Dear editor,Vaccines are the most efficient and effective means to prevent infectious diseases,but improving the long-term protective efficacy is still a major challenge in contemporary vaccine development.1 The wanin...Dear editor,Vaccines are the most efficient and effective means to prevent infectious diseases,but improving the long-term protective efficacy is still a major challenge in contemporary vaccine development.1 The waning immunity varies depending on the diversification of the pathogen and the number of booster doses.1 Strategies to overcome this warrant is using adjuvants that amplify the immune response,and drive the production of memory B and T cells or long-lived plasma cells that recognize the pathogen for durable protection.2–4 Although existing adjuvants have achieved promising results,research on generating durable protective immunity is lacking in promoting vaccine development and staying ahead of global pandemics such as coronavirus disease 2019(COVID-19).The precisely designed nanoadjuvants can enhance lymph node targeting and increase antigenpresenting cell(APCs)uptake,achieving the co-delivery of adjuvants and antigens and activating innate and adaptive immune responses.5 Previously,we reported a manganese nanoadjuvant(MnARK)and receptor-binding domain(RBD)monomer antigen formulated nanovaccine.6 MnARK transported antigens to lymph nodes,activated the STING pathway,elicited strong neutralizing abilities and increased immune memory T cell percentage against the infection of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).6 Regarding the long-term protection potential of MnARK for subunit vaccine development,we further explored the durable immune regulation abilities of MnARK to a SARS-CoV-2 RBD dimer antigen,which has been used in an approved COVID-19 subunit vaccine ZF2001 with aluminum adjuvant(alum).7,8 TEM result revealed that RBD dimer could interact with BSA on MnARK surface and epitope can be well preserved(Supplementary Fig.1a).The size and zeta potential of MnARK-RBD dimer nanovaccine was~58 nm and-14 mV,respectively(Supplementary Fig.1b,c).展开更多
With continuous mutations of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the severe immune escape of Omicron sub-variants urges the development of next-generation broad-spectrum vaccines,especially as ...With continuous mutations of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the severe immune escape of Omicron sub-variants urges the development of next-generation broad-spectrum vaccines,especially as booster jabs after high-level vaccination coverage of inactivated vaccines in China and many other countries.Previously,we developed a coronavirus disease 2019(COVID-19)protein subunit vaccine ZF2001?based on the tandem homo-prototype receptor-binding domain(RBD)-dimer of the SARS-CoV-2 spike protein.We upgraded the antigen into a hetero-chimeric prototype(PT)-Beta or Delta-BA.1 RBD-dimer to broaden the cross-protection efficacy and prove its efficiency with protein subunit and mRNA vaccine platforms.Herein,we further explored the hetero-chimeric RBD-dimer mRNA vaccines and evaluated their broad-spectrum activities as booster jabs following two doses of inactivated vaccine(Ⅳ)in mice.Our data demonstrated that the chi-meric vaccines significantly boosted neutralizing antibody levels and specific T-cell responses against the vari-ants,and PT-Beta was superior to Delta-BA.1 RBD as a booster in mice,shedding light on the antigen design for the next-generation COVID-19 vaccines.展开更多
Current attempts in vaccine delivery systems concentrate on replicating the natural dissemination of live pathogens,but neglect that pathogens evolve to evade the immune system rather than to provoke it.In the case of...Current attempts in vaccine delivery systems concentrate on replicating the natural dissemination of live pathogens,but neglect that pathogens evolve to evade the immune system rather than to provoke it.In the case of enveloped RNA viruses,it is the natural dissemination of nucleocapsid protein(NP,core antigen)and surface antigen that delays NP exposure to immune surveillance.Here,we report a multi-layered aluminum hydroxide-stabilized emulsion(MASE)to dictate the delivery sequence of the antigens.In this manner,the receptor-binding domain(RBD,surface antigen)of the spike protein was trapped inside the nanocavity,while NP was absorbed on the outside of the droplets,enabling the burst release of NP before RBD.Compared with the natural packaging strategy,the inside-out strategy induced potent type I interferon-mediated innate immune responses and triggered an immune-potentiated environment in advance,which subsequently boosted CD40+DC activations and the engagement of the lymph nodes.In both H1N1 influenza and SARS-CoV-2 vaccines,rMASE significantly increased antigen-specific antibody secretion,memory T cell engagement,and Th1-biased immune response,which diminished viral loads after lethal challenge.By simply reversing the delivery sequence of the surface antigen and core antigen,the inside-out strategy may offer major implications for enhanced vaccinations against the enveloped RNA virus.展开更多
Respiratory syncytial virus(RSV)is one of the leading pathogens that cause lower respiratory tract infections in infants and the elderly.Passive immunoprophylaxis with monoclonal antibody(mAb)has been approved to prev...Respiratory syncytial virus(RSV)is one of the leading pathogens that cause lower respiratory tract infections in infants and the elderly.Passive immunoprophylaxis with monoclonal antibody(mAb)has been approved to prevent morbidity and mortality from RSV infection in infants.Here we report the isolation of two neutralizing mAbs against RSV from convalescent children by prefusion form of fusion(F)glycoprotein as bait.One mAb RV11 exhibited good potency in neutralization of RSV strains from both A and B subtypes in cell-based assay,and protected mice from RSV infection in vivo.An RV11 escape mutant was identified,which contains an S443P mutation in F protein.Crystal structure showed the RV11 bound to a conserved prefusion epitope across the antigenic sites IV and V of the F glycoprotein.RV11 showed a strong synergistic effect when combined with two RSV antivirals,an F-targeting small molecular inhibitor ziresovir and a siteØneutralizing mAb D25(the parental mAb for nirsevimab).The study extended our knowledge to the neutralizing and protective epitopes of RSV,and the mAb RV11 deserves further development for clinical translation.展开更多
OriginalTranslation The avian influenza A(H7N9)virus is a zoonotic virus that is closely associated with live poultry markets.It has caused infections in humans in China since 2013.Five waves of the H7N9 influenza epi...OriginalTranslation The avian influenza A(H7N9)virus is a zoonotic virus that is closely associated with live poultry markets.It has caused infections in humans in China since 2013.Five waves of the H7N9 influenza epidemic occurred in China between March 2013 and September 2017.H7N9 with low-pathogenicity dominated in the first four waves,whereas highly pathogenic H7N9 influenza emerged in poultry and spread to humans during the fifth wave,causing wide concern.Specialists and officials from China and other countries responded quickly,controlled the epidemic well thus far,and characterized the virus by using new technologies and surveillance tools that were made possible by their preparedness efforts.Here,we review the characteristics of the H7N9 viruses that were identified while controlling the spread of the disease.It was summarized and discussed from the perspectives of molecular epidemiology,clinical features,virulence and pathogenesis,receptor binding,T-cell responses,monoclonal antibody development,vaccine development,and disease burden.These data provide tools for minimizing the future threat of H7N9 and other emerging and re-emerging viruses,such as SARS-CoV-2.展开更多
The yellow fever virus(YFV)is a life-threatening human pathogen.Owing to the lack of available therapeutics,non-vaccinated individuals are at risk.Here,we isolated eight human monoclonal antibodies that neutralize YFV...The yellow fever virus(YFV)is a life-threatening human pathogen.Owing to the lack of available therapeutics,non-vaccinated individuals are at risk.Here,we isolated eight human monoclonal antibodies that neutralize YFV infection.Five recognized overlapping epitopes and exhibited potent neutralizing activity.Two(YD6 and YD73)were ultra-potent and conferred complete protection against the lethal challenge of YFV as both prophylactics and therapeutics in a mouse model.Crystal structures revealed that YD6 engaged the YFV envelope protein in both pre-and post-fusion states,suggesting viral inhibition by a“double-lock”mechanism.The recognition determinants for YD6 and YD73 are clustered at the premembrane(prM)-binding site.Notably,antibodies targeting this site were present in minute traces in YFV-infected individuals but contributed significantly to neutralization,suggesting a vulnerable supersite of YFV.We provide two promising candidates for immunotherapy against YFV,and the supersite represents an ideal target for epitope-based vaccine design.展开更多
Studies on influenza virus by Chinese Academy of Sciences(CAS)could be traced back as early as 2005 by the CAS Key Laboratory of Pathogenic Microbiology and Immunology(CASPMI),who discovered that Qinghai-like Clade 2....Studies on influenza virus by Chinese Academy of Sciences(CAS)could be traced back as early as 2005 by the CAS Key Laboratory of Pathogenic Microbiology and Immunology(CASPMI),who discovered that Qinghai-like Clade 2.2H5N1 subtype highly pathogenic avian influenza virus(HPAIV)first caused severe outbreak in wild birds in Qinghai Lake(Liu et al.,2005).展开更多
基金supported by the National Basic Research Program of China(2022YFA1603701 and 2021YFA1200900)the National Natural Science Foundation of China(82341044,22027810)+2 种基金the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Science(CIFMS 2019-I2M-5-018)Strategic Priority Research Program of the Chinese Academy of Sciences(XDB36000000)the China Postdoctoral Science Foundation(2021TQ0085,2022M720932)。
文摘Dear editor,Vaccines are the most efficient and effective means to prevent infectious diseases,but improving the long-term protective efficacy is still a major challenge in contemporary vaccine development.1 The waning immunity varies depending on the diversification of the pathogen and the number of booster doses.1 Strategies to overcome this warrant is using adjuvants that amplify the immune response,and drive the production of memory B and T cells or long-lived plasma cells that recognize the pathogen for durable protection.2–4 Although existing adjuvants have achieved promising results,research on generating durable protective immunity is lacking in promoting vaccine development and staying ahead of global pandemics such as coronavirus disease 2019(COVID-19).The precisely designed nanoadjuvants can enhance lymph node targeting and increase antigenpresenting cell(APCs)uptake,achieving the co-delivery of adjuvants and antigens and activating innate and adaptive immune responses.5 Previously,we reported a manganese nanoadjuvant(MnARK)and receptor-binding domain(RBD)monomer antigen formulated nanovaccine.6 MnARK transported antigens to lymph nodes,activated the STING pathway,elicited strong neutralizing abilities and increased immune memory T cell percentage against the infection of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).6 Regarding the long-term protection potential of MnARK for subunit vaccine development,we further explored the durable immune regulation abilities of MnARK to a SARS-CoV-2 RBD dimer antigen,which has been used in an approved COVID-19 subunit vaccine ZF2001 with aluminum adjuvant(alum).7,8 TEM result revealed that RBD dimer could interact with BSA on MnARK surface and epitope can be well preserved(Supplementary Fig.1a).The size and zeta potential of MnARK-RBD dimer nanovaccine was~58 nm and-14 mV,respectively(Supplementary Fig.1b,c).
基金This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(grant number XDB29040203)the National Key Research and Development Program of China(grant number 2021YFA1301404 and 2020YFA0907102)+2 种基金the National Natural Science Foundation of China(grant numbers 82225021 and 32171428)In addition,Qihui Wang was supported by the CAS Project for Young Scientists in Basic Research(grant number YSBR-010)the Youth Innovation Promotion Association of the CAS(grant number Y2022037).We thank Professor Xiao Zhao from the National Center for Nanoscience and Technology for sharing the LNP encapsulation and DLS platforms.We thank Dr.Kun Xu for his help during the revision of this manuscript.We thank Linjie Li for sharing recombinant RBD proteins.We thank the Institutional Center for Shared Technology and Facilitates in the Institute of Microbiology,CAS,and the Institute of Zoology,CAS.
文摘With continuous mutations of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the severe immune escape of Omicron sub-variants urges the development of next-generation broad-spectrum vaccines,especially as booster jabs after high-level vaccination coverage of inactivated vaccines in China and many other countries.Previously,we developed a coronavirus disease 2019(COVID-19)protein subunit vaccine ZF2001?based on the tandem homo-prototype receptor-binding domain(RBD)-dimer of the SARS-CoV-2 spike protein.We upgraded the antigen into a hetero-chimeric prototype(PT)-Beta or Delta-BA.1 RBD-dimer to broaden the cross-protection efficacy and prove its efficiency with protein subunit and mRNA vaccine platforms.Herein,we further explored the hetero-chimeric RBD-dimer mRNA vaccines and evaluated their broad-spectrum activities as booster jabs following two doses of inactivated vaccine(Ⅳ)in mice.Our data demonstrated that the chi-meric vaccines significantly boosted neutralizing antibody levels and specific T-cell responses against the vari-ants,and PT-Beta was superior to Delta-BA.1 RBD as a booster in mice,shedding light on the antigen design for the next-generation COVID-19 vaccines.
基金supported by the National Natural Science Foundation of China(92169113)the CAS Project for Young Scientists in Basic Research(YSBR-010)+1 种基金the National Key R&D Program of China(2022YFC2302900)the Key Research Program of Frontier Sciences of CAS(ZDBS-LY-SM025)。
基金supported by the National Key Research and Development Program of China(2021YFE020527,2021YFC2302605,2021YFC2300142),"From 0 to 1"Original Innovation Project of Basic Frontier Scientific Research Program of Chinese Academy of Sciences(ZDBS-LY-SLH040)Bejing Nova Program(Z201100006820139)the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(Grant No.21821005)+4 种基金CAS Project for Young Scientists in Basic Research(YSBR-010)the Pilot Project of Chinese Academy of Sciences(Grant No.XDB29040303)The National Natural Science Fund for Outstanding Young Scholar(T2222022)National Natural Science Foundation of China(Grant No.32030062),Youth Innovation Promotion Association of the Chinese Academy of Sciences(NO.2020000053)the foundation of Innovation Academy for Green Manufacture Institute,Chinese Academy of Sciences(Grand No.IAGM2020C30).
文摘Current attempts in vaccine delivery systems concentrate on replicating the natural dissemination of live pathogens,but neglect that pathogens evolve to evade the immune system rather than to provoke it.In the case of enveloped RNA viruses,it is the natural dissemination of nucleocapsid protein(NP,core antigen)and surface antigen that delays NP exposure to immune surveillance.Here,we report a multi-layered aluminum hydroxide-stabilized emulsion(MASE)to dictate the delivery sequence of the antigens.In this manner,the receptor-binding domain(RBD,surface antigen)of the spike protein was trapped inside the nanocavity,while NP was absorbed on the outside of the droplets,enabling the burst release of NP before RBD.Compared with the natural packaging strategy,the inside-out strategy induced potent type I interferon-mediated innate immune responses and triggered an immune-potentiated environment in advance,which subsequently boosted CD40+DC activations and the engagement of the lymph nodes.In both H1N1 influenza and SARS-CoV-2 vaccines,rMASE significantly increased antigen-specific antibody secretion,memory T cell engagement,and Th1-biased immune response,which diminished viral loads after lethal challenge.By simply reversing the delivery sequence of the surface antigen and core antigen,the inside-out strategy may offer major implications for enhanced vaccinations against the enveloped RNA virus.
基金supported by the National Natural Science Foundation of China(NSFC)(81991494 and 82122031)the National Key R&D Program of China(2020YFA0907100)+3 种基金the Chinese Academy of Sciences(YSBR-010)the CAMS Innovation Fund for Medical Sciences(CIFMS)(2019-I2M-5-026)Beijing Natural Science Foundation(L222076)L.D.is supported by the Youth Innovation Promotion Association CAS,China(2018113).
文摘Respiratory syncytial virus(RSV)is one of the leading pathogens that cause lower respiratory tract infections in infants and the elderly.Passive immunoprophylaxis with monoclonal antibody(mAb)has been approved to prevent morbidity and mortality from RSV infection in infants.Here we report the isolation of two neutralizing mAbs against RSV from convalescent children by prefusion form of fusion(F)glycoprotein as bait.One mAb RV11 exhibited good potency in neutralization of RSV strains from both A and B subtypes in cell-based assay,and protected mice from RSV infection in vivo.An RV11 escape mutant was identified,which contains an S443P mutation in F protein.Crystal structure showed the RV11 bound to a conserved prefusion epitope across the antigenic sites IV and V of the F glycoprotein.RV11 showed a strong synergistic effect when combined with two RSV antivirals,an F-targeting small molecular inhibitor ziresovir and a siteØneutralizing mAb D25(the parental mAb for nirsevimab).The study extended our knowledge to the neutralizing and protective epitopes of RSV,and the mAb RV11 deserves further development for clinical translation.
基金This study was supported by the Shenzhen Science and Technology Research and Development Project(No.JCYJ201604271519-20801)Innovation Unit for Emerging and Re-emerging Virus Adaptive Evolution Study and the Applications in Disease Control(No.2019-I2M-5-009)+3 种基金National Mega-projects for Infectious Diseases(No.2020ZX10001016-005-001)W.J.L.is supported by the Excellent Young Scientist Program of the NSFC(No.81822040)and Beijing New-star Plan of Science and Technology(No.Z181100006218080)H.X.is supported by Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project(No.TSBICIP-KJGG-004-04)G.F.G.is a leading principal investigator of the National Natural Science Foundation of China Innovative Research Group(No.81621091).
文摘OriginalTranslation The avian influenza A(H7N9)virus is a zoonotic virus that is closely associated with live poultry markets.It has caused infections in humans in China since 2013.Five waves of the H7N9 influenza epidemic occurred in China between March 2013 and September 2017.H7N9 with low-pathogenicity dominated in the first four waves,whereas highly pathogenic H7N9 influenza emerged in poultry and spread to humans during the fifth wave,causing wide concern.Specialists and officials from China and other countries responded quickly,controlled the epidemic well thus far,and characterized the virus by using new technologies and surveillance tools that were made possible by their preparedness efforts.Here,we review the characteristics of the H7N9 viruses that were identified while controlling the spread of the disease.It was summarized and discussed from the perspectives of molecular epidemiology,clinical features,virulence and pathogenesis,receptor binding,T-cell responses,monoclonal antibody development,vaccine development,and disease burden.These data provide tools for minimizing the future threat of H7N9 and other emerging and re-emerging viruses,such as SARS-CoV-2.
基金Y.Chen and Z.Yang(Institute of Biophysics,CAS)for technical help with Biacore T100 and Octet RED96,and J.Jia(Institute of Biophysics,CAS)and T.Zhao(Institute of Microbiology,CAS)for technical support during BD FACSAria III and CaliburmanipulationX.Lu(Tianjin Institute of Industrial Biotechnology,CAS)for providing pET 21a-YFV-sE plasmid.This work was supported by the National Key R&D Program of China(2021YFA1300803,2021YFC2300200)+1 种基金Strategic Priority Research Program of the Chinese Academy of Sciences(grant nos.XDB29040201,XDB37030204)National Natural Science Foundation of China(grant nos.31970854,32090014,81830050,81991494).L.Dai is supported by Youth Innovation Promotion Association CAS(2018113).
文摘The yellow fever virus(YFV)is a life-threatening human pathogen.Owing to the lack of available therapeutics,non-vaccinated individuals are at risk.Here,we isolated eight human monoclonal antibodies that neutralize YFV infection.Five recognized overlapping epitopes and exhibited potent neutralizing activity.Two(YD6 and YD73)were ultra-potent and conferred complete protection against the lethal challenge of YFV as both prophylactics and therapeutics in a mouse model.Crystal structures revealed that YD6 engaged the YFV envelope protein in both pre-and post-fusion states,suggesting viral inhibition by a“double-lock”mechanism.The recognition determinants for YD6 and YD73 are clustered at the premembrane(prM)-binding site.Notably,antibodies targeting this site were present in minute traces in YFV-infected individuals but contributed significantly to neutralization,suggesting a vulnerable supersite of YFV.We provide two promising candidates for immunotherapy against YFV,and the supersite represents an ideal target for epitope-based vaccine design.
基金supported by the National Key R&D Program of China(2016YFE0205800)National Science and Technology Major Project(2016ZX10004222)+5 种基金Emergency Technology Research Issue on Prevention and Control for Human Infection with A(H7N9)Avian Influenza Virus(10600100000015001206)intramural special grants for influenza virus research from the Chinese Academy of Sciences(KJZD-EWL15)Tianjin Research Program of the Application Foundation and Advanced Technology(14JCYBJC24400)the research project RFBR 17-04-01919a leading principal investigator of the NSFC Innovative Research Group(81621091)supported by the Youth Innovation Promotion Association of Chinese Academy of Sciences(CAS)(2017122)
文摘Studies on influenza virus by Chinese Academy of Sciences(CAS)could be traced back as early as 2005 by the CAS Key Laboratory of Pathogenic Microbiology and Immunology(CASPMI),who discovered that Qinghai-like Clade 2.2H5N1 subtype highly pathogenic avian influenza virus(HPAIV)first caused severe outbreak in wild birds in Qinghai Lake(Liu et al.,2005).