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Neutralization of Variant Under Investigation B.1.617.1 With Sera of BBV152 Vaccinees
Abstract
To the Editor—The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in places where the virus is uncontained poses a global threat from the perspective of public health and vaccine efficacy. Peng et al [1] recently reported on the increased transmissibility with the newly emerged Variant of Concern (VOC) (20C/S:452R and 20C/S:452R) with the L452R mutation in San Francisco. We report the immunological characteristics of a Variant under Investigation (VUI) B.1.617.1, playing a critical role in the current surge of coronavirus disease 2019 (COVID-19) in the western state of Maharashtra, India.
Several SARS-CoV-2 variants—B.1.1.7, B.1.351, and B.1.1.28.1—have been reported in India during 2021 [2, 3]. We had sequenced 146 nasopharyngeal/oropharyngeal swabs of COVID-19 cases [4]. Among these, 15 sequences had a combination of L452R and E484Q mutations, which raised concern as both are found in the receptor-binding domain (RBD) of the spike protein. However, the combined effect of these mutations is still unknown.
... Although a result of the reduced neutralizing capacity of sera is caused an increase in breakthrough. [30][31][32][33] The variant B.1.617.2 is also an Indian variant named as delta variant, in which the S-protein substitutions are T19R and G142D and the deletions are E156 and F157; R158G, L452R, T478K, D614G, P681R, and D950N substitutions ( Figure 4). This variant has some main attributes, such as increased transmissibility, reduced neutralization by post vaccination sera and monoclonal antibody treatments. ...
... The main attribute of this variant is, potential neutralization reduction by some monoclonal antibody treatments and reduced neutralization by the post vaccinations, although an increase in breakthrough infections may arise as a result of the reduced neutralizing capacity of sera. [28][29][30][31] This Indian variant is also known as double mutant, which is mutated in the RBD region of S-protein. Before perform the MD simulation, the structure of this mutated RBD with ACE2 complex was energy minimized. ...
Currently, no approved drug is available as a causative agent of coronavirus disease 2019 (COVID-19) except for some repurposed drugs. The first structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in late 2019, based on that some vaccines and repurposed drugs were approved to prevent people from COVID-19 during the pandemic situation. Since then, new types of variants emerged and notably, the receptor binding domain (RBD) adopted different binding modes with angiotensin-converting enzyme 2 (ACE2); this made significant changes in the progression of COVID-19. Some of the new variants are highly infectious spreading fast and dangerous. The present study is focused on understanding the binding mode of the RBD of different mutated SARS-CoV-2 variants of concern (alpha to omicron) with the human ACE2 using molecular dynamics simulation. Notably, some variants adopted a new binding mode of RBD with ACE2 and formed different interactions, which is unlike the wild type; this was confirmed from the comparison of interaction between RBD-ACE2 of all variants with its wild-type structure. Binding energy values confirm that some mutated variants exhibit high binding affinity. These findings demonstrate that the variations in the sequence of SARS-CoV-2 S-protein altered the binding mode of RBD; this may be the reason that the virus has high transmissibility and causes new infections. This in-silico study on mutated variants of SARS-CoV-2 RBD with ACE2 insights into their binding mode, binding affinity, and stability. This information may help to understand the RBD-ACE2 binding domains, which allows for designing newer drugs and vaccines.
... B.1.617.2 has a set of S protein substitutions, and several are also present in other variants of interest/concern. Two critical mutations in the RBD domain, L452R and E484Q, affect the neutralizing antibodies' evasion [67][68][69]. It is the first strain where these two mutations were seen together. ...
... According to the CDC and some research trials, this variant has a potential reduction in neutralization by some EUA monoclonal antibody treatments and slightly reduced neutralization by post-vaccination [4,38,39,47,69]. of eight COVID-19 convalescents who were infected during the beginning of the pandemic than the original virus. The Mu variant shows a pronounced resistance to the antibodies elicited by natural SARS-CoV-2 infection and the BNT162b2 mRNA vaccine [72,73]. ...
Although the chief of the World Health Organization (WHO) has declared the end of the coronavirus disease 2019 (COVID-19) as a global health emergency, the disease is still a global threat. To be able to manage such pandemics in the future, it is necessary to develop proper strategies and opportunities to protect human life. The data on the SARS-CoV-2 virus must be continuously analyzed, and the possibilities of mutation and the emergence of new, more infectious variants must be anticipated, as well as the options of using different preventive and therapeutic techniques. This is because the fast development of severe acute coronavirus 2 syndrome (SARS-CoV-2) variants of concern have posed a significant problem for COVID-19 pandemic control using the presently available vaccinations. This review summarizes data on the SARS-CoV-2 variants that are responsible for severe COVID-19 and the clinical efficacy of the most commonly used vaccines in clinical practice. The consequences after the disease (long COVID or post-COVID conditions) continue to be the subject of studies and research, and affect social and economic life worldwide.
... The E484Q, L452R, as well as P681R mutations were the main circulatory variants (WHO, 2021 (Kumar, 2021). Following analytical results of Yadav et al. (2022), they deduced that the influence of this lineage was found to be deactivated by the presently available COVID-19 vaccine, and that the variant has no recorded effect on immune evasion and therapies. ...
The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has spurred global interest. Since the first recognition of SARS-CoV-2, thousands of genomic mutations have been developed and more are still to come for the ability of SARS-CoV-2 to rapidly evolve and adapt is due to its high mutability, which allows new lineages and variants to emerge. These mutations result in changes to the virus properties, such as severity and transmissibility, making it even more difficult to contain. Hence, the increased release of data that are sequencing-related; more mutations as well as genetic SARS-CoV-2 diversity were declared to understand the viral variants, therefore, is useful in countries with little or no facilities for surveillance. In this review, our research team summarized several literatures including: Clinical reports, cohort studies, reviews, case series, and editorials to present a descriptive impression of the variation in the basic molecular structure of SARS-CoV-2. Thus, providing an overview of the nomenclature of all circulating variants, characteristics of mutant variants and possible consequences of mutation of variants of interest in Nigeria.
... These changes include emergent mutations, the absence of certain established mutations, and alterations in mutation frequency distributions. For instance, the L452R mutation, recognized for its pivotal role in Delta Variant's heightened viral infectivity and attributed to augmented viral binding affinity towards angiotensin-converting enzyme (ACE) with intensified viral replication, was notably absent in the lung tissue of cats from the FIV-negative groups and those concurrently FIV+/AZT (n = four out of five cats) [65][66][67][68]. This may be related to the influence of host species on viral genomic adaptation. ...
People living with human immunodeficiency virus (PLWH) are a significant population globally. Research delineating our understanding of coinfections in PLWH is critical to care for those navigating infection with other pathogens. The recent COVID-19 pandemic underscored the urgent need for studying the effects of SARS-CoV-2 infections in therapy-controlled and uncontrolled immunodeficiency viral infections. This study established the utility of a feline model for the in vivo study of coinfections. Domestic cats are naturally infected with SARS-CoV-2 and Feline Immunodeficiency Virus, a lentivirus molecularly and pathogenically similar to HIV. In this study, comparisons are made between FIV-positive and FIV-negative cats inoculated with SARS-CoV-2 (B.1.617.2.) in an experimental setting. Of the FIV+ cats, three received Zidovudine (AZT) therapy in the weeks leading up to SARS-CoV-2 inoculation, and two did not. SARS-CoV-2 viral RNA was quantified, histopathologic comparisons of respiratory tissues were made, and T-cell populations were analyzed for immune phenotype shifts between groups. CD4+ T lymphocyte responses varied, with FIV+-untreated cats having the poorest CD4+ response to SARS-CoV-2 infection. While all cats had significant pulmonary inflammation, key histopathologic features of the disease differed between groups. Additionally, viral genomic analysis was performed, and results were analyzed for the presence of emerging, absent, amplified, or reduced mutations in SARS-CoV-2 viral RNA after passage through the feline model. Positive selection is noted, especially in FIV+ cats untreated with AZT, and mutations with potential relevance were identified; one FIV+-untreated cat had persistent, increasing SARS-CoV-2 RNA in plasma five days post-infection. These findings and others support the utility of the feline model for studying coinfection in people with HIV and highlight the importance of antiretroviral therapy in clearing SARS-CoV-2 coinfections to minimize transmission and emergence of mutations that may have deleterious effects.
... According to Kadoma et al. (2006), the antioxidants and anti-hypertensive secondary metabolites alpha, beta, and delta-tocotrienol inhibit protein kinase C activity and cell proliferation, hence reducing the activity of smooth muscle. neuroprotective sugar derivative called glucosylsiaresinolate 3-arabinoside (Yadav et al., 2022). In addition to proteins, the diverse class of metabolites including saturated and unsaturated fatty acids along with esterderivatives were also detected in the hydrolysates. ...
Background and Objectives
To optimize the utilization of rice by‐products, the rice bran protein hydrolysate (RBPH) was subjected to a process of separation and purification using ultrafiltration and reversed‐phase high‐performance liquid chromatography (RP‐HPLC). Subsequently, the identification of peptide sequences was carried out using mass spectrometer hybrid quadrupole‐time‐of‐flight and nontargeted metabolomic profiling done using UHPLC‐QTOF‐IMS profiling to identify antioxidant and antihypertensive amino acids.
Findings
Three novel bioactive peptides, namely, STCCK, FMKSK, and KICILVFTLTTC, were identified within RBPH through enzymatic digestion using alcalase, pepsin, and trypsin. These peptides showed significant antioxidant activity and angiotensin‐converting enzyme (ACE) inhibitory activity. Molecular docking analyses elucidated various interaction mechanisms between these peptides and the ACE receptor protein, including hydrogen bonding and hydrophobic interactions. This suggested that the peptides effectively suppress ACE by forming hydrogen bonds with the active pockets of human ACE with a high affinity.
Conclusion
In summary, peptides derived from rice bran protein exhibited distinguished antihypertensive and antioxidant properties, underscoring their potential for valuable utilization in addressing utilization of rice by‐products.
Significance and Novelty
The study advances scientific knowledge and offers practical solutions for health improvement and sustainable agriculture.
... The sugar content was found to be highest in PB1121, with derivatives such as (R)-1-O-[b-D-Glucopyranosyl-(1->6)-b-D-glucopyranoside] and 1,3-octanediol being most abundant in PB1121 and lowest in PB1509. PB1121 also exhibited the highest quantity of glucosylsiaresinolate 3-arabinoside, a sugar derivative known for its anti-cancer, anti-inflammatory, and neuroprotective effects (Yadav et al., 2022). Lipids were detected in RBPH as well. ...
In the present study, rice bran protein (RBP) from the PB1121 variety was hydrolysed using trypsin and subjected to non‐targeted IMS profiling to identify antioxidant and antihypertensive amino acids in the resulting RBP hydrolysates. The hydrolysate was then separated into three fractions using ultrafiltration, and each fraction was tested for antioxidant and ACE inhibitory activities. The ACE activity was assessed using the tripeptide hippuryl‐histidyl‐leucine (HHL) as a model peptide via HPLC‐DAD. The fraction with the molecular weight (>3000 Da) displayed the strongest antioxidant and ACE inhibitory activity. This fraction was further divided into five fractions using gel Sephadex G‐25, and the greatest levels of antioxidant and ACE inhibitory activity were found in fraction F3B. Fraction F3B was then fractionated using HPLC, and the fraction with ACE inhibitory activity (IC50 of 43 mg mL⁻¹) was analysed using MALDI‐TOF‐TOF mass spectrometry to determine its exact molecular mass and amino acid sequence. The amino acid sequence FMKSK (phe‐met‐lys‐ser‐lys) with a Mw of 655.376 Da was detected, and the molecular docking investigation revealed that FMKSK suppresses ACE by forming strong hydrogen bonds with the active pockets of human ACE. These findings suggest that rice bran contains bioactive peptides with antioxidant and ACE inhibitory effects, making it a promising raw material for the production of beneficial products.
... The SARS-Cov-2 B.1.617 lineage was found in India first [4] but quickly spread to other countries. The lineage includes three main subtypes: B1.617.1 (Kappa), B.1.617.2 (Delta), and B.617.3 (None-typed). ...
Since 2019, the antigens from Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) have evolved from the initial D614 wild strain in the first epidemic wave, to D614G mutant in the second wave, to Delta mutant in the third wave, and to Omicron mutant in the fourth wave. Were the virulence and infectivity associated with different fragments in the Delta subtype of SARS-CoV-2? It is needed to analyze the sequences of the virus. The longest four glycine-free antigen fragments with tryptophan, longer or equal to 37 amino acids in length, were selected. The four fragment sequences in D614, D614G, N148, and I358 Omicron subtype were searched from the National Center of Biological Information website. The standard deviation (SD) of the molecular weight of the contained amino acids in the fragments was calculated to be the indicator of their antigen precession. The longest fragment was analyzed for the relationship between antigen precession and virus infectivity. On the other hand, 10 mutations in the Delta subtype were found in eight mutated fragments, and their antigen precession was used to analyze the correlation with virus virulence. The longest antigen fragments determined virus infectivity. Whole mutated fragments determined the virulence. Both were associated with different mutated fragments with varied antigen precession in the Delta subtype of SARS-CoV-2.
... New lineages of SARS-CoV-2 continue to evolve through genetic mutations, recombination, immune evasion or viral adaptation to the hosts [2,3], which is an ongoing public health concern. Consistent genetic changes have a profound impact on the physical and biological properties of viruses, leading to emerging variants, including variants of concern (VOC) [4][5][6][7]. As of today, five VOCs, including Alpha, Beta, Gamma, Delta and Viruses 2023, 15, 1940 2 of 11 Omicron, have been identified [8,9], of which the Omicron variant became more prevalent and overtook the other four VOCs. ...
SARS-CoV-2 caused a life-threatening COVID-19 pandemic outbreak worldwide. The Southeastern Region of Wisconsin, USA (SERW) includes large urban Milwaukee and six suburban counties, namely Kenosha, Ozaukee, Racine, Walworth, Washington and Waukesha. Due to the lack of detailed SARS-CoV-2 genomic surveillance in the suburban populations of the SERW, whole-genome sequencing was employed to investigate circulating SARS-CoV-2 lineages and characterize dominant XBB lineages among this SERW population from November 2021 to April 2023. For an unbiased data analysis, we combined our 6709 SARS-CoV-2 sequences with 1520 sequences from the same geographical region submitted by other laboratories. Our study shows that SARS-CoV-2 genomes were distributed into 357 lineages/sublineages belonging to 13 clades, of which 88.8% were from Omicron. We document dominant sublineages XBB.1.5 and surging XBB.1.16 and XBB.1.9.1 with a few additional functional mutations in Spike, which are known to contribute to higher viral reproduction, enhanced transmission and immune evasion. Mutational profile assessment of XBB.1.5 Spike identifies 38 defining mutations with high prevalence occurring in 49.8–99.6% of the sequences studied, of which 32 mutations were in three functional domains. Phylogenetic and genetic relatedness between XBB.1.5 sequences reveal potential virus transmission occurring within households and within and between Southeastern Wisconsin counties. A comprehensive phylogeny of XBB.1.5 with global sub-dataset sequences confirms the wide spread of genetically similar SARS-CoV-2 strains within the same geographical area. Altogether, this study identified proportions of circulating Omicron variants and genetic characterization of XBB.1.5 in the SERW population, which helped state and national public health agencies to make compelling mitigation efforts to reduce COVID-19 transmission in the communities and monitor emerging lineages for their impact on diagnostics, treatments and vaccines.
... With first and second waves dominated by viruses belonging to B.1 and C.36 lineages, followed by a third wave linked to the circulation of C.36 lineage that acquired several mutations in spike protein and evolved into sub-lineages. We show Fig. 5 Number of cases and incidence of COVID-19 in the omicron period compared to previous periods, Egypt 2020-2022 that the delta variants had greater genetic diversity, with 39 different Pango lineages, followed by omicron, with 21 different Pango lineages and most dominant variant during the fourth wave and replacing previously circulating variants, the delta variant had additional mutations hat contributed to its increased transmissibility and rapid spread worldwide [17][18][19].Studies reported that the evolution of SARS-CoV-2 to the omicron variant has resulted in mutations conferring a more-contagious nature and vaccine escape [20][21][22]. Many of the mutations in the spike protein of omicron could impair the antibodies' ability to bind to the virus, reducing the effectiveness of a vaccine or prior infection at preventing new infections. ...
Background:
The o severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic has killed millions of people and caused widespread concern around the world. Multiple genetic variants of SARS-CoV-2 have been identified as the pandemic continues. Concerns have been raised about high transmissibility and lower vaccine efficacy against omicron. There is an urgent need to better describe how omicron will impact clinical presentation and vaccine efficacy. This study aims at comparing the epidemiologic, clinical, and genomic characteristics of the omicron variant prevalent during the fifth wave with those of other VOCs between May 2020 and April 2022.
Methods:
Epidemiological data were obtained from the National Electronic Diseases Surveillance System. Secondary data analysis was performed on all confirmed COVID-19 patients. Descriptive data analysis was performed for demographics and patient outcome and the incidence of COVID-19 was calculated as the proportion of SARS-CoV-2 confirmed patients out of the total population of Egypt. Incidence and characteristics of the omicron cohort from January- April 2022, were compared to those confirmed from May 2020-December 2021. We performed the whole-genome sequencing of SARS-CoV-2 on 1590 specimens using Illumina sequencing to describe the circulation of the virus lineages in Egypt.
Results:
A total of 502,629 patients enrolled, including 60,665 (12.1%) reported in the fifth wave. The incidence rate of omicron was significantly lower than the mean of incidences in the previous subperiod (60.1 vs. 86.3/100,000 population, p < 0.001). Symptoms were reported less often in the omicron cohort than in patients with other variants, with omicron having a lower hospitalization rate and overall case fatality rate as well. The omicron cohort tended to stay fewer days at the hospital than did those with other variants. We analyzed sequences of 2433 (1590 in this study and 843 were obtained from GISAID platform) Egyptian SARS-CoV-2 full genomes. The first wave that occurred before the emergence of global variants of concern belonged to the B.1 clade. The second and third waves were associated with C.36. Waves 4 and 5 included B.1.617.2 and BA.1 clades, respectively.
Conclusions:
The study indicated that Omicron-infected patients had milder symptoms and were less likely to be hospitalized; however, patients hospitalized with omicron had a more severe course and higher fatality rates than those hospitalized with other variants. Our findings demonstrate the importance of combining epidemiological data and genomic analysis to generate actionable information for public health decision-making.
... Early viral strains that have been defined as Variants Of Concern (VOC) include Alpha [15] and Beta [16][17][18][19][20][21][22][23][24][25][26][27][28], which were quickly dominated by Delta variant that causes severe clinical symptoms [29][30][31]. To battle against the waning of vaccine-elicited antibody immune response to emerging VOCs, a third dose of vaccine was approved in mid-2021, first in Israel and later worldwide. ...
The rapid spread and dominance of the Omicron SARS-CoV-2 lineages have posed severe health challenges worldwide. While extensive research on the role of the Receptor Binding Domain (RBD) in promoting viral infectivity and vaccine sensitivity has been well documented, the functional significance of the 681PRRAR/SV687 polybasic motif of the viral spike is less clear. In this work, we monitored the infectivity levels and neutralization potential of the wild-type human coronavirus 2019 (hCoV-19), Delta, and Omicron SARS-CoV-2 pseudoviruses against sera samples drawn four months post administration of a third dose of the BNT162b2 mRNA vaccine. Our findings show that in comparison to hCoV-19 and Delta SARS-CoV-2, Omicron lineages BA.1 and BA.2 exhibit enhanced infectivity and a sharp decline in their sensitivity to vaccine-induced neutralizing antibodies. Interestingly, P681 mutations within the viral spike do not play a role in the neutralization potential or infectivity of SARS Cov-2 pseudoviruses carrying mutations in this position. The P681 residue however, dictates the ability of the spike protein to promote fusion and syncytia formation between infected cells. While spike from hCoV-19 (P681) and Omicron (H681) promote only modest cell fusion and formation of syncytia between cells that express the spike-protein, Delta spike (R681) displays enhanced fusogenic activity and promotes syncytia formation. Additional analysis shows that a single P681R mutation within the hCoV-19 spike, or H681R within the Omicron spike, restores fusion potential to similar levels observed for the Delta R681 spike. Conversely, R681P point mutation within the spike of Delta pseudovirus abolishes efficient fusion and syncytia formation. Our investigation also demonstrates that spike proteins from hCoV-19 and Delta SARS-CoV-2 are efficiently incorporated into viral particles relative to the spike of Omicron lineages. We conclude that the third dose of the Pfizer-BNT162b2 provides appreciable protection against the newly emerged Omicron sub-lineages. However, the neutralization sensitivity of these new variants is diminished relative to that of the hCoV-19 or Delta SARS-CoV-2. We further show that the P681 residue within spike dictates cell fusion and syncytia formation with no effects on the infectivity of the specific viral variant and on its sensitivity to vaccine-mediated neutralization.
... Glucosylsiaresinolate-3-arabinoside, a sugar derivative, shows the highest concentration in RBI. These compounds are shown to have anti-cancer, anti-inflammatory and neuroprotective properties (Yadav et al., 2022). Istamycin AO and istamycin AP are the type of amino sugars present in MBI which is shown to regulate protein function and when combined with other compounds, they form antibiotics. ...
Rice bran protein isolates and seven legume protein isolates (moong bean, green pea, white pea, black chickpea and white chickpea, soya bean and lentil) were evaluated for functional, structural and metabolomic properties. Rice bran protein isolates (RBI) had higher solubility, foaming, oil absorption capacity and water absorption capacity but lower denaturing temperature compared to legume proteins. The functionality of proteins isolates impacted significantly with structural characteristics. The β‐sheet, α‐helix, β‐turn and anti‐parallel β‐sheets proportions were evaluated by FTIR. RBI revealed lower molecular weight, less rigid conformational structure and lower proportion of β‐sheet. The evaluation of untargeted metabolomics compounds was determined by ultraperformance liquid chromatography quadruple time‐of‐flight ion mobility mass spectrometry (UHPLC‐QTOF‐IMS), evaluated using PCA and presented as a heatmap. Analysis revealed 46 metabolites including sugars, amino acids, lipids, terpenoid, phenolics, saponins and their derivatives. Significant differences in selected compounds from 126 identified metabolites among protein isolates were observed. This work provides new insights into metabolite distribution among protein isolates and also presents future implementations for applications in food and nutraceuticals.
... The recent upsurge of COVID cases in India was due to the double mutant variant of the SARS-CoV-2, identified by sequence analysis of the samples (15). The COVID cases from western Maharashtra had mutations in spike protein at E484Q and L452R and developed as a separate lineage in India (16). The linage B.1.617 ...
Human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and 2019 novel coronavirus (2019-nCoV), also known as SARS-CoV-2, have caused global epidemics with high morbidity and mortality. Active research on finding effective drugs against 2019-nCoV/SARS-CoV-2 is going on. In silico screening represents the best approach for hits identification and could shorten the time and reduce cost compared to de novo drug discovery. Recently, CoV2 mutations have been a big concern in India, particularly on non-structural proteins (NSPs) and Spike Protein (B.1.617) which are the key targets that play a pivotal role in mediating viral replication and transcription. Herein, this study analyzed the NSPs and spike’s structural aspects of mutant strains of SARS-CoV-2. The three-dimensional structures of NSPs and S Spike proteins were retrieved from the protein data bank or modeled. And a dataset of an antiviral compound library containing 490,000 drug-like ligands and structurally diverse biologically active scaffolds was used for our studies. Initially, the molecular alignment was performed for library compounds with the reference drug molecule to find targets that match the field points. Antiviral compounds having a similarity score >0.6; were selected for further docking studies with wild and mutant NSPs and S Spike protein of SARS-CoV-2 variant B.1.617. The docking studies identified a potent analog MA-11, which exhibited the highest binding affinity towards wild and mutant proteins. Further, molecular dynamics simulation studies of selected compounds confirmed their perfect fitting into NSP12 and spike active sites and offer direction for further lead optimization and rational drug design.
... The details on name of the vaccines and variants of SARS-CoV-2 concern strains with their references. [127] No significant reduction in neutralizing activity [29] Significant reduction neutralizing activity [29] Reduction in neutralizing activity [128] Reduction in neutralizing activity [127] Sinopharm 79% VE [127] Faintly declines the neutralizing activity of vaccine era [130] Resistance to post vaccination sera with partial reduction in neutralizing activity [130] NA NA Sinovac Biotech 50.7% VE [131] NA NA NA 49.6% VE [131] BNT162b2 NA 90% VE [132] 75% VE [132] Reduction in neutralizing activity [128,133,134] [128,133,134] Neutralizing activity of vaccine era [135] Ad26.CoV2.S NA 72% VE [136] 64% VE [136] Reduction in neutralizing activity [137,138] 64% VE [136] ChAdOx1 [143] Reduction in neutralizing activity [143] Reduction in neutralizing activity [144] Reduction in neutralizing activity [145] BBIBP-CorV NA No reduction [143] No reduction [130,143] NA NA Corona Vac NA NA NA NA Reduction in neutralizing activity [140,146] Abbreviations: NA-not available. Table 7 Effectiveness of vaccines against variant of interests of SARS-CoV-2 strains. ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious and pathogenic virus that first appeared in late December 2019. This SARS-CoV-2 causes an infection of an acute respiratory disease called "coronavirus infectious disease-2019 (COVID-19). The World Health Organization (WHO) declared this SARS-CoV-2 outbreak a great pandemic on March 11, 2020. As of January 31, 2023, SARS-CoV-2 recorded more than 67 million cases and over 6 million deaths. Recently, novel mutated variants of SARS-CoV are also creating a serious health concern worldwide, and the future novel variant is still mysterious. As infection cases of SARS-CoV-2 are increasing daily, scientists are trying to combat the disease using numerous antiviral drugs and vaccines against SARS-CoV-2. To our knowledge, this is the first comprehensive review that summarized the dynamic nature of SARS-CoV-2 transmission, SARS-CoV-2 variants (a variant of concern and variant of interest), antiviral drugs and vaccines utilized against SARS-CoV-2 at a glance. Hopefully, this review will enable the researcher to gain knowledge on SARS-CoV-2 variants and vaccines, which will also pave the way to identify efficient novel vaccines against forthcoming SARS-CoV-2 strains.
... Besides, miR-33a inhibits AMP-activated kinase (AMPK) resulting in an increase in intracellular cholesterol and fatty acid levels [90]. In addition, miR-122 regulates many enzymes, including pyruvate kinase [91,92] and AMPK [93]. As a result, serum miR-33a and miR-122 could be valuable noninvasive biomarkers for the diagnosis of metabolic syndrome [92,94]. ...
In recent decades, obesity has extensively emerged to the level of pandemics. It's significantly associated with serious co-morbidities that could decrease life quality and even life expectancy. Obesity has several determinants, such as age, sex, endocrine, and genetic factors. The miRNAs have emerged as genetic factors affecting obesity. The miRNAs are small noncoding nucleic acids that can modify gene expression and hence, control biological processes. The miRNAs can greatly affect many biological processes in obesity, such as adipogenesis, lipid metabolism, and homeostasis. As a result, the entry of miRNAs in obesity therapeutic approaches has been strongly advised as miRNAs mimics, inhibitors, and stimulators. Hence, this review aims to point out a summarized and updated overview of miRNAs and their roles in obesity and its included processes, such as adipogenesis and lipid metabolism. Besides, we also review recent applications of miRNAs as a treatment approach for obesity.
... Previous studies have shown that L452R, E484Q/K, P681R, and T478K may play a role in imparting greater transmissibility. However, the molecular basis for this observation remains inconclusive [34][35][36]. ...
Introduction:
This study aimed to perform mutation and phylogenetic analyses of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Delta variants and analyze the characteristic signs and symptoms of patients infected with SARS-CoV-2 Delta variant originated from Makassar during the Delta outbreak.Methods: We collected samples from patients who were infected with coronavirus disease 2019 (COVID-19) between June and October 2021. We selected the Quantitative Reverse Transcription-Polymerase Chain Reaction (PCR)-positive samples with a cycle threshold value of <30 for whole genome sequencing. Total viral ribonucleic acid (RNA) was isolated from 34 PCR-positive nasopharyngeal swab samples, and whole genome sequencing was performed using the Oxford Nanopore GridlON sequencer. Phylogenetic and maximum clade credibility analyses were performed using the Bayesian Markov chain Monte Carlo method.
Results:
It was found that 33 patients were infected with the SARS-CoV-2 Delta variant in this cohort study, among whom 63.6% (21) patients were female. According to the clinical data, 24 (72.7%), 7 (21.2%), and 2 (6.1%) patients had mild, moderate, and severe COVID-19 infections. Phylogenetic analysis based on the spike and RNA-dependent RNA polymerase (RdRp) genes showed that the collected samples were clustered in the main lineage of B.1.617.2 (Delta variant). The Delta variants had a high frequency of distinct mutations in the spike protein region, including T19R (94.12%), L452R (88.23%), T478K (91.17%), D614G (97%), P681R (97%), and D950 N (97%). Other unique mutations found in a smaller frequency in our samples were present in the N-terminal domain, including A27T (2.94%) and A222V (14.70%), and in the receptor-binding domain, including Q414K (5.88%), G446V (2.94%), and T470 N (2.94%).
Conclusion:
This study revealed the unique mutations in the S protein region of Delta variants. T19R, L452R, T478K/T478R, D614G, P681R, and D950 N were the most common substitutions in Makassar's Delta variant.
... Antibodies generated after vaccination can neutralize two different variants B.1.1.7 as well as B.1.617 (Sapkal et al., 2021;Yadav et al., 2022). This implies neutralizing antibodies that are able to recognize different variants of SARS-CoV-2 showed multispecificity. ...
Antibodies represent key effectors of the adaptive immune system. The specificity of antibodies is an established hallmark of the immune response. However, a certain proportion of antibodies exhibit limited promiscuity or multireactivity. Germline antibodies display plasticity which imparts multispecificity to enhance the antibody repertoire. Surprisingly, even affinity matured antibodies display such plasticity and multireactivity enabling their binding to more than one antigen. We propose that antibody multispecificity is a physiological requirement to expand the antibody repertoire at the germline level and to tolerate plasticity in antigens at the mature level. This property of the humoral immune response may attenuate the ability of infectious RNA viruses such as influenza, HIV and SARS-CoV-2 to acquire mutations that render resistance to neutralizing antibodies.
... Lineage was noticed in October in India in the year 2020, which was named B.1.617, which is also labeled as Delta (δ) variant [157]. Till January 2021, a few cases were reported. ...
COVID-19 is a worldwide pandemic caused by SARS-coronavirus-2 (SARS-CoV-2). Less than a year after the emergence of the Covid-19 pandemic, many vaccines have arrived on the market with innovative technologies in the field of vaccinology. Based on the use of messenger RNA (mRNA) encoding the Spike SARS-Cov-2 protein or Abbreviations: ACE2, angiotensin-converting enzyme 2; BIBP, Beijing Institute of biological products; CD, cluster of differentiation; CDC, Centers for Disease 2 Variants Pandemic disease Vaccines on the use of recombinant adenovirus vectors enabling the gene encoding the Spike protein to be introduced into our cells, these strategies make it possible to envisage the vaccination in a new light with tools that are more scalable than the vaccine strategies used so far. Faced with the appearance of new variants, which will gradually take precedence over the strain at the origin of the pandemic, these new strategies will allow a much faster update of vaccines to fight against these new variants, some of which may escape neutralization by vaccine antibodies. However, only a vaccination policy based on rapid and massive vaccination of the population but requiring a supply of sufficient doses could make it possible to combat the emergence of these variants. Indeed, the greater the number of infected individuals, the faster the virus multiplies, with an increased risk of the emergence of variants in these RNA viruses. This review will discuss SARS-CoV-2 pathophysiology and evolution approaches in altered transmission platforms and emphasize the different mutations and how they influence the virus characteristics. Also, this article summarizes the common vaccines and the implication of the mutations and genetic variety of SARS-CoV-2 on the COVID-19 biomedical arbitrations.
... Considering the spike protein is a major determinant of pathogenicity, out of nine mutations noted in the sequence, seven were nonsynonymous and produced consequent amino acid changes (Table 5). These substitutions and deletions in the spike protein of SARS-CoV-2 typically matched with the previously described changes in the SARS-CoV-2 delta variant [6,12,28]. Further, the functional significance of the changes was deciphered through earlier reports [6,12]. ...
Since December 2019, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been spreading worldwide, triggering one of the most challenging pandemics in the human population. In light of the reporting of this virus in domestic and wild animals from several parts of the world, a systematic surveillance study was conceptualized to detect SARS-CoV-2 among species of veterinary importance. Nasal and/or rectal samples of 413 animals (dogs n= 195, cattle n = 64, horses n = 42, goats n = 41, buffaloes n = 39, sheep n = 19, cats n = 6, camels n = 6, and a monkey n = 1) were collected from different places in the Gujarat state of India. RNA was extracted from the samples and subjected to RT-qPCR-based quantification of the target sequences in viral nucleoprotein (N), spike (S), and ORF1ab genes. A total of 95 (23.79%) animals were found positive, comprised of n = 67 (34.35%) dogs, n= 15 (23.43%) cattle, and n = 13 (33.33%) buffaloes. Whole SARS-CoV-2 genome sequencing was done from one sample (ID-A4N, from a dog), where 32 mutations, including 29 single-nucleotide variations (SNV) and 2 deletions, were detected. Among them, nine mutations were located in the receptor binding domain of the spike (S) protein. The consequent changes in the amino acid sequence revealed T19R, G142D, E156-, F157-, A222V, L452R, T478K, D614G, and P681R mutations in the S protein and D63G, R203M, and D377Y in the N protein. The lineage assigned to this SARS-CoV-2 sequence is B.1.617.2. Thus, the present study highlights the transmission of SARS-CoV-2 infection from human to animals and suggests being watchful for zoonosis.
... Furthermore, VOC Gamma harboring K417T and E484K emerged in regions of Brazil with high seroprevalence, despite naturally acquired immunity against prototypic SARS-CoV-2 13 . VOC Delta was first identified in October 2020 in India 14 and became the predominant SARS-CoV-2 lineage worldwide in 2021, driven by a substantially increased transmissibility 15 . In late November 2021, a new VOC Omicron (B.1.1.529) ...
Current COVID-19 vaccines are based on prototypic spike sequences from ancestral 2019 SARS-CoV-2 strains. However, the ongoing pandemic is fueled by variants of concern (VOC) escaping vaccine-mediated protection. Here we demonstrate how immunization in hamsters using prototypic spike expressed from yellow fever 17D (YF17D) as vector blocks ancestral virus (B lineage) and VOC Alpha (B.1.1.7) yet fails to fully protect from Beta (B.1.351). However, the same YF17D vectored vaccine candidate with an evolved antigen induced considerably improved neutralizing antibody responses against VOCs Beta, Gamma (P.1) and the recently predominant Omicron (B.1.1.529), while maintaining immunogenicity against ancestral virus and VOC Delta (B.1.617.2). Thus vaccinated animals resisted challenge by all VOCs, including vigorous high titre exposure to the most difficult to cover Beta, Delta and Omicron variants, eliminating detectable virus and markedly improving lung pathology. Finally, vaccinated hamsters did not transmit Delta variant to non-vaccinated cage mates. Overall, our data illustrate how current first-generation COVID-19 vaccines may need to be updated to maintain efficacy against emerging VOCs and their spread at community level.
A novel coronavirus, named severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has spread in Wuhan, China, and caused the global pandemic infectious disease. This disease has been known as coronavirus disease 2019 (COVID-19). It continued to spread around the world and created outrageous effects on the healthcare and economic system throughout the world. Various strategies have been designed to diminish the morbidity and mortality of this infectious disease. Among them, the development of vaccines is the most effective method to prevent and treat the viral infection. Novel vaccines have been developed and proved to be effective in multiple clinical reports indicating a significant decline in the risk of COVID-19 infection. However, the emergence of new variants of SARS-CoV-2 with immune-evasive characteristics raised questions concerning the effectiveness of the vaccines. This review provides a brief introduction to developed vaccines, as well as emerging variant strains and vaccine effectiveness against these variants. In this article, we also reviewed the general biological features of SARS-CoV-2 and its pathogenesis and explained the clinical symptoms, transmission, diagnostic and treatment approaches to monitor and control emerging COVID-19 infection.
Vaccine-induced T cells and neutralizing antibodies are essential for protection against SARS-CoV-2. Previously, we demonstrated that an antigen delivery system, pullulan nanogel (PNG), delivers vaccine antigen to lymph node medullary macrophages and thereby enhances the induction of specific CD8+ T cells. In this study, we revealed that medullary macrophage-selective delivery by PNG depends on its binding to a C-type lectin SIGN-R1. In a K18-hACE2 mouse model of SARS-CoV-2 infection, vaccination with a PNG-encapsulated receptor-binding domain of spike protein decreased the viral load and prolonged the survival in the CD8+ T cell- and B cell-dependent manners. T cell receptor repertoire analysis revealed that although the vaccine induced T cells at various frequencies, low-frequency specific T cells mainly promoted virus clearance. Thus, the induction of specific CD8+ T cells that respond quickly to viral infection, even at low frequencies, is important for vaccine efficacy and can be achieved by SIGN-R1+ medullary macrophage-targeted antigen delivery.
The emergence of SARS-CoV-2 in 2019 and its rapid global spread led to infrequent problems for human society. This vast spreading and high mortality rate were related mainly to the potential of this virus to develop mutated variants. Due to the emergence of hyper mutated strains escaping from vaccine-induced immune responses, the pandemic is still ongoing despite the discovery of various vaccines, and there is little chance that it will be eradicated in the near future. Therefore, it is crucial to monitor covid-19 mutations globally in order to develop new control measures. The SARS-CoV-2 mutation’s emergence and molecular characteristics have been the major talking points of this article, with a focus on significant variants classified as variants of concern (VOC).
In December, 2019 a new public health crisis threatened the world with the emergence of new zoonotic virus, the 2019 novel coronavirus. SARS-CoV-2 or severe acute respiratory syndrome coronavirus-2 belongs to the family of coronaviruses named for the crown-like spikes on its surfaces. SARS-CoV-2 causes COVID-19 (Coronavirus Disease-2019), a contagious viral infection that attacks primarily throat and lungs causing pneumonia-like symptoms. It is speculated that SARS-CoV-2 seem to have come from a bat, but the intermediate reservoir is still unknown. This review will address SARS-CoV-2 structure, clinical features, SARS-CoV-2 genome and its different variant, diagnosis, and treatment and also gives a bird's eye view on the epidemiology and pathology based on current evidence.
Las variantes genéticas del SARS-CoV-2 han estado surgiendo y extendiéndose por todo el mundo. La región de las Américas ha tenido 537.678 casos confirmados; representando el 34,4 % del total de los casos notificados en todo el mundo con 19 309 muertes en el 2020. El objetivo de esta investigación fue analizar la prevalencia y complicaciones de las variantes de SARS-CoV-2 en la población adulta. El estudio fue de diseño documental con carácter descriptivo de corte transversal y retrospectivo, en bases de datos PubMed, Scielo Springer, Google Scholar, ELSEVIER, publicados durante los últimos 5 años en idiomas español, inglés y portugués a partir de la búsqueda avanzada con los términos MeSH, SARS-CoV-2, COVID-19, variantes, adultos. Entre los resultados se encontró que en el continente asiático predominaba la variante ómicron, el americano y europeo predominaba la variante alfa y delta, dichas variantes se relacionaron a causas de neumonía e infecciones maternas más graves, ómicron a más casos de ataques cardiacos y neumonía, y beta a insuficiencia respiratoria aguda. Entre las afectaciones en la salud mental se encontró que la depresión y la ansiedad tuvieron mayor impacto en todo tipo población desde profesionales de la salud hasta las personas adultas en general. Se concluye que la variante ómicron mostró una alta prevalencia en el continente asiático, cada variante está asociada con diferentes tipos de complicaciones en los pacientes infectados por COVID-19 y su impacto en la salud mental de los pacientes adultos ha puesto en manifiesto una serie de efectos negativos significativos
Introduction
The COVID-19 pandemic has caused widespread morbidity, mortality, and socio-economic disruptions worldwide. Vaccination has proven to be a crucial strategy in controlling the spread of the virus and mitigating its impact.
Objective
The study focuses on assessing the effectiveness of COVID-19 vaccination in reducing the incidence of positive cases, hospitalizations, and ICU admissions. The presented study is focused on the COVID-19 fully vaccinated population by considering the data from the first positive case reported until 20 September 2021.
Methods
Using data from multiple countries, time series analysis is deployed to investigate the variations in the COVID-19 positivity rates, hospitalization rates, and ICU requirements after successful vaccination campaigns at the country scale.
Results
Analysis of the COVID-19 positivity rates revealed a substantial decline in countries with high pre-vaccination rates. Within 1–3 months of vaccination campaigns, these rates decreased by 20–44%. However, certain countries experienced an increase in positivity rates with the emergence of the new Delta variant, emphasizing the importance of ongoing monitoring and adaptable vaccination strategies. Similarly, the analysis of hospitalization rates demonstrated a steady decline as vaccination drive rates rose in various countries. Within 90 days of vaccination, several countries achieved hospitalization rates below 200 per million. However, a slight increase in hospitalizations was observed in some countries after 180 days of vaccination, underscoring the need for continued vigilance. Furthermore, the ICU patient rates decreased as vaccination rates increased across most countries. Within 120 days, several countries achieved an ICU patient rate of 20 per million, highlighting the effectiveness of vaccination in preventing severe cases requiring intensive care.
Conclusion
COVID-19 vaccination has proven to be very much effective in reducing the incidence of cases, hospitalizations, and ICU admissions. However, ongoing surveillance, variant monitoring, and adaptive vaccination strategies are crucial for maximizing the benefits of vaccination and effectively controlling the spread of the virus.
Among the different drug targets of SARS-CoV-2, a multi-domain protein known as NSP3
is a critical element of the translational and replication machinery. The macrodomain-I, in particular,
has been reported to have an essential role in the viral attack on the innate immune response. In
this study, we explore natural medicinal compounds and identify potential inhibitors to target the
SARS-CoV-2–NSP3 macrodomain-I. Computational modeling and simulation tools were utilized
to investigate the structural-dynamic properties using triplicates of 100 ns MD simulations. In
addition, the MM/GBSA method was used to calculate the total binding free energy of each inhibitor
bound to macrodomain-I. Two significant hits were identified: 3,5,7,40-tetrahydroxyflavanone
30-(4-hydroxybenzoic acid) and 2-hydroxy-3-O-beta-glucopyranosyl-benzoic acid. The structuraldynamic
investigation of both compounds with macrodomain-I revealed stable dynamics and
compact behavior. In addition, the total binding free energy for each complex demonstrated a
robust binding affinity, of DG 61.98 � 0.9 kcal/mol for Compound A, while for Compound B, the
DG was 45.125 � 2.8 kcal/mol, indicating the inhibitory potential of these compounds. In silico
bioactivity and dissociation constant (KD) determination for both complexes further validated the
inhibitory potency of each compound. In conclusion, the aforementioned natural products have the
potential to inhibit NSP3, to directly rescue the host immune response. The current study provides
the basis for novel drug development against SARS-CoV-2 and its variants.
Being the second most populous country in the world, India presents valuable lessons for the world about dealing with the SARS-CoV-2 pandemic. From this perspective, we attempted a retrospective evaluation of India’s SARS-CoV-2 genomic surveillance strategy and also gave some recommendations for undertaking effective genomic surveillance. The dynamics of the COVID-19 pandemic are continuously evolving, and there is a dire need to modulate the genomic surveillance strategy accordingly. The pandemic is now settling towards a low positivity rate scenario, so it is required to revise the practices and policies formulated for a high positivity rate scenario. The perspective also recommends adopting a decentralised approach for SARS-CoV-2 genomic surveillance with a focus on optimising the workflow of SARS-CoV-2 genomic surveillance to ensure early detection of emerging variants, especially in the low positivity rate scenario. The perspective emphasises a key observation that the SARS-CoV-2 genomic surveillance is an important mitigation effort during the pandemic, the guards of such mitigation efforts should not be lowered during the low positivity rate scenario. We attempt to highlight the limitations faced by the Indian healthcare administration during the SARS-CoV-2 genomic surveillance and, simultaneously, suggest policy interventions derived from our first-hand experience, which may be implementable in a vast, populated country like India.
The emergence of variants of the SARS-CoV-2 virus is certainly a serious threat to controlling the COVID-19 pandemic. After its irruption, some variants disappear or are irrelevant and others persist and are concerning because of its potential health repercussions and the immune response of vaccines that are being administered with great effort. One of the reasons why the SARS-CoV-2 virus is generating variants and will continue to do so is because a relatively few people in the world are immune and protected. The virus replicating is communicating to us that it is going to exhibit a lot of changes. Acquiring the infection involves risks of serious illness and death, so immunization is more logical, convincing and indispensable. It is also a better recourse for slowing viral replication, since infection offers viruses the opportunity to improve their performance. In addition, since multiple treatments, including antibody-based treatments, are often administered in severe infections, the surviving escape variants may be more resistant to these therapies effective against earlier versions of the virus. Two contenders (the surviving virus and the immune system) will be confronted with each other in an attempt to win, with the virus utilizing new weapons and subterfuges in a race that will lead to an evolutionary deadlock. A rising concern is whether available vaccines and those under investigation have a reduced or inadequate level of protection against emerging variants of SARS-CoV-2, particularly the variants of concern with changes in the spike protein. Despite these ongoing threats, at this time the general preventive measures and protection offered by the available SARS-CoV-2 vaccines are already a fundamental resource in the fight against COVID-19 and its variants, and a very hopeful measure for the immediate future. In the current situation, people should be aware of and learn to live with the virus variants and how to optimize its prevention and control.
Identifying SARS-CoV-2-specific T cell epitope-derived peptides is critical for the development of effective vaccines and measuring the duration of specific SARS-CoV-2 cellular immunity. In this regard, we previously identified T cell epitope-derived peptides within topologically and structurally essential regions of SARS-CoV-2 spike and nucleocapsid proteins by applying an immunoinformatics pipeline. In this study, we selected 30 spike- and nucleocapsid-derived peptides and assessed whether these peptides induce T cell responses and avoid major mutations found in SARS-CoV-2 variants of concern. Our peptide pool was highly specific, with only a single peptide driving cross-reactivity in people unexposed to SARS-COV-2, and immunogenic, inducing a polyfunctional response in CD4+ and CD8+ T cells from COVID-19 recovered individuals. All peptides were immunogenic and individuals recognized broad and diverse peptide repertoires. Moreover, our peptides avoided most mutations/deletions associated with all four SARS-CoV-2 variants of concern while retaining their physicochemical properties even when genetic changes are introduced. This study contributes to an evolving definition of individual CD4+ and CD8+ T cell epitopes that can be used for specific diagnostic tools for SARS-CoV-2 T cell responses and is relevant to the development of variant-resistant and durable T cell-stimulating vaccines.
Since 2020 the COVID-19 pandemic has led scientists to search for strategies to predict the transmissibility and virulence of new severe acute respiratory syndrome coronavirus 2 variants based on the estimation of the affinity of the spike receptor binding domain (RBD) for the human angiotensin-converting enzyme 2 (ACE2) receptor and/or neutralizing antibodies. In this context, our lab developed a computational pipeline to quickly quantify the free energy of interaction at the spike RBD/ACE2 protein-protein interface, reflecting the incidence trend observed in the transmissibility/virulence of the investigated variants. In this new study, we used our pipeline to estimate the free energy of interaction between the RBD from 10 variants, and 14 antibodies (ab), or 5 nanobodies (nb), highlighting the RBD regions preferentially targeted by the investigated ab/nb. Our structural comparative analysis and interaction energy calculations allowed us to propose the most promising RBD regions to be targeted by future ab/nb to be designed by site-directed mutagenesis of existing high-affinity ab/nb, to increase their affinity for the target RBD region, for preventing spike-RBD/ACE2 interactions and virus entry in host cells. Furthermore, we evaluated the ability of the investigated ab/nb to simultaneously interact with the three RBD located on the surface of the trimeric spike protein, which can alternatively be in up- or down- (all-3-up-, all-3-down-, 1-up-/2-down-, 2-up-/1-down-) conformations.
As of June 2022, more than 530 million people worldwide have become ill with coronavirus disease 2019 (COVID-19). Although COVID-19 is most commonly associated with respiratory distress (severe acute respiratory syndrome), meta-analysis have indicated that liver dysfunction also occurs in patients with severe symptoms. Current studies revealed distinctive patterning in the receptors on the hepatic cells that helps in viral invasion through the expression of angiotensin-converting enzyme receptors. It has also been reported that in some patients with COVID-19, therapeutic strategies, including repurposed drugs (mitifovir, lopinavir/ritonavir, tocilizumab, etc.) triggered liver injury and cholestatic toxicity. Several proven indicators support cytokine storm-induced hepatic damage. Because there are 1.5 billion patients with chronic liver disease worldwide, it becomes imperative to critically evaluate the molecular mechanisms concerning hepatotropism of COVID-19 and identify new potential therapeutics. This review also designated a comprehensive outlook of comorbidities and the impact of lifestyle and genetics in managing patients with COVID-19.
The coronavirus disease 2019 (COVID-19) pandemic can hardly end with the emergence of different variants over time. In the past 2 years, several variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), such as the Delta and Omicron variants, have emerged with higher transmissibility, immune evasion and drug resistance, leading to higher morbidity and mortality in the population. The prevalent variants of concern (VOCs) share several mutations on the spike that can affect virus characteristics, including transmissibility, antigenicity, and immune evasion. Increasing evidence has demonstrated that the neutralization capacity of sera from COVID-19 convalescent or vaccinated individuals is decreased against SARS-CoV-2 variants. Moreover, the vaccine effectiveness of current COVID-19 vaccines against SARS-CoV-2 VOCs is not as high as that against wild-type SARS-CoV-2. Therefore, more attention might be paid to how the mutations impact vaccine effectiveness. In this review, we summarized the current studies on the mutations of the SARS-CoV-2 spike, particularly of the receptor binding domain, to elaborate on how the mutations impact the infectivity, transmissibility and immune evasion of the virus. The effects of mutations in the SARS-CoV-2 spike on the current therapeutics were highlighted, and potential strategies for future vaccine development were suggested.
The 2019 novel coronavirus (SARS-CoV-2) causes severe pneumonia called COVID-19 and leads to severe acute respiratory syndrome with a high mortality rate. The SARS-CoV-2 virus in the human body leads to jumpstarting immune reactions and multi-organ inflammation, which has poorer outcomes in the presence of predisposing conditions, including hypertension, dyslipidemia, dysglycemia, abnormal adiposity, and even endothelial dysfunction via biomolecular mechanisms. In addition, leucopenia, hypoxemia, and high levels of both cytokines and chemokines in the acute phase of this disease, as well as some abnormalities in chest CT images, were reported in most patients. The spike protein in SARS-CoV-2, the primary cell surface protein, helps the virus anchor and enter the human host cells. Additionally, new mutations have mainly happened for spike protein, which has promoted the infection's transmissibility and severity, which may influence manufactured vaccines' efficacy. The exact mechanisms of the pathogenesis, besides molecular aspects of COVID-19 related to the disease stages, are not well known. The altered molecular functions in the case of immune responses, including T CD4+, CD8+, and NK cells, besides the overactivity in other components and outstanding factors in cytokines like interleukin-2, were involved in severe cases of SARS-CoV-2. Accordingly, it is highly needed to identify the SARSCoV-2 biomolecular characteristics to help identify the pathogenesis of COVID-19. This study aimed to investigate the biomolecular aspects of SARSCoV-2 infection, focusing on novel SARS-CoV-2 variants and their effects on vaccine efficacy.
The SARS-CoV-2 virus has infected innumerable individuals and continues to result in numerous unintended
fatalities throughout the world. The Coronaviridae family includes the beta coronavirus that causes SARS-CoV-2.
Over the past few months, novel spike protein mutations have become more prevalent in clinically important
variants. These alterations cause the host immune system to stop recognising them. The current version of concern,
according to WHO, contains the following: Alpha (B.1.1.7 9), Beta (B.1.351), Delta (B.1.617), Gamma (P.1), and
Omicron (BA.1). These variants have several mutations in common with an increasing SARS-CoV-2 Variants that
have just been discovered. Immune system invasion and vaccination evasion are caused by spike protein mutations.
Increased transmissibility, mortality, morbidity, and possibly delayed diagnosis and treatment are the results of
these impacts. The present review article discusses the numerous variants of SARS-CoV-2 with a prime focus on the
Variants of Concern as per WHO. The article provides insights into the structural mutations, disease severity, and
vaccine efficacy of the variants. The ongoing monitoring and control of these variants are crucial for preventing and
controlling the spread of the virion.
The emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was initially described in late 2019 in Wuhan City, China, and was reported to the World Health Organization (WHO) in December 2019 (Wang et al. 2020). The virus was identified among patients who had pneumonia and were linked to a wet-seafood market. This virus was initially known as novel coronavirus 2019 (nCoV-19) and then later was designated as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (Gorbalenya et al. 2020). This chapter summarizes the current understanding of the disease, the emergence of variants, and outcome.
Introduction
A rapid increase in COVID-19 cases due to the spread of the Delta and Omicron variants in vaccinated populations has raised concerns about the hospitalization risk associated with, and the effectiveness of, COVID-19 vaccines.
Method
This case–control study aims to determine the hospitalization risk associated with the inactivated BBIBP-CorV (Sinopharm) and mRNA BNT162b2 (Pfizer–BionTech) vaccines, and their effectiveness reducing the rate of hospital admission between 28 May 2021 and 13 January 2022, during the Delta and Omicron outbreaks. The estimation of vaccine effectiveness of 4,618 samples was based on the number of patients hospitalized at different vaccination statuses, adjusted for confounding variables.
Results
Hospitalization risk increases in patients affected with the Omicron variant if patients are aged ≤ 18 years (OR 6.41, 95% CI 2.90 to 14.17; p < 0.001), and in patients affected with the Delta variant if they are aged > 45 years (OR 3.41, 95% CI 2.21 to 5.50; p < 0.001). Vaccine effectiveness reducing the rate of hospital admission for fully vaccinated participants infected with the Delta and Omicron variants was similar for both the BBIBP-CorV (94%, 95% CI 90% to 97%; 90%, 95% CI 74% to 96%) and BNT162b2 vaccines (95%, 95% CI 61% to 99.3%; 94%, 95% CI 53% to 99%), respectively.
Discussion
The BBIBP-CorV and BNT162b2 vaccines utilized in the UAE vaccination program were highly effective in reducing the rate of COVID-19-related hospitalization during the Delta and Omicron outbreaks, and further effort must be taken to achieve high vaccine coverage rates in children and adolescents in the global context to reduce the hospitalization risk associated with COVID-19 on an international scale.
Background and Aim: So far, extensive research has been conducted on the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus and its disease in different regions of the world. The aim of these studies is to present practical findings and suggestions about more familiarity with the characteristics of this virus, including its structural and genetic characteristics, origin of genesis, evolution, genomic changes, biological cycle and pathological function, that can be used to adopt efficient strategies in controlling and treating the pandemic.
Material and Methods: In order to perform genomic analysis, the complete sequence of the desired coronaviruses with accession numbers obtained from GenBank or GISAID was stored from databases such as NCBI and ViPR, and then the sequences were aligned with Workbench CLC Main software. In the next step, the phylogenetic tree was drawn by Neighbor-Joining method with 1000 repetitions (bootstrap) by MEGA X software and FigTree v1.4.4 was used to display the tree more clearly.
Ethical considerations: All ethical principles in writing this article have been observed according to the instructions of the National Ethics Committee and the COPE regulations.
Findings: In the current study, mutations and the effect they may have on transmissibility, pathogenicity and vaccine effectiveness, molecular features, epidemiology and the place of emergence of coronaviruses, focusing on variant of
concern (VOC) including alpha (B.1.1.7), beta (B.1.351), gamma (P.1), delta (B.1.617.2) and omicron (B.1.1.529) are presented.
Conclusion: The occurrence of mutations and continuous evolution have led to the rapid and simultaneous emergence of different variants, each of these changes can contribute to the escape of therapeutic methods such as neutralizing antibodies (Nab) and convalescent plasma, as well as reducing the effectiveness of vaccines. Therefore, increasing monitoring for documentation, understanding the spread of different lineages and more detailed study of these mutations in identifying variants and effectively dealing with them is of great importance.
Keywords: COVID-19, Neutralizing antibodies, Pandemic, SARS‐CoV‐2, Vaccine efficacy, Variants of concern (VOCs), Virus evolution
The B.1.6179 Delta variant of the severe acute metabolic process syndrome corona virus (SARS –COV-2). The virus that causes corona virus unwellness 2019 (covid -19), has contributed to a surge in cases of Republic of India and has currently been detected across the world, as well as a notable increase in cases within the UK. Delta and (B.167.2.1/(Ay.1) could be a new variant of the SARS- CoV-2. corona virus came in existence because of a mutation within the delta strain of the virus (B.1.617.2 variant). It is technically successive generation of SARS-COV-2. This mutant of delta was initial detected in Europe march 2021.The delta virus that was initial detected in Republic of India (in February 2021) eventually became an enormous downside for the total world. However, the delta variant at the moment, is restricted to smaller areas within the country. Individual’s reportable symptoms like headaches, sore throats, fluid noses, and fever. The world health organization (WHO)is following this variant as a part of the delta variant as well as for different variants of concern with extra mutations. This review provides detail idea about delta virus its treatment, prevention and methods for reduction of sensitivity.
Even if many countries are against it since vaccinations are not readily available, industrialized countries continue to make some vaccines designated under the World Health Organization's emergency use listing mandatory for entry into their countries. The first half of 2021 has seen the introduction of SARS-CoV-2 vaccinations in several countries, after the exceptional speed of vaccine development and testing in 2020. Using keywords in online databases such as Pubmed, Scopus, Web of Science, Cochrane, and Embase, this systematic search was carried out. The findings were collected into a report. We were unable to do an adequate human study because we included so many different kinds of vaccinations. A look at current vaccination-controlled trials and actual facts on immunization success is also presented. The efficacy of new vaccines is continually being tested in ongoing vaccine trials. Increasing the alternatives for global vaccine production to manufacture sufficient vaccine shots for international usage and to enhance the statistics for the potential utility of various vaccination platforms in forthcoming pandemics are also a result of this.
The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic has led to an unprecedented public health crisis. The collective global response has led to production of multiple safe and effective vaccines utilizing novel platforms to combat the virus that have propelled the field of vaccinology forward. Significant challenges to universal vaccine effectiveness remain, including immune evasion by SARS-CoV-2 variants, waning of immune response, inadequate knowledge of correlates of protection, and dosing in special populations. This review serves as a detailed evaluation of the development of the current SARS-CoV-2 vaccines, their effectiveness, and challenges to their deployment as a preventive tool.
The SARS-CoV-2 virus has infected innumerable individuals and continues to result in numerous unintended fatalities throughout the world. The Coronaviridae family includes the beta coronavirus that causes SARS-CoV-2. Over the past few months, novel spike protein mutations have become more prevalent in clinically important variants. These alterations cause the host immune system to stop recognising them. The current version of concern, according to WHO, contains the following: Alpha (B.1.1.7 9), Beta (B.1.351), Delta (B.1.617), Gamma (P.1), and Omicron (BA.1). These variants have several mutations in common with an increasing SARS-CoV-2 Variants that have just been discovered. Immune system invasion and vaccination evasion are caused by spike protein mutations. Increased transmissibility, mortality, morbidity, and possibly delayed diagnosis and treatment are the results of these impacts. The present review article discusses the numerous variants of SARS-CoV-2 with a prime focus on the Variants of Concern as per WHO. The article provides insights into the structural mutations, disease severity, and vaccine efficacy of the variants. The ongoing monitoring and control of these variants are crucial for preventing and controlling the spread of the virion.
Unlike pandemics in the past, the outbreak of coronavirus disease 2019 (COVID-19), which rapidly spread worldwide, was met with a different approach to control and measures implemented across affected countries. The lack of understanding of the fundamental nature of the outbreak continues to make COVID-19 challenging to manage for both healthcare practitioners and the scientific community. Challenges to vaccine development and evaluation, exclusive therapeutic options, convalescent plasma therapy, herd immunity, and the emergence of reinfection and new variants remain the major obstacles to combating COVID-19. This review discusses these challenges in the management of COVID-19 at length and highlights the mechanisms needed to provide better understanding of this pandemic.
HLA-presented antigenic peptides are central components of T cell-based immunity in infectious disease. Beside HLA molecules on cell surfaces, soluble HLA molecules (sHLA) are released in the blood suggested to impact cellular immune responses. We demonstrated that sHLA levels were significantly increased in COVID-19 patients and convalescent individuals compared to a control cohort and positively correlated with SARS-CoV-2-directed cellular immunity. Of note, patients with severe courses of COVID-19 showed reduced sHLA levels. Mass spectrometry-based characterization of sHLA-bound antigenic peptides, the so-called soluble immunopeptidome, revealed a COVID-19-associated increased diversity of HLA-presented peptides and identified a naturally presented SARS-CoV-2-derived peptide from the viral nucleoprotein in the plasma of COVID-19 patients. Interestingly, sHLA serum levels directly correlated with the diversity of the soluble immunopeptidome. Together, these findings suggest an inflammation-driven release of sHLA in COVID-19, directly influencing the diversity of the soluble immunopeptidome with implications for SARS-CoV-2-directed T cell-based immunity and disease outcome.
New variants of SARS-CoV-2 continue to evolve. The novel SARS-CoV-2 variant of concern (VOC) B.1.1.529 (Omicron) was particularly menacing due to the presence of numerous consequential mutations. In this study, we reviewed about 12 million SARS-CoV-2 genomic and associated metadata using extensive bioinformatic approaches to understand how evolutionary and mutational changes affect Omicron variant properties. Subsampled global data based analysis of molecular clock in the phylogenetic tree showed 29.56 substitutions per year as the evolutionary rate of five VOCs. We observed extensive mutational changes in the spike structural protein of the Omicron variant. A total of 20% of 7230 amino acid and structural changes exclusive to Omicron’s spike protein were detected in the receptor binding domain (RBD), suggesting differential selection pressures exerted during evolution. Analyzing key drug targets revealed mutation-derived differential binding affinities between Delta and Omicron variants. Nine single-RBD substitutions were detected within the binding site of approved therapeutic monoclonal antibodies. T-cell epitope prediction revealed eight immunologically important functional hotspots in three conserved non-structural proteins. A universal vaccine based on these regions may likely protect against all these SARS-CoV-2 variants. We observed key structural changes in the spike protein, which decreased binding affinities, indicating that these changes may help the virus escape host cellular immunity. These findings emphasize the need for continuous genomic surveillance of SARS-CoV-2 to better understand how novel mutations may impact viral spread and disease outcome.
Objectives: This study aims to provide a comprehensive review on the analysis of COVID-19 pandemic in India and address economic impact, diagnosis approaches, and vaccine acceptance and hesitation.
Method: We retrieved articles published in 2020 and 2021 and current data from official websites that narrate the strategy for COVID-19 testing, issues, and challenges, healthcare system insufficiency, statistics of cases, deaths, vaccination, and vaccine acceptance barriers, and beliefs.
Results: India being the 2nd largest populated country with a population of 1.4 billion faced massive difficulty in controlling the transmission of SARS-CoV-2. This crisis dramatically impeded the economy of the nation. India witnessed 2nd highest number (43,019,453) of confirmed cases and 3rd highest number of deaths (521,004) across the world.
Conclusion: The major cause of the collapse of COVID-19 is the high population of India, pre-existing weak healthcare system, and the lack of awareness among the people. The fall, rise, and statistics provided in the review will help in comparing the current status with other countries and in making strong strategies to combat future calamities.
Background:
Escherichia coli is the leading cause of bloodstream infections, associated with a significant mortality. Recent genomic analyses revealed that few clonal lineages are involved in bloodstream infections and captured the emergence of some of them. However, data on within sequence type (ST) population genetic structure evolution are rare.
Methods:
We compared whole genome sequences of 912 E. coli isolates responsible for bloodstream infections from two multicenter clinical trials that were conducted in the Paris area, France, 12 years apart, in teaching hospitals belonging to the same institution ("Assistance Publique-Hôpitaux de Paris"). We analyzed the strains at different levels of granularity, i.e., the phylogroup, the ST complex (STc), and the within STc clone taking into consideration the evolutionary history, the resistance, and virulence gene content as well as the antigenic diversity of the strains.
Results:
We found a mix of stability and changes overtime, depending on the level of comparison. Overall, we observed an increase in antibiotic resistance associated to a restricted number of genetic determinants and in strain plasmidic content, whereas phylogroup distribution and virulence gene content remained constant. Focusing on STcs highlighted the pauci-clonality of the populations, with only 11 STcs responsible for more than 73% of the cases, dominated by five STcs (STc73, STc131, STc95, STc69, STc10). However, some STcs underwent dramatic variations, such as the global pandemic STc131, which replaced the previously predominant STc95. Moreover, within STc131, 95 and 69 genomic diversity analysis revealed a highly dynamic pattern, with reshuffling of the population linked to clonal replacement sometimes coupled with independent acquisitions of virulence factors such as the pap gene cluster bearing a papGII allele located on various pathogenicity islands. Additionally, STc10 exhibited huge antigenic diversity evidenced by numerous O:H serotype/fimH allele combinations, whichever the year of isolation.
Conclusions:
Altogether, these data suggest that the bloodstream niche is occupied by a wide but specific phylogenetic diversity and that highly specialized extra-intestinal clones undergo frequent turnover at the within ST level. Additional worldwide epidemiological studies overtime are needed in different geographical and ecological contexts to assess how generalizable these data are.
Background
Sequencing of the SARS-CoV-2 viral genome from patient samples is an important epidemiological tool for monitoring and responding to the pandemic, including the emergence of new mutations in specific communities.
Methods
SARS-CoV-2genomicsequencesweregeneratedfrompositivesamplescollected,alongwithepidemiologicalmetadata,atawalk-up, rapid testing site in the Mission District of San Francisco, California during November 22-December 1, 2020 and January 10-29, 2021. Secondary household attack rates and mean sample viral load were estimated and compared across observed variants.
Results
A total of 12,124 tests were performed yielding 1,099 positives. From these, 928 high quality genomes were generated. Certain viral lineages bearing spike mutations, defined in part by L452R, S13I, and W152C, comprised 54.4% of the total sequences from January, compared to 15.7% in November. Household contacts exposed to the “California” or “West Coast” variants (B.1.427 and B.1.429) were at higher risk of infection compared to household contacts exposed to lineages lacking these variants (0.36 vs 0.29, RR=1.28; 95% CI:1.00-1.64). The reproductive number was estimated to be modestly higher than other lineages spreading in California during the second half of 2020. Viral loads were similar among persons infected with West Coast versus non-West Coast strains, as was the proportion of individuals with symptoms (60.9% vs 64.3%).
Conclusions
The increase in prevalence, relative household attack rates, and reproductive number are consistent with a modest transmissibility increase of the West Coast variants.
Background. Sequencing of the SARS-CoV-2 viral genome from patient samples is an important epidemiological tool for monitoring and responding to the pandemic, including the emergence of new mutations in specific communities.
Methods. SARS-CoV-2 genomic sequences were generated from positive samples collected, along with epidemiological metadata, at a walk-up, rapid testing site in the Mission District of San Francisco, California during November 22-December 2, 2020 and January 10-29, 2021. Secondary household attack rates and mean sample viral load were estimated and compared across observed variants.
Results. A total of 12,124 tests were performed yielding 1,099 positives. From these, 811 high quality genomes were generated. Certain viral lineages bearing spike mutations, defined in part by L452R, S13I, and W152C, comprised 54.9% of the total sequences from January, compared to 15.7% in November. Household contacts exposed to "West Coast" variants were at higher risk of infection compared to household contacts exposed to lineages lacking these variants (0.357 vs 0.294, RR=1.29; 95% CI:1.01-1.64). The reproductive number was estimated to be modestly higher than other lineages spreading in California during the second half of 2020. Viral loads were similar among persons infected with West Coast versus non-West Coast strains, as was the proportion of individuals with symptoms (60.9% vs 64.1%).
Conclusions. The increase in prevalence, relative household attack rates, and reproductive number are consistent with a modest transmissibility increase of the "West Coast" variants; however, additional laboratory and epidemiological studies are required to better understand differences between these variants.
We have isolated the new severe acute respiratory syndrome coronavirus-2 variant of concern 202 012/01 from the positive coronavirus disease 2019 cases that travelled from the UK to India in the month of December 2020. This emphasizes the need for the strengthened surveillance system to limit the local transmission of this new variant.
Background
To mitigate the effects of COVID-19, a vaccine is urgently needed. BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine formulated with a toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG) or alum (Algel).
Methods
We did a double-blind, multicentre, randomised, controlled phase 1 trial to assess the safety and immunogenicity of BBV152 at 11 hospitals across India. Healthy adults aged 18–55 years who were deemed healthy by the investigator were eligible. Individuals with positive SARS-CoV-2 nucleic acid and/or serology tests were excluded. Participants were randomly assigned to receive either one of three vaccine formulations (3 μg with Algel-IMDG, 6 μg with Algel-IMDG, or 6 μg with Algel) or an Algel only control vaccine group. Block randomisation was done with a web response platform. Participants and investigators were masked to treatment group allocation. Two intramuscular doses of vaccines were administered on day 0 (the day of randomisation) and day 14. Primary outcomes were solicited local and systemic reactogenicity events at 2 h and 7 days after vaccination and throughout the full study duration, including serious adverse events. Secondary outcome was seroconversion (at least four-fold increase from baseline) based on wild-type virus neutralisation. Cell-mediated responses were evaluated by intracellular staining and ELISpot. The trial is registered at ClinicalTrials.gov (NCT04471519).
Findings
Between July 13 and 30, 2020, 827 participants were screened, of whom 375 were enrolled. Among the enrolled participants, 100 each were randomly assigned to the three vaccine groups, and 75 were randomly assigned to the control group (Algel only). After both doses, solicited local and systemic adverse reactions were reported by 17 (17%; 95% CI 10·5–26·1) participants in the 3 μg with Algel-IMDG group, 21 (21%; 13·8–30·5) in the 6 μg with Algel-IMDG group, 14 (14%; 8·1–22·7) in the 6 μg with Algel group, and ten (10%; 6·9–23·6) in the Algel-only group. The most common solicited adverse events were injection site pain (17 [5%] of 375 participants), headache (13 [3%]), fatigue (11 [3%]), fever (nine [2%]), and nausea or vomiting (seven [2%]). All solicited adverse events were mild (43 [69%] of 62) or moderate (19 [31%]) and were more frequent after the first dose. One serious adverse event of viral pneumonitis was reported in the 6 μg with Algel group, unrelated to the vaccine. Seroconversion rates (%) were 87·9, 91·9, and 82·8 in the 3 μg with Algel-IMDG, 6 μg with Algel-IMDG, and 6 μg with Algel groups, respectively. CD4⁺ and CD8⁺ T-cell responses were detected in a subset of 16 participants from both Algel-IMDG groups.
Interpretation
BBV152 led to tolerable safety outcomes and enhanced immune responses. Both Algel-IMDG formulations were selected for phase 2 immunogenicity trials. Further efficacy trials are warranted.
Funding
Bharat Biotech International.
Background
The incidence of bloodstream infections (BSIs) caused by Escherichia coli and Klebsiella pneumoniae is increasing, with substantial associated morbidity, mortality and antimicrobial resistance. Unbiased serotyping studies to guide vaccine target selection are limited.
Methods
We conducted unselected, population-level genomic surveillance of bloodstream E. coli and Klebsiella pneumoniae isolates from 2008-2018 in Oxfordshire, UK. We supplemented this with an analysis of publicly available global sequencing data (n=3678).
Results
We sequenced 3478 E. coli isolates (3278 passed quality control) and 556 K. pneumoniae isolates (535 (K-antigen) and 549 (O-antigen) passed quality control). The four most common E. coli O-antigens (O1/O2/O6/O25) were identified in 1499/3278 isolates; the incidence of these O-types increased over time (IRRy=1.14, 95% CI:1.11-1.16). These O-types accounted for 616/1434 multidrug resistant (MDR) and 173/256 extended-spectrum beta-lactamase(ESBL)-resistant isolates in Oxfordshire, but only 19/90 carbapenem-resistant isolates across all studies. For Klebsiella pneumoniae, the most common O-antigens (O2v2/O1v1/O3b/O1v2) accounted for 410/549 isolates; the incidence of BSIs caused by these also increased annually (IRRy=1.09; 95% CI:1.05-1.12). These O-types accounted for 122/148 MDR and 106/123 ESBL isolates in Oxfordshire and 557/734 carbapenem-resistant isolates across all studies. Conversely we observed substantial capsular antigen diversity. Analysis of 3678 isolates from global studies demonstrated the generalisability of these findings. For E. coli, based on serotyping, the ExPEC4V and ExPEC10V vaccines under investigation would cover 46% and 72% of Oxfordshire isolates respectively, and 47% and 71% of MDR isolates.
Conclusions
O-antigen targeted vaccines may be useful in reducing the morbidity, mortality and antimicrobial resistance associated with E. coli and K. pneumoniae BSIs.
Background & objectives:
: The global pandemic caused by SARS-CoV-2 virus has challenged public health system worldwide due to the unavailability of approved preventive and therapeutic options. Identification of neutralizing antibodies (NAb) and understanding their role is important. However, the data on kinetics of NAb response among COVID-19 patients are unclear. To understand the NAb response in COVID-19 patients, we compared the findings of microneutralization test (MNT) and plaque reduction neutralization test (PRNT) for the SARS-CoV-2. Further, the kinetics of NAb response among COVID-19 patients was assessed.
Methods:
: A total of 343 blood samples (89 positive, 58 negative for SARS-CoV-2 and 17 cross-reactive and 179 serum from healthy individuals) were collected and tested by MNT and PRNT. SARS-CoV-2 virus was prepared by propagating the virus in Vero CCL-81 cells. The intra-class correlation was calculated to assess the correlation between MNT and PRNT. The neutralizing endpoint as the reduction in the number of plaque count by 90 per cent (PRNT 90) was also calculated.
Results:
: The analysis of MNT and PRNT quantitative results indicated that the intra-class correlation was 0.520. Of the 89 confirmed COVID-19 patients, 64 (71.9%) showed NAb response.
Interpretation & conclusions:
: The results of MNT and PRNT were specific with no cross-reactivity. In the early stages of infection, the NAb response was observed with variable antibody kinetics. The neutralization assays can be used for titration of NAb in recovered/vaccinated or infected COVID-19 patients.
The ongoing pandemic spread of a new human coronavirus, SARS-CoV-2, which is associated with severe pneumonia/disease (COVID-19), has resulted in the generation of tens of thousands of virus genome sequences. The rate of genome generation is unprecedented, yet there is currently no coherent nor accepted scheme for naming the expanding phylogenetic diversity of SARS-CoV-2. Here, we present a rational and dynamic virus nomenclature that uses a phylogenetic framework to identify those lineages that contribute most to active spread. Our system is made tractable by constraining the number and depth of hierarchical lineage labels and by flagging and delabelling virus lineages that become unobserved and hence are probably inactive. By focusing on active virus lineages and those spreading to new locations, this nomenclature will assist in tracking and understanding the patterns and determinants of the global spread of SARS-CoV-2.
Escherichia coli
associated with urinary tract infections and bacteremia has been intensively investigated, including recent work focusing on the virulent, globally disseminated, multidrug-resistant lineage ST131. To contextualize ST131 within the broaderE. colipopulation associated with disease, we used genomics to analyze a systematic 11-yr hospital-based survey ofE. coliassociated with bacteremia using isolates collected from across England by the British Society for Antimicrobial Chemotherapy and from the Cambridge University Hospitals NHS Foundation Trust. Population dynamics analysis of the most successful lineages identified the emergence of ST131 and ST69 and their establishment as two of the five most common lineages along with ST73, ST95, and ST12. The most frequently identified lineage was ST73. Compared to ST131, ST73 was susceptible to most antibiotics, indicating that multidrug resistance was not the dominant reason for prevalence ofE. colilineages in this population. Temporal phylogenetic analysis of the emergence of ST69 and ST131 identified differences in the dynamics of emergence and showed that expansion of ST131 in this population was not driven by sequential emergence of increasingly resistant subclades. We showed that over time, theE. colipopulation was only transiently disturbed by the introduction of new lineages before a new equilibrium was rapidly achieved. Together, these findings suggest that the frequency ofE. colilineages in invasive disease is driven by negative frequency-dependent selection occurring outside of the hospital, most probably in the commensal niche, and that drug resistance is not a primary determinant of success in this niche.
Escherichia coli ranks among the organisms most frequently isolated from cases of bacteremia. The relative contribution of the host and bacteria
to E. coli bacteremia severity remains unknown. We conducted a prospective multicenter cohort study to identify host and bacterial factors
associated with E. coli bacteremia severity. The primary endpoint was in-hospital death, up to 28 days after the first positive blood culture. Among
1,051 patients included, 136 (12.9%) died. Overall, 604 (57.5%) patients were female. The median age was 70 years, and 202
(19.2%) episodes were nosocomial. The most frequent comorbidities were immunocompromised status (37.9%), tobacco addiction
(21.5%), and diabetes mellitus (20.1%). The most common portal of entry was the urinary tract (56.9%). Most E. coli isolates belonged to phylogenetic group B2 (52.0%). The multivariate analysis retained the following factors as predictive
of death: older age (odds ratio [OR] = 1.25 [95% confidence interval {CI}, 1.09 to 1.43] for each 10-year increment), cirrhosis
(OR = 4.85 [95% CI, 2.49 to 9.45]), hospitalization before bacteremia (OR = 4.13 [95% CI, 2.49 to 6.82]), being an immunocompromised
patient not hospitalized before bacteremia (OR = 3.73 [95% CI, 2.25 to 6.18]), and a cutaneous portal of entry (OR = 6.45
[95% CI, 1.68 to 24.79]); a urinary tract portal of entry and the presence of the ireA virulence gene were negatively correlated with death (OR = 0.46 [95% CI, 0.30 to 0.70] and OR = 0.53 [95% CI, 0.30 to 0.91],
respectively). In summary, host factors and the portal of entry outweigh bacterial determinants for predicting E. coli bacteremia severity.
Background
BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3 μg or 6 μg) formulated with a toll-like receptor 7/8 agonist molecule (IMDG) adsorbed to alum (Algel). We previously reported findings from a double-blind, multicentre, randomised, controlled phase 1 trial on the safety and immunogenicity of three different formulations of BBV152 (3 μg with Algel-IMDG, 6 μg with Algel-IMDG, or 6 μg with Algel) and one Algel-only control (no antigen), with the first dose administered on day 0 and the second dose on day 14. The 3 μg and 6 μg with Algel-IMDG formulations were selected for this phase 2 study. Herein, we report interim findings of the phase 2 trial on the immunogenicity and safety of BBV152, with the first dose administered on day 0 and the second dose on day 28.
Methods
We did a double-blind, randomised, multicentre, phase 2 clinical trial to evaluate the immunogenicity and safety of BBV152 in healthy adults and adolescents (aged 12–65 years) at nine hospitals in India. Participants with positive SARS-CoV-2 nucleic acid and serology tests were excluded. Participants were randomly assigned (1:1) to receive either 3 μg with Algel-IMDG or 6 μg with Algel-IMDG. Block randomisation was done by use of an interactive web response system. Participants, investigators, study coordinators, study-related personnel, and the sponsor were masked to treatment group allocation. Two intramuscular doses of vaccine were administered on day 0 and day 28. The primary outcome was SARS-CoV-2 wild-type neutralising antibody titres and seroconversion rates (defined as a post-vaccination titre that was at least four-fold higher than the baseline titre) at 4 weeks after the second dose (day 56), measured by use of the plaque-reduction neutralisation test (PRNT50) and the microneutralisation test (MNT50). The primary outcome was assessed in all participants who had received both doses of the vaccine. Cell-mediated responses were a secondary outcome and were assessed by T-helper-1 (Th1)/Th2 profiling at 2 weeks after the second dose (day 42). Safety was assessed in all participants who received at least one dose of the vaccine. In addition, we report immunogenicity results from a follow-up blood draw collected from phase 1 trial participants at 3 months after they received the second dose (day 104). This trial is registered at ClinicalTrials.gov, NCT04471519.
Findings
Between Sept 5 and 12, 2020, 921 participants were screened, of whom 380 were enrolled and randomly assigned to the 3 μg with Algel-IMDG group (n=190) or 6 μg with Algel-IMDG group (n=190). Geometric mean titres (GMTs; PRNT50) at day 56 were significantly higher in the 6 μg with Algel-IMDG group (197·0 [95% CI 155·6–249·4]) than the 3 μg with Algel-IMDG group (100·9 [74·1–137·4]; p=0·0041). Seroconversion based on PRNT50 at day 56 was reported in 171 (92·9% [95% CI 88·2–96·2] of 184 participants in the 3 μg with Algel-IMDG group and 174 (98·3% [95·1–99·6]) of 177 participants in the 6 μg with Algel-IMDG group. GMTs (MNT50) at day 56 were 92·5 (95% CI 77·7–110·2) in the 3 μg with Algel-IMDG group and 160·1 (135·8–188·8) in the 6 μg with Algel-IMDG group. Seroconversion based on MNT50 at day 56 was reported in 162 (88·0% [95% CI 82·4–92·3]) of 184 participants in the 3 μg with Algel-IMDG group and 171 (96·6% [92·8–98·8]) of 177 participants in the 6 μg with Algel-IMDG group. The 3 μg with Algel-IMDG and 6 μg with Algel-IMDG formulations elicited T-cell responses that were biased to a Th1 phenotype at day 42. No significant difference in the proportion of participants who had a solicited local or systemic adverse reaction in the 3 μg with Algel-IMDG group (38 [20·0%; 95% CI 14·7–26·5] of 190) and the 6 μg with Algel-IMDG group (40 [21·1%; 15·5–27·5] of 190) was observed on days 0–7 and days 28–35; no serious adverse events were reported in the study. From the phase 1 trial, 3-month post-second-dose GMTs (MNT50) were 39·9 (95% CI 32·0–49·9) in the 3μg with Algel-IMDG group, 69·5 (53·7–89·9) in the 6 μg with Algel-IMDG group, 53·3 (40·1–71·0) in the 6 μg with Algel group, and 20·7 (14·5–29·5) in the Algel alone group.
Interpretation
In the phase 1 trial, BBV152 induced high neutralising antibody responses that remained elevated in all participants at 3 months after the second vaccination. In the phase 2 trial, BBV152 showed better reactogenicity and safety outcomes, and enhanced humoral and cell-mediated immune responses compared with the phase 1 trial. The 6 μg with Algel-IMDG formulation has been selected for the phase 3 efficacy trial.
Funding
Bharat Biotech International.
Translation
For the Hindi translation of the abstract see Supplementary Materials section.
Background:
Escherichia coli bloodstream infections (BSIs) account for high mortality rates (5%-30%). Determinants of death are unclear, especially since the emergence of ESBL producers.
Objectives:
To determine the relative weight of host characteristics, bacterial virulence and antibiotic resistance in the outcome of patients suffering from E. coli BSI.
Methods:
All consecutive patients suffering from E. coli BSI in seven teaching hospitals around Paris were prospectively included for 10 months. E. coli isolates were sequenced using Illumina NextSeq technology to determine the phylogroup, ST/ST complex (STc), virulence and antimicrobial resistance gene content. Risk factors associated with death at discharge or Day 28 were determined.
Results:
Overall, 545 patients (mean ± SD age 68.5 ± 16.5 years; 52.5% male) were included. Mean Charlson comorbidity index (CCI) was 5.6 (± 3.1); 19.6% and 12.8% presented with sepsis and septic shock, respectively. Portals of entry were mainly urinary (51.9%), digestive (41.9%) and pulmonary (3.5%); 98/545 isolates (18%) were third-generation cephalosporin resistant (3GC-R), including 86 ESBL producers. In-hospital death (or at Day 28) was 52/545 (9.5%). Factors independently associated with death were a pulmonary portal of entry [adjusted OR (aOR) 6.54, 95% CI 2.23-19.2, P = 0.0006], the iha_17 virulence gene (aOR 4.41, 95% CI 1.23-15.74, P = 0.022), the STc88 (aOR 3.62, 95% CI 1.30-10.09, P = 0.014), healthcare-associated infections (aOR 1.98, 95% CI 1.04-3.76, P = 0.036) and high CCI (aOR 1.14, 95% CI 1.04-1.26, P = 0.006), but not ESBL/3GC-R.
Conclusions:
Host factors, portal of entry and bacterial characteristics remain major determinants associated with mortality in E. coli BSIs. Despite a high prevalence of ESBL producers, antibiotic resistance did not impact mortality. (ClinicalTrials.gov identifier: NCT02890901.).
Background
S. pneumoniae carriage by children is a major source of pneumococcal transmission, and the initial step prior to infection. Pilus type 1, reported in ~30% of pneumococcal strains in the pre-vaccine era, contributes to pneumococcal colonization and virulence. In this study, we report the impact of the pneumococcal conjugate vaccine (PCV), PCV7/PCV13 sequential implementation on serotype distribution, and on the prevalence of piliated strains among carried pneumococci during the pre- and post-vaccine eras.
Methods
During 2002-2016, 12 repeated cross-sectional surveillances of nasopharyngeal S. pneumoniae carriage were conducted among 8,473 children <5.5 years old visiting primary care physicians in Central Israel. Seven biannual surveillances in the pre-PCV period, 2 surveillances after PCV7 was licensed but before implementation in the National Immunization Plan, and 3 additional surveillances in the post-PCV period. S. pneumoniae serotype distribution and prevalence of piliated strains were assessed.
Results
Carriage of S. pneumoniae was relatively stable (45.4%). The prevalence of serotypes included in PCV13 was 65.7%, in the pre-vaccine period and the pilus was present in 26.4% of isolates. The distribution of serotypes and the pilus prevalence in the pre-PCV period was relatively stable except for a decrease in prevalence of piliated 19F, observed following the first study year. Following PCV7/PCV13 implementation, vaccine type 13 (VT13) strains were nearly eliminated to 3.3% by 2016. Piliated strains, which were primarily of VT13 serotypes, initially followed a similar trend and were nearly eliminated by 2014 (1.7%). Yet, two years later, pilus prevalence re-emerged among non-VT strains to 12.8% of all pneumococci.
Conclusions
Following PCV implementation, a dramatic and rapid decrease in VT strains prevalence was observed with a concomitant increase in non-VT strains. Piliated strains were nearly eliminated, yet re-emerged 7 years following PCV7/PCV13 implementation in various non-VT strains. This suggests that the pilus confers an advantage in colonization.
Background:
ExPEC4V (JNJ-63871860) is a bioconjugate vaccine, containing O-antigens from Escherichia coli serotypes O1A, O2, O6A, and O25B, developed for the prevention of invasive extra-intestinal pathogenic E coli (ExPEC) disease. We aimed to assess safety, reactogenicity, and immunogenicity of ExPEC4V in healthy adults.
Methods:
In this phase 2 randomised, double-blind placebo-controlled study, we recruited healthy adults (≥18 years with a body-mass index of 35 kg/m2 or less) between Nov 16, 2015, and Aug 8, 2017, and randomly assigned them to receive a single dose of ExPEC4V (antigen O1A:O2:O6A:O25B content 4:4:4:4 μg [group 1]; 4:4:4:8 μg [group 2], 8:8:8:8 μg [group 3], 8:8:8:16 μg [group 4], or 16:16:16:16 μg [group 5]) or placebo. The primary objectives were evaluation of the safety, tolerability, and immunogenicity of ExPEC4V and determination of its dose-dependent immunogenicity 15 days after vaccination by ELISA in individuals who had received at least one vaccination dose. Antibody titres and safety evaluation were used to select two ExPEC4V doses for assessment up to day 360. This trial is registered at ClinicalTrials.gov, number NCT02546960.
Findings:
Of 848 enrolled participants, 843 (99%) received the ExPEC4V vaccine (757) or placebo (86) and were included in the safety analysis. Of 757 participants vaccinated with ExPEC4V, 222 (29%) had a solicited local adverse event and 325 (43%) had any solicited systemic adverse event, compared with 11 (13%) and 30 (35%) of 86 participants in the control group. Symptoms were mild-to-moderate. The most frequently reported solicited local adverse event was pain or tenderness (205 [27·1%] of 757 in combined ExPEC4V groups) and the most frequently reported solicited systemic adverse event was fatigue (208 [27·6%] of 757). Only 13 (2%) of 843 had a grade 3 event. At day 15, 80% or more of all participants achieved a two times or greater increase in serotype-specific IgG antibodies (except O25B at the lowest dose, 103 [72%] of 144). At day 360, 66% (95% CI 56·47-74·33) of participants in group 2 and 71% (62·13-78·95) of participants in group 4 selected for long-term follow-up maintained a two times or greater increase in serotype-specific antibody compared with baseline.
Interpretation:
EXPEC4V seemed well tolerated and elicited robust and functional antibody responses across all serotypes, doses, and age groups. For the two dosages evaluated (4:4:4:8 μg and 8:8:8:16 μg), the immune response persisted for 1 year.
Funding:
Janssen Pharmaceuticals.
An unknown virus was repeatedly isolated from hard tick (Haemaphysalis spinigera) during a proactive arbovirus survey in ticks conducted in 1957, in India. The virus remained uncharacterized for a long time. The passages of this virus in different vertebrate and invertebrate cells along with human and monkey-derived cell culture showed no cytopathic effect. It was identified later to be a member of Kaisodi group among Phlebovirus genus in the family Phenuiviridae (Order: Bunyavirales) by serological methods. Due to its genomic diversity, sequencing of this virus was a challenge for a while. In this study, we were able to sequence the complete genome of this virus isolate using next-generation sequencing (NGS) platform. The unknown virus was identified to be Kaisodi virus (KASDV) using NGS analysis. De novo genome assembly derived three genomic segments for the KASDV which encode for RNA-dependent RNA polymerase, glycoprotein precursor, and nucleoprotein. Functional as well as conserved domains for Kaisodi serogroup viruses were predicted and compared to a known representative of the genus Phlebovirus. The phylogenetic tree revealed its closeness to Silverwater virus, of Kaisodi serogroup with nucleotide (69%, 62%, and 61%) and amino acid (52%, 51%, and 62%) identity for L, M, and S segment, respectively. The study demonstrates the presence of a conserved motif (72TRGNK76) around the RNA binding motif region in tick-borne phleboviruses. The intergenic region encompassing the S segment of Kaisodi serogroup was GC-rich whereas the other Phlebovirus had AT-rich genome. KASDV has the largest intergenic region and larger loops, suggesting stem-loops formed due to larger loops as a possible factor for instability and cause of transcription termination. This paper also describes the real-time RT-PCR and RT-PCR assays developed and used for the detection of KASDV RNA in ticks from Karnataka, Kerala and Maharashtra State, India. The KASDV positivity observed in the recently collected tick pools indicates that the KASDV, isolated from Karnataka state in 1957, is also circulating in the adjoining Kerala state. On the basis of the current study, it should be possible to develop diagnostic assays which would facilitate an in-depth field survey exploring the veterinary and medical significance of KASDV.
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