Background:The aim was to elucidate the function of IL-37 in middle east respiratory syndrome coronavirus(MERS-CoV)infection,thereby providing a novel therapeutic strategy for managing the clinical treatment of inflam...Background:The aim was to elucidate the function of IL-37 in middle east respiratory syndrome coronavirus(MERS-CoV)infection,thereby providing a novel therapeutic strategy for managing the clinical treatment of inflammatory response caused by respiratory virus infection.Methods:We investigated the development of MERS by infecting hDPP4 mice with hCoV-EMC(107 TCID50[50%tissue culture infectious dose])intranasally.We infected A549 cells with MERS-CoV,which concurrently interfered with IL-37,detecting the viral titer,viral load,and cytokine expression at certain points postinfection.Meanwhile,we administered IL-37(12.5μg/kg)intravenously to hDPP4 mice 2 h after MERS-CoV-2 infection and collected the serum and lungs 5 days after infection to investigate the efficacy of IL-37 in MERS-CoV infection.Results:The viral titer of MERS-CoV-infected A549 cells interfering with IL-37 was significantly reduced by 4.7-fold,and the viral load of MERS-CoV-infected hDPP4 mice was decreased by 59-fold in lung tissue.Furthermore,the administration of IL-37 suppressed inflammatory cytokine and chemokine(monocyte chemoattractant protein 1,interferon-γ,and IL-17A)expression and ameliorated the infiltration of inflammatory cells in hDPP4 mice.Conclusion:IL-37 exhibits protective properties in severe pneumonia induced by MERS-CoV infection.This effect is achieved through attenuation of lung viral load,suppression of inflammatory cytokine secretion,reduction in inflammatory cell infiltration,and mitigation of pulmonary injury.展开更多
Background:New variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continue to drive global epidemics and pose significant health risks.The pathogenicity of these variants evolves under immune press...Background:New variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continue to drive global epidemics and pose significant health risks.The pathogenicity of these variants evolves under immune pressure and host factors.Understanding these changes is crucial for epidemic control and variant research.Methods:Human angiotensin-converting enzyme 2(hACE2)transgenic mice were in-tranasally challenged with the original strain WH-09 and the variants Delta,Beta,and Omicron BA.1,while BALB/c mice were challenged with Omicron subvariants BA.5,BF.7,and XBB.1.To compare the pathogenicity differences among variants,we con-ducted a comprehensive analysis that included clinical symptom observation,meas-urement of viral loads in the trachea and lungs,evaluation of pulmonary pathology,analysis of immune cell infiltration,and quantification of cytokine levels.Results:In hACE2 mice,the Beta variant caused significant weight loss,severe lung inflammation,increased inflammatory and chemotactic factor secretion,greater mac-rophage and neutrophil infiltration in the lungs,and higher viral loads with prolonged shedding duration.In contrast,BA.1 showed a significant reduction in pathogenicity.The BA.5,BF.7,and XBB.1 variants were less pathogenic than the WH-09,Beta,and Delta variants when infected in BALB/c mice.This was evidenced by reduced weight loss,diminished pulmonary pathology,decreased secretion of inflammatory factors and chemokines,reduced macrophage and neutrophil infiltration,as well as lower viral loads in both the trachea and lungs.Conclusion:In hACE2 mice,the Omicron variant demonstrated the lowest pathogenic-ity,while the Beta variant exhibited the highest.Pathogenicity of the Delta variant was comparable to the original WH-09 strain.Among BALB/c mice,Omicron subvari-ants BA.5,BF.7,and XBB.1 showed no statistically significant differences in virulence.展开更多
Background:The Omicron(B.1.1.529)SARS-COV-2 variant has raised serious concerns because of its unprecedented rapid rate of spreading and the fact that there are 36 mutations in the spike protein.Since the vaccine-indu...Background:The Omicron(B.1.1.529)SARS-COV-2 variant has raised serious concerns because of its unprecedented rapid rate of spreading and the fact that there are 36 mutations in the spike protein.Since the vaccine-induced neutralizing antibody targets are the spike protein,this may lead to the possibility of vaccine-induced hu-moral immunity escape.Methods:We measured the neutralizing activity in vitro for Omicron and compared this with wild type(WH-09)and Delta variants in human and monkey sera from different types of immunity.The monkey sera samples were collected at 1 and 3 months post three-dose inactivated(PiCoVacc)and recombinant protein(ZF2001)vaccination.Human sera were collected from 1 month post three-dose inactivated vaccination.Results:In inactivated vaccine sera,at 1/3 months post three-dose,geometric mean titers(GMTs)of neutralization antibody(NAb)against the Omicron variant were 4.9/5.2-fold lower than those of the wild type.In recombinant protein vaccine sera,GMTs of NAb against Omicron were 15.7/8.9-fold lower than those of the wild type.In human sera,at 1 month post three-dose inactivated vaccination,GMTs of NAb against Omicron were 3.1-fold lower than those of the wild type.Conclusion:This study demonstrated that despite a reduction in neutralization titers,cross-neutralizing activity against Omicron and Delta variants was still observed after three doses of inactivated and recombinant protein vaccination.展开更多
Background:New Omicron subvariants are emerging rapidly from BA.1 to BA.4 and BA.5.Their pathogenicity has changed from that of wild-type(WH-09)and Omicron variants have over time become globally dominant.The spike pr...Background:New Omicron subvariants are emerging rapidly from BA.1 to BA.4 and BA.5.Their pathogenicity has changed from that of wild-type(WH-09)and Omicron variants have over time become globally dominant.The spike proteins of BA.4 and BA.5 that serve as the target for vaccine-induced neutralizing antibodies have also changed compared to the previous subvariants,which is likely to cause immune es-cape and the reduction of the protective effect of the vaccine.Our study addresses the above issues and provides a basis for formulating relevant prevention and control strategies.Methods:We collected cellular supernatant and cell lysates and measured the viral titers,viral RNA loads,and E subgenomic RNA(E sgRNA)loads in different Omicron subvariants grown in Vero E6 cells,using WH-09 and Delta variants as a reference.Additionally,we evaluated the in vitro neutralizing activity of different Omicron sub-variants and compared it to the WH-09 and Delta variants using macaque sera with different types of immunity.Results:As the SARS-CoV-2 evolved into Omicron BA.1,the replication ability in vitro began to decrease.Then with the emergence of new subvariants,the replication ability gradually recovered and became stable in the BA.4 and BA.5 subvariants.In WH-09-inactivated vaccine sera,geometric mean titers of neutralization antibodies against different Omicron subvariants declined by 3.7~15.4-fold compared to those against WH-09.In Delta-inactivated vaccine sera,geometric mean titers of neutrali-zation antibodies against Omicron subvariants declined by 3.1~7.4-fold compared to those against Delta.Conclusion:According to the findings of this research,the replication efficiency of all Omicron subvariants declined compared with WH-09 and Delta variants,and was lower in BA.1 than in other Omicron subvariants.After two doses of inactivated(WH-09 or Delta)vaccine,cross-neutralizing activities against various Omicron subvariants were seen despite a decline in neutralizing titers.展开更多
Dear Editor,The case fatality rate of early SARS-CoV-2 infection is 3%(Ghebreyesus,2020),and the severe case rate is 24.3%(Sun et al.,2020).From the prototypic SARS-CoV-2 strain to the emergence of Alpha,Beta,and Delt...Dear Editor,The case fatality rate of early SARS-CoV-2 infection is 3%(Ghebreyesus,2020),and the severe case rate is 24.3%(Sun et al.,2020).From the prototypic SARS-CoV-2 strain to the emergence of Alpha,Beta,and Delta variants,which ultimately led to the outbreak of Omicron variants,these strains have undergone a series of evolutionary changes.Starting from BA.1,BA.2,BA.4,and BA.5 lineage to XBB lineage before branching out into the current dominant JN.1 lineage.展开更多
The global spread of Severe Acute Respiratory Syndrome Coronavirus 2.(SARS-CoV-2)and its variant strains,including Alpha,Beta,Gamma,Delta,and now Omicron,pose a significant challenge.With the constant evolution of the...The global spread of Severe Acute Respiratory Syndrome Coronavirus 2.(SARS-CoV-2)and its variant strains,including Alpha,Beta,Gamma,Delta,and now Omicron,pose a significant challenge.With the constant evolution of the virus,Omicron and its subtypes BA.1,BA.2,BA.3,BA.4,and BA.5 have developed the capacity to evade neutralization induced by previous vaccination or infection.This evasion highlights the urgency in discovering new monoclonal antibodies(mAbs)with neutralizing activity,especially broadly neutralizing antibodies(bnAbs),to combat the virus.In the current study,we introduced a fully human neutralizing mAb,CR9,that targets Omicron variants.We demonstrated the mAb’s effectiveness in inhibiting Omicron replication both in vitro and in vivo.Structural analysis using cryo-electron microscopy(cryo-EM)revealed that CR9 binds to an epitope formed by RBD residues,providing a molecular understanding of its neutralization mechanism.Given its potency and specificity,CR9 holds promise as a potential adjunct therapy for treating Omicron infections.Our findings highlight the importance of continuous mAb discovery and characterization in addressing the evolving threat of COVID-19.展开更多
Background:Since December 2019,an outbreak of the Corona Virus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2)in Wuhan,China,has become a public health emergency of internatio...Background:Since December 2019,an outbreak of the Corona Virus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2)in Wuhan,China,has become a public health emergency of international concern.The high fatality of aged cases caused by SARS-CoV-2 was a need to explore the possible age-related phenomena with non-human primate models.Methods:Three 3-5 years old and two 15 years old rhesus macaques were intratracheally infected with SARS-CoV-2,and then analyzed by clinical signs,viral replication,chest X-ray,histopathological changes and immune response.Results:Viral replication of nasopharyngeal swabs,anal swabs and lung in old monkeys was more active than that in young monkeys for 14 days after SARS-CoV-2 challenge.Monkeys developed typical interstitial pneumonia characterized by thickened alveolar septum accompanied with inflammation and edema,notably,old monkeys exhibited diffuse severe interstitial pneumonia.Viral antigens were detected mainly in alveolar epithelial cells and macrophages.Conclusion:SARS-CoV-2 caused more severe interstitial pneumonia in old monkeys than that in young monkeys.Rhesus macaque models infected with SARS-CoV-2 provided insight into the pathogenic mechanism and facilitated the development of vaccines and therapeutics against SARS-CoV-2 infection.展开更多
Severe pandemic influenza A(H1N1)2009 virus(pH1N1)infection causes significant morbidity and mortality.We and other groups have reported that immunopathological damage induced by excessive pulmonary inflammation plays...Severe pandemic influenza A(H1N1)2009 virus(pH1N1)infection causes significant morbidity and mortality.We and other groups have reported that immunopathological damage induced by excessive pulmonary inflammation plays a critical role in the pathogenesis of severe pneumonia and provides novel strategies for the treatment of severe influenza infection[1–3].The complement system plays critical roles in both innate and adaptive immunity by activating the classical,alternative and lectin pathways[4].展开更多
Dear Editor,Coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus-2(SARS-CoV-2),has rapidly swept through the worldwide,with more than 3 million confirmed cases.Until now,no vaccine...Dear Editor,Coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus-2(SARS-CoV-2),has rapidly swept through the worldwide,with more than 3 million confirmed cases.Until now,no vaccine or effective therapeutic measures are provided to prevent the SARS-CoV-2 infection.Existing medicines have some strong advantages on pharmacokinetics,known side effects,safety and dosing regimens.1 Although remdesivir and chloroquine could effectively inhibit the replication of SARS-CoV-2 in vitro,2 no medicine candidates have been evaluated in vivo by using animal models with SARS-CoV-2 infection.展开更多
Influenza A virus may circulate simultaneously with the SARS-CoV-2 virus,leading to more serious respiratory diseases during this winter.However,the influence of these viruses on disease outcome when both influenza A ...Influenza A virus may circulate simultaneously with the SARS-CoV-2 virus,leading to more serious respiratory diseases during this winter.However,the influence of these viruses on disease outcome when both influenza A and SARS-CoV-2 are present in the host remains unclear.Using a mammalian model,sequential infection was performed in ferrets and in K18-MCE2 mice,with SARS-CoV-2 infection following H1N1.We found that co-infection with H1N1 and SARS-CoV-2 extended the duration of clinical manifestation of COVID-19,and enhanced pulmonary damage,but reduced viral shedding of throat swabs and viral loads in the lungs of ferrets.Moreover,mortality was increased in sequentially infected mice compared with single-infection mice.Compared with singlevaccine inoculation,co-inoculation of PiCoVacc(a SARS-CoV-2 vaccine)and the flu vaccine showed no significant differences in neutralizing antibody titers or virus-specific immune responses.Combined immunization effectively protected K18-MCE2 mice against both H1N1 and SARS-CoV-2 infection.Our findings indicated the development of systematic models of co-infection of H1N1 and SARS-CoV-2,which together notably enhanced pneumonia in ferrets and mice,as well as demonstrated that simultaneous vaccination against HINT and SARS-CoV-2 may be an effective prevention strategy for the coming winter.展开更多
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is transmitted on mink farms between minks and humans in many countries.However,the systemic pathological features of SARS-CoV-2-infected minks are mostly unk...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is transmitted on mink farms between minks and humans in many countries.However,the systemic pathological features of SARS-CoV-2-infected minks are mostly unknown.Here,we demonstrated that minks were largely permissive to SARS-CoV-2,characterized by severe and diffuse alveolar damage,and lasted at least 14 days post inoculation(dpi).We first reported that infected minks displayed multiple organ-system lesions accompanied by an increased inflammatory response and widespread viral distribution in the cardiovascular,hepatobiliary,urinary,endocrine,digestive,and immune systems.The viral protein partially co-localized with activated Mac-2+macrophages throughout the body.Moreover,we first found that the alterations in lipids and metabolites were correlated with the histological lesions in infected minks,especially at 6 dpi,and were similar to that of patients with severe and fatal COVID-19.Particularly,altered metabolic pathways,abnormal digestion,and absorption of vitamins,lipids,cholesterol,steroids,amino acids,and proteins,consistent with hepatic dysfunction,highlight metabolic and immune dysregulation.Enriched kynurenine in infected minks contributed to significant activation of the kynurenine pathway and was related to macrophage activation.Melatonin,which has significant anti-inflammatory and immunomodulating effects,was significantly downregulated at 6 dpi and displayed potential as a targeted medicine.Our data first illustrate systematic analyses of infected minks to recapitulate those observations in severe and fetal COVID-19 patients,delineating a useful animal model to mimic SARS-CoV-2-induced systematic and severe pathophysiological features and provide a reliable tool for the development of effective and targeted treatment strategies,vaccine research,and potential biomarkers.展开更多
Enterovirus A71(EV-A71) causes major outbreaks of hand,foot,and mouth disease(HFMD) in many countries,most frequently affecting children,and a small proportion of cases may lead to death.Currently,no vaccine is availa...Enterovirus A71(EV-A71) causes major outbreaks of hand,foot,and mouth disease(HFMD) in many countries,most frequently affecting children,and a small proportion of cases may lead to death.Currently,no vaccine is available in most endemic regions,and no licenced treatments for EV-A71 infection are available.Here,we characterize a human monoclonal antibody(Hu MAb),E1,by screening a Fab antibody phage library derived from patients who recovered from EV-A71 infection.E1 exhibits strong neutralizing activity against EV-A71 virus in cells.The cryo-electron microscopy(cryo-EM) structures of the EV-A71 virion in complex with E1 Fab fragments demonstrated that E1 recognized an epitope formed by residues in the BC and HI loops of VP1.In a mouse model,E1 effectively protected against lethal EV-A71 challenge in both prophylactic and therapeutic treatment.In particular,E1 significantly reduces virus titers and muscle damage.E1 might represent a potential adjunct to EV-A71 treatment.展开更多
Evidence suggests associations between COVID-19 patients or vaccines and glycometabolic dysfunction and an even higher risk of the occurrence of diabetes.Herein,we retrospectively analyzed pancreatic lesions in autops...Evidence suggests associations between COVID-19 patients or vaccines and glycometabolic dysfunction and an even higher risk of the occurrence of diabetes.Herein,we retrospectively analyzed pancreatic lesions in autopsy tissues from 67 SARS-CoV-2 infected non-human primates(NHPs)models and 121 vaccinated and infected NHPs from 2020 to 2023 and COVID-19 patients.Multi-label immunofluorescence revealed direct infection of both exocrine and endocrine pancreatic cells by the virus in NHPs and humans.Minor and limited phenotypic and histopathological changes were observed in adult models.Systemic proteomics and metabolomics results indicated metabolic disorders,mainly enriched in insulin resistance pathways,in infected adult NHPs,along with elevated fasting C-peptide and C-peptide/glucose ratio levels.Furthermore,in elder COVID-19 NHPs,SARS-CoV-2 infection causes loss of beta(β)cells and lower expressed-insulin in situ characterized by islet amyloidosis and necrosis,activation ofα-SMA and aggravated fibrosis consisting of lower collagen in serum,an increase of pancreatic inflammation and stress markers,ICAM-1 and G3BP1,along with more severe glycometabolic dysfunction.In contrast,vaccination maintained glucose homeostasis by activating insulin receptorαand insulin receptorβ.Overall,the cumulative risk of diabetes post-COVID-19 is closely tied to age,suggesting more attention should be paid to blood sugar management in elderly COVID-19 patients.展开更多
Variants of concern(VOCs)like Delta and Omicron,harbor a high number of mutations,which aid these viruses in escaping a majority of known SARS-CoV-2 neutralizing antibodies(NAbs).In this study,Rhesus macaques immunize...Variants of concern(VOCs)like Delta and Omicron,harbor a high number of mutations,which aid these viruses in escaping a majority of known SARS-CoV-2 neutralizing antibodies(NAbs).In this study,Rhesus macaques immunized with 2-dose inactivated vaccines(Coronavac)were boosted with an additional dose of homologous vaccine or an RBD-subunit vaccine,or a bivalent inactivated vaccine(Beta and Delta)to determine the effectiveness of sequential immunization.The booster vaccination significantly enhanced the duration and levels of neutralizing antibody titers against wild-type.展开更多
基金the National Natural Science Foundation of China,Grant/Award Number:32000358the CAMS initiative for Innovative Medicine of China,Grant/Award Number:2021-I2M-1-035Young Elite Scientists Sponsorship Program by CAST(YESS),Grant/Award Number:2020QNRC001。
文摘Background:The aim was to elucidate the function of IL-37 in middle east respiratory syndrome coronavirus(MERS-CoV)infection,thereby providing a novel therapeutic strategy for managing the clinical treatment of inflammatory response caused by respiratory virus infection.Methods:We investigated the development of MERS by infecting hDPP4 mice with hCoV-EMC(107 TCID50[50%tissue culture infectious dose])intranasally.We infected A549 cells with MERS-CoV,which concurrently interfered with IL-37,detecting the viral titer,viral load,and cytokine expression at certain points postinfection.Meanwhile,we administered IL-37(12.5μg/kg)intravenously to hDPP4 mice 2 h after MERS-CoV-2 infection and collected the serum and lungs 5 days after infection to investigate the efficacy of IL-37 in MERS-CoV infection.Results:The viral titer of MERS-CoV-infected A549 cells interfering with IL-37 was significantly reduced by 4.7-fold,and the viral load of MERS-CoV-infected hDPP4 mice was decreased by 59-fold in lung tissue.Furthermore,the administration of IL-37 suppressed inflammatory cytokine and chemokine(monocyte chemoattractant protein 1,interferon-γ,and IL-17A)expression and ameliorated the infiltration of inflammatory cells in hDPP4 mice.Conclusion:IL-37 exhibits protective properties in severe pneumonia induced by MERS-CoV infection.This effect is achieved through attenuation of lung viral load,suppression of inflammatory cytokine secretion,reduction in inflammatory cell infiltration,and mitigation of pulmonary injury.
基金National Science and Technology Infrastructure of China,Grant/Award Number:National Pathogen Resource Center-NPRC-32National Key Research and Development Program of China,Grant/Award Number:2023YFF0724800CAMS Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-035。
文摘Background:New variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continue to drive global epidemics and pose significant health risks.The pathogenicity of these variants evolves under immune pressure and host factors.Understanding these changes is crucial for epidemic control and variant research.Methods:Human angiotensin-converting enzyme 2(hACE2)transgenic mice were in-tranasally challenged with the original strain WH-09 and the variants Delta,Beta,and Omicron BA.1,while BALB/c mice were challenged with Omicron subvariants BA.5,BF.7,and XBB.1.To compare the pathogenicity differences among variants,we con-ducted a comprehensive analysis that included clinical symptom observation,meas-urement of viral loads in the trachea and lungs,evaluation of pulmonary pathology,analysis of immune cell infiltration,and quantification of cytokine levels.Results:In hACE2 mice,the Beta variant caused significant weight loss,severe lung inflammation,increased inflammatory and chemotactic factor secretion,greater mac-rophage and neutrophil infiltration in the lungs,and higher viral loads with prolonged shedding duration.In contrast,BA.1 showed a significant reduction in pathogenicity.The BA.5,BF.7,and XBB.1 variants were less pathogenic than the WH-09,Beta,and Delta variants when infected in BALB/c mice.This was evidenced by reduced weight loss,diminished pulmonary pathology,decreased secretion of inflammatory factors and chemokines,reduced macrophage and neutrophil infiltration,as well as lower viral loads in both the trachea and lungs.Conclusion:In hACE2 mice,the Omicron variant demonstrated the lowest pathogenic-ity,while the Beta variant exhibited the highest.Pathogenicity of the Delta variant was comparable to the original WH-09 strain.Among BALB/c mice,Omicron subvari-ants BA.5,BF.7,and XBB.1 showed no statistically significant differences in virulence.
基金National Research and Development Project of China,Grant/Award Number:2021YFC0863300Special Funds of the National Natural Science Foundation of China,Grant/Award Number:82061138007 and 92169210CAMS Initiative for Innovative Medicine of China。
文摘Background:The Omicron(B.1.1.529)SARS-COV-2 variant has raised serious concerns because of its unprecedented rapid rate of spreading and the fact that there are 36 mutations in the spike protein.Since the vaccine-induced neutralizing antibody targets are the spike protein,this may lead to the possibility of vaccine-induced hu-moral immunity escape.Methods:We measured the neutralizing activity in vitro for Omicron and compared this with wild type(WH-09)and Delta variants in human and monkey sera from different types of immunity.The monkey sera samples were collected at 1 and 3 months post three-dose inactivated(PiCoVacc)and recombinant protein(ZF2001)vaccination.Human sera were collected from 1 month post three-dose inactivated vaccination.Results:In inactivated vaccine sera,at 1/3 months post three-dose,geometric mean titers(GMTs)of neutralization antibody(NAb)against the Omicron variant were 4.9/5.2-fold lower than those of the wild type.In recombinant protein vaccine sera,GMTs of NAb against Omicron were 15.7/8.9-fold lower than those of the wild type.In human sera,at 1 month post three-dose inactivated vaccination,GMTs of NAb against Omicron were 3.1-fold lower than those of the wild type.Conclusion:This study demonstrated that despite a reduction in neutralization titers,cross-neutralizing activity against Omicron and Delta variants was still observed after three doses of inactivated and recombinant protein vaccination.
基金National Research and Development Project of China,Grant/Award Number:2022YFC0867600CAMS initiative for Innovative Medicine of China,Grant/Award Number:2021-I2M-1-035。
文摘Background:New Omicron subvariants are emerging rapidly from BA.1 to BA.4 and BA.5.Their pathogenicity has changed from that of wild-type(WH-09)and Omicron variants have over time become globally dominant.The spike proteins of BA.4 and BA.5 that serve as the target for vaccine-induced neutralizing antibodies have also changed compared to the previous subvariants,which is likely to cause immune es-cape and the reduction of the protective effect of the vaccine.Our study addresses the above issues and provides a basis for formulating relevant prevention and control strategies.Methods:We collected cellular supernatant and cell lysates and measured the viral titers,viral RNA loads,and E subgenomic RNA(E sgRNA)loads in different Omicron subvariants grown in Vero E6 cells,using WH-09 and Delta variants as a reference.Additionally,we evaluated the in vitro neutralizing activity of different Omicron sub-variants and compared it to the WH-09 and Delta variants using macaque sera with different types of immunity.Results:As the SARS-CoV-2 evolved into Omicron BA.1,the replication ability in vitro began to decrease.Then with the emergence of new subvariants,the replication ability gradually recovered and became stable in the BA.4 and BA.5 subvariants.In WH-09-inactivated vaccine sera,geometric mean titers of neutralization antibodies against different Omicron subvariants declined by 3.7~15.4-fold compared to those against WH-09.In Delta-inactivated vaccine sera,geometric mean titers of neutrali-zation antibodies against Omicron subvariants declined by 3.1~7.4-fold compared to those against Delta.Conclusion:According to the findings of this research,the replication efficiency of all Omicron subvariants declined compared with WH-09 and Delta variants,and was lower in BA.1 than in other Omicron subvariants.After two doses of inactivated(WH-09 or Delta)vaccine,cross-neutralizing activities against various Omicron subvariants were seen despite a decline in neutralizing titers.
基金supported by the National Research and Development Project of China(grant no.2023YFF0724800)the CAMS Initiative for Innovative Medicine of China(grant no.2021-I2M-1-035)+1 种基金the Sector Fund(2060302)Young Elite Scientists Sponsorship Program by CAST(YESS)(grant no:2020QNRC001)。
文摘Dear Editor,The case fatality rate of early SARS-CoV-2 infection is 3%(Ghebreyesus,2020),and the severe case rate is 24.3%(Sun et al.,2020).From the prototypic SARS-CoV-2 strain to the emergence of Alpha,Beta,and Delta variants,which ultimately led to the outbreak of Omicron variants,these strains have undergone a series of evolutionary changes.Starting from BA.1,BA.2,BA.4,and BA.5 lineage to XBB lineage before branching out into the current dominant JN.1 lineage.
基金supported by the CAMS Innovation Fund for Medical Sciences(2021-I2M-1-037,2021-I2M-1-038)the National Research and Development Project of China(grant no.2023YFF0724800)+2 种基金the CAMS Initiative for Innovative Medicine of China(grant no.2021-I2M-1-035)the National Science and Technology Infrastructure of China(Project No.National Pathogen Resource Center-NPRC-32)We thank Changwen Ke from Guangdong Provincial Center for Disease Control and Prevention for providing SARS-CoV-2 BA.2,BA.2.12.1,BA.4,and BA.5 as a gift.We thank the Scripps Institute for providing the pComb3H and PIGG vectors.
文摘The global spread of Severe Acute Respiratory Syndrome Coronavirus 2.(SARS-CoV-2)and its variant strains,including Alpha,Beta,Gamma,Delta,and now Omicron,pose a significant challenge.With the constant evolution of the virus,Omicron and its subtypes BA.1,BA.2,BA.3,BA.4,and BA.5 have developed the capacity to evade neutralization induced by previous vaccination or infection.This evasion highlights the urgency in discovering new monoclonal antibodies(mAbs)with neutralizing activity,especially broadly neutralizing antibodies(bnAbs),to combat the virus.In the current study,we introduced a fully human neutralizing mAb,CR9,that targets Omicron variants.We demonstrated the mAb’s effectiveness in inhibiting Omicron replication both in vitro and in vivo.Structural analysis using cryo-electron microscopy(cryo-EM)revealed that CR9 binds to an epitope formed by RBD residues,providing a molecular understanding of its neutralization mechanism.Given its potency and specificity,CR9 holds promise as a potential adjunct therapy for treating Omicron infections.Our findings highlight the importance of continuous mAb discovery and characterization in addressing the evolving threat of COVID-19.
基金This work was supported by the National Research and Development Project of China(Grant No.2020YFC0841100)Fundamental Research Funds for CAMS of China(Grant No.2020HY320001)+3 种基金National Key Research and Development Project of China(Grant No.2016YFD0500304)CAMS initiative for Innovative Medicine of China(Grant No.2016-I2M-2-006)National Mega projects of China for Major Infectious Diseases(Grant No.2017ZX10304402)and National Key Research and Development Programme of China(2016YFD0500301,2020YFC0840800,2020YFC0840900).
文摘Background:Since December 2019,an outbreak of the Corona Virus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2)in Wuhan,China,has become a public health emergency of international concern.The high fatality of aged cases caused by SARS-CoV-2 was a need to explore the possible age-related phenomena with non-human primate models.Methods:Three 3-5 years old and two 15 years old rhesus macaques were intratracheally infected with SARS-CoV-2,and then analyzed by clinical signs,viral replication,chest X-ray,histopathological changes and immune response.Results:Viral replication of nasopharyngeal swabs,anal swabs and lung in old monkeys was more active than that in young monkeys for 14 days after SARS-CoV-2 challenge.Monkeys developed typical interstitial pneumonia characterized by thickened alveolar septum accompanied with inflammation and edema,notably,old monkeys exhibited diffuse severe interstitial pneumonia.Viral antigens were detected mainly in alveolar epithelial cells and macrophages.Conclusion:SARS-CoV-2 caused more severe interstitial pneumonia in old monkeys than that in young monkeys.Rhesus macaque models infected with SARS-CoV-2 provided insight into the pathogenic mechanism and facilitated the development of vaccines and therapeutics against SARS-CoV-2 infection.
基金This work was supported by grants from National Natural Science Foundation of China(82071747,81373114)Beijing Municipal Natural Science Foundation,China(7182013).
文摘Severe pandemic influenza A(H1N1)2009 virus(pH1N1)infection causes significant morbidity and mortality.We and other groups have reported that immunopathological damage induced by excessive pulmonary inflammation plays a critical role in the pathogenesis of severe pneumonia and provides novel strategies for the treatment of severe influenza infection[1–3].The complement system plays critical roles in both innate and adaptive immunity by activating the classical,alternative and lectin pathways[4].
基金supported by the National Key Research and Development Project of China(Grant No.2016YFD0500304)CAMS initiative for Innovative Medicine of China(Grant No.2016-I2M-2-006)+1 种基金National Mega projects of China for Major Infectious Diseases(Grant Nos.2017ZX10304402,2018ZX10301403)Fundamental Research Funds for CAMS of China(Grant No.2020HY320001).
文摘Dear Editor,Coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus-2(SARS-CoV-2),has rapidly swept through the worldwide,with more than 3 million confirmed cases.Until now,no vaccine or effective therapeutic measures are provided to prevent the SARS-CoV-2 infection.Existing medicines have some strong advantages on pharmacokinetics,known side effects,safety and dosing regimens.1 Although remdesivir and chloroquine could effectively inhibit the replication of SARS-CoV-2 in vitro,2 no medicine candidates have been evaluated in vivo by using animal models with SARS-CoV-2 infection.
基金supported by the CAMS Initiative for Innovative Medicine of China(Grant Nos.2020-I2M-COV19-009,2016-I2M-2-006,2018-I2M-1-003)the Special Funds of the National Natural Science Foundation of China(Grant No.82041035)+3 种基金the National Research and Development Project of China(Grant No.2020YFC0841100)the National Mega projects of China for Major Infectious Diseases(Grant Nos.2017ZX10304402,2018ZX10301403)the National Key Research and Development Project of China(Grant No.2016YFD0500304)the Fundamental Research Funds for the Central Public Welfare Research Institutes(Grant No.ZZ13-035-03).
文摘Influenza A virus may circulate simultaneously with the SARS-CoV-2 virus,leading to more serious respiratory diseases during this winter.However,the influence of these viruses on disease outcome when both influenza A and SARS-CoV-2 are present in the host remains unclear.Using a mammalian model,sequential infection was performed in ferrets and in K18-MCE2 mice,with SARS-CoV-2 infection following H1N1.We found that co-infection with H1N1 and SARS-CoV-2 extended the duration of clinical manifestation of COVID-19,and enhanced pulmonary damage,but reduced viral shedding of throat swabs and viral loads in the lungs of ferrets.Moreover,mortality was increased in sequentially infected mice compared with single-infection mice.Compared with singlevaccine inoculation,co-inoculation of PiCoVacc(a SARS-CoV-2 vaccine)and the flu vaccine showed no significant differences in neutralizing antibody titers or virus-specific immune responses.Combined immunization effectively protected K18-MCE2 mice against both H1N1 and SARS-CoV-2 infection.Our findings indicated the development of systematic models of co-infection of H1N1 and SARS-CoV-2,which together notably enhanced pneumonia in ferrets and mice,as well as demonstrated that simultaneous vaccination against HINT and SARS-CoV-2 may be an effective prevention strategy for the coming winter.
基金This work was supported by the National Natural Science Foundation of China(Grant No.32070543)the National Key Research and Development Project of China(Grant No.2020YFA0707803 and 2021YFC0863300)the CAMS Innovation Fund for Medical Sciences(CIFMS)grant(2021-1-I2M-035,2021-1-I2M-034).
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is transmitted on mink farms between minks and humans in many countries.However,the systemic pathological features of SARS-CoV-2-infected minks are mostly unknown.Here,we demonstrated that minks were largely permissive to SARS-CoV-2,characterized by severe and diffuse alveolar damage,and lasted at least 14 days post inoculation(dpi).We first reported that infected minks displayed multiple organ-system lesions accompanied by an increased inflammatory response and widespread viral distribution in the cardiovascular,hepatobiliary,urinary,endocrine,digestive,and immune systems.The viral protein partially co-localized with activated Mac-2+macrophages throughout the body.Moreover,we first found that the alterations in lipids and metabolites were correlated with the histological lesions in infected minks,especially at 6 dpi,and were similar to that of patients with severe and fatal COVID-19.Particularly,altered metabolic pathways,abnormal digestion,and absorption of vitamins,lipids,cholesterol,steroids,amino acids,and proteins,consistent with hepatic dysfunction,highlight metabolic and immune dysregulation.Enriched kynurenine in infected minks contributed to significant activation of the kynurenine pathway and was related to macrophage activation.Melatonin,which has significant anti-inflammatory and immunomodulating effects,was significantly downregulated at 6 dpi and displayed potential as a targeted medicine.Our data first illustrate systematic analyses of infected minks to recapitulate those observations in severe and fetal COVID-19 patients,delineating a useful animal model to mimic SARS-CoV-2-induced systematic and severe pathophysiological features and provide a reliable tool for the development of effective and targeted treatment strategies,vaccine research,and potential biomarkers.
基金supported by the CAMS Innovation Fund for Medical Sciences(CIFMS)(2016-I2M-1-014)the National Natural Science Foundation of China(31500757 and 12034006)。
文摘Enterovirus A71(EV-A71) causes major outbreaks of hand,foot,and mouth disease(HFMD) in many countries,most frequently affecting children,and a small proportion of cases may lead to death.Currently,no vaccine is available in most endemic regions,and no licenced treatments for EV-A71 infection are available.Here,we characterize a human monoclonal antibody(Hu MAb),E1,by screening a Fab antibody phage library derived from patients who recovered from EV-A71 infection.E1 exhibits strong neutralizing activity against EV-A71 virus in cells.The cryo-electron microscopy(cryo-EM) structures of the EV-A71 virion in complex with E1 Fab fragments demonstrated that E1 recognized an epitope formed by residues in the BC and HI loops of VP1.In a mouse model,E1 effectively protected against lethal EV-A71 challenge in both prophylactic and therapeutic treatment.In particular,E1 significantly reduces virus titers and muscle damage.E1 might represent a potential adjunct to EV-A71 treatment.
基金supported by the Institute of Basic Medical Sciences,the Chinese Academy of Medical Sciences,the Neuroscience Center,the China Human Brain Banking Consortium,the ALS Brain Bank Initiative in China,and Home for Heal and Help for their assistance in this paper.This work was supported by the National Natural Science Foundation of China(82141204,82061138007,82221004,82041008)the National Key Research and Development Project of China(2020YFA0707803)+2 种基金the CAMS Innovation Fund for Medical Sciences(CIFMS)grant(2021-1-I2M-035,2021-1-I2M-034 and 2021-CAMS-JZ002)Bill&Melinda Gates Foundation(INV-006371)Key-Area Research and Development Program of Guangdong Province(2022B1111020005).
文摘Evidence suggests associations between COVID-19 patients or vaccines and glycometabolic dysfunction and an even higher risk of the occurrence of diabetes.Herein,we retrospectively analyzed pancreatic lesions in autopsy tissues from 67 SARS-CoV-2 infected non-human primates(NHPs)models and 121 vaccinated and infected NHPs from 2020 to 2023 and COVID-19 patients.Multi-label immunofluorescence revealed direct infection of both exocrine and endocrine pancreatic cells by the virus in NHPs and humans.Minor and limited phenotypic and histopathological changes were observed in adult models.Systemic proteomics and metabolomics results indicated metabolic disorders,mainly enriched in insulin resistance pathways,in infected adult NHPs,along with elevated fasting C-peptide and C-peptide/glucose ratio levels.Furthermore,in elder COVID-19 NHPs,SARS-CoV-2 infection causes loss of beta(β)cells and lower expressed-insulin in situ characterized by islet amyloidosis and necrosis,activation ofα-SMA and aggravated fibrosis consisting of lower collagen in serum,an increase of pancreatic inflammation and stress markers,ICAM-1 and G3BP1,along with more severe glycometabolic dysfunction.In contrast,vaccination maintained glucose homeostasis by activating insulin receptorαand insulin receptorβ.Overall,the cumulative risk of diabetes post-COVID-19 is closely tied to age,suggesting more attention should be paid to blood sugar management in elderly COVID-19 patients.
基金ACKNOWLEDGEMENTS We thank Sinovac Biotech Ltd for providing the inactivated vaccines as a gift for these prospective studies.This work was supported by the National Research and Development Project of China(Grant Nos.2021YFC0863300,2020YFA0707500,2018YFA0900801)the CAMS Initiative for Innovative Medicine of China(Grant No.2021-I2M-1-035)+2 种基金the Strategic Priority Research Program(XDB29010000,XDB37030000),CAS(YSBR-010)the Special Funds of the National Natural Science Foundation of China(Grant Nos.82061138007 and 92169210)Xiangxi Wang was supported by the Ten Thousand Talent Program and the NSFS Innovative Research Group(No.81921005).
文摘Variants of concern(VOCs)like Delta and Omicron,harbor a high number of mutations,which aid these viruses in escaping a majority of known SARS-CoV-2 neutralizing antibodies(NAbs).In this study,Rhesus macaques immunized with 2-dose inactivated vaccines(Coronavac)were boosted with an additional dose of homologous vaccine or an RBD-subunit vaccine,or a bivalent inactivated vaccine(Beta and Delta)to determine the effectiveness of sequential immunization.The booster vaccination significantly enhanced the duration and levels of neutralizing antibody titers against wild-type.
