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2.
Journal of inflammation research ; 15:3467-3475, 2022.
Article in English | EuropePMC | ID: covidwho-1898370

ABSTRACT

Purpose To detect antibody responses to inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in patients undergoing hemodialysis and to investigate vaccine-related adverse events. Patients and Methods A total of 120 hemodialysis (HD) patients and 24 healthy controls (HCs) who had not been previously infected with SARS-CoV-2 and had received their first dose of the inactivated vaccine (CoronaVac;Sinovac Biotech Ltd) were recruited for this study. All participants were scheduled to receive a second dose of inactivated SARS-CoV-2 vaccine. Serum-specific immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies against the SARS-CoV-2 were detected at least 14 days after the second dose of vaccine using a commercial kit. Positive and negative results were defined as a sample/cutoff (S/CO) ratio≥1.00 and <1.00, respectively. Vaccination-related adverse events were assessed using a standardized questionnaire. Results There were no significant differences regarding the seroprevalences of IgG and IgM antibodies against SARS-CoV-2 and the self-reported vaccination-related adverse events between HD patients and HCs. The analysis results for HD patients suggest that 82 (68.3%) and 27 (22.5%) tested positive for IgG and IgM, respectively. The levels of IgG were higher than IgM levels (P<0.0001). In addition, the IgG-positive group had significantly higher serum albumin levels than the IgG-negative group (P<0.05). Only mild vaccine-related adverse events were observed in two patients (1.66%) and in one healthy individual (4.2%). Conclusion The seroprevalences of IgG and IgM antibodies against SARS-CoV-2 and vaccination-related adverse effects are similar between HD and HCs. The inactivated SARS-CoV-2 vaccine is effective and safe in inducing near-term immunity in hemodialysis patients.

3.
International journal of clinical practice ; 2022, 2022.
Article in English | EuropePMC | ID: covidwho-1888332

ABSTRACT

Aim To explore the potential relationship between NLR and micronutrient deficiency in patients with severe COVID-19 infection. Methods Sixteen patients were categorized into the mild group (mild COVID-19) and severe group (severe COVID-19) based on the guideline of the management of COVID-19. The lactate dehydrogenase (LDH);superoxide dismutase (SOD), the inflammatory markers (neutrophil lymphocyte ratio (NLR)), erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), selenium (Se), iron (Fe), zinc (Zn), nickel (Ni), copper (Cu), chromium (Cr), cadmium (Cd), arsenic (As), and manganese (Mn) were measured in the blood. Results Compared to the mild group, the NLR (P < 0.05) and the level of Se (P < 0.01), Fe (P < 0.05), and Zn (P < 0.05) were significantly decreased in the severe group. The level of Se, Fe, and Zn was significantly correlated to NLR levels. Furthermore, close positive correlation was found between NLR and severity of COVID-19. Conclusion The micronutrient deficiency in the blood is associated with NLR in the severity of COVID-19 patients.

4.
Front Immunol ; 13: 838132, 2022.
Article in English | MEDLINE | ID: covidwho-1809394

ABSTRACT

The majority of COVID-19 patients experience mild to moderate disease course and recover within a few weeks. An increasing number of studies characterized the long-term changes in the specific anti-SARS-CoV-2 immune responses, but how COVID-19 shapes the innate and heterologous adaptive immune system after recovery is less well known. To comprehensively investigate the post-SARS-CoV-2 infection sequelae on the immune system, we performed a multi-omics study by integrating single-cell RNA-sequencing, single-cell ATAC-sequencing, genome-wide DNA methylation profiling, and functional validation experiments in 14 convalescent COVID-19 and 15 healthy individuals. We showed that immune responses generally recover without major sequelae after COVID-19. However, subtle differences persist at the transcriptomic level in monocytes, with downregulation of the interferon pathway, while DNA methylation also displays minor changes in convalescent COVID-19 individuals. However, these differences did not affect the cytokine production capacity of PBMCs upon different bacterial, viral, and fungal stimuli, although baseline release of IL-1Ra and IFN-γ was higher in convalescent individuals. In conclusion, we propose that despite minor differences in epigenetic and transcriptional programs, the immune system of convalescent COVID-19 patients largely recovers to the homeostatic level of healthy individuals.


Subject(s)
COVID-19 , Convalescence , Disease Progression , Humans , Leukocytes, Mononuclear , SARS-CoV-2
5.
Preprint in English | bioRxiv | ID: ppbiorxiv-448958

ABSTRACT

The spike (S) protein receptor-binding domain (RBD) of SARS-CoV-2 is an attractive target for COVID-19 vaccine developments, which naturally exists in a trimeric form. Here, guided by structural and computational analyses, we present a mutation-integrated trimeric form of RBD (mutI tri-RBD) as a broadly protective vaccine candidate, in which three RBDs were individually grafted from three different circulating SARS-CoV-2 strains including the prototype, Beta (B.1.351) and Kappa (B.1.617). The three RBDs were then connected end-to-end and co-assembled to possibly mimic the native trimeric arrangements in the natural S protein trimer. The recombinant expression of the mutI tri-RBD, as well as the homo-tri-RBD where the three RBDs were all truncated from the prototype strain, by mammalian cell exhibited correct folding, strong bio-activities, and high stability. The immunization of both the mutI tri-RBD and homo-tri-RBD plus aluminum adjuvant induced high levels of specific IgG and neutralizing antibodies against the SARS-CoV-2 prototype strain in mice. Notably, regarding to the "immune-escape" Beta (B.1.351) variant, mutI tri-RBD elicited significantly higher neutralizing antibody titers than homo-tri-RBD. Furthermore, due to harboring the immune-resistant mutations as well as the evolutionarily convergent hotspots, the designed mutI tri-RBD also induced strong broadly neutralizing activities against various SARS-CoV-2 variants, especially the variants partially resistant to homo-tri-RBD. Homo-tri-RBD has been approved by the China National Medical Products Administration to enter clinical trial (No. NCT04869592), and the superior broad neutralization performances against SARS-CoV-2 support the mutI tri-RBD as a more promising vaccine candidate for further clinical developments.

6.
Preprint in English | medRxiv | ID: ppmedrxiv-20248602

ABSTRACT

BackgroundA safe and effective coronavirus disease 2019 (COVID-19) vaccine is urgently needed to control the ongoing pandemic. Although progress has been made recently with several candidates reporting positive efficacy results, COVID-19 vaccines developed so far cannot meet the global vaccine demand. We developed a protein subunit vaccine against COVID-19, using dimeric form of receptor-binding domain (RBD) as the antigen. We aimed to assess the safety and immunogenicity of this vaccine in humans and determine the appropriate dose and schedule for an efficacy study. MethodsWe did two randomized, double-blind, placebo-controlled, phase 1 and 2 trials for an RBD-based protein subunit vaccine, ZF2001. In phase 1 study, 50 healthy adults aged 18-59 years were enrolled and randomly allocated to three groups to receive three doses of vaccine (25 g or 50 g RBD-dimer, with adjuvant) or placebo (adjuvant-only) intramuscularly, 30 days apart. In phase 2 study, 900 healthy adults aged 18-59 years were enrolled and randomly allocated to six groups to receive vaccine (25 g or 50 g RBD-dimer, with adjuvant) or placebo (adjuvant-only) intramuscularly, with the former 3 groups given two doses and the latter 3 groups given three doses, 30 days apart. For phase 1 trial, the primary outcome was safety, as measured by the occurrence of adverse events and serious adverse events. The secondary outcome was immunogenicity as measured by the seroconversion rate and magnitude of antigen-binding antibodies, neutralizing antibodies and T-cell cytokine production. For phase 2 trial, the primary outcome included both safety and immunogenicity. These trials are registered with ClinicaTrials.gov, NCT04445194 and NCT04466085. FindingsBetween June 22 and September 15, 2020, 50 participants were enrolled to the phase 1 study (mean age 32.6 years) and 900 participants were enrolled to phase 2 study (mean age 43.5 years), to receive vaccine or placebo with a two-dose or three-dose schedule. For both trials, local and systemic adverse reactions were absent or mild in most participants. There were no serious adverse events related to vaccine in either trial. After three doses, neutralizing antibodies were detected in all participants receiving either 25 g or 50 g dose of vaccine in phase 1 study, and in 97% (the 25 g group) and 93% (the 50 g group) of participants, respectively, in phase 2 study. The SARS-CoV-2-neutralizing geometric mean titres (GMTs) were 94.5 for the 25 g group and 117.8 for the 50 g group in phase 1, and 102.5 for the 25 g group and 69.1 for the 50 g group in phase 2, exceeding the level of a panel of COVID-19 convalescent samples (GMT, 51). Vaccine induced balanced TH1 and TH2 responses. The 50 g group did not show enhanced immunogenicity compared with the 25 g group. InterpretationThe protein subunit vaccine ZF2001 is well-tolerated and immunogenic. The safety and immunogenicity data from phase 1 and 2 trials for ZF2001 support the use of 25 g vaccine dose with three-dose schedule to an ongoing phase 3 large-scale evaluation for safety and efficacy. FundingNational Program on Key Research Project of China, National Science and Technology Major Projects of Drug Discovery, Strategic Priority Research Program of the Chinese Academy of Sciences, and Anhui Zhifei Longcom Biopharmaceutical.

7.
Preprint in English | bioRxiv | ID: ppbiorxiv-402339

ABSTRACT

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to infect people globally. The increased COVID-19 cases and no licensed vaccines highlight the need to develop safe and effective vaccines against SARS-CoV-2 infection. Multiple vaccines candidates are under pre-clinical or clinical trails with different strengths and weaknesses. Here we developed a pilot scale production of a recombinant subunit vaccine (RBD-Fc Vacc) with the Receptor Binding Domain of SARS-CoV-2 S protein fused with the Fc domain of human IgG1. RBD-Fc Vacc induced SARS-CoV-2 specific neutralizing antibodies in non-human primates and human ACE2 transgenic mice. The antibodies induced in macaca fascicularis neutralized three divergent SARS-CoV2 strains, suggesting a broader neutralizing ability. Three times immunizations protected Macaca fascicularis (20ug or 40ug per dose) and mice (10ug or 20ug per dose) from SARS-CoV-2 infection respectively. These data support clinical development of SARS-CoV-2 vaccines for humans. RBD-Fc Vacc is currently being assessed in randomized controlled phase 1/II human clinical trails. SummaryThis study confirms protective efficacy of a SARS-CoV-2 RBD-Fc subunit vaccine.

8.
Preprint in English | bioRxiv | ID: ppbiorxiv-323915

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 pandemic. Computer simulations of complete viral particles can provide theoretical insights into large-scale viral processes including assembly, budding, egress, entry, and fusion. Detailed atomistic simulations, however, are constrained to shorter timescales and require billion-atom simulations for these processes. Here, we report the current status and on-going development of a largely "bottom-up" coarse-grained (CG) model of the SARS-CoV-2 virion. Structural data from a combination of cryo-electron microscopy (cryo-EM), x-ray crystallography, and computational predictions were used to build molecular models of structural SARS-CoV-2 proteins, which were then assembled into a complete virion model. We describe how CG molecular interactions can be derived from all-atom simulations, how viral behavior difficult to capture in atomistic simulations can be incorporated into the CG models, and how the CG models can be iteratively improved as new data becomes publicly available. Our initial CG model and the detailed methods presented are intended to serve as a resource for researchers working on COVID-19 who are interested in performing multiscale simulations of the SARS-CoV-2 virion. Significance StatementThis study reports the construction of a molecular model for the SARS-CoV-2 virion and details our multiscale approach towards model refinement. The resulting model and methods can be applied to and enable the simulation of SARS-CoV-2 virions.

9.
Christoph Muus; Malte D Luecken; Gokcen Eraslan; Avinash Waghray; Graham Heimberg; Lisa Sikkema; Yoshihiko Kobayashi; Eeshit Dhaval Vaishnav; Ayshwarya Subramanian; Christopher Smillie; Karthik Jagadeesh; Elizabeth Thu Duong; Evgenij Fiskin; Elena Torlai Triglia; Christophe Becavin; Meshal Ansari; Peiwen Cai; Brian Lin; Justin Buchanan; Jian Shu; Adam L Haber; Hattie Chung; Daniel T Montoro; Taylor Adams; Hananeh Aliee; Samuel J Allon; Zaneta Andrusivova; Ilias Angelidis; Orr Ashenberg; Kevin Bassler; Inbal Benhar; Joseph Bergenstrahle; Ludvig Bergenstrahle; Liam Bolt; Emelie Braun; Linh T Bui; Mark Chaffin; Evgeny Chichelnitskiy; Joshua Chiou; Thomas M Conlon; Michael S Cuoco; Marie Deprez; David S Fischer; Astrid Gillich; Joshua Gould; Austin J Gutierrez; Arun C Habermann; Tyler Harvey; Peng He; Xiaomeng Hou; Lijuan Hu; Alok Jaiswal; Peiyong Jiang; Theodoros Kapellos; Christin S Kuo; Ludvig Larsson; Michael A Leney-Greene; Kyungtae Lim; Monika Litvinukova; Ji Lu; Leif S Ludwig; Wendy Luo; Henrike Maatz; Elo Maddissoon; Lira Mamanova; Kasidet Manakongtreecheep; Ian Mbano; Alexi M McAdams; Ross J Metzger; Ahmad N Nabhan; Sarah K Nyquist; Jose Ordovas-Montanes; Lolita Penland; Olivier B Poirion; Segio Poli; CanCan Qi; Daniel Reichart; Ivan Rosas; Jonas Schupp; Rahul Sinha; Rene V Sit; Kamil Slowikowski; Michal Slyper; Neal Smith; Alex Sountoulidis; Maximilian Strunz; Dawei Sun; Carlos Talavera-Lopez; Peng Tan; Jessica Tantivit; Kyle J Travaglini; Nathan R Tucker; Katherine Vernon; Marc H Wadsworth III; Julia Waldman; Xiuting Wang; Wenjun Yan; Ali Onder Yildirim; William Zhao; Carly G K Ziegler; Aviv Regev; - The NHLBI LungMAP Consortium; - The Human Cell Atlas Lung Biological Network.
Preprint in English | bioRxiv | ID: ppbiorxiv-049254

ABSTRACT

The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, creates an urgent need for identifying molecular mechanisms that mediate viral entry, propagation, and tissue pathology. Cell membrane bound angiotensin-converting enzyme 2 (ACE2) and associated proteases, transmembrane protease serine 2 (TMPRSS2) and Cathepsin L (CTSL), were previously identified as mediators of SARS-CoV2 cellular entry. Here, we assess the cell type-specific RNA expression of ACE2, TMPRSS2, and CTSL through an integrated analysis of 107 single-cell and single-nucleus RNA-Seq studies, including 22 lung and airways datasets (16 unpublished), and 85 datasets from other diverse organs. Joint expression of ACE2 and the accessory proteases identifies specific subsets of respiratory epithelial cells as putative targets of viral infection in the nasal passages, airways, and alveoli. Cells that co-express ACE2 and proteases are also identified in cells from other organs, some of which have been associated with COVID-19 transmission or pathology, including gut enterocytes, corneal epithelial cells, cardiomyocytes, heart pericytes, olfactory sustentacular cells, and renal epithelial cells. Performing the first meta-analyses of scRNA-seq studies, we analyzed 1,176,683 cells from 282 nasal, airway, and lung parenchyma samples from 164 donors spanning fetal, childhood, adult, and elderly age groups, associate increased levels of ACE2, TMPRSS2, and CTSL in specific cell types with increasing age, male gender, and smoking, all of which are epidemiologically linked to COVID-19 susceptibility and outcomes. Notably, there was a particularly low expression of ACE2 in the few young pediatric samples in the analysis. Further analysis reveals a gene expression program shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues, including genes that may mediate viral entry, subtend key immune functions, and mediate epithelial-macrophage cross-talk. Amongst these are IL6, its receptor and co-receptor, IL1R, TNF response pathways, and complement genes. Cell type specificity in the lung and airways and smoking effects were conserved in mice. Our analyses suggest that differences in the cell type-specific expression of mediators of SARS-CoV-2 viral entry may be responsible for aspects of COVID-19 epidemiology and clinical course, and point to putative molecular pathways involved in disease susceptibility and pathogenesis.

10.
Chinese Journal of Infectious Diseases ; (12): E015-E015, 2020.
Article in Chinese | WPRIM (Western Pacific), WPRIM (Western Pacific) | ID: covidwho-6385

ABSTRACT

Objective@#To observe theepidemiology, clinical manifestations, laboratory tests, imaging findings, treatment and prognosis of patients with novel coronavirus pneumonia.@*Methods@#Clinical data of 109 patients with suspected and definite novel coronavirus pneumonia admitted to Wuhan Sixth Hospital from December 24, 2019 to January 28, 2020 were retrospectively analyzed. Statistical analysiswas performed by using t test or chi-square test.@*Results@#Among the 109 patients, 48 (44%) were male and 61 (56%) were female, with the average age of (52.5±10.8) years. Fifty-four patients (49.5%) had definite contact history. Among the 109 patients, 104 (95.5%) presentedwith fever, 37(33.7%) with headache, 78 (71.9%) with general pain, 88 (80.8%) with fatigue and poor appetite, 23 (21.3%) with diarrhea, 94 (86.5%) withcoughing, 23 (21.3%) with shortness of breath, 57 (52.8%) withpalpitation, 45 (41.5%) with chest distress, 4 (3.3%) with chest pain, 40 (37.0%) with lung rales. Forty-two cases (38.5%) had leukocyte count <4×109/L, 58 cases (53.2%) had lymphocyte count <1.5×109/L, 7 cases (24.8%) had hemoglobin <120g/L, 37 cases(33.9%) had LDH >230 mmol/L, 29 cases (26.6%) had brain natriuretic peptide precursor>300 ng/mL, 87 cases (79.8%) had hypersensitive C-reactive protein >10mg/L, 26 cases (23.9%) had D-dimer >0.5 mg/L, 35 cases (32.1%) had coagulation disorder. The leukocyte counts, LDH, brain natriuretic peptide precursor and D-dimer of severe/critical cases[(11.33±4.87)×109/L, (527.51±260.87) mmol/L, (722.88±189.56) ng/mL, (1.89±4.24) mg/L, respectively] were all significantly higher than those of common cases [(4.02±1.49)×109/L, (159.75±30.31)mmol/L, (428.22±124.76)ng/mLand (0.41±0.22)mg/L, respectively], while the lymphocyte count of severe/critical cases [(0.60±0.17)×109/L] was significantly lower than common cases [(1.13±0.43)×109/L] (t=11.36, 11.33,9.81,2.81 and 7.77,all P<0.05). On admission, chest CT showed that 27 cases (24.8%) of pneumonia were unilateral, 82 cases (75.2%) werebilateral, and most of them were ground glass. The pneumonia progressed in a short time and reached the peak within 10 days. The comprehensive treatment included antiviral drugs, prevention ofbacterialinfection and supportive treatment, and glucocorticoid and respiratory support treatment wereadministrated when necessary.@*Conclusions@#The novel coronavirus pneumonia is characterized by highly infectious, rapid progress, and diverse clinical and imaging features. Early diagnosis and active comprehensive treatment could improve theprognosis and reduce themortality.

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