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1
Yazhini, Arangasamy. "D614G substitution at the hinge region enhances the stability of trimeric SARS-CoV-2 spike protein." Bioinformation 17, no. 3 (2021): 439–45. http://dx.doi.org/10.6026//97320630017439.
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Mutations in the spike protein of SARS-CoV-2 are the major causes for the modulation of ongoing COVID-19 infection. Currently, the D614G substitution in the spike protein has become dominant worldwide. It is associated with higher infectivity than the ancestral (D614) variant. We demonstrate using Gaussian network model-based normal mode analysis that the D614G substitution occurs at the hinge region that facilitates domain-domain motions between receptor binding domain and S2 region of the spike protein. Computer-aided mutagenesis and inter-residue energy calculations reveal that contacts involving D614 are energetically frustrated. However, contacts involving G614 are energetically favourable, implying the substitution strengthens residue contacts that are formed within as well as between protomers. We also find that the free energy difference (ΔΔG) between two variants is -2.6 kcal/mol for closed and -2.0 kcal/mol for 1-RBD up conformation. Thus, the hermodynamic stability has increased upon D614G substitution. Whereas the reverse mutation in spike protein structures having G614 substitution has resulted in the free energy differences of 6.6 kcal/mol and 6.3 kcal/mol for closed and 1-RBD up conformations, respectively, indicating that the overall thermodynamic stability has decreased. These results suggest that the D614G substitution modulates the flexibility of spike protein and confers enhanced thermodynamic stability irrespective of conformational states. This data concurs with the known information demonstrating increased availability of the functional form of spike protein trimer upon D614G substitution.
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Hernandez Avila, Carlos Enrique, Carlos Alexander Ortega ´Perez, Noé Rigoberto Rivera, and Xochitl Sandoval López. "Análisis de la mutación D614G encontrada en secuencias del genoma completo de SARS-CoV-2 en El Salvador." Alerta, Revista científica del Instituto Nacional de Salud 4, no. 1 (2021): 72–77. http://dx.doi.org/10.5377/alerta.v4i1.10683.
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Se realizó durante el mes de octubre del 2020 la secuenciación del genoma de muestras autóctonas de SARS-CoV-2. Objetivo. Analizar in silico las mutaciones D614G en las secuencias aisladas en El Salvador. Metodología. Se analizaron secuencias utilizando la plataforma bioinformática SOPHiA-DDM-V5.7.10 para la determinación de las variantes por mutaciones con sentido erróneo. utilizando la plataforma Nexclade beta v0.8.1. se visualizó y comparo la proteína S silvestre (D614: PDB ID: 6VXX) y de la variante mutada (D614G: PDB ID: 6XS6). El modelamiento y generación de imágenes de los detalles moleculares de las proteínas se utilizó Pymol-v1.7.2.3. Resultados. El análisis de los cristales de la proteína S silvestre y mutada muestra diferencias a nivel molecular incluyendo la pérdida de interacciones entre el residuo G614 del dominio S1 y la treonina 859 de dominio S2, favoreciendo de esta manera la conformación abierta de la proteína S, la cual es necesaria para la interacción de S con el receptor ACE2.Conclusión. El predominio mundial de la D614G y las evidencias de laboratorio y bioinformáticas publicadas hasta la fecha, apuntan hacia una posible mayor infectividad y transmisibilidad conferida por la variante D614G detectada en las secuencias del SARS-CoV-2 en El Salvador.
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Kullappan, Malathi, Jenifer M Ambrose, and Surapaneni Krishna Mohan. "Lead Identification for Severe Acute Respiratory Syndrome Coronavirus-2 Spike D614G Variant of COVID-19: A virtual Screening Process." Biomedical and Pharmacology Journal 14, no. 4 (2021): 1929–39. http://dx.doi.org/10.13005/bpj/2291.
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COVID-19, a pandemic disease caused by single-stranded RNA virus Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The structural spike (S) protein of SARS-CoV-2 plays a vital role in host cell entry, where the Angiotensin-Converting Enzyme-2 (ACE2) receptor of the human cell binds to the Receptor Binding Domain (RBD) region of the S1 domain and makes cell entry. The binding affinity of SARS-CoV-2-ACE2 is tenfold higher than the SARS-CoV-1-ACE2. Recent studies expose that the SARS-CoV-2 S D614G variant is highly infectious than D614 protein, also the D614G variant is highly stable than D614. So far, there is no effective viral-specific regimen for COVID-19. To overcome such problems, in our study, we have utilized the ZINC database to screen potent leads against the highly transmitting SARS-CoV-2 spike D614G protein, through a virtual screening procedure. We have applied three computational tools iGEMDOCK server, AutoDock version 4.2.6 and admetSAR to get active leads. The ZINC000150588351 (Elbasvir), ZINC000064540179 (Sofosbuvir analogue) and ZINC000137700912 (Sofosbuvir analogue) molecules have a greater binding affinity with the high binding energies of -8.22 kcal/mol, -8.13 kcal/mol and -7.64 kcal/mol respectively. The molecules ZINC000064540179 and ZINC000137700912 have high binding energy than their core molecule Sofosbuvir (ZINC100074252) of -4.06 kcal/mol. The ADMET prediction of these molecules reveals satisfactory human intestinal absorption and non-mutagenic property. Our results deliver valuable contributions to the design of inhibitors against COVID-19.
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Benton, Donald J., Antoni G. Wrobel, Chloë Roustan, et al. "The effect of the D614G substitution on the structure of the spike glycoprotein of SARS-CoV-2." Proceedings of the National Academy of Sciences 118, no. 9 (2021): e2022586118. http://dx.doi.org/10.1073/pnas.2022586118.
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The majority of currently circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses have mutant spike glycoproteins that contain the D614G substitution. Several studies have suggested that spikes with this substitution are associated with higher virus infectivity. We use cryo-electron microscopy to compare G614 and D614 spikes and show that the G614 mutant spike adopts a range of more open conformations that may facilitate binding to the SARS-CoV-2 receptor, ACE2, and the subsequent structural rearrangements required for viral membrane fusion.
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Wang, Hai-xin, Li Zhang, Zi-teng Liang, et al. "Infectivity and antigenicity of pseudoviruses with high-frequency mutations of SARS-CoV-2 identified in Portugal." Archives of Virology 167, no. 2 (2022): 459–70. http://dx.doi.org/10.1007/s00705-021-05327-0.
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AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a major impact on global human health. During the spread of SARS-CoV-2, weakened host immunity and the use of vaccines with low efficacy may result in the development of more-virulent strains or strains with resistance to existing vaccines and antibodies. The prevalence of SARS-CoV-2 mutant strains differs between regions, and this variation may have an impact on the effectiveness of vaccines. In this study, an epidemiological investigation of SARS-CoV-2 in Portugal was performed, and the VSV-ΔG-G* pseudovirus system was used to construct 12 spike protein epidemic mutants, D614G, A222V+D614G, B.1.1.7, S477N+D614G, P1162R+D614G+A222V, D839Y+D614G, L176F+D614G, B.1.1.7+L216F, B.1.1.7+M740V, B.1.258, B.1.258+L1063F, and B.1.258+N751Y. The mutant pseudoviruses were used to infect four susceptible cell lines (Huh7, hACE2-293T-293T, Vero, and LLC-MK2) and 14 cell lines overexpressing ACE2 from different species. Mutant strains did not show increased infectivity or cross-species transmission. Neutralization activity against these pseudoviruses was evaluated using mouse serum and 11 monoclonal antibodies. The neutralizing activity of immunized mouse serum was not significantly reduced with the mutant strains, but the mutant strains from Portugal could evade nine of the 11 monoclonal antibodies tested. Neutralization resistance was mainly caused by the mutations S477N, N439K, and N501Y in the spike-receptor binding domain. These findings emphasize the importance of SARS-CoV-2 mutation tracking in different regions for epidemic prevention and control.
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González-Puelma, Jorge, Jacqueline Aldridge, Marco Montes de Oca, et al. "Mutation in a SARS-CoV-2 Haplotype from Sub-Antarctic Chile Reveals New Insights into the Spike’s Dynamics." Viruses 13, no. 5 (2021): 883. http://dx.doi.org/10.3390/v13050883.
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The emergence of SARS-CoV-2 variants, as observed with the D614G spike protein mutant and, more recently, with B.1.1.7 (501Y.V1), B.1.351 (501Y.V2) and B.1.1.28.1 (P.1) lineages, represent a continuous threat and might lead to strains of higher infectivity and/or virulence. We report on the occurrence of a SARS-CoV-2 haplotype with nine mutations including D614G/T307I double-mutation of the spike. This variant expanded and completely replaced previous lineages within a short period in the subantarctic Magallanes Region, southern Chile. The rapid lineage shift was accompanied by a significant increase of cases, resulting in one of the highest incidence rates worldwide. Comparative coarse-grained molecular dynamic simulations indicated that T307I and D614G belong to a previously unrecognized dynamic domain, interfering with the mobility of the receptor binding domain of the spike. The T307I mutation showed a synergistic effect with the D614G. Continuous surveillance of new mutations and molecular analyses of such variations are important tools to understand the molecular mechanisms defining infectivity and virulence of current and future SARS-CoV-2 strains.
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Ahangarzadeh, Shahrzad, Alireza Yousefi, Mohammad Mehdi Ranjbar, et al. "Association of Clinical Features with Spike Glycoprotein Mutations in Iranian COVID-19 Patients." Journal of Clinical Medicine 11, no. 21 (2022): 6315. http://dx.doi.org/10.3390/jcm11216315.
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Background: Mutations in spike glycoprotein, a critical protein of SARS-CoV-2, could directly impact pathogenicity and virulence. The D614G mutation, a non-synonymous mutation at position 614 of the spike glycoprotein, is a predominant variant circulating worldwide. This study investigated the occurrence of mutations in the crucial zone of the spike gene and the association of clinical symptoms with spike mutations in isolated viruses from Iranian patients infected with SARS-CoV-2 during the second and third waves of the COVID-19 epidemic in Isfahan, the third-largest city in Iran. Methods: The extracted RNA from 60 nasopharyngeal samples of COVID-19 patients were subjected to cDNA synthesis and RT-PCR (in three overlapping fragments). Each patient’s reverse transcriptase polymerase chain reaction (RT-PCR) products were assembled and sequenced. Information and clinical features of all sixty patients were collected, summarized, and analyzed using the GENMOD procedure of SAS 9.4. Results: Analysis of 60 assembled sequences identified nine nonsynonymous mutations. The D614G mutation has the highest frequency among the amino acid changes. In our study, in 31 patients (51.66%), D614G mutation was determined. For all the studied symptoms, no significant relationship was observed with the incidence of D614G mutation. Conclusions: D614G, a common mutation among several of the variants of SARS-CoV-2, had the highest frequency among the studied sequences and its frequency increased significantly in the samples of the third wave compared to the samples of the second wave of the disease.
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Choi, Kwang-Eun, Jeong-Min Kim, JeeEun Rhee, Ae Kyung Park, Eun-Jin Kim, and Nam Sook Kang. "Molecular Dynamics Studies on the Structural Characteristics for the Stability Prediction of SARS-CoV-2." International Journal of Molecular Sciences 22, no. 16 (2021): 8714. http://dx.doi.org/10.3390/ijms22168714.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the COVID-19 pandemic in the world. The spike protein of the various proteins encoded in SARS-CoV-2 binds to human ACE2, fuses, and enters human cells in the respiratory system. Spike protein, however, is highly variable, and many variants were identified continuously. In this study, Korean mutants for spike protein (D614G and D614A-C terminal domain, L455F and F456L-RBD, and Q787H-S2 domain) were investigated in patients. Because RBD in spike protein is related to direct interaction with ACE2, almost all researches were focused on the RBD region or ACE2-free whole domain region. The 3D structure for spike protein complexed with ACE2 was recently released. The stability analysis through RBD distance among each spike protein chain and the binding free energy calculation between spike protein and ACE2 were performed using MD simulation depending on mutant types in 1-, 2-, and 3-open-complex forms. D614G mutant of CT2 domain, showing to be the most prevalent in the global pandemic, showed higher stability in all open-complex forms than the wild type and other mutants. We hope this study will provide an insight into the importance of conformational fluctuation in the whole domain, although RBD is involved in the direct interaction with ACE2.
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Mat Jusoh, Siti Asmaa, Parisa Foroozandeh, Yan Fen Lee, Mardani Abdul Halim, Manoj Kumar Laskmanan, and Shaharum Shamsuddin. "COVID-19 Mini-Review: D614G Mutation as an Independent Risk-Factor to the Expression of ACE2 and DPP4 Associated Increased Severity in COVID-19." Sains Malaysiana 50, no. 4 (2021): 1175–86. http://dx.doi.org/10.17576/jsm-2021-5004-27.
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The novel coronavirus 2019 (COVID-19) has struck more than 99 million people worldwide and had claimed more than 2 million lives as of 23 January 2021, which affecting 221 countries/nations. Until now, the pandemic has not shown signals of slowing down, with no proven vaccine in sight. People are speculating on this unprecedented event. It is well documented that the receptor-binding domain (RBD) of the viral spiked S1 glycoprotein directly bind angiotensin-converting enzyme 2 (ACE2) and dipeptidyl-peptidase-4 (DPP4) or CD26 (cluster of differentiation 26) receptors lead to their entry. The latest evidence demonstrated that SAR-CoV-2 possesses genetic heterogeneity, lead to the existence of a new SAR-CoV-2 variant, such as D614G encoded the spiked S1. The mutation involved changes in amino acid sequence of D (aspartic acid) into G (guanine) at position 614. D614G was reported to confer high infectivity and became the dominant form of the virus globally. Interestingly, current evidence found that D614G protein increases its infectivity dependent on the ACE2 receptor, and its co-binding receptor, DPP4. This proclaims implied to COVID-19 high-risk groups; the aging population and the people with comorbidities; hypertension, cardiovascular disease, and diabetes, which constituted the most of lethal cases, that overexpressed ACE2 and DPP4. The review aims to find an association between COVID-19 infectivity and severity relating to D614G mutation with the expression of ACE2 or DPP4 in these groups. We proposed that D614G mutation and expressions of ACE2 and DPP4 were mutually inclusive for increase infectivity, but not severity in COVID-19’s patients.
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Sukhova, Maria, Maria Byazrova, Artem Mikhailov, et al. "Humoral Immune Responses in Patients with Severe COVID-19: A Comparative Pilot Study between Individuals Infected by SARS-CoV-2 during the Wild-Type and the Delta Periods." Microorganisms 11, no. 9 (2023): 2347. http://dx.doi.org/10.3390/microorganisms11092347.
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Since the onset of the COVID-19 pandemic, humanity has experienced the spread and circulation of several SARS-CoV-2 variants that differed in transmissibility, contagiousness, and the ability to escape from vaccine-induced neutralizing antibodies. However, issues related to the differences in the variant-specific immune responses remain insufficiently studied. The aim of this study was to compare the parameters of the humoral immune responses in two groups of patients with acute COVID-19 who were infected during the circulation period of the D614G and the Delta variants of SARS-CoV-2. Sera from 48 patients with acute COVID-19 were tested for SARS-CoV-2 binding and neutralizing antibodies using six assays. We found that serum samples from the D614G period demonstrated 3.9- and 1.6-fold increases in RBD- and spike-specific IgG binding with wild-type antigens compared with Delta variant antigens (p < 0.01). Cluster analysis showed the existence of two well-separated clusters. The first cluster mainly consisted of D614G-period patients and the second cluster predominantly included patients from the Delta period. The results thus obtained indicate that humoral immune responses in D614G- and Delta-specific infections can be characterized by variant-specific signatures. This can be taken into account when developing new variant-specific vaccines.
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Banerjee, Shuvam, Sreejita Dutta, Shrinjana Dhar, and Pritha Bhattacharjee. "Analysis of mutational spectra in SARS-CoV-2 spike protein and its course of evolution to predict the ‘Alarming Variants’ for the upcoming wave of pandemic." Journal of Scientific Research 66, no. 05 (2022): 24–33. http://dx.doi.org/10.37398/jsr.2022.660505.
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COVID-19 disease extended to different parts of the globe developing variations in the SARS-CoV-2 viral sequence since its emergence. Some of those variations had functional implications with major concerns, which the WHO termed as ‘Variant of Concern’ during the second wave of infection. The signatures of VOCs are specific to countries where they are observed and are popularly recognized with the country names. It is noteworthy to mention that some new mutations are always evolving and it is expected that some of these new mutations could play a havoc role in hitting the upcoming wave of the pandemic. This work aimed to list all the mutations of the Spike protein that evolved with time and how they have increased their presence in a given course of time (three-time point analysis) and stabilized in the SARS-COV-2 infected population. The mutations that will play predominant role in the upcoming pandemic wave are mentioned here:T19I, V213G, D405N, R408S,G142D, G339D, K417N, N440K, D614G, Q954H, N969K mutations in India; G142D, G339D, S373P, S375F, K417N, N440K, S477N, T478K, Q493R, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, N969K in South Africa; T95I, G339D, S373P, S375F, N501Y, D614G, H655Y in Brazil; G339D, S373P, S375F, K417N, N440K, N501Y, D614G, P681H in the UK.
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Vergori, Alessandra, Alessandro Cozzi-Lepri, Giulia Matusali, et al. "SARS-CoV-2 Omicron Variant Neutralization after Third Dose Vaccination in PLWH." Viruses 14, no. 8 (2022): 1710. http://dx.doi.org/10.3390/v14081710.
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The aim was to measure neutralizing antibody levels against the SARS-CoV-2 Omicron (BA.1) variant in serum samples obtained from vaccinated PLWH and healthcare workers (HCW) and compare them with those against the Wuhan-D614G (W-D614G) strain, before and after the third dose of a mRNA vaccine. We included 106 PLWH and 28 HCWs, for a total of 134 participants. Before the third dose, the proportion of participants with undetectable nAbsT against BA.1 was 88% in the PLWH low CD4 nadir group, 80% in the high nadir group and 100% in the HCW. Before the third dose, the proportion of participants with detectable nAbsT against BA.1 was 12% in the PLWH low nadir group, 20% in the high nadir group and 0% in HCW, respectively. After 2 weeks from the third dose, 89% of the PLWH in the low nadir group, 100% in the high nadir group and 96% of HCW elicited detectable nAbsT against BA.1. After the third dose, the mean log2 nAbsT against BA.1 in the HCW and PLWH with a high nadir group was lower than that seen against W-D614G (6.1 log2 (±1.8) vs. 7.9 (±1.1) and 6.4 (±1.3) vs. 8.6 (±0.8)), respectively. We found no evidence of a different level of nAbsT neutralization by BA.1 vs. W-D614G between PLWH with a high CD4 nadir and HCW (0.40 (−1.64, 2.43); p = 0.703). Interestingly, in PLWH with a low CD4 nadir, the mean log2 difference between nAbsT against BA.1 and W-D614G was smaller in those with current CD4 counts 201–500 vs. those with CD4 counts < 200 cells/mm3 (−0.80 (−1.52, −0.08); p = 0.029), suggesting that in this target population with a low CD4 nadir, current CD4 count might play a role in diversifying the level of SARS-CoV-2 neutralization.
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Lusvarghi, Sabrina, Charles B. Stauft, Russell Vassell, et al. "Effects of N-glycan modifications on spike expression, virus infectivity, and neutralization sensitivity in ancestral compared to Omicron SARS-CoV-2 variants." PLOS Pathogens 19, no. 11 (2023): e1011788. http://dx.doi.org/10.1371/journal.ppat.1011788.
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The SARS-CoV-2 spike glycoprotein has 22 potential N-linked glycosylation sites per monomer that are highly conserved among diverse variants, but how individual glycans affect virus entry and neutralization of Omicron variants has not been extensively characterized. Here we compared the effects of specific glycan deletions or modifications in the Omicron BA.1 and D614G spikes on spike expression, processing, and incorporation into pseudoviruses, as well as on virus infectivity and neutralization by therapeutic antibodies. We found that loss of potential glycans at spike residues N717 and N801 each conferred a loss of pseudovirus infectivity for Omicron but not for D614G or Delta variants. This decrease in infectivity correlated with decreased spike processing and incorporation into Omicron pseudoviruses. Oligomannose-enriched Omicron pseudoviruses generated in GnTI- cells or in the presence of kifunensine were non-infectious, whereas D614G or Delta pseudoviruses generated under similar conditions remained infectious. Similarly, growth of live (authentic) SARS-CoV-2 in the presence of kifunensine resulted in a greater reduction of titers for the BA.1.1 variant than Delta or D614G variants relative to their respective, untreated controls. Finally, we found that loss of some N-glycans, including N343 and N234, increased the maximum percent neutralization by the class 3 S309 monoclonal antibody against D614G but not BA.1 variants, while these glycan deletions altered the neutralization potency of the class 1 COV2-2196 and Etesevimab monoclonal antibodies without affecting maximum percent neutralization. The maximum neutralization by some antibodies also varied with the glycan composition, with oligomannose-enriched pseudoviruses conferring the highest percent neutralization. These results highlight differences in the interactions between glycans and residues among SARS-CoV-2 variants that can affect spike expression, virus infectivity, and susceptibility of variants to antibody neutralization.
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Al-jaf, Sirwan M. A., and Sherko S. Niranji. "Detection of SARS-CoV-2 Reinfections by Rapid Inexpensive Methods." ARO-THE SCIENTIFIC JOURNAL OF KOYA UNIVERSITY 10, no. 1 (2022): 44–48. http://dx.doi.org/10.14500/aro.10916.
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New SARS-CoV-2 infections are difficult to beverified, whether they are reinfections or persistent infections. The most prominent factors used for differentiating reinfections from persistent infections are whole-genome sequencing and phylogenetic analyses that require time and funds, which may not be feasible in most developing countries. This study explores reinfections with COVID-19 that harbors D614G and N501Y mutations by rapid inexpensive methods. It exploits the previously developed rapid economic methods that identified both D614G and N501Y mutations in clinical samples using real-time reverse transcriptase polymerase chain reaction (rRT-PCR) probes and conventional PCR specific primers. In the present study, an immunocompetent patient has been found with a SARS-CoV-2 N501Y reinfection without comorbidities. According to the obtained results, this study suggests that the initial infection was due to a variant that contained only D614G mutation whereas the reinfection was potentially a result of alpha variant contained three mutations confirmed by DNA sequencing, including D614G, N501Y, and A570D mutations. These techniques will support rapid detection of SARS-CoV-2 reinfections through the identification of common spike mutations in the developing countries where sequencing tools are unavailable. Furthermore, seven cases of reinfections were also confirmed by these methods. These rapid methods can also be applied to large samples of reinfections that may increase our understanding epidemiology of the pandemic.
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Huang, Szu-Wei, Sorin O. Miller, Chia-Hung Yen, and Sheng-Fan Wang. "Impact of Genetic Variability in ACE2 Expression on the Evolutionary Dynamics of SARS-CoV-2 Spike D614G Mutation." Genes 12, no. 1 (2020): 16. http://dx.doi.org/10.3390/genes12010016.
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) glycoprotein D614G mutation became the predominant globally circulating variant after its emergence in the early coronavirus disease 2019 (COVID-19) pandemic. Studies showed that this mutation results in an open conformation of the S glycoprotein receptor-binding domain (RBD), and increased angiotensin 1-converting enzyme 2 (ACE2) binding and fusion, which result in an increase in SARS-CoV-2 transmissibility and infectivity. Dynamic tracking of SARS-CoV-2 showed that the D614G variant became predominant after emergence in Europe and North America, but not in China. The current absence of selective pressures from antiviral treatment suggests that the driving force for viral evolution could be variations in human population genetics. Results show that ACE2 expression is higher in Asian populations than that in European, North American, and African populations. This supports the idea that lower ACE2 expression is a driving force in the positive selection for the D614G mutation. This study suggests that the dynamics of the SARS-CoV-2 D614G mutation during the early-to-mid pandemic is associated with enhanced transmission efficiency in populations with lower ACE2 expression. Understanding the role that human genetic diversity plays in the adaptive evolution of SARS-CoV-2 may have an important impact on public health and measures to control the pandemic.
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Warwicker, Jim. "A model for pH coupling of the SARS-CoV-2 spike protein open/closed equilibrium." Briefings in Bioinformatics 22, no. 2 (2021): 1499–507. http://dx.doi.org/10.1093/bib/bbab056.
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Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative agent of the coronavirus disease 2019 (COVID-19) pandemic, is thought to release its RNA genome at either the cell surface or within endosomes, the balance being dependent on spike protein stability, and the complement of receptors, co-receptors and proteases. To investigate possible mediators of pH-dependence, pKa calculations have been made on a set of structures for spike protein ectodomain and fragments from SARS-CoV-2 and other coronaviruses. Dominating a heat map of the aggregated predictions, three histidine residues in S2 are consistently predicted as destabilizing in pre-fusion (all three) and post-fusion (two of the three) structures. Other predicted features include the more moderate energetics of surface salt–bridge interactions and sidechain–mainchain interactions. Two aspartic acid residues in partially buried salt-bridges (D290–R273 and R355–D398) have pKas that are calculated to be elevated and destabilizing in more open forms of the spike trimer. These aspartic acids are most stabilized in a tightly closed conformation that has been observed when linoleic acid is bound, and which also affects the interactions of D614. The D614G mutation is known to modulate the balance of closed to open trimer. It is suggested that D398 in particular contributes to a pH-dependence of the open/closed equilibrium, potentially coupled to the effects of linoleic acid binding and D614G mutation, and possibly also A570D mutation. These observations are discussed in the context of SARS-CoV-2 infection, mutagenesis studies, and other human coronaviruses.
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Mat Jusoh, Siti Asmaa, Danesh Thangeswaran, Muhammad Syahir Hakimi Mohd Hazli, Mohd Firdaus Raih, Nurulasma Abdullah, and Shaharum Shamsuddin. "Construction of Multi-Epitopes Vaccine Candidate against SARS-CoV-2 D614G Variant." Sains Malaysiana 51, no. 9 (2022): 2985–97. http://dx.doi.org/10.17576/jsm-2022-5109-19.
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COVID-19 caused by the SARS-CoV-2 virus has become a real threat due to the emergence of new variants which are more deadly with higher infectivity. Vaccine constructs that target specific SARS-CoV-2 variants are needed for stemming COVID-19 fatality. The spike (S) glycoprotein is the major antigenic component that triggers the host immune response. Reverse vaccinology strategy was applied to the S protein of COVID-19 variant D614G to identify highly ranked antigenic proteins. In this study, a multi-epitope synthetic gene was designed using computational strategies for the COVID-19 D614G variant. The SARS-CoV-2 D614G variant protein sequence was retrieved from the NCBI database. The prediction of linear B-cell epitopes was carried out using Artificial Neural Network (ANN)-based ABCpred and BepiPred 2.0 software. The top 15 highly antigenic epitopes sequences were then selected. Propred 1 and Propred servers were used to identify major histocompatibility complex (MHC) class I and class II binding epitopes within pre-determined B-cell epitopes to predict T-cell epitopes. The top 5 MHC class I and class II were selected. Further in-silico testing for its solubility, allergenicity, antigenicity, and other physiochemical properties was analyzed using Bpred. The constructed gene was subjected to assembly PCR and the gene product was confirmed by Sanger sequencing. The findings from this study suggested that a highly antigenic specific region of the SARS-CoV-2 D614G variant can be predicted in-silico and amplified using the assembly PCR method. The designed synthetic gene was shown to elicit specific humoral and cell-mediated immune responses towards the SARS-CoV-2 variants.
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Li, Gen, Zhongcheng Zhou, Peng Du, et al. "The SARS-CoV-2 spike L452R-E484Q variant in the Indian B.1.617 strain showed significant reduction in the neutralization activity of immune sera." Precision Clinical Medicine 4, no. 3 (2021): 149–54. http://dx.doi.org/10.1093/pcmedi/pbab016.
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Abstract To assess the impact of the key non-synonymous amino acid substitutions in the RBD of the spike protein of SARS-CoV-2 variant B.1.617.1 (dominant variant identified in the current India outbreak) on the infectivity and neutralization activities of the immune sera, L452R and E484Q (L452R-E484Q variant), pseudotyped virus was constructed (with the D614G background). The impact on binding with the neutralizing antibodies was also assessed with an ELISA assay. Pseudotyped virus carrying a L452R-E484Q variant showed a comparable infectivity compared with D614G. However, there was a significant reduction in the neutralization activity of the immune sera from non-human primates vaccinated with a recombinant receptor binding domain (RBD) protein, convalescent patients, and healthy vaccinees vaccinated with an mRNA vaccine. In addition, there was a reduction in binding of L452R-E484Q-D614G protein to the antibodies of the immune sera from vaccinated non-human primates. These results highlight the interplay between infectivity and other biologic factors involved in the natural evolution of SARS-CoV-2. Reduced neutralization activities against the L452R-E484Q variant will have an impact on health authority planning and implications for the vaccination strategy/new vaccine development.
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Lestari, Nur Ayu, Muhammad Isrul, Dwi Syah Fitrah Ramadhan, and Fatahu. "Skrining Virtual Berbasis Farmakofor Dari Database Bahan Alam Sebagai Inhibitor Alosterik Mutan T790M/C797 EGFR Untuk Penemuan Obat Kanker Paru." Jurnal Pharmacia Mandala Waluya 3, no. 3 (2024): 168–86. http://dx.doi.org/10.54883/jpmw.v3i3.102.
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Virus korona merupakan penyakit menular berbahaya yang disebabkan oleh virus baru (SARS-CoV-2). Usaha untuk mengeksplorasi bahan-bahan alam aktif sebagai anti-virus terus dilakukan. Salah satu tanaman lokal Indonesia yang dapat menghambat SARS-CoV-2 protein spike yaitu herba sambiloto (Andrographis paniculata) secara in silico, akan tetapi aktivitasnya terhadap mutan D614G SARS-CoV-2 belum diketahui. Tujuan dari penelitian ini yaitu untuk mengkaji aktivitas metabolit andrographolide dan turunannya dalam herba sambiloto (Andrographis paniculata) terhadap mutasi D614G SARS-CoV-2 protein spike secara in silico.Penelitian ini menggunakan metode in silico yaitu penambatan molekul. Penambatan molekul dilakukan menggunakan Autodock Tools 1.5.6 dan dianalisis interaksi ikatannya menggunakan BIOVIA Discovery Studio 2017, kemudian diprediksi ADME menggunakan software Swiss ADME dan sofware PASS online untuk mengetahui toksisitasnya.Hasil penelitian menunjukkan bahwa diperoleh dari 23 senyawa turunan andrographolide yang memiliki stabilitas ikatan lebih baik dari pada senyawa andrographolide yaitu senyawa 14-Acetyl-3,19-isopropylideneandrographolide yang dapat menghambat reseptor non-mutasi (6VSB) dengan energi ikatan -5.34 kcal/mol dan mutan D614G (7KDL) dengan energi ikatan -5.72 kcal/mol dengan hasil prediksi ADME memenuhi aturan lipinski dan tidak menunjukan adanya aktivitas toksisitas hepatotoksik dan nefrotoksik yang bermakna.
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Seadawy, Mohamed G., Abdel Rahman N. Zekri, Aya A. Saeed, Emmanuel James San, and Amr M. Ageez. "Candidate Multi-Epitope Vaccine against Corona B.1.617 Lineage: In Silico Approach." Life 12, no. 11 (2022): 1715. http://dx.doi.org/10.3390/life12111715.
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Various mutations have accumulated since the first genome sequence of SARS-CoV2 in 2020. Mutants of the virus carrying the D614G and P681R mutations in the spike protein are increasingly becoming dominant all over the world. The two mutations increase the viral infectivity and severity of the disease. This report describes an in silico design of SARS-CoV-2 multi-epitope carrying the spike D614G and P681R mutations. The designed vaccine harbors the D614G mutation that increases viral infectivity, fitness, and the P681R mutation that enhances the cleavage of S to S1 and S2 subunits. The designed multi-epitope vaccine showed an antigenic property with a value of 0.67 and the immunogenicity of the predicted vaccine was calculated and yielded 3.4. The vaccine construct is predicted to be non-allergenic, thermostable and has hydrophilic nature. The combination of the selected CTL and HTL epitopes in the vaccine resulted in 96.85% population coverage globally. Stable interactions of the vaccine with Toll-Like Receptor 4 were tested by docking studies. The multi-epitope vaccine can be a good candidate against highly infecting SARS-CoV-2 variants.
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Vitasari, Riski, Muhammad Isrul, and Dwi Syah Fitrah Ramadhan. "Kajian Aktivitas Metabolit Andrographolide dan Turunannya Dalam Herba Sambiloto (Andrographis paniculata) Terhadap Mutasi D614G SARS-CoV-2 Protein Spike Secara In Silico." Jurnal Pharmacia Mandala Waluya 1, no. 6 (2022): 290–304. http://dx.doi.org/10.54883/28296850.v1i6.282.
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Virus korona merupakan penyakit menular berbahaya yang disebabkan oleh virus baru (SARS-CoV-2). Usaha untuk mengeksplorasi bahan-bahan alam aktif sebagai anti-virus terus dilakukan. Salah satu tanaman lokal Indonesia yang dapat menghambat SARS-CoV-2 protein spike yaitu herba sambiloto (Andrographis paniculata) secara in silico, akan tetapi aktivitasnya terhadap mutan D614G SARS-CoV-2 belum diketahui. Tujuan dari penelitian ini yaitu untuk mengkaji aktivitas metabolit andrographolide dan turunannya dalam herba sambiloto (Andrographis paniculata) terhadap mutasi D614G SARS-CoV-2 protein spike secara in silico.Penelitian ini menggunakan metode in silico yaitu penambatan molekul. Penambatan molekul dilakukan menggunakan Autodock Tools 1.5.6 dan dianalisis interaksi ikatannya menggunakan BIOVIA Discovery Studio 2017, kemudian diprediksi ADME menggunakan software Swiss ADME dan sofware PASS online untuk mengetahui toksisitasnya.Hasil penelitian menunjukkan bahwa diperoleh dari 23 senyawa turunan andrographolide yang memiliki stabilitas ikatan lebih baik dari pada senyawa andrographolide yaitu senyawa 14-Acetyl-3,19-isopropylideneandrographolide yang dapat menghambat reseptor non-mutasi (6VSB) dengan energi ikatan -5.34 kcal/mol dan mutan D614G (7KDL) dengan energi ikatan -5.72 kcal/mol dengan hasil prediksi ADME memenuhi aturan lipinski dan tidak menunjukan adanya aktivitas toksisitas hepatotoksik dan nefrotoksik yang bermakna.
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Villarino, Elsa, Xianding Deng, Carol A. Kemper, et al. "Introduction, Transmission Dynamics, and Fate of Early Severe Acute Respiratory Syndrome Coronavirus 2 Lineages in Santa Clara County, California." Journal of Infectious Diseases 224, no. 2 (2021): 207–17. http://dx.doi.org/10.1093/infdis/jiab199.
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Abstract We combined viral genome sequencing with contact tracing to investigate introduction and evolution of severe acute respiratory syndrome coronavirus 2 lineages in Santa Clara County, California, from 27 January to 21 March 2020. From 558 persons with coronavirus disease 2019, 101 genomes from 143 available clinical samples comprised 17 lineages, including SCC1 (n = 41), WA1 (n = 9; including the first 2 reported deaths in the United States, with postmortem diagnosis), D614G (n = 4), ancestral Wuhan Hu-1 (n = 21), and 13 others (n = 26). Public health intervention may have curtailed the persistence of lineages that appeared transiently during February and March. By August, only D614G lineages introduced after 21 March were circulating in Santa Clara County.
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Radion, Elizaveta I., Vladimir E. Mukhin, Alyona V. Kholodova, et al. "Functional Characteristics of Serum Anti-SARS-CoV-2 Antibodies against Delta and Omicron Variants after Vaccination with Sputnik V." Viruses 15, no. 6 (2023): 1349. http://dx.doi.org/10.3390/v15061349.
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Anti-SARS-CoV-2 vaccination leads to the production of neutralizing as well as non-neutralizing antibodies. In the current study, we investigated the temporal dynamics of both sides of immunity after vaccination with two doses of Sputnik V against SARS-CoV-2 variants Wuhan-Hu-1 SARS-CoV-2 G614-variant (D614G), B.1.617.2 (Delta), and BA.1 (Omicron). First, we constructed a SARS-CoV-2 pseudovirus assay to assess the neutralization activity of vaccine sera. We show that serum neutralization activity against BA.1 compared to D614G is decreased by 8.16-, 11.05-, and 11.16- fold in 1, 4, and 6 months after vaccination, respectively. Moreover, previous vaccination did not increase serum neutralization activity against BA.1 in recovered patients. Next, we used the ADMP assay to evaluate the Fc-mediated function of vaccine-induced serum antibodies. Our results show that the antibody-dependent phagocytosis triggered by S-proteins of the D614G, B.1.617.2 and BA.1 variants did not differ significantly in vaccinated individuals. Moreover, the ADMP efficacy was retained over up to 6 months in vaccine sera. Our results demonstrate differences in the temporal dynamics of neutralizing and non-neutralizing antibody functions after vaccination with Sputnik V.
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Goldman, Jason D., Kai Wang, Katharina Röltgen, et al. "Reinfection with SARS-CoV-2 and Waning Humoral Immunity: A Case Report." Vaccines 11, no. 1 (2022): 5. http://dx.doi.org/10.3390/vaccines11010005.
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Recovery from COVID-19 is associated with production of anti-SARS-CoV-2 antibodies, but it is uncertain whether these confer immunity. We describe viral RNA shedding duration in hospitalized patients and identify patients with recurrent shedding. We sequenced viruses from two distinct episodes of symptomatic COVID-19 separated by 144 days in a single patient, to conclusively describe reinfection with a different strain harboring the spike variant D614G. This case of reinfection was one of the first cases of reinfection reported in 2020. With antibody, B cell and T cell analytics, we show correlates of adaptive immunity at reinfection, including a differential response in neutralizing antibodies to a D614G pseudovirus. Finally, we discuss implications for vaccine programs and begin to define benchmarks for protection against reinfection from SARS-CoV-2.
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Koenig, Paul-Albert, and Florian I. Schmidt. "Spike D614G — A Candidate Vaccine Antigen Against Covid-19." New England Journal of Medicine 384, no. 24 (2021): 2349–51. http://dx.doi.org/10.1056/nejmcibr2106054.
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Marín-Palma, Damariz, Jorge H. Tabares-Guevara, María I. Zapata-Cardona, et al. "Curcumin Inhibits In Vitro SARS-CoV-2 Infection In Vero E6 Cells through Multiple Antiviral Mechanisms." Molecules 26, no. 22 (2021): 6900. http://dx.doi.org/10.3390/molecules26226900.
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Due to the scarcity of therapeutic approaches for COVID-19, we investigated the antiviral and anti-inflammatory properties of curcumin against SARS-CoV-2 using in vitro models. The cytotoxicity of curcumin was evaluated using MTT assay in Vero E6 cells. The antiviral activity of this compound against SARS-CoV-2 was evaluated using four treatment strategies (i. pre–post infection treatment, ii. co-treatment, iii. pre-infection, and iv. post-infection). The D614G strain and Delta variant of SARS-CoV-2 were used, and the viral titer was quantified by plaque assay. The anti-inflammatory effect was evaluated in peripheral blood mononuclear cells (PBMCs) using qPCR and ELISA. By pre–post infection treatment, Curcumin (10 µg/mL) exhibited antiviral effect of 99% and 99.8% against DG614 strain and Delta variant, respectively. Curcumin also inhibited D614G strain by pre-infection and post-infection treatment. In addition, curcumin showed a virucidal effect against D614G strain and Delta variant. Finally, the pro-inflammatory cytokines (IL-1β, IL-6, and IL-8) released by PBMCs triggered by SARS-CoV-2 were decreased after treatment with curcumin. Our results suggest that curcumin affects the SARS-CoV-2 replicative cycle and exhibits virucidal effect with a variant/strain independent antiviral effect and immune-modulatory properties. This is the first study that showed a combined (antiviral/anti-inflammatory) effect of curcumin during SARS-CoV-2 infection. However, additional studies are required to define its use as a treatment for the COVID-19.
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Anggraini, Nina Bunga, and Dwi Listyorini. "S-D614G Mutation Reveals the Euro-America and East-Asia Origin SARS-CoV-2 Virus Spread in Indonesia." Jurnal Riset Biologi dan Aplikasinya 3, no. 2 (2021): 45–53. http://dx.doi.org/10.26740/jrba.v3n2.p45-53.
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COVID-19 is a pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. The first case was found in the city of Wuhan, Hubei province, China. The first case in Indonesia was reported in March 2020 and currently there are 0.5 million cases with a death rate of 3.1%. This rapid increase in cases is thought to due to presence of the mutant strain S-D614G, which causes a faster rate of infection and spread. The purpose of this study was to determine the presence of S-D614G mutations in Indonesian samples in order to find the origin of COVID-19 which was spread in Indonesia based on the Spike gene sequences and the RdRp genes from 25 countries, and one control sequence China/Wuhan-Hu-1 obtained from the NCBI and GISAID databases. Mutation analysis was carried out through multiple alignments using BioEdit software. Phylogenetic tree reconstruction using MEGA6 software with the Neighbor Joining method. This study found mutation of S-D614G in one Indonesian sample, namely the Indonesian/SBY9 sample along with 23 samples from Europe, America, and Africa. The phylogenetic tree reconstruction confirmed these findings; the mutated samples were closely related to samples from these continents, while the non-mutated Indonesian samples were closely related to sample from East Asia. These findings indicate that the origin of the SARS-CoV-2 virus in Indonesia possibly came from the East Asia cluster and the European-American cluster.
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Trinité, Benjamin, Edwards Pradenas, Silvia Marfil, et al. "Previous SARS-CoV-2 Infection Increases B.1.1.7 Cross-Neutralization by Vaccinated Individuals." Viruses 13, no. 6 (2021): 1135. http://dx.doi.org/10.3390/v13061135.
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With the spread of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is a need to assess the protection conferred by both previous infections and current vaccination. Here we tested the neutralizing activity of infected and/or vaccinated individuals against pseudoviruses expressing the spike of the original SARS-CoV-2 isolate Wuhan-Hu-1 (WH1), the D614G mutant and the B.1.1.7 variant. Our data show that parameters of natural infection (time from infection and nature of the infecting variant) determined cross-neutralization. Uninfected vaccinees showed a small reduction in neutralization against the B.1.1.7 variant compared to both the WH1 strain and the D614G mutant. Interestingly, upon vaccination, previously infected individuals developed more robust neutralizing responses against B.1.1.7, suggesting that vaccines can boost the neutralization breadth conferred by natural infection.
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Percivalle, Elena, Josè Camilla Sammartino, Irene Cassaniti, et al. "Macrophages and Monocytes: “Trojan Horses” in COVID-19." Viruses 13, no. 11 (2021): 2178. http://dx.doi.org/10.3390/v13112178.
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We aimed to explore whether variants of SARS-CoV-2 (Chinese-derived strain (D614, lineage A), Italian strain PV10734 (D614G, lineage B.1.1) and Alpha strain (lineage B.1.1.7)) were able to infect monocytes (MN) and monocyte-derived macrophages (MDM) and whether these infected cells may, in turn, be vectors of infection. For this purpose, we designed an in vitro study following the evolution of MN and MDM infection at different time points in order to confirm whether these cells were permissive for SARS-CoV-2 replication. Finally, we investigated whether, regardless of viral replication, the persistent virus can be transferred to non-infected cells permissive for viral replication. Thus, we co-cultured the infected MN/MDM with permissive VERO E6 cells verifying the viral transmission. This is a further in vitro demonstration of the important role of MN and MDM in the dissemination of SARS-CoV-2 and evolution of the COVID-19 disease.
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Wang, Yunxiang, Hong Chen, Hongjuan Wei, Zhen Rong, and Shengqi Wang. "Tetra-primer ARMS-PCR combined with dual-color fluorescent lateral flow assay for the discrimination of SARS-CoV-2 and its mutations with a handheld wireless reader." Lab on a Chip 22, no. 8 (2022): 1531–41. http://dx.doi.org/10.1039/d1lc01167g.
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Wild-type SARS-CoV-2 or its D614G and N501Y mutations can be selectively amplified by tetra-primer ARMS-PCR and detected by two test lines on a single dual-color fluorescent test strip with a handheld wireless device.
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Zhou, Hao, Belinda M. Dcosta, Nathaniel R. Landau, and Takuya Tada. "Resistance of SARS-CoV-2 Omicron BA.1 and BA.2 Variants to Vaccine-Elicited Sera and Therapeutic Monoclonal Antibodies." Viruses 14, no. 6 (2022): 1334. http://dx.doi.org/10.3390/v14061334.
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The recent emergence of the Omicron BA.1 and BA.2 variants with heavily mutated spike proteins has posed a challenge to the effectiveness of current vaccines and to monoclonal antibody therapy for severe COVID-19. After two immunizations of individuals with no history of previous SARS-CoV-2 infection with BNT162b2 vaccine, neutralizing titer against BA.1 and BA.2 were 20-fold decreased compared to titers against the parental D614G virus. A third immunization boosted overall neutralizing titers by about 5-fold but titers against BA.1 and BA.2 remained about 10-fold below that of D614G. Both Omicron variants were highly resistant to several of the emergency use authorized therapeutic monoclonal antibodies. The variants were highly resistant to Regeneron REGN10933 and REGN10987 and Lilly LY-CoV555 and LY-CoV016 while Vir-7831 and the mixture of AstraZeneca monoclonal antibodies AZD8895 and AZD1061 were significantly decreased in neutralizing titer. Strikingly, a single monoclonal antibody LY-CoV1404 potently neutralized both Omicron variants.
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Hao, Zhaonian, Ruyuan Li, Chengyi Hao, Haoyuan Zhao, Xueyan Wan, and Dongsheng Guo. "Global Evidence of Temperature Acclimation of COVID‐19 D614G Linage." Global Challenges 5, no. 6 (2021): 2000132. http://dx.doi.org/10.1002/gch2.202000132.
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Shi, Aria C., and Xuping Xie. "Making sense of spike D614G in SARS-CoV-2 transmission." Science China Life Sciences 64, no. 7 (2021): 1062–67. http://dx.doi.org/10.1007/s11427-020-1893-9.
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Zhou, Bin, Tran Thi Nhu Thao, Donata Hoffmann, et al. "SARS-CoV-2 spike D614G change enhances replication and transmission." Nature 592, no. 7852 (2021): 122–27. http://dx.doi.org/10.1038/s41586-021-03361-1.
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Plante, Jessica A., Yang Liu, Jianying Liu, et al. "Author Correction: Spike mutation D614G alters SARS-CoV-2 fitness." Nature 595, no. 7865 (2021): E1. http://dx.doi.org/10.1038/s41586-021-03657-2.
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Al-Jaf, Sirwan M. A., Sherko S. Niranji, and Zana H. Mahmood. "Rapid, inexpensive methods for exploring SARS CoV-2 D614G mutation." Meta Gene 30 (December 2021): 100950. http://dx.doi.org/10.1016/j.mgene.2021.100950.
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Sia, Boon Zhan, Wan Xin Boon, Yoke Yee Yap, Shalini Kumar, and Chong Han Ng. "Prediction of the effects of the top 10 nonsynonymous variants from 30229 SARS-CoV-2 strains on their proteins." F1000Research 11 (May 18, 2022): 9. http://dx.doi.org/10.12688/f1000research.72904.2.
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Background: SARS-CoV-2 virus is a highly transmissible pathogen that causes COVID-19. The outbreak originated in Wuhan, China in December 2019. A number of nonsynonymous mutations located at different SARS-CoV-2 proteins have been reported by multiple studies. However, there are limited computational studies on the biological impacts of these mutations on the structure and function of the proteins. Methods: In our study nonsynonymous mutations of the SARS-CoV-2 genome and their frequencies were identified from 30,229 sequences. Subsequently, the effects of the top 10 highest frequency nonsynonymous mutations of different SARS-CoV-2 proteins were analyzed using bioinformatics tools including co-mutation analysis, prediction of the protein structure stability and flexibility analysis, and prediction of the protein functions. Results: A total of 231 nonsynonymous mutations were identified from 30,229 SARS-CoV-2 genome sequences. The top 10 nonsynonymous mutations affecting nine amino acid residues were ORF1a nsp5 P108S, ORF1b nsp12 P323L and A423V, S protein N501Y and D614G, ORF3a Q57H, N protein P151L, R203K and G204R. Many nonsynonymous mutations showed a high concurrence ratio, suggesting these mutations may evolve together and interact functionally. Our result showed that ORF1a nsp5 P108S, ORF3a Q57H and N protein P151L mutations may be deleterious to the function of SARS-CoV-2 proteins. In addition, ORF1a nsp5 P108S and S protein D614G may destabilize the protein structures while S protein D614G may have a more open conformation compared to the wild type. Conclusion: The biological consequences of these nonsynonymous mutations of SARS-CoV-2 proteins should be further validated by in vivo and in vitro experimental studies in the future.
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Leung, Kathy, Yao Pei, Gabriel M. Leung, Tommy TY Lam, and Joseph T. Wu. "Estimating the transmission advantage of the D614G mutant strain of SARS-CoV-2, December 2019 to June 2020." Eurosurveillance 26, no. 49 (2021). http://dx.doi.org/10.2807/1560-7917.es.2021.26.49.2002005.
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Introduction The SARS-CoV-2 lineages carrying the amino acid change D614G have become the dominant variants in the global COVID-19 pandemic. By June 2021, all the emerging variants of concern carried the D614G mutation. The rapid spread of the G614 mutant suggests that it may have a transmission advantage over the D614 wildtype. Aim Our objective was to estimate the transmission advantage of D614G by integrating phylogenetic and epidemiological analysis. Methods We assume that the mutation D614G was the only site of interest which characterised the two cocirculating virus strains by June 2020, but their differential transmissibility might be attributable to a combination of D614G and other mutations. We define the fitness of G614 as the ratio of the basic reproduction number of the strain with G614 to the strain with D614 and applied an epidemiological framework for fitness inference to analyse SARS-CoV-2 surveillance and sequence data. Results Using this framework, we estimated that the G614 mutant is 31% (95% credible interval: 28–34) more transmissible than the D614 wildtype. Therefore, interventions that were previously effective in containing or mitigating the D614 wildtype (e.g. in China, Vietnam and Thailand) may be less effective against the G614 mutant. Conclusion Our framework can be readily integrated into current SARS-CoV-2 surveillance to monitor the emergence and fitness of mutant strains such that pandemic surveillance, disease control and development of treatment and vaccines can be adjusted dynamically.
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Daniloski, Zharko, Tristan X. Jordan, Juliana K. Ilmain, et al. "The Spike D614G mutation increases SARS-CoV-2 infection of multiple human cell types." eLife 10 (February 11, 2021). http://dx.doi.org/10.7554/elife.65365.
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A novel variant of the SARS-CoV-2 virus carrying a point mutation in the Spike protein (D614G) has recently emerged and rapidly surpassed others in prevalence. This mutation is in linkage disequilibrium with an ORF1b protein variant (P314L), making it difficult to discern the functional significance of the Spike D614G mutation from population genetics alone. Here, we perform site-directed mutagenesis on wild-type human-codon-optimized Spike to introduce the D614G variant. Using multiple human cell lines, including human lung epithelial cells, we found that the lentiviral particles pseudotyped with Spike D614G are more effective at transducing cells than ones pseudotyped with wild-type Spike. The increased transduction with Spike D614G ranged from 1.3- to 2.4-fold in Caco-2 and Calu-3 cells expressing endogenous ACE2 and from 1.5- to 7.7-fold in A549ACE2 and Huh7.5ACE2 overexpressing ACE2. Furthermore, trans-complementation of SARS-CoV-2 virus with Spike D614G showed an increased infectivity in human cells. Although there is minimal difference in ACE2 receptor binding between the D614 and G614 Spike variants, the G614 variant is more resistant to proteolytic cleavage, suggesting a possible mechanism for the increased transduction.
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Wu, Jianhua, Hong-Xing Zhang, and Jilong Zhang. "Investigation on the interaction mechanism of different SARS-CoV-2 spike variants with hACE2: insights from molecular dynamics simulations." Physical Chemistry Chemical Physics, 2023. http://dx.doi.org/10.1039/d2cp04349a.
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SARS-CoV-2 RBDs after single (D614G), double (D614G + L452R and D614G + N501Y), triple (D614G + N501Y + E484K), and quadruple (D614G + N501Y + E484K + K417T) mutations result in variants with different binding affinities for hACE2 receptor protein.
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Liang, Ziteng, Jincheng Tong, Ziqi Sun, et al. "Rational prediction of immunogenicity clustering through cross‐reactivity analysis of thirteen SARS‐CoV‐2 variants." Journal of Medical Virology 96, no. 1 (2024). http://dx.doi.org/10.1002/jmv.29314.
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AbstractSARS‐CoV‐2 breakthrough infections in vaccinated individuals underscore the threat posed by continuous mutating variants, such as Omicron, to vaccine‐induced immunity. This necessitates the search for broad‐spectrum immunogens capable of countering infections from such variants. This study evaluates the immunogenicity relationship among SARS‐CoV‐2 variants, from D614G to XBB, through Guinea pig vaccination, covering D614G, Alpha, Beta, Gamma, Delta, BA.1, BA.2, BA.2.75, BA.2.75.2, BA.5, BF.7, BQ.1.1, and XBB, employing three immunization strategies: three‐dose monovalent immunogens, three‐dose bivalent immunogens, and a two‐dose vaccination with D614G followed by a booster immunization with a variant strain immunogen. Three distinct immunogenicity clusters were identified: D614G, Alpha, Beta, Gamma, and Delta as cluster 1, BA.1, BA.2, and BA.2.75 as cluster 2, BA.2.75.2, BA.5, BF.7, BQ.1.1, and XBB as cluster 3. Broad‐spectrum protection could be achieved through a combined immunization strategy using bivalent immunogens or D614G and XBB, or two initial D614G vaccinations followed by two XBB boosters. A comparison of neutralizing antibody levels induced by XBB boosting and equivalent dosing of D614G and XBB revealed that the XBB booster produced higher antibody levels. The study suggests that vaccine antigen selection should focus on the antigenic alterations among variants, eliminating the need for updating vaccine components for each variant.
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Vaira, L. A., J. R. Lechien, G. Deiana, et al. "Prevalence of olfactory dysfunction in D614G, alpha, delta and omicron waves: a psychophysical case-control study." Rhinology journal, October 22, 2022, 0. http://dx.doi.org/10.4193/rhin22.294.
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Background: The purpose of this study was to compare the prevalence of olfactory dysfunction (OD) at different stages of the COVID-19 pandemic by evaluating subjects diagnosed with SARS-CoV-2 infection during the Omicron wave with psychophysical tests and comparing the results with those obtained from patients infected during the D614G, Alpha and Delta waves and with those of a control group. Methodology: The study included adult patients diagnosed with SARS-CoV-2 infection. Depending on the time of diagnosis, the subjects were divided into four study groups: D614G; Alpha, Delta and Omicron variant groups. A group of uninfected individuals was used as control. All subjects underwent psychophysical evaluation of the olfactory function with the Connecticut Chemosensory Clinical Research Center olfactory test (D614G and Alpha groups) or the extended version of the Sniffin'Sticks test (Delta, Omicron and control groups). Results: 372 cases (134 D614G group, 118 Alpha group, 32 in Delta group and 88 Omicron group) were recruited and evaluated within 10 days of infection, alongside 80 controls. Patients self-reported olfactory loss in 72.4% of cases in the D614G group, in 75.4% of cases in the Alpha group, in 65.6% of cases in the Delta group and in 18.1% in the Omicron group. Psychophysical evaluation revealed a prevalence of OD: 80.6%, 83.0%, 65.6% and 36.3% in the D614G, Alpha, Delta and Omicron group respectively. The differences between the D614G, Alpha and Delta groups were not statistically significant. The Omicron group demonstrated a significantly lower prevalence of OD than the other variants but still significantly higher than the controls. Conclusions: During the Omicron wave OD was less prevalent than during the D614G, Alpha and Delta periods. One-third of patients have reduced olfactory function on psychophysical evaluation during the Omicron wave. Our results should be considered with caution as the VOC has not been determined with certainty.
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Martins, Mathias, Mohammed Nooruzzaman, Jessie Lee Cunningham, et al. "The SARS-CoV-2 Spike is a virulence determinant and plays a major role on the attenuated phenotype of Omicron virus in a feline model of infection." Journal of Virology, February 29, 2024. http://dx.doi.org/10.1128/jvi.01902-23.
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ABSTRACT The role of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.1 Spike (S) on disease pathogenesis was investigated. For this, we generated recombinant viruses harboring the S D614G mutation (rWA1-D614G) and the Omicron BA.1 S gene (rWA1-Omi-S) in the backbone of the ancestral SARS-CoV-2 WA1 strain genome. The recombinant viruses were characterized in vitro and in vivo . Viral entry, cell-cell fusion, plaque size, and the replication kinetics of the rWA1-Omi-S virus were markedly impaired when compared to the rWA1-D614G virus, demonstrating a lower fusogenicity and ability to spread cell-to-cell of rWA1-Omi-S. To assess the contribution of the Omicron BA.1 S protein to SARS-CoV-2 pathogenesis, the pathogenicity of rWA1-D614G and rWA1-Omi-S viruses was compared in a feline model. While the rWA1-D614G-inoculated cats were lethargic and showed increased body temperatures on days 2 and 3 post-infection (pi), rWA1-Omi-S-inoculated cats remained subclinical and gained weight throughout the 14-day experimental period. Animals inoculated with rWA1-D614G presented higher infectious virus shedding in nasal secretions, when compared to rWA1-Omi-S-inoculated animals. In addition, tissue replication of the rWA1-Omi-S was markedly reduced compared to the rWA1-D614G, as evidenced by lower viral load in tissues on days 3 and 5 pi. Histologic examination of the nasal turbinate and lungs revealed intense inflammatory infiltration in rWA1-D614G-inoculated animals, whereas rWA1-Omi-S-inoculated cats presented only mild to modest inflammation. Together, these results demonstrate that the S protein is a major virulence determinant for SARS-CoV-2 playing a major role for the attenuated phenotype of the Omicron virus. IMPORTANCE We have demonstrated that the Omicron BA.1.1 variant presents lower pathogenicity when compared to D614G (B.1) lineage in a feline model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There are over 50 mutations across the Omicron genome, of which more than two-thirds are present in the Spike (S) protein. To assess the role of the Omicron BA.1 S on virus pathogenesis, recombinant viruses harboring the S D614G mutation (rWA1-D614G) and the Omicron BA.1 Spike gene (rWA1-Omi-S) in the backbone of the ancestral SARS-CoV-2 WA1 were generated. While the Omicron BA.1 S promoted early entry into cells, it led to impaired fusogenic activity and cell-cell spread. Infection studies with the recombinant viruses in a relevant naturally susceptible feline model of SARS-CoV-2 infection here revealed an attenuated phenotype of rWA1-Omi-S, demonstrating that the Omi-S is a major determinant of the attenuated disease phenotype of Omicron strains.
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"The Specification of Observed COVID-19 in England: A Review of Auto-Mutation." Biointerface Research in Applied Chemistry 11, no. 6 (2021): 14794–808. http://dx.doi.org/10.33263/briac116.1479414808.
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Genomic sequencing helps us understand COVID-19 and its spread. It can also help guide treatments in the future and see the impact of interventions. In epidemics, genome structure is important for recognizing any small change in the COVID-19 behavior at any population scale to understand the spreading mechanism and whether different strains are emerging. The viral spike (S) protein amino acid sequence viral genomic sequences and other mutated spike proteins are related to the advanced genome of mRNA We analyzed some major S protein mutation which was represented in a high percentage of all the analyzed sequences. Spike-D614G mutation is a terrible phenomenon that has been spread in Europe in early February and has been started rapidly to become the dominant form in new regions. In the United States, the genotypic distribution in California and Washington was similar to Asian countries, while other US states' distribution was comparable to Europe. To gain insight into the D614G mutation consequences, homology modeling using a multi-template threading mechanism with ab initio structural refinement was performed for the S protein region. The D614 model predicted a random coil structure in the Furin domain, and this mutation may confer a competitive advantage at the Furin binding domain that may contribute to the rise of the D614G virus mutant. Due to resistance to any pandemic interventions, mutations should be evaluated in viewpoints of time and geographical situation in the wide phylogenetic domains to announce an early warning system for new mutations.
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Goldswain, Hannah, Xiaofeng Dong, Rebekah Penrice-Randal, et al. "The P323L substitution in the SARS-CoV-2 polymerase (NSP12) confers a selective advantage during infection." Genome Biology 24, no. 1 (2023). http://dx.doi.org/10.1186/s13059-023-02881-5.
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Abstract Background The mutational landscape of SARS-CoV-2 varies at the dominant viral genome sequence and minor genomic variant population. During the COVID-19 pandemic, an early substitution in the genome was the D614G change in the spike protein, associated with an increase in transmissibility. Genomes with D614G are accompanied by a P323L substitution in the viral polymerase (NSP12). However, P323L is not thought to be under strong selective pressure. Results Investigation of P323L/D614G substitutions in the population shows rapid emergence during the containment phase and early surge phase during the first wave. These substitutions emerge from minor genomic variants which become dominant viral genome sequence. This is investigated in vivo and in vitro using SARS-CoV-2 with P323 and D614 in the dominant genome sequence and L323 and G614 in the minor variant population. During infection, there is rapid selection of L323 into the dominant viral genome sequence but not G614. Reverse genetics is used to create two viruses (either P323 or L323) with the same genetic background. L323 shows greater abundance of viral RNA and proteins and a smaller plaque morphology than P323. Conclusions These data suggest that P323L is an important contribution in the emergence of variants with transmission advantages. Sequence analysis of viral populations suggests it may be possible to predict the emergence of a new variant based on tracking the frequency of minor variant genomes. The ability to predict an emerging variant of SARS-CoV-2 in the global landscape may aid in the evaluation of medical countermeasures and non-pharmaceutical interventions.
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Bauer, Lisa, Melanie Rissmann, Feline F. W. Benavides, et al. "In vitro and in vivo differences in neurovirulence between D614G, Delta And Omicron BA.1 SARS-CoV-2 variants." Acta Neuropathologica Communications 10, no. 1 (2022). http://dx.doi.org/10.1186/s40478-022-01426-4.
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AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with various neurological complications. Although the mechanism is not fully understood, several studies have shown that neuroinflammation occurs in the acute and post-acute phase. As these studies have predominantly been performed with isolates from 2020, it is unknown if there are differences among SARS-CoV-2 variants in their ability to cause neuroinflammation. Here, we compared the neuroinvasiveness, neurotropism and neurovirulence of the SARS-CoV-2 ancestral strain D614G, the Delta (B.1.617.2) and Omicron BA.1 (B.1.1.529) variants using in vitro and in vivo models. The Omicron BA.1 variant showed reduced neurotropism and neurovirulence compared to Delta and D614G in human induced pluripotent stem cell (hiPSC)-derived cortical neurons co-cultured with astrocytes. Similar differences were obtained in Syrian hamsters inoculated with D614G, Delta and the Omicron BA.1 variant 5 days post infection. Replication in the olfactory mucosa was observed in all hamsters, but most prominently in D614G inoculated hamsters. Furthermore, neuroinvasion into the CNS via the olfactory nerve was observed in D614G, but not Delta or Omicron BA.1 inoculated hamsters. Furthermore, neuroinvasion was associated with neuroinflammation in the olfactory bulb of hamsters inoculated with D614G. Altogether, our findings suggest differences in the neuroinvasive, neurotropic and neurovirulent potential between SARS-CoV-2 variants using in vitro hiPSC-derived neural cultures and in vivo in hamsters during the acute phase of the infection.
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Wu, Jiajing, Li Zhang, Yue Zhang, et al. "The Antigenicity of Epidemic SARS-CoV-2 Variants in the United Kingdom." Frontiers in Immunology 12 (June 17, 2021). http://dx.doi.org/10.3389/fimmu.2021.687869.
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To determine whether the neutralization activity of monoclonal antibodies, convalescent sera and vaccine-elicited sera was affected by the top five epidemic SARS-CoV-2 variants in the UK, including D614G+L18F+A222V, D614G+A222V, D614G+S477N, VOC-202012/01(B.1.1.7) and D614G+69-70del+N439K, a pseudovirus-neutralization assay was performed to evaluate the relative neutralization titers against the five SARS-CoV-2 variants and 12 single deconvolution mutants based on the variants. In this study, 18 monoclonal antibodies, 10 sera from convalescent COVID-19 patients, 10 inactivated-virus vaccine-elicited sera, 14 mRNA vaccine-elicited sera, nine RBD-immunized mouse sera, four RBD-immunized horse sera, and four spike-encoding DNA-immunized guinea pig sera were tested and analyzed. The N501Y, N439K, and S477N mutations caused immune escape from nine of 18 mAbs. However, the convalescent sera, inactivated virus vaccine-elicited sera, mRNA vaccine-elicited sera, spike DNA-elicited sera, and recombinant RBD protein-elicited sera could still neutralize these variants (within three-fold changes compared to the reference D614G variant). The neutralizing antibody responses to different types of vaccines were different, whereby the response to inactivated-virus vaccine was similar to the convalescent sera.
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Raghav, Sunil, Arup Ghosh, Jyotirmayee Turuk, et al. "Analysis of Indian SARS-CoV-2 Genomes Reveals Prevalence of D614G Mutation in Spike Protein Predicting an Increase in Interaction With TMPRSS2 and Virus Infectivity." Frontiers in Microbiology 11 (November 23, 2020). http://dx.doi.org/10.3389/fmicb.2020.594928.
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Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has emerged as a global pandemic worldwide. In this study, we used ARTIC primers–based amplicon sequencing to profile 225 SARS-CoV-2 genomes from India. Phylogenetic analysis of 202 high-quality assemblies identified the presence of all the five reported clades 19A, 19B, 20A, 20B, and 20C in the population. The analyses revealed Europe and Southeast Asia as two major routes for introduction of the disease in India followed by local transmission. Interestingly, the19B clade was found to be more prevalent in our sequenced genomes (17%) compared to other genomes reported so far from India. Haplotype network analysis showed evolution of 19A and 19B clades in parallel from predominantly Gujarat state in India, suggesting it to be one of the major routes of disease transmission in India during the months of March and April, whereas 20B and 20C appeared to evolve from 20A. At the same time, 20A and 20B clades depicted prevalence of four common mutations 241 C &gt; T in 5′ UTR, P4715L, F942F along with D614G in the Spike protein. D614G mutation has been reported to increase virus shedding and infectivity. Our molecular modeling and docking analysis identified that D614G mutation resulted in enhanced affinity of Spike S1–S2 hinge region with TMPRSS2 protease, possibly the reason for increased shedding of S1 domain in G614 as compared to D614. Moreover, we also observed an increased concordance of G614 mutation with the viral load, as evident from decreased Ct value of Spike and the ORF1ab gene.
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Zhang, Lizhou, Cody B. Jackson, Huihui Mou, et al. "SARS-CoV-2 spike-protein D614G mutation increases virion spike density and infectivity." Nature Communications 11, no. 1 (2020). http://dx.doi.org/10.1038/s41467-020-19808-4.
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AbstractSARS-CoV-2 variants with spike (S)-protein D614G mutations now predominate globally. We therefore compare the properties of the mutated S protein (SG614) with the original (SD614). We report here pseudoviruses carrying SG614 enter ACE2-expressing cells more efficiently than those with SD614. This increased entry correlates with less S1-domain shedding and higher S-protein incorporation into the virion. Similar results are obtained with virus-like particles produced with SARS-CoV-2 M, N, E, and S proteins. However, D614G does not alter S-protein binding to ACE2 or neutralization sensitivity of pseudoviruses. Thus, D614G may increase infectivity by assembling more functional S protein into the virion.
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Ouarab, Maha, Elarbi Bouaiti, Zineb Rhazzar, et al. "Immunogenicity of two‐dose sinopharm BBIB‐CorV vaccine in Morocco: One‐year follow‐up and neutralizing activity against severe acute respiratory syndrome coronavirus 2 variants of concern." Immunity, Inflammation and Disease 12, no. 11 (2024). http://dx.doi.org/10.1002/iid3.1359.
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AbstractBackgroundThis study aimed to evaluate the immunogenicity of a two‐dose Sinopharm BBIB‐CorV (Vero cells) vaccine against SARS‐CoV‐2, at 28 days, 6 months, and 1‐year postvaccination. And assess the capacity of two‐dose vaccine recipients to neutralize SARS‐CoV‐2 strains B.1 (Wuhan/D614G), B.1.1.7 (Alpha), AY.33 (Delta), or BA.5.2.2 (Omicron) variants of concern (VOCs).MethodsA prospective matched case–control cohort study was conducted at the Military Hospital of Rabat, Morocco between February 2021 and 2022. Immunogenicity was evaluated by standard Microneutralization (MN) assay against four variants (Wuhan D614G, Alpha, Delta, and Omicron).ResultsThe overall positive neutralizing rates for vaccine recipients against B.1 D614G were 72.09%, 74.82%, and 75.19% on 28‐, 180‐, 365‐ day respectively. The proportion of NAbs targeting the Wuhan D614G, and Alpha variants under the BBIBP‐CorV vaccination was high on Day 28‐ and 6 months postvaccination.ConclusionThe immunogenic response to the newly emerging SARS‐CoV‐2 variants of concern (VOCs), such as Delta and Omicron was comparatively reduced. As a result, it is recommended that additional boost vaccinations be considered.