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Globally 58.83% human population received at least one dose of the COVID-19 vaccines as of 5 January 2021. COVID-19 vaccination rollout is progressing at varied rates globally and data on the impact of mass vaccination on infection and case-fatality rates require definition. We compared the global reported cumulative case-fatality rate (rCFR) between top-20 countries with COVID-19 vaccination rates (>125 doses/100 people) and the rest of the world, before and after commencement of vaccination programmes. We considered the 28th day of receiving the first vaccine in the world as a cut-off to compare the pre-vaccine period (Jan 1, 2020 - Jan 5, 2021) and the post-vaccine period (Jan 6, 2021-Jan 5, 2022). We used a Generalized linear mixed model (GLMM) with a beta distribution to investigate the association between the CFR and potential predictors of each country and reported the relative risk (RR) of each variable. The mean rCFR of COVID-19 in the top-20 countries with vaccination rates was 1.83 (95% CI: 1.24-2.43) on 5 Jan 2021 and 1.18 (95% CI: 0.73-1.62) on 5 Jan 2022. The CFR for the rest of the world on 5 Jan 2021 was 2.32 (95% CI: 1.86-2.79) and 2.20 (95% CI: 1.86-2.55) on 5 January 2022. In Sub-Saharan Africa, the CFR remained roughly unchanged at 1.97 (95% CI: 1.59-2.35) on 5 Jan 2021 and 1.98 (95% CI:1.58-2.37) on 5 Jan 2022. The GLMM showed vaccination (/100 population) (RR:0.37) and Stringency Index (RR:0.88) were strong protective factors for the countrys COVID-19 CFR indicating that both vaccination and lockdown measures help in the reduction of COVID-19 CFR. The rCFR of COVID-19 continues to decline, although at a disproportionate rate between top vaccinated countries and the rest of the world. Vaccine equity and faster roll-out across the world is critically important in reducing COVID-19 transmission and CFR. Key Questions What is already knownO_LIVaccination can reduce the case-fatality rate of COVID-19. Globally, the COVID-19 vaccination rollout is progressing at varied rates. C_LI What are the new findingsO_LIIn the top-20 countries with vaccination, >200 doses of vaccines are given per 100 people on 5th Jan 2022, In the rest of the word, the figure is 105, and in Sub-Saharan Africa (SSA) only 15.72 C_LIO_LIAfter the introduction of COVID-19 vaccination the reported case-fatality rate (rCFR) of COVID-19 has reduced by 35% in the top-20 countries with vaccination, 8% in the rest of the world roughly unchanged in SSA. C_LIO_LIThe doses of COVID-19 vaccines (/100 people) and rCFR has a negative correlation on 5 Jan 2022 (r=-0.296, p<0.001). C_LIO_LIThe COVID-19 vaccination and Stringency Index are strong protective factors for the countrys COVID-19 rCFR indicating that both vaccination and lockdown measures help in reduction of COVID-19 rCFR. C_LI What do the new findings implyO_LIThe disproportionate case-fatality rate of COVID-19 between top vaccinated countries and the rest of the world demand fast and equitable vaccine rollout globally to reduce COVID-19 transmission and CFR C_LI
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In the last months, many studies have clearly described several mechanisms of SARS-CoV-2 infection at cell and tissue level. Host conditions and comorbidities were identified as risk factors for severe and fatal disease courses, but the mechanisms of interaction between host and SARS-CoV-2 determining the grade of COVID- 19 severity, are still unknown. We provide a network analysis on protein-protein interactions (PPI) between viral and host proteins to better identify host biological responses, induced by both whole proteome of SARS-CoV-2 and specific viral proteins. A host-virus interactome was inferred on published PPI, using an explorative algorithm (Random Walk with Restart) triggered by all the 28 proteins of SARS-CoV-2, or each single viral protein one-by-one. The functional analysis for all proteins, linked to many aspects of COVID-19 pathogenesis, allows to identify the subcellular districts, where SARS-CoV-2 proteins seem to be distributed, while in each interactome built around one single viral protein, a different response was described, underlining as ORF8 and ORF3a modulated cardiovascular diseases and pro-inflammatory pathways, respectively. Finally, an explorative network-based approach was applied to Bradykinin Storm, highlighting a possible direct action of ORF3a and NS7b to enhancing this condition. This network-based model for SARS-CoV-2 infection could be a framework for pathogenic evaluation of specific clinical outcomes. We identified possible host responses induced by specific proteins of SARS-CoV-2, underlining the important role of specific viral accessory proteins in pathogenic phenotypes of severe COVID-19 patients.
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BACKGROUNDTreatment of severe Corona Virus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC-MSCs) to treat severe COVID-19 patients with lung damage, based on our phase 1 data. METHODSIn this randomized, double-blind, and placebo-controlled trial, we recruited 101 severe COVID-19 patients with lung damage. They were randomly assigned to receive either UC-MSCs (4 x 107 cells per infusion) or placebo on day 0, 3, and 6. The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28. Other imaging outcomes, 6-minute walk test, maximum vital capacity, diffusing capacity, and adverse events were recorded and analysed. RESULTS100 COVID-19 patients were finally recruited to receive either UC-MSCs (n = 65) or placebo (n = 35). UC-MSCs administration exerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo (the median difference was -13.31%, 95%CI -29.14%, 2.13%, P=0.080). UC-MSCs significantly reduced the proportions of solid component lesion volume compared with the placebo (median difference: -15.45%; 95% CI -30.82%, -0.39%; P=0.043). The 6-minute walk test showed an increased distance in patients treated with UC-MSCs (difference: 27.00 m; 95% CI 0.00, 57.00; P=0.057). The incidence of adverse events was similar in the two groups. CONCLUSIONSUC-MSCs treatment is a safe and potentially effective therapeutic approach for COVID-19 patients with lung damage. (Funded by The National Key R&D Program of China and others. ClinicalTrials.gov number, NCT04288102.)
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In COVID-19 caused by SARS-CoV-2 infection, the relationship between disease severity and the host immune response is not fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of five healthy donors and 13 COVID-19 patients including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in COVID-19 patients showed a strong interferon-alpha response, and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4+ Effector-GNLY (Granulysin), CD8+ Effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during the disease progression.
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SARS-CoV-2 is a novel coronavirus, not encountered before by humans. The wide spectrum of clinical expression of SARS-CoV-2 illness suggests that individual immune responses to SARS-CoV-2 play a crucial role in determining the clinical course after first infection. Immunological studies have focussed on patients with moderate to severe disease, demonstrating excessive inflammation in tissues and organ damage. In order to understand the basis of the protective immune response in COVID-19, we performed a longitudinal follow-up, flow-cytometric and serological analysis of innate and adaptive immunity in 64 adults with a spectrum of clinical presentations: 28 healthy SARS-CoV-2-negative contacts of COVID-19 cases; 20 asymptomatic SARS-CoV-2-infected cases; 8 patients with Mild COVID-19 disease and 8 cases of Severe COVID-19 disease. Our data show that high frequency of NK cells and early and transient increase of specific IgA, IgM and, to a lower extent, IgG are associated to asymptomatic SARS-CoV-2 infection. By contrast, monocyte expansion and high and persistent levels of IgA and IgG, produced relatively late in the course of the infection, characterize severe disease. Modest increase of monocytes and different kinetics of antibodies are detected in mild COVID-19. The importance of innate NK cells and the short-lived antibody response of asymptomatic individuals and patients with mild disease suggest that only severe COVID-19 may result in protective memory established by the adaptive immune response.
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BackgroundEpidemiological, virological and pathogenetic characteristics of SARS-CoV-2 infection are under evaluation. A better understanding of the pathophysiology associated with COVID-19 is crucial to improve treatment modalities and to develop effective prevention strategies. Transcriptomic and proteomic data on the host response against SARS-CoV-2 still have anecdotic character; currently available data from other coronavirus infections are therefore a key source of information. MethodsWe investigated selected molecular aspects of three human coronavirus (HCoV) infections, namely SARS-CoV, MERS-CoV and HCoV-229E, through a network based-approach. A functional analysis of HCoV-host interactome was carried out in order to provide a theoretic host-pathogen interaction model for HCoV infections and in order to translate the results in prediction for SARS-CoV-2 pathogenesis. The 3D model of S-glycoprotein of SARS-CoV-2 was compared to the structure of the corresponding SARS-CoV, HCoV-229E and MERS-CoV S-glycoprotein. SARS-CoV, MERS-CoV, HCoV-229E and the host interactome were inferred through published protein-protein interactions (PPI) as well as gene co-expression, triggered by HCoV S-glycoprotein in host cells. ResultsAlthough the amino acid sequences of the S-glycoprotein were found to be different between the various HCoV, the structures showed high similarity, but the best 3D structural overlap shared by SARS-CoV and SARS-CoV-2, consistent with the shared ACE2 predicted receptor. The host interactome, linked to the S-glycoprotein of SARS-CoV and MERS-CoV, mainly highlighted innate immunity pathway components, such as Toll Like receptors, cytokines and chemokines. ConclusionsIn this paper, we developed a network-based model with the aim to define molecular aspects of pathogenic phenotypes in HCoV infections. The resulting pattern may facilitate the process of structure-guided pharmaceutical and diagnostic research with the prospect to identify potential new biological targets.