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Intro: Viruses, including SARS-CoV-2, which causes COVID-19, are constantly changing. These genetic changes (aka mutations) occur over time and can lead to the emergence of new variants that may have different characteristics. After the first SARS-CoV-2 genome was published in early 2020, scientists all over the world soon realized the immediate need to obtain as much genetic information from as many strains as possible. However, understanding the functional significance of the mutations harbored by a variant is important to assess its impact on transmissibility, disease severity, immune escape, and the effectiveness of vaccines and therapeutics. Method(s): Here in Canada, we have developed an interactive framework for visualizing and reporting mutations in SARS-CoV-2 variants. This framework is composed of three stand-alone yet connected components;an interactive visualization (COVID-MVP), a manually curated functional annotation database (pokay), and a genomic analysis workflow (nf-ncov-voc). Finding(s): COVID-MVP provides (i) an interactive heatmap to visualize and compare mutations in SARS-CoV-2 lineages classified across different VOCs, VOIs, and VUMs;(ii) mutation profiles including the type, impact, and contextual information;(iii) annotation of biological impacts for mutations where functional data is available in the literature;(iv) summarized information for each variant and/or lineage in the form of a surveillance report;and (v) the ability to upload raw genomic sequence(s) for rapid processing and annotating for real-time classification. Discussion(s): This comprehensive comparison allows microbiologists and public health practitioners to better predict how the mutations in emerging variants will impact factors such as infection severity, vaccine resistance, hospitalization rates, etc. Conclusion(s): This framework is cloud-compatible & standalone, which makes it easier to integrate into other genomic surveillance tools as well. COVID-MVP is integrated into the Canadian VirusSeq data portal (https://virusseqdataportal.ca) - a national data hub for SARS-COV-2 genomic data. COVID-MVP is also used by the CanCOGeN and CoVaRR networks in national COVID-19 genomic surveillance.Copyright © 2023
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Background: In mid-2022, New York City (NYC) became the epicenter of the US mpox epidemic. Health authorities were in need of forecasts to anticipate the timing and magnitude of the outbreak. We provided mathematical modelbased projections with methodologies that evolved alongside the epidemic. Here, we retrospectively evaluate our mpox case projections and reflect on potential reasons for accuracies and inaccuracies. Method(s): Early in the outbreak (July 1 - 15, 2022), when the size of the at-risk population was unknown, we performed short-term (2-week) forecasting using exponential regression. Once epidemic growth was no longer exponential (July 15 - Aug. 9), we consulted with the NYC Department of Health and Mental Hygiene regarding populations most-at-risk of mpox based on available epidemiological data. Modelers and epidemiologists collaboratively developed an estimate of 70,180 people at risk, informed by estimates of LGBTQ adults with male sex at birth who had 2+ partners in the last 3 months. We combined this with NYC case count data, NYC vaccination data, and global mpox natural history data to develop a Susceptible-Exposed-Infected-Recovered (SEIR) model, taking into account immunity accrued through vaccination and prior exposure, for longer-term forecasting. Result(s): Initial exponential forecasts of the NYC mpox outbreak were only accurate for very short-term predictions (< 2 weeks) (Figure, top panel). Forecasts were more accurate after 1 week (mean absolute error: 83.0 cases/ wk) than after 2 weeks (mean absolute error: 351.4 cases/wk). In contrast, the SEIR model accurately predicted the decline in cases through the end of Sept. 2022, when cases fell to < 70/wk. Over the period from Aug. 10 to Sept. 24 2022, the mean absolute error of the SEIR-based projection was 8.2 cases per week (Figure, bottom panel). Conclusion(s): Model-based NYC mpox projections provided only short-term accuracy in the early epidemic, but long-term accuracy once the epidemic exited exponential growth and an SEIR model was developed. Cumulative cases and vaccinations when exiting exponential growth, and the epidemiology of those most-at-risk, provided evidence for the likely size of the most-at-risk population - a crucial input for an accurate SEIR model. The ability of the SEIR model to accurately forecast mpox cases was in part attributable to lack of vaccine or immune escape by mpox, in contrast to more rapidly-evolving viruses such as SARS-CoV-2.
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The incidence of the omicron variant of SARS-CoV-2 has increased rapidly around the entire planet, even in vaccinated people. Sequencing results indicated that they were all from a new and genetically distinct lineage of SARS-CoV-2. This lineage was designated variant of concern and named omicron on the recommendation of the Technical Advisory Group on SARS-CoV-2. The main predominant subvariants in Mexico, the reasons for the immune escape and the current proposal to contain SARS-CoV-2 are presented.Copyright © 2023 The authors.
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Background: Five variants of concern (VOCs) have dominated COVID-19 disease etiology since 2020-Alpha, Beta, Gamma, Delta, and Omicron-possessing over 150 defining genomic alterations. Here, we used global proteomic and genomic approaches to study the host responses and selective forces driving VOC evolution. Method(s): We infected Calu-3 human lung epithelial cells with 5 VOCs and 2 wave 1 (W1) controls and performed mass spectrometry abundance proteomics, phosphoproteomics, and mRNA sequencing at 10 and 24 hours post infection. We additionally performed affinity purification mass spectrometry (APMS) by individually expressing all VOC mutant viral proteins (52) and corresponding W1 forms in human cells to quantify differential virus-host protein-protein interactions. Data was integrated using network modeling and bioinformatics to pinpoint VOC-specific differences. Four novel mutant viruses were developed using reverse genetics technology to validate the impact of specific genomic alterations. Result(s): We discovered VOCs evolved convergent molecular strategies to remodel the host response by modulating viral RNA and protein levels (most notably of N, Orf9b, and Orf6), altering nucleocapsid phosphorylation, and rewiring virus-host protein complexes. Integrative systems analyses revealed that Alpha, Beta, Gamma, and Delta ultimately converged in the suppression of interferon stimulated genes (ISGs) relative to W1 viruses, but Omicron BA.1 did not, and Delta induced more pro-inflammatory genes compared to other VOCs. Altered regulation of ISGs correlated with the expression of viral innate immune antagonist proteins, including Orf6, N, and Orf9b;for example, Omicron BA.1 depicted a 2-fold decrease in Orf6 expression. We identified mutations that alter expression of Orf9b (N D3L and N -3A del) and the novel VOC protein N* (N R203K/G204R), and confirmed Orf6 innate immune antagonism using recombinant virus technology. Remarkably, Omicron BA.4 and BA.5 regained strengthened innate immune antagonism compared to BA.1, which again correlated with enhanced Orf6 expression, though dampened in BA.4 by a mutation (D61L) that we discovered disrupts the Orf6-nuclear pore interaction. Conclusion(s): Collectively, our findings suggest SARS-CoV-2 convergent evolution overcomes human innate immune barriers, laying the groundwork to understand future coronavirus evolution associated with immune escape and enhanced human-to-human transmission.
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Virus evolution shapes the epidemiological patterns of infectious disease, particularly via evasion of population immunity. At the individual level, host immunity itself may drive viral evolution towards antigenic escape. Using compartmental SIR-style models with imperfect vaccination, we allow the probability of immune escape to differ in vaccinated and unvaccinated hosts. As the relative contribution to selection in these different hosts varies, the overall effect of vaccination on the antigenic escape pressure at the population level changes. We find that this relative contribution to escape is important for understanding the effects of vaccination on the escape pressure and we draw out some fairly general patterns. If vaccinated hosts do not contribute much more than unvaccinated hosts to the escape pressure, then increasing vaccination always reduces the overall escape pressure. In contrast, if vaccinated hosts contribute significantly more than unvaccinated hosts to the population level escape pressure, then the escape pressure is maximised for intermediate vaccination levels. Past studies find only that the escape pressure is maximal for intermediate levels with fixed extreme assumptions about this relative contribution. Here we show that this result does not hold across the range of plausible assumptions for the relative contribution to escape from vaccinated and unvaccinated hosts. We also find that these results depend on the vaccine efficacy against transmission, particularly through the partial protection against infection. This work highlights the potential value of understanding better how the contribution to antigenic escape pressure depends on individual host immunity.
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Viruses , Humans , Vaccination , Population DynamicsABSTRACT
This study aims to fill a knowledge gap in our understanding of Omicron variant receptor-binding domain (RBD) interactions with host cell receptor, angiotensin-converting enzyme 2 (ACE2). Protein-protein docking, scoring, and filtration were all performed using the HDOCK server. A coarse-grained prediction of the changes in binding free energy caused by point mutations in Omicron RBD was requested from the Binding Affinity Changes upon Mutation (BeAtMuSiC) tools. GROMACS was utilized to perform molecular dynamics simulations (MD). Within the 15 mutations in Omicron RBD, several mutations have been linked to increased receptor affinity, immunological evasion, and inadequate antibody response. Wild-type (wt) SARS-CoV-2 and its Omicron variant have 92.27% identity. Nonetheless, Omicron RBD mutations resulted in a slight increase in the route mean square deviations (RMSD) of the Omicron structural model during protein-protein docking, as evidenced by RMSDs of 0.47 and 0.85 A for the wt SARS-CoV-2 and Omicron RBD-ACE2 complexes, respectively. About five-point mutations had essentially an influence on binding free energy, namely G6D, S38L, N107K, E151A, and N158Y. The rest of the mutations were expected to reduce the binding affinity of Omicron RBD and ACE2. The MD simulation supports the hypothesis that Omicron RBD is more stably bound to ACE2 than wt SARS-CoV-2 RBD. Lower RMSD and greater radius of gyration (Rg) imply appropriate Omicron structure 3D folding and stability. However, the increased solvent accessible surface area (SASA) with a greater Omicron shape may have a different interaction with receptor binding and regulate virus entrance. Omicron RBD's mutations help it maintain its structural stability, compactness, ACE2 binding, and immune evasion.Copyright © 2022 AEPress, s.r.o.. All rights reserved.
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The Omicron variant of SARS-CoV-2 is a new variant of concern after Alpha, Beta, Gamma and Delta variants. The amino acid mutations in the viral antigens, especially in the receptor binding region (RBD) of spike protein, were significantly more than those of other variants, which lead to the significant increase of infectivity, transmissibility and immune escape of Omicron variant. In addition, those spike mutations impaired the protective effect of vaccination. When compared to the infection of other variants, the latency of Omicron variant infection was significantly shortened, and the pathogenicity decreased markedly, which is in consistence with the fact that the vast majority of infected individuals showed no symptoms or only mild disease. Exacerbations in patients infected by Omicron variant were often associated with the progress of underlying disease. Early detection and medical isolation of infected persons, careful personal protection measures to cut off transmission routes, and active vaccination to protect susceptible people are key measures to prevent the spread of Omicron variant epidemic. A small number of patients infected with Omicron variant may develop so-called long COVID-19, post-COVID-19 syndrome, or post-COVID-19 condition, which means that long-term follow-up is needed in those patients. Effective anti-Omicron variant therapy can shorten the course of infection, promote the recovery from infection, and also contribute to the control of infection. Therefore, the development of antiviral drugs with ideal cost-benefit ratio and convenient administration is one of the research hotspot in the future.Copyright © 2022 Authors. All rights reserved.
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The Conference on Retroviruses and Opportunistic Infections (CROI) serves as one of the most highly visible platforms upon which researchers gather to share the most recent findings on HIV/AIDS and, recently, on SARS-CoV-2 research. Research presentations on the novel coronavirus SARS-CoV-2 have become an increasing fixture at the conference since it was first covered at last year's conference. Although CROI 2021 was virtual, the organizers coordinated a seamless platform for presentations and poster sessions that effectively engaged the audience. CROI 2021 had a strong showing in terms of basic science presentations on HIV-1 and on SARS-CoV-2. Highlights included new insights into some of the more elusive steps in the viral replication cycle as well as new findings on immune escape strategies employed by SARS-CoV-2. The new investigator workshop has become a valuable resource that can be used by early stage and established investigators alike to receive state-of-the-art updates on research areas that might be outside their immediate areas of research. The new investigator workshop featured engaging presentations on novel aspects of HIV-1 and SARS-CoV-2 replication, impact of host immunity on HIV-1 and SARS-CoV-2, and approaches to assessing viral reservoir dynamics and strategies for viral reservoir elimination.Copyright © 2021, IAS-USA. All rights reserved.
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Background: COVID-19 convalescent plasma (CCP) remains a potential therapy of COVID-19, e.g. for new variants and for patients with impaired immune response. The trial COVIC-19 takes into account lessons learned from previous trials and combines it to a novel approach: * CCP with very high levels of SARS-CoV-2 antibodies from donors with previous SARS-CoV-2 infection (inf) and vaccination (vax) * Treatment early after symptom onset * Treatment of vulnerable persons (e.g. immunocompromised) * Study of immune escape Methods: We report the initial experience of collection of very high-titer plasma units (defined as >=4.000 BAU/ml in the QuantiVac ELISA) for this COVIC-19 trial. We recruited 348 potential donors (151 male, 197 female) who had passed initial eligibility check. S-Ab were measured by anti-SARS-CoV-2 QuantiVac ELISA (Euroimmun): mean 4229 BAU/ml (IQR 2.239-5.486 BAU/ml). High S-Ab in the QuantiVac assay correlated with high neutralizing capacity in the GenScript surrogat neutralization assay. S-Ab was >=4.000 BAU/ml in 25.1% of the individuals and did not significantly differ by gender or ABO type, but were higher among those who had received 3 vax (median 4.231 BAU/ml) or 2 vax (median 2.954 BAU/ml) or 1 vax (median 1.832 BAU/ml)(p<0.01). Result(s): We analyzed the association between the order of immunizing events and S-Ab. Highest S-Ab were observed among those with a breakthrough infection after 2 vax, followed by a booster (3rd dose post inf.) (median 5.840 BAU/ml;76.7% >=4.000 BAU/ml) or breakthrough inf after 3 vax (no further booster;median 3.841 BAU/ml;47.9% >=4.000 BAU/ml). S-Ab were lower in those with inf before vax followed by 1 vax (median 1.806 BAU/ml;18.1% >=4.000 BAU/ml) or >1 vax (median 2.586 BAU/ ml). S-Ab declined rapidly: 42% of donors with S-Ab >=4.000 BAU/ml had declined below this threshold in the short interval until 1st plasmapheresis and further 6% until 2nd apheresis. Further follow-up will be presented. Conclusion(s): Taking into account all eligibility criteria only 8.6% of individuals willing to donate could provide plasma units meeting the criteria of high-titer plasma for COVIC-19. Collection of very-high titer plasma from super-immunized individuals with previous infection and vaccination is feasible, but requires substantial donor selection and rapid screening and immediate start of apheresis to take advantage of the short period of very high mAb.
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Background. We aimed to estimate COVID-19 Vaccine Effectiveness (VE) and its durability against severe disease (intubation) and death in the Greek population, for all vaccines currently in use. Methods. Nationwide active surveillance and vaccination registry data between January 2021 - April 2022 were used to estimate VE via quasi-Poisson regression as one minus Incidence Rate Ratio, adjusted for age and calendar time. Interaction terms were included to assess VE by age group, by variant (delta vs omicron) and by time since vaccination (compared to the first month after vaccination). Results. VE results are summarized in Figures 1-3. After 2-doses (of any vaccine) VE was >95% against delta and >85% against omicron in the 15-59 and 60-79 age groups, but waned significantly at 6 months by 5-10% in the 15-59 group and 15-20% in the 60-79 group. In the 80+ age group, 2-dose VE was much lower against omicron at around 60%, waning to 50% at 6 months. With 3 vaccine doses VE surged to >95% against both delta and omicron in all age groups except 80+, who had VE against omicron of =90%;however there was again substantial waning at 6 months by about 10-15% in all groups. In the 80+ age group, VE against omicron dropped to 81.4% (95% CI 76.7-85.2%) for death and 57.7% (95% CI 38.5-70.9%) for intubation. There was little to no evidence of variation in VE between combinations of different vaccines (BNT162b2, mRNA-1273, ChAdOx1 nCov-19 and Ad26.COV2.S), although the majority of the population received 2- or 3-dose BNT162b2. Vaccination prevented an estimated 39,018 COVID-19 deaths (95% CI: 37,791- 40,608) over the study period. Conclusion. COVID-19 vaccination remains extremely effective in preventing severe disease and death, even in the context of the omicron variant, as long as 3 doses have been administered. Even after 3 doses, however, effectiveness wanes substantially in the course of 6 months. Additional strategies will be therefore needed in order to minimize COVID-19 mortality and morbidity, including boosting doses especially in the elderly, improved vaccines, early diagnosis and treatment of high-risk groups and measures to reduce community transmission of current or novel SARS-CoV-2 immune escape variants.
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Background. The emergence of the highly infectious Omicron variant at the end of 2021 changed the pandemic dynamics, also causing an increase inCOVID-19 re-infections. Our aim was to investigate suspected re-infections and the characteristics of individuals with multiple infections since the beginning of the pandemic until early April 2022. Methods. Since the beginning of the pandemic, all COVID-19 positive tests (Rapid Antigen Tests - RAT and PCR) have been recorded in the COVID-19 National Electronic Registry. Cases were extracted and reported daily based on the first positive test for each individual (first episodes). Establishment of the Omicron variant, associated with a re-infection surge, triggered the decision for modifying case definition and applying a different methodology to include suspected re-infections in the number of daily reported cases after 3rd of April. Suspected re-infections were defined as 'positive PCR or RAT sample >=90 days following a previous positive PCR or RAT'. The number of re-infections were estimated retrospectively on the Registry's data. Results. Overall, 6,348 suspected re-infections were recorded up to 15/12/2021 (0.6% of the laboratory confirmed tests), whereas until 3/4/22 the number was increased at 115.201, raising the percentage to 4%. Distribution of the number of reinfections per ISO week is depicted in Figure 1, along with the number of first episodes. Suspected re-infections stand for 3.7% of the total number of first episodes recorded up to 3/4/22 (3,077,711), with their integration having a noticeable effect on case counting. Among them, 99.3% represent a second episode of infection and 0.7% multiple re-infections. Median age of suspected re-infections was 29 years (IQR: 19-44) (Figure 2). The median length of the time interval between two subsequent infections was 8 months (IQR: 5-12) (Figure 3). Conclusion. Up until mid-December 2021, COVID-19 re-infection was uncommon, changing to higher rates after the emergence of Omicron variant, thus documenting the immune escape capacity of this variant. Besides the improvement in surveillance, knowledge about the re-infections and their characteristics provides a proxy of the immune protection from previous exposure to COVID-19, against circulating variants over time.
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Background. Quantifying neutralising capacity of circulating SARS-COV-2 antibodies is critical in evaluating protective humoral immune responses generated postinfection/post-vaccination. Here we describe a novel medium-throughput flow cytometry based micro-neutralisation assay to evaluate Neutralising Antibody (NAb) responses against live SARS-CoV-2 Wild Type (D641G) and Variants of Concern (VoC) in convalescent/vaccinated populations. Methods. Micro-Neutralisation assay (Micro-NT) was performed in 96-well plates using clinical isolate 2019-nCoV/Italy-INMI1, D641G (SARS-CoV-2/human/ IRL/AIIDV1446/2020) and/or VOCs Beta (SARS-CoV-2/human/IRL/AIIDV1752/ 2021) and Omicron (SARS-Cov-2/human/IRL/AIIDV2326/2021). Plasma samples (All Ireland Infectious Diseases (AIID) Cohort) were serially diluted (8 points, halflog) from 1/20 and pre-incubated with SARS-CoV-2 (1h, 37degreeC). Virus-plasma mixture were added onto VERO E6/VERO-E6 TMPRSS2 cells for 18h. Percentage infected cells was analysed by automated flow cytometry following trypsinisation,fixation and SARS-CoV-2 Nucleoprotein intracellular staining. Half-maximal Neutralisation Titres (NT50) was determined using four-parameter logistic regression. Our assay was compared to Plaque Reduction Neutralisation Test (PRNT) and validated against WHO anti-SARS-CoV-2 Immunoglobulin Standards. Results. Using WHO Standards with low, medium or high anti-SARS-CoV-2 IgG, both Micro-NT and PRNT achieved comparable NT50 values (Table 1). Micro-NT was found to be highly reproducible (inter-assay CV of 11.39%). Screening 190 convalescent samples and 11 COVID-19 naive controls (AIID cohort) we achieved an assay sensitivity of 90% and specificity of 81%. We demonstrated that Micro-NT has broad dynamic range differentiating NT50s < 1/20 to > 1/5000 (Figure 1). We could also characterise immune-escape VoC, observing up to 10-fold reduction in NT50 against Beta (Figure 2). Table 1: NT50s of Low, Medium and High Titre Anti-SARS-CoV-2 IgG Standards measured against Live SARS-CoV-2 using PRNT and Micro-NT Neutralising Capacity of low, medium and high-titre anti-SARS-CoV-2 IgG (WHO, International Standards) against live SARS-CoV-2 (2019-nCoV/Italy-INMI1) measured using PRNT and Micro-NT Assays on Vero E6 cells, as well as the potency of NAbs in each sample in International Units (IU/ml) as determined by the WHO. Figure 1: Dynamic Range of Micro-NT Micro-NT has a broad Dynamic Range, distinguishing low (A), medium (B) and high (C) neutralising plasma samples against live SARS-CoV-2 (2019-nCoV/Italy-INMI1) from a cohort of COVID-19 convalescent individuals (AIID cohort), as well as negative samples from COVID-19 naive samples (D). Graphs show 3 representative samples of each NT50 range. (E) shows the population distribution of 190 Convalescent plasma samples as measured by Micro-NT on Vero E6 cells. Figure 2: Reduced Neutralisation Capacities measured against SARS-CoV-2 VoC using Micro-NT Low (A), Medium (B) and High (C) anti-SARS-CoV-2 IgG (WHO Standards) show different neutralising capacities against WT (D614G) SARS-CoV-2 and variants Beta and Omicron, measured using Micro-NT on Vero-E6-TMPRSS2 cells. Conclusion. Our flow-cytometry-based Micro-NT is a robust and reliable assay to quantify NAb titres, an important evaluation endpoint in clinical trials. It has higher throughput (96 well format versus 12 well) and reduced infection time (18h vs 48-96h) compared to the gold standard PRNT.
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The genetic evolution of SARS-CoV-2 began in February 2020, with G614 spike protein strains superseding D614 strains globally. Since then with each subsequent mutations, the SARS-CoV-2 variants of concern, namely Alpha, Beta, Gamma, Delta and Omicron, superseded the previous one to become the dominant strain during the pandemic. By the end of November 2022, the Omicron variant and its descendent lineages account for 99.9% of sequences reported globally. All five VOCs have mutations located in the RBD of the spike protein, resulting in increased affinity of the spike protein to the ACE2 receptors resulting in enhanced viral attachment and its subsequent entry into the host cells. In vitro studies showed the mutations in spike protein help increase the viral fitness, enhancing both transmissibility and replication. In general, Alpha, Beta, Gamma, and Delta variants, were reported with higher transmissibility of 43-90%, around 50%, 170-240%, or 130-170% than their co-circulating VOCs, respectively. The Omicron however was found to be 2.38 times and 3.20 times more transmissible than Delta among the fully-vaccinated and booster-vaccinated households. Even the SARS-Cov-2 Omicron subvariants appear to be inherently more transmissible than the ones before. With the broader distribution, enhanced evasion, and improved transmissibility, SARS-CoV-2 variants infection cause severe diseases due to immune escape from host immunity and faster replication. Reports have shown that each subsequent VOC, except Omicron, cause increased disease severity compared with those infected with other circulating variants. The Omicron variant infection however, appears to be largely associated with a lower risk of hospitalisation, ICU admission, mechanical ventilation, and even a shorter length of hospital stay. It has been shown that the relatively much slower replication of the Omicron variants in the lung, resulted in a less severe disease. Copyright © 2022, Malaysian Society of Pathologists. All rights reserved.
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Introduction. The circulation of SARS-CoV-2 virus variants raises concerns about their potential evasion of the immune response and associated clinical consequences. Decay in the magnitude of the immune response over time after completion of the vaccination schedule has been evidenced. The aim of this study was to evaluate the kinetics of neutralizing antibodies after vaccination and the impact of circulating variants. Materials and methods. Prospective longitudinal study' with a cohort of 60 Colombian adults' who received the complete BNT162b2 vaccine schedule' and were followed for 6 months to determine the kinetics of antibodies. Plaque reduction neutralization assays were performed with live virus' using the B.1 lineage (D614G)' and the Gamma' Alpha' Delta' Mu and Omicron variants of the SARS-CoV-2 virus. Results. Neutralizing capacity against all variants was observed in all individuals after 1 month of vaccination;however' a progressive decrease in neutralizing capacity was observed after 3 and 6 months. Compared to the B.1 lineage' the neutralizing response against the Delta' Mu and Omicron variants presented the greatest decrease' evidencing their immune escape capacity' followed by the Gamma and Alpha variants. The decrease in antibody titers was more evident in men older than 40 years. Conclusions. Despite the safety and effectiveness of the vaccines' it is important to improve and monitor them in order to improve the protective response they can offer.
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Objectives. The main goal of the study was to develop laboratory-developed tests (LDT) for monitoring SARS-CoV-2 variants of concern (VOC) currently present in Latvia. METHODS. We have studied the latest scientific articles to prognose specific mutations that could be indicators of VOC. Mutations responsible for immune escape were chosen as targets for our LDTs. Multiple TaqMan RT-PCR LDTs detecting alfa, beta, gamma, delta and omicron strains in nasopharyngeal swab and saliva samples were developed and validated in our laboratory. RESULTS. More than 15,000 SARS-CoV-2 positive samples were tested. In total, 10,874 different VOCs of SARS-CoV-2 were found by our LDTs. Beta, delta and omicron strains were first detected in Latvia by E. Gulbis Laboratory. Sanger sequencing methods for RT-PCR result confirmation were also developed. The first cases of VOCs detected by the RT-PCR method were also confirmed in our laboratory by Sanger sequencing. Our results were later confirmed by the National Reference Laboratory. CONCLUSIONS. Using our laboratory capacity and intellectual potential, we have developed skills for an urgent response to future VOCs of SARS-CoV-2 or other potentially harmful infectious diseases.
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The repeated emergence of SARS-CoV-2 escape mutants from host immunity has obstructed the containment of the current pandemic and poses a serious threat to humanity. Prolonged infection in immunocompromised patients has received increasing attention as a driver of immune escape, and accumulating evidence suggests that viral genomic diversity and emergence of immune-escape mutants are promoted in immunocompromised patients. However, because immunocompromised patients comprise a small proportion of the host population, whether they have a significant impact on antigenic evolution at the population level is unknown. We consider an evolutionary epidemiological model that combines antigenic evolution and epidemiological dynamics. Applying this model to a heterogeneous host population, we study the impact of immunocompromised hosts on the evolutionary dynamics of pathogen antigenic escape from host immunity. We derived analytical formulae of the speed of antigenic evolution in heterogeneous host populations and found that even a small number of immunocompromised hosts in the population significantly accelerates antigenic evolution. Our results demonstrate that immunocompromised hosts play a key role in viral adaptation at the population level and emphasize the importance of critical care and surveillance of immunocompromised hosts.
Subject(s)
Antigenic Drift and Shift , COVID-19 , Humans , SARS-CoV-2 , Genome, Viral , Immunocompromised HostABSTRACT
The Omicron variant (B.1.1.529) is a variant of SARS-CoV-2 with more than 50 mutations;this led to increase transmissibility or lead to immune escape. Therefore, WHO predicts it to be more dangerous than the previous variant, although it is not as severe as the previous variant. This review aims to provide an overview of SARS-CoV-2 symptoms, severity, mutations, and the effectiveness of treatments and vaccines against this novel coronavirus, as well as the effectiveness of current diagnostic tests.
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A number of variants of the SARS-CoV-2 virus are now causing special concern all around the world due to its purported ability to evade the immune response in previously immunized people. Therefore, many governments, including that of Spain, have implemented non-pharmaceutical interventions (NPI) in an attempt to prevent variants of concern (VOCs) from being imported and, if they are, facilitate their timely detection and control their expansion throughout new regions. In this report, the real efficacy of the current NPI is subjected to examination, using the first COVID-19 outbreak of P.1 lineage (Gamma variant) arisen in Cantabria as a practical example. Likewise, the usefulness of genomic surveillance in keeping a pandemic situation under control is also assessed. Finally, the issue of whether there really exists in Spain, as well as in every Autonomous Community, the capacity to perform sufficiently broad genetic analyses, in a sufficiently short time and in a sufficient amount of samples, as to have real-time data on the evolution of the variants is addressed here. The COVID-19 outbreak reported in this work was kept under control and its expansion was avoided. However, analysing the facts, this success seems to be largely due to a surprisingly low transmission capacity of this strain of the virus, while not so much to a high efficiency of the existing NPI. Indeed, the attack rate of this outbreak has been as low as 3.5%.
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Introduction & Objectives: After the early and dramatic induction of inflammatory cytokines, IL-6 emerged to be associated with severe outcomes in patients with COVID-19. Likewise, high IL-10 plasma levels have been reported, and central hypogonadism has been recently observed in male patients with severe clinical outcomes (i.e., Intensive Care Unit (ICU) admission or death) of COVID-19. We aimed to investigate the role of IL-10 over the pathophysiology of COVID-19 and its relationship with hypogonadism in males. Materials & Methods: Plasma from 281 voluntary healthy males (HC) and 258 laboratory-confirmed COVID-19 males (i.e., asymptomatic (n=24);symptomatic (n=155);ICU patients (n=48);and, deceased (n=31)) was collected to measure levels of total testosterone (TT), IL-10 and the nonclassical MHC class I HLA-G (HLA-G) molecule - associated to IL-10 and involved in immune escape after viral infection - by specific enzyme-linked immunosorbent assay. Results: An inverse correlation between TT and IL-10 levels was identified, with TT levels progressively decreasing from HC (median (IQR) 10.4 (8.1-13.4) nmol/L) to asymptomatic COVID-19 (3.9 (3.1-5.3) nmol/L), to symptomatic COVID-19 (3.0 (1.8-5.7) nmol/L), ICU (1.0 (0.5-1.8) nml/L) and deceased (0.7 (0.3-2.3) nmol/L) patients, respectively (p<0.0001). Conversely, IL-10 levels progressively decreased from deceased COVID-19 patients (11.3 (4.5-37.7) pg/ml), to ICU (8.0 (2.6-16.7) pg/mL), symptomatic (6.0 (3.0-10.9) pg/mL), asymptomatic COVID-19 patients (6.0 (1.6-6.0) pg/mL), and HC (3.0 (1.3-3.0) pg/mL), respectively (p<0.0001). Similarly, HLA-G levels, progressively increased from HC to COVID-19 patients with most severe clinical outcomes. Conclusions: These data indicate that circulating TT is inversely associated to both IL-10 and HLA-G levels in men with COVID-19, where lower TT and higher IL-10 levels are associated with the most severe clinical outcomes. Further investigations are required to better define whether TT and IL-10 might be early effective biomarkers of clinical severity in males with COVID-19 and to exploit if TT is involved in promoting IL-10 and HLA-G induction.
ABSTRACT
Background. The impact of COVID-19 has been profound with >170,000,000 confirmed cases worldwide and emerging variants being a cause of global concern. Defects in T-cell function and trafficking have been described among those with severe illness, and immunodeficiency is a risk factor for persistent viral shedding and prolonged symptoms. Because of our prior clinical data demonstrating that allogeneic, off-the-shelf virus-specific T cells (VSTs) can safely and effectively treat viral infections, we investigated the feasibility of targeting COVID-19 using banked, SARS-CoV-2-specific VSTs. Methods. We first screened PBMCs from convalescent individuals against 18 structural and non-structural/accessory (NSPs/APs) SARS-CoV-2 proteins and identified 5 [Spike (S), Membrane (M), Nucleoprotein (N), NSP4, and AP7a] as immunodominant which were then advanced to our VST production process. Results. Using overlapping peptide libraries spanning these antigens as a stimulus, we achieved a mean 7.6±0.9 fold expansion (n=13) of VSTs (96±0.5%), with a mixture of cytotoxic (CD8+) and helper (CD4+) T cells that expressed activation and central/effector memory markers. These VSTs were potent, Th1-polarized and polyfunctional, producing IFNγ, TNFα, GM-CSF and Granzyme B. Moreover, the VSTs were able to kill pepmix-loaded autologous targets with no evidence of auto- or alloreactivity, attesting to their virus selectivity and safety for clinical use (Figure 1). Finally, though initially generated against the reference strain NC-045512.2 (Wuhan), these VSTs were able to recognize other clinically important variants including B1.1.7 (UK), B1.351 (South Africa) and P1 (Brazil). This demonstrates the cross-reactive potential of these polyclonal and diverse VSTs, which were developed to provide potent antiviral effects and minimize the risk of immune escape due to sequence variation. Figure 1: SARS-CoV-2 Specific T cells Have Demonstrated Selective Cytolytic Activity against SARS-CoV-2 While Leaving Non-Virus Infected Targets Intact. Conclusion. In conclusion, it is feasible to generate polyclonal SARS-CoV-2 VSTs that provide coverage against variant strains using GMP-compliant manufacturing methodologies. We have advanced this product to the bedside for administration in a Phase I, randomized clinical trial [VSTs+ standard of care (SOC) vs SOC] in high-risk patients hospitalized with COVID-19 (NCT04401410).