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1.
Frontiers in microbiology ; 13, 2022.
Article in English | EuropePMC | ID: covidwho-1837508

ABSTRACT

The Coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented public health crisis worldwide. Although several vaccines are available, the global supply of vaccines, particularly within developing countries, is inadequate, and this necessitates a need for the development of less expensive, accessible vaccine options. To this end, here, we used the Escherichia coli expression system to produce a recombinant fusion protein comprising the receptor binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2;residues 319–541) and the fragment A domain of Cross-Reacting Material 197 (CRM197);hereafter, CRMA-RBD. We show that this CRMA-RBD fusion protein has excellent physicochemical properties and strong reactivity with COVID-19 convalescent sera and representative neutralizing antibodies (nAbs). Furthermore, compared with the use of a traditional aluminum adjuvant, we find that combining the CRMA-RBD protein with a nitrogen bisphosphonate-modified zinc-aluminum hybrid adjuvant (FH-002C-Ac) leads to stronger humoral immune responses in mice, with 4-log neutralizing antibody titers. Overall, our study highlights the value of this E. coli-expressed fusion protein as an alternative vaccine candidate strategy against COVID-19.

2.
Cell Reports ; : 110862, 2022.
Article in English | ScienceDirect | ID: covidwho-1821171

ABSTRACT

Summary The rapidly spreading Omicron variant is highly resistant to vaccines, convalescent sera and neutralizing antibodies (nAbs), highlighting the urgent need for potent therapeutic nAbs. Here, a panel of human nAbs from SARS-CoV-2 convalescent patients show diverse neutralization against Omicron, of which XMA01 and XMA04 maintain nanomolar affinities and excellent neutralization (IC50: ∼ 20 ng/ml). nAb XMA09 shows weak but unattenuated neutralization against all VOCs as well as SARS-CoV. Structural analysis reveals that the above three antibodies could synergistically bind to the RBDs of both wild-type and Omicron spikes and defines the critical determinants for nAb-mediated broad neutralizations. Three nAbs confer synergistic neutralization against Omicron, resulting from the inter-antibody interaction between XMA04 and XMA01(or XMA09). Furthermore, the XMA01/XMA04 cocktail provides synergistic protective against Beta and Omicron variants infection in hamsters. In summary, our results provide insights for the rational design of antibody cocktail therapeutics or universal vaccines against Omicron.

3.
International Journal of Infectious Diseases ; 2022.
Article in English | ScienceDirect | ID: covidwho-1804270

ABSTRACT

Background : As several vaccine candidates for SARS-CoV-2 have been developed, a large proportion of people has be vaccinated worldwide so far. The rapid and accurate immunoassays are urgently demanded for detecting specific virus-neutralizing antibody (NAb), which reflect the protective effect of the vaccines among different populations. Methods : In this study, we designed a quantum-dot lateral flow immunoassay strip (QD-LFIA) on smartphone for detection of specific IgG or neutralizing antibodies to SARS-CoV-2 in human serum or whole blood samples. The recombinant receptor binding domain (RBD) of SARS-CoV-2 spike protein was used as the antigen to combine with NAb or angiotensin-converting enzyme 2 (ACE2). Results : Among 81 recovered COVID-19 patients diagnosed with NAT initially, 98.8% (80/81) were positive for IgG and 88.9% (72/81) were positive for NAb by QD-LFIA. Among 64 inactivated vaccine and 6 subunit vaccine inoculated vaccinees, 90% (63/70) were positive for IgG and 82.9% (58/70) were positive for NAb by QD-LFIA, while no cross-reaction was found from 150 healthy blood donor, 2 Flu B and 3 common cold patients. Conclusions : The established platform could achieve a rapid and accurate detection of NAb specific to SARS-CoV-2, which could be used for detecting the protective effect of the vaccines in epidemic areas of world.

4.
International Journal of Biological Macromolecules ; 2022.
Article in English | ScienceDirect | ID: covidwho-1796724

ABSTRACT

SARS-CoV-2 engages with human cells through the binding of its Spike receptor-binding domain (S-RBD) to the receptor ACE2. Molecular blocking of this engagement represents a proven strategy to treat COVID-19. Here, we report a single-chain antibody (nanobody, DL4) isolated from immunized alpaca with picomolar affinity to RBD. DL4 neutralizes SARS-CoV-2 pseudoviruses with an IC50 of 0.101 μg mL−1 (6.2 nM). A crystal structure of the DL4-RBD complex at 1.75-Å resolution unveils the interaction detail and reveals a direct competition mechanism for DL4's ACE2-blocking and hence neutralizing activity. The structural information allows us to rationally design a mutant with higher potency. Our work adds diversity of neutralizing nanobodies against SARS-CoV-2 and should encourage protein engineering to improve antibody affinities in general.

6.
Kidney360 ; 2(6): 996-1001, 2021 Jun 24.
Article in English | MEDLINE | ID: covidwho-1776830

ABSTRACT

Increased risk of SARS-CoV-2 infection was associated with community prevalence.Increased risk of SARS-CoV-2 infection was associated with exposure to infected family members and personal infection prevention measures.


Subject(s)
COVID-19 , COVID-19/epidemiology , Delivery of Health Care , Humans , Outpatients , Renal Dialysis/adverse effects , Risk Factors , SARS-CoV-2
7.
Acta Pharmaceutica Sinica B ; 2022.
Article in English | ScienceDirect | ID: covidwho-1750948

ABSTRACT

T cells, including both CD4+ and CD8+ T cells, play a pivotal role in mediating various inflammation and immune disorders. A long-standing challenge in T cell-based immunotherapy is to precisely inactivate or delete the pathogenic T cells in inflammation and autoimmune diseases, or to selectively expand the immunocompetent T cell in tumor or other immune compromised situations, without inducing global immunosuppression or zealous immune activation respectively. To achieve this, a specific marker is needed to differentiate the pathogenic or immunocompetent T cell among the rests. Indeed, recent progress of immunology strongly suggests that CXC chemokine receptor 6 (CXCR6, CD186) is such a kind of marker. Here, we review the emerging role of CXCR6 as a novel target for immunotherapy and discuss the underlying mechanism. We propose that CXCR6-based immunotherapy will play a significant role in autoimmune, nonalcoholic steatohepatitis (NASH), tumor, coronavirus disease 2019 (COVID-19) and even ageing-related inflammatory infliction.

9.
Chaos Solitons Fractals ; 156: 111825, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1729620

ABSTRACT

As people around the world work to stop the COVID-19 pandemic, mutated COVID-19 (Delta strain) that are more contagious are emerging in many places. How to develop effective and reasonable plans to prevent the spread of mutated COVID-19 is an important issue. In order to simulate the transmission of mutated COVID-19 (Delta strain) in China with a certain proportion of vaccination, we selected the epidemic situation in Jiangsu Province as a case study. To solve this problem, we develop a novel epidemic model with a vaccinated population. The basic properties of the model is analyzed, and the expression of the basic reproduction number R 0 is obtained. We collect data on the Delta strain epidemic in Jiangsu Province, China from July 20, to August 5, 2021. The weighted nonlinear least square estimation method is used to fit the daily asymptomatic infected people, common infected people and severe infected people. The estimated parameter values are obtained, the approximate values of the basic reproduction number are calculated R 0 ≈ 1.378 . Through the global sensitivity analysis, we identify some parameters that have a greater impact on the prevalence of the disease. Finally, according to the evaluation results of parameter influence, we consider three control measures (vaccination, isolation and nucleic acid testing) to control the spread of the disease. The results of the study found that the optimal control measure is to dynamically adjust the three control measures to achieve the lowest number of infections at the lowest cost. The research in this paper can not only enrich theoretical research on the transmission of COVID-19, but also provide reliable control suggestions for countries and regions experiencing mutated COVID-19 epidemics.

10.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-329405

ABSTRACT

Antibody therapeutics for the treatment of COVID-19 has been highly successful while faces a challenge of the recent emergence of the Omicron variant which escapes the majority of existing SARS-CoV-2 neutralizing antibodies (nAbs). Here, we successfully generated a panel of SARS-CoV-2/SARS-CoV cross-neutralizing antibodies by sequential immunization of the two pseudoviruses. Of which, nAbs X01, X10 and X17 showed broadly neutralizing breadths against most variants of concern (VOCs) and X17 was further identified as a Class 5 nAb with undiminished neutralization against the Omicron variant. Cryo-EM structures of three-antibody in complex with the spike proteins of prototyped SARS-CoV-2, Delta, Omicron and SARS-CoV defined three non-overlapping conserved epitopes on the receptor-binding domain (RBD). The triple antibody cocktail exhibited enhanced resistance to viral escape and effective protection against the infection of Beta variant in hamsters. Our finding will aid the development of both antibody therapeutics and broad vaccines against SARS-CoV-2 and emerging variants.

12.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-315306

ABSTRACT

The emergence of numerous variants of SARS-CoV-2, the causative agent of COVID-19, has presented new challenges to the global efforts to control the still ravaging COVID-19 pandemic. Here, we obtain two cross-neutralizing antibodies (7D6 and 6D6) that target Sarbecoviruses’ receptor binding domain (RBD) with sub-picomolar affinities and potently neutralize authentic SARS-CoV-2. Crystal structures show that both antibodies bind a cryptic site different from that recognized by existing antibodies and highly conserved across Sarbecovirus isolates. Binding of these two antibodies to the RBD clashes with the adjacent N-terminal domain and disrupts the viral spike. Significantly, both antibodies confer good mutation resistance to the currently circulating SARS-CoV-2 variants. Thus, our results have direct relevance to public health as options for passive antibody therapeutics and even active prophylactics, and can also inform the design of pan-sarbecovirus vaccines.

13.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-315302

ABSTRACT

Corona Virus Disease 2019 (COVID-19) caused by the emerged coronavirus SARS-CoV-2 is spreading globally. The origin of SARS-Cov-19 and its evolutionary relationship is still ambiguous. Several reports attempted to figure out this critical issue by genome-based phylogenetic analysis, with limited progress. Here we applied phylogenetic supertree analysis to study the origin and evolution of SARS-CoV-2. Phylogenetic supertree analysis firmly disputes the accuracy of bat coronavirus RaTG13 be the last common ancestor of SARS- CoV-2s reported in other phylogenetic tree analysis based on viral genome sequences, although RaTG13 shows 96.5% similarity with SARS-CoV-2 in the genome. Therefore, viewing RaTG13 as the last common ancestor of SARS-CoV-2 would seriously mislead phylogenetic inference of SARS-CoV-2. Importantly, the discovery of evolution and mutation in SARS-CoV-2s was achieved by phylogenetic supertree analysis. Taken together, the phylogenetic supertree showed extraordinary priority on the SARS-CoV-2 evolution inference relative to the normal phylogenetic tree based on full-length genomic sequences.

14.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-313429

ABSTRACT

Accumulating mutations on SARS-CoV-2 Spike (S) protein may increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, in a panel of receptor binding domain (S-RBD) specific monoclonal antibodies (mAbs) with high neutralizing potency against authentic SARS-CoV-2, at least 6 of them were found to efficiently block the pseudovirus of 501Y.V2, a highly transmissible SARS-CoV-2 variant with escape mutations. The top 3 neutralizing Abs (13G9, 58G6 and 510A5) exhibited comparative ultrapotency as those being actively pursued for clinical development. Interestingly, the antigenic sites for the majority of our neutralizing Abs overlapped with a single epitope (13G9e) on S-RBD. Further, the 3-dimensional structures of 2 ultrapotent neutralizing Abs 13G9 or 58G6 in complex with SARS-CoV-2 S trimer demonstrated that both Abs bound to a steric region within S 472–490 . Moreover, a specific linear region (S 450–457 ) was identified as an additional target for 58G6. Importantly, our cryo-electron microscopy (cryo-EM) analysis revealed a unique phenomenon that the S-RBDs interacting with the fragments of antigen binding (Fabs) of 13G9 or 58G6 encoded by the IGHV1-58 and the IGKV3-20 gene segments were universally in the ‘up’ conformation in all observed particles. The potent neutralizing Abs presented in the current study may be promising candidates to fulfill the urgent needs for the current pandemic of SARS-CoV-2, and may of fundamental value for the next-generation vaccine development.

15.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-311951

ABSTRACT

After the epidemic of COVID-19, neutralizing antibodies (NAbs) against SARS-CoV-2 has been developed for the preventative and therapeutic purposes. However, few methodologies are reported in detail on how to rapidly and efficiently generate NAbs of interest. Here, we present a strategically optimized screening method for NAbs, which has enabled us to obtain SARS-CoV-2 receptor-binding domain (RBD) specific monoclonal Abs within 4 days, followed by additional 2 days to evaluate their neutralizing activities. Using this method, we obtained 198 specific Abs against SARS-CoV-2 RBD from the blood samples of COVID-19 convalescent patients, and 96 of them showed neutralizing activity. At least 20% of these NAbs exhibited high neutralizing potency. The top 2 NAbs showed the half-maximal inhibitory concentration (IC50) to block authentic SARS-CoV-2 at 9.88 and 11.13 ng/ml, respectively. Altogether, our study provides a fundamental methodology for discovering NAbs with potential preventative and therapeutic value for emerging infectious diseases.

16.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-310876

ABSTRACT

Objective: Exploring the relationship between diabetes mellitus targets and DPP4 of the receptor of novel coronavirus (2019-nCoV) through a protein interaction network to provide new perspective for clinical medication. Methods: : Diabetes mellitus targets were obtained from GeneCards database. Targets with a relevance score exceeding 20 were included, and DPP4 protein was added manually. The initial protein interaction network was obtained through String. The targets directly related to DPP4 were selected as the final analysis targets. Importing them into String again to obtain the protein interaction network. Module identification, GO analysis and KEGG pathway analysis were carried out respectively. The impact of DPP4 on the whole network was analyzed by scoring the module where it located. Results: : 43 DPP4-related proteins were finally selected from the diabetes mellitus targets and three functional modules were found by the cluster analysis. Module 1 was involved in insulin secretion and glucagon signaling pathway, module 2 and module 3 were involved in signaling receptor binding. The scoring results showed that LEP and apoB in module 1 were the highest, and the scores of INS, IL6 and ALB of cross module associated proteins of module 1 were the highest. Conclusions: : DPP4 is widely associated with key proteins in diabetes mellitus. COVID-19 may affect DPP4 in patients with diabetes mellitus, leading to high mortality of diabetes mellitus combined with COVID-19. DPP4 inhibitors and IL-6 antagonists can be considered to reduce the effect of COVID-19 infection on diabetic patients.

17.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-309724

ABSTRACT

Background: COVID-19 showed a significant difference in case fatality rate between different regions at the early stage of the epidemic. In addition to the well-known factors such as age structure, detection efficiency, and race, there was also a possibility that medical resource shortage caused the increase of the case fatality rate in some regions. Methods: : Medline, Cochrane Library, Embase, Web of Science, CBM, CNKI, and Wan fang of identified articles were searched through 29 June 2020. Cohort studies and case series with duration information on COVID-19 patients were included. Two independent reviewers extracted the data using a standardized data collection form and assessed the risk of bias. Data were synthesized through description and analysis methods including a meta-analysis. Results: : A total of 109 articles were retrieved. The time interval from onset to the first medical visit of COVID-19 patients in China was 3.38±1.55 days (corresponding intervals in Hubei province, non-Hubei provinces, Wuhan, Hubei provinces without Wuhan were 4.22±1.13 days, 3.10±1.57 days, 4.20±0.97 days, and 4.34±1.72 days, respectively). The time interval from onset to the hospitalization of COVID-19 patients in China was 8.35±6.83 days (same corresponding intervals were 12.94±7.43 days, 4.17±1.45 days, 14.86±7.12 days, and 5.36±1.19 days, respectively), and when it was outside China, this interval was 5.27±1.19 days. Conclusion: In the early stage of the COVID-19 epidemic, patients with COVID-19 did not receive timely treatment, resulting in a higher case fatality rate in Hubei province, partly due to the relatively insufficient and unequal medical resources. This research suggested that additional deaths caused by the out-of-control epidemic can be avoided if prevention and control work is carried out at the early stage of the epidemic. PROSPERO registration number CRD42020195606.

18.
Chaos, solitons, and fractals ; 2022.
Article in English | EuropePMC | ID: covidwho-1661240

ABSTRACT

As people around the world work to stop the COVID-19 pandemic, mutated COVID-19 (Delta strain) that are more contagious are emerging in many places. How to develop effective and reasonable plans to prevent the spread of mutated COVID-19 is an important issue. In order to simulate the transmission of mutated COVID-19 (Delta strain) in China with a certain proportion of vaccination, we selected the epidemic situation in Jiangsu Province as a case study. To solve this problem, we develop a novel epidemic model with a vaccinated population. The basic properties of the model is analyzed, and the expression of the basic reproduction number

19.
Sci Rep ; 12(1): 188, 2022 01 07.
Article in English | MEDLINE | ID: covidwho-1612207

ABSTRACT

Patients with diabetes are more likely to be infected with Coronavirus disease 2019 (COVID-19), and the risk of death is significantly higher than ordinary patients. Dipeptidyl peptidase-4 (DPP4) is one of the functional receptor of human coronavirus. Exploring the relationship between diabetes mellitus targets and DPP4 is particularly important for the management of patients with diabetes and COVID-19. We intend to study the protein interaction through the protein interaction network in order to find a new clue for the management of patients with diabetes with COVID-19. Diabetes mellitus targets were obtained from GeneCards database. Targets with a relevance score exceeding 20 were included, and DPP4 protein was added manually. The initial protein interaction network was obtained through String. The targets directly related to DPP4 were selected as the final analysis targets. Importing them into String again to obtain the protein interaction network. Module identification, gene ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were carried out respectively. The impact of DPP4 on the whole network was analyzed by scoring the module where it located. 43 DPP4-related proteins were finally selected from the diabetes mellitus targets and three functional modules were found by the cluster analysis. Module 1 was involved in insulin secretion and glucagon signaling pathway, module 2 and module 3 were involved in signaling receptor binding. The scoring results showed that LEP and apoB in module 1 were the highest, and the scores of INS, IL6 and ALB of cross module associated proteins of module 1 were the highest. DPP4 is widely associated with key proteins in diabetes mellitus. COVID-19 may affect DPP4 in patients with diabetes mellitus, leading to high mortality of diabetes mellitus combined with COVID-19. DPP4 inhibitors and IL-6 antagonists can be considered to reduce the effect of COVID-19 infection on patients with diabetes.


Subject(s)
COVID-19/metabolism , Diabetes Mellitus, Type 2/metabolism , Dipeptidyl Peptidase 4/metabolism , Protein Interaction Maps , SARS-CoV-2/physiology , COVID-19/complications , COVID-19/drug therapy , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Drug Discovery , Humans , Protein Interaction Maps/drug effects
20.
Mathematical Methods in the Applied Sciences ; n/a(n/a), 2021.
Article in English | Wiley | ID: covidwho-1588998

ABSTRACT

As the first-wave COVID-19 has passed in 2020, people's awareness of self-protection began to decline gradually. How to prevent and control the second-wave COVID-19 has become an important issue in many countries and regions. By analyzing the transmission of the second-wave COVID-19 caused by an imported case in Tonghua City, Jilin Province, China, in January 2021, we establish a new mathematical COVID-19 model to simulate the transmission characteristics of the second-wave COVID-19. First, we analyze the basic properties of the model, prove the existence of the equilibrium point, and obtain the expression of the basic reproduction number with important biological significance. Secondly, we use the weighted nonlinear least square estimation method to fit the cases in Tonghua City of Jilin Province in January 2021, and get the estimated value of the parameters. The basic reproduction number of the second-wave COVID-19 in Tonghua City is R0=1.0695, which is much smaller than that of the first-wave COVID-19 in Wuhan in 2020. Finally, in the optimal control part, we consider two control methods (keeping social distance and nucleic acid detection of all people in the city) to simulate the control of the disease. The results show that the control intensity of the two control methods needs to be dynamically changed and adjusted, so that the cost can be minimized with the least infection. The results of this paper can not only provide suggestions for health management departments, but also provide a reference for the analysis of the second-wave COVID-19 in other countries or regions.

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