunoglobulin (Ig) G and IgM antibodies gradually increased after disease onset. Thirty-five (53.03%) children were tested positive for antibodies in 4-12 days. IgG increased gradually, while IgM decreased obviously in about 15 days after disease onset. The cycle threshold values of open reading frame 1ab and nucleocapsid protein gene in the severe acute respiratory syndrome coronavirus 2 genomes increased gradually on the 3rd, 6th, 9th, and 12th days after disease onset, compared with those in day 0. CONCLUSIONS: The symptoms of children with B.1.617.2 (Delta) variant of COVID-19 were mild. The description and analysis of the clinical characteristics and laboratory data can help medical staff to evaluate the condition of children with COVID-19 and to accumulate more clinical experience.

12.
Transbound Emerg Dis ; 2022 Mar 09.
Article in English | MEDLINE | ID: covidwho-1735979

ABSTRACT

Against the backdrop of the second wave of COVID-19 pandemic in India that started in March 2021, we have monitored the spike (S) protein mutations in all the reported (GISAID portal) whole-genome sequences of SARS-CoV-2 circulating in India from 1 January 2021 to 31 August 2021. In the 43,102 SARS-CoV-2 genomic sequences analysed, we have identified 24,260 amino acid mutations in the S protein, based on which 265 Pango lineages could be categorized. The dominant lineage in most of the 28 states of India and its 8 union territories was B.1.617.2 (the delta variant). However, the states Madhya Pradesh, Jammu & Kashmir, and Punjab had B.1.1.7 (alpha variant) as the major lineage, while the Himachal Pradesh state reported B.1.36 as the dominating lineage. A detailed analysis of various domains of S protein was carried out for detecting mutations having a prevalence of >1%; 70, 18, 7, 3, 9, 4, and 1 (N = 112) such mutations were observed in the N-terminal domain, receptor binding domain, C -terminal domain, fusion peptide region, heptapeptide repeat (HR)-1 domains, signal peptide domain, and transmembrane region, respectively. However, no mutations were recorded in the HR-2 and cytoplasmic domains of the S protein. Interestingly, 13.39% (N = 15) of these mutations were reported to increase the infectivity and pathogenicity of the virus; 2% (N = 3) were known to be vaccine breakthrough mutations, and 0.89% (N = 1) were known to escape neutralizing antibodies. The biological significance of 82% (N = 92) of the reported mutations is yet unknown. As SARS-CoV-2 variants are emerging rapidly, it is critical to continuously monitor local viral mutations to understand national trends of virus circulation. This can tremendously help in designing better preventive regimens in the country, and avoid vaccine breakthrough infections.

13.
Vet Microbiol ; 268: 109395, 2022 Mar 11.
Article in English | MEDLINE | ID: covidwho-1735038

ABSTRACT

SARS-CoV-2 has exhibited varying pathogenesis in a variety of Mammalia family's including Canidae, Mustelidae, Hominidae, Cervidae, Hyaenidae, and Felidae. Novel SARS-CoV-2 variants characterized by spike protein mutations have recently resulted in clinical and epidemiological concerns, as they potentially have increased infectious rates, increased transmission, or reduced neutralization by antibodies produced via vaccination. Many variants have been identified at this time, but the variant of continuing concern has been the Delta variant (B.1.617.2), due to its increased transmissibility and infectious rate. Felines vaccinated using an experimental SARS-CoV-2 spike protein-based veterinary vaccine mounted a robust immune response to the SARS-CoV-2 spike protein. Using a reporter virus particle system and feline serum, we have verified that vaccinated felines produce antibodies that neutralize the SARS-CoV-2 Wuhan strain and variant B.1.617.2 at comparable levels.

15.
BMC Med ; 20(1): 102, 2022 03 03.
Article in English | MEDLINE | ID: covidwho-1724486

ABSTRACT

BACKGROUND: The COVID-19 pandemic is caused by the betacoronavirus SARS-CoV-2. In November 2021, the Omicron variant was discovered and immediately classified as a variant of concern (VOC), since it shows substantially more mutations in the spike protein than any previous variant, especially in the receptor-binding domain (RBD). We analyzed the binding of the Omicron RBD to the human angiotensin-converting enzyme-2 receptor (ACE2) and the ability of human sera from COVID-19 patients or vaccinees in comparison to Wuhan, Beta, or Delta RBD variants. METHODS: All RBDs were produced in insect cells. RBD binding to ACE2 was analyzed by ELISA and microscale thermophoresis (MST). Similarly, sera from 27 COVID-19 patients, 81 vaccinated individuals, and 34 booster recipients were titrated by ELISA on RBDs from the original Wuhan strain, Beta, Delta, and Omicron VOCs. In addition, the neutralization efficacy of authentic SARS-CoV-2 wild type (D614G), Delta, and Omicron by sera from 2× or 3× BNT162b2-vaccinated persons was analyzed. RESULTS: Surprisingly, the Omicron RBD showed a somewhat weaker binding to ACE2 compared to Beta and Delta, arguing that improved ACE2 binding is not a likely driver of Omicron evolution. Serum antibody titers were significantly lower against Omicron RBD compared to the original Wuhan strain. A 2.6× reduction in Omicron RBD binding was observed for serum of 2× BNT162b2-vaccinated persons. Neutralization of Omicron SARS-CoV-2 was completely diminished in our setup. CONCLUSION: These results indicate an immune escape focused on neutralizing antibodies. Nevertheless, a boost vaccination increased the level of anti-RBD antibodies against Omicron, and neutralization of authentic Omicron SARS-CoV-2 was at least partially restored. This study adds evidence that current vaccination protocols may be less efficient against the Omicron variant.


Subject(s)
COVID-19 , COVID-19/prevention & control , Humans , Pandemics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
16.
Cell Rep ; 38(7): 110394, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1719436

ABSTRACT

The emergence of the SARS-CoV-2 Delta variant (B.1.617.2) raises concerns about potential reduced sensitivity of the virus to antibody neutralization and subsequent vaccine breakthrough infections. Here, we use a live virus neutralization assay with sera from Pfizer- and Moderna-vaccinated individuals to examine neutralizing antibody titers against SARS-CoV-2 and observe a 3.9- and 2.7-fold reduction, respectively, in neutralizing antibody titers against the Delta variant compared with an early isolate bearing only a D614G substitution in its spike protein. We observe similar reduced sensitivity with sera from hamsters that were previously infected with an early isolate of SARS-CoV-2. Despite this reduction in neutralizing antibody titers against the Delta variant, hamsters previously infected (up to 15 months earlier) with an early isolate are protected from infection with the Delta variant, suggesting that the immune response to the first infection is sufficient to provide protection against subsequent infection with the Delta variant.


Subject(s)
Adaptive Immunity , COVID-19/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/transmission , COVID-19/virology , COVID-19 Vaccines/immunology , Cricetinae , Disease Models, Animal , Humans , Reinfection/immunology , Reinfection/transmission , Reinfection/virology , SARS-CoV-2/genetics , Viral Load
17.
J Med Virol ; 94(4): 1641-1649, 2022 04.
Article in English | MEDLINE | ID: covidwho-1718410

ABSTRACT

Emerging severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) variants, especially those of concern, may have an impact on the virus's transmissibility and pathogenicity, as well as diagnostic equipment performance and vaccine effectiveness. Even though the SARS-CoV-2 Delta variant (B.1.617.2) emerged during India's second wave of infections, Delta variants have grown dominant internationally and are still evolving. On November 26, 2021, World Health Organization identified the variant B.1.1.529 as a variant of concern, naming it Omicron, based on evidence that Omicron contains numerous mutations that may influence its behavior. However, the mode of transmission and severity of the Omicron variant remains unknown. We used computational studies to examine the Delta and Omicron variants in this study and found that the Omicron variant had a higher affinity for human angiotensin-converting enzyme 2 (ACE2) than the Delta variant due to a significant number of mutations in the SARS-CoV-2 receptor-binding domain (RBD), indicating a higher potential for transmission. Based on docking studies, the Q493R, N501Y, S371L, S373P, S375F, Q498R, and T478K mutations contribute significantly to high binding affinity with human ACE2. In comparison to the Delta variant, both the entire spike protein and the RBD in Omicron include a high proportion of hydrophobic amino acids such as leucine and phenylalanine. These amino acids are located within the protein's core and are required for structural stability. We observed a disorder-order transition in the Omicron variant between spike protein RBD regions 468-473, and it may be significant in the influence of disordered residues/regions on spike protein stability and binding to ACE2. A future study might investigate the epidemiological and biological consequences of the Omicron variant.


Subject(s)
SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Angiotensin-Converting Enzyme 2/chemistry , Binding Sites , COVID-19/virology , Humans , Hydrophobic and Hydrophilic Interactions , Molecular Docking Simulation , Mutation , Protein Binding , Protein Stability , Protein Structure, Secondary , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
18.
Informatics in Medicine Unlocked ; : 100900, 2022.
Article in English | ScienceDirect | ID: covidwho-1712708

ABSTRACT

Background and objective The B.1.617.2 known as the Delta-variant harbors diverse Spike-mutations with developed transmissibility and immune-evasion more than wild/D614G/N501Y variants. The Delta-variant claimed comparatively a large number of lives globally. In the present study, the binding-affinities of these variants’ spikes to the human lung-ACE2 were investigated. Further, a certain portion of the spike-protein with a desired mutation was tested in-silico to block the ACE2. Methods Structure of spike-variants were retrieved from PDB/GISAID and used for homology-modeling (SWISS-MODEL). A different combination of spike-ACE2 binding 1:1 or competitive blind-docking was performed using the Haddock 2.4 web-server. Eventually, two cut-segments (84 amino-acid of wild-spike, 432–516 Cut1) and its mutant T500S;Cut 2 were screened (Swiss-model Expasy-server) as blocker/inhibitor of all spike-variants (PyMOL-V2.2.2). Results It is shown that the stability and energy of the Delta binding-affinity to ACE2 is far more than others. The number H-bonding (5), their lengths (1.7 Å-2.8 Å) and energy, Van-der-Walls energy, Haddock-score were highly favorable for more stable-binding of Delta-RBD to ACE2. The Ramachandran-plot (Zlab/UMassMed Bioinfo) data supports this. We observed the best Haddock score as −120.8±2.6 for Delta with Van-der-Walls and electrostatic-energy as −62.9 and −208.7, respectively. The highest binding-affinity (ΔG) was −10.7 kcal/mol. Its THR500 and GLN506 strongly bind with the LYS353 of ACE2. The Cut1 and its mutant T500S completely blocked Delta-spike binding to ACE2 with ΔG -8.4 and −10.6 kcal/mol, respectively. But during the comparison between 2 Cuts, Cut1 showed better results. Conclusions Fractioned spike-protein from the conserved Receptor-Binding-Domain (RBD) could universally block the virus at entry-level, thus completely protecting any intercellular metabolism. Bioinformatics is an emerging field for screening of some drug/therapeutic targets from numerous options, minimizing time and expenses.

19.
Clin Infect Dis ; 2021 Aug 23.
Article in English | MEDLINE | ID: covidwho-1702780

ABSTRACT

BACKGROUND: he impact of SARS-CoV-2 variants of concern (VOCs) on disease severity is unclear. In this retrospective study, we compared outcomes of patients infected with B.1.1.7, B.1.351, and B.1.617.2 with those with wild-type strains from early 2020. METHODS: National surveillance data from 1-January-2021 to 22-May-2021 were obtained from the Ministry of Health, and outcomes in relation to VOC were explored. Detailed patient level data from all patients with VOC infection admitted to our center between 20-December-2020 and 12-May-2021 were analyzed. Clinical outcomes were compared with a cohort of 846 patients admitted from January-April 2020. RESULTS: 829 patients in Singapore in the study period were infected with these 3 VOCs. After adjusting for age and sex, B.1.617.2 was associated with higher odds of oxygen requirement, ICU admission, or death (adjusted odds ratio (aOR) 4.90, [95% CI 1.43-30.78]). 157 of these patients were admitted to our center. After adjusting for age, sex, comorbidities, and vaccination, aOR for pneumonia with B.1.617.2 was 1.88 [95% CI 0.95-3.76]) compared with wild-type. These differences were not seen with B.1.1.7 and B.1.351. Vaccination status was associated with decreased severity. B.1.617.2 was associated with significantly lower PCR Ct values and longer duration of Ct value ≤30 (median duration 18 days for B.1.617.2, 13 days for wild-type). CONCLUSIONS: There was a signal toward increased severity associated with B.1.617.2. The association of B.1.617.2 with lower Ct value and longer viral shedding provides a potential mechanism for increased transmissibility. These findings provide an impetus for the rapid implementation of vaccination programs.

20.
Math Biosci Eng ; 19(4): 3591-3596, 2022 02 07.
Article in English | MEDLINE | ID: covidwho-1704200

ABSTRACT

In this work, we report a large-scale synchronized replacement pattern of the Alpha (B.1.1.7) variant by the Delta (B.1.617.2) variant of SARS-COV-2. We argue that this phenomenon is associated with the invasion timing and the transmissibility advantage of the Delta (B.1.617.2) variant. Alpha (B.1.1.7) variant skipped some countries/regions, e.g. India and neighboring countries/regions, which could have led to a mild first wave before the invasion of the Delta (B.1.617.2) variant, in term of reported COVID-deaths per capita.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/epidemiology , Humans , India/epidemiology , Pandemics , SARS-CoV-2/genetics
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