Immune imprinting,or original antigenic sin,challenges the control of evolving severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).How the quantity and quality of pre-existing immunity modulate the recall anti...Immune imprinting,or original antigenic sin,challenges the control of evolving severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).How the quantity and quality of pre-existing immunity modulate the recall antibody response upon re-exposure remains poorly understood.We immunized hamsters with a recombinant ancestral spike protein(S-2P)formulated with one of four distinct adjuvants to assess the impact of adjuvant-induced immunity on protective efficacy.Furthermore,we analyzed the modulatory effect of the adjuvant on the potency,breadth,and evolution of antibody responses after homologous viral challenge.We found that vaccination with Montanide ISA720-adjuvanted S-2P(S-2P:ISA720)not only induced higher initial neutralizing antibody titers and conferred stronger protection but also established a pre-existing immune state capable of cross-neutralizing the antigenically distant Omicron BA.1 variant.In contrast,aluminum hydroxide adjuvanted S-2P(S-2P:Al)elicited comparatively lower neutralizing titers and showed no cross-neutralization against BA.1.Following viral challenge,the S-2P:ISA720 group exhibited significant affinity maturation toward conserved epitopes,which markedly enhanced cross-neutralization against BA.1 without increasing neutralizing titers or affinity against the homologous strain or the antigenically related Delta variant.Conversely,the S-2P:Al group mounted a narrow,imprinting-facilitated response,characterized by boosting of strain-specific antibodies without substantial improvement in BA.1 neutralization.These findings suggest that in S-2P:ISA720-immunized animals,high-affinity antibodies mediate epitope masking of immunodominant sites,thereby redirecting responses toward subdominant conserved epitopes with cross-neutralizing potential.In conclusion,our study demonstrates that adjuvants can critically guide recall immune responses toward breadth and affinity maturation,offering a rational strategy for developing next-generation vaccines against SARS-CoV-2 and other variable pathogens.展开更多
The coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARSCoV-2)is a global crisis.Clinical candidates with high efficacy,ready availability,and that do not develop r...The coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARSCoV-2)is a global crisis.Clinical candidates with high efficacy,ready availability,and that do not develop resistance are in urgent need.Despite that screening to repurpose clinically approved drugs has provided a variety of hits shown to be effective against SARS-CoV-2 infection in cell culture,there are few confirmed antiviral candidates in vivo.In this study,94 compounds showing high antiviral activity against SARS-CoV-2 in Vero E6 cells were identified from 2,580 FDA-approved small-molecule drugs.Among them,24 compounds with low cytotoxicity were selected,and of these,17 compounds also effectively suppressed SARS-CoV-2 infection in He La cells transduced with human ACE2.Six compounds disturb multiple processes of the SARSCoV-2 life cycle.Their prophylactic efficacies were determined in vivo using Syrian hamsters challenged with SARS-CoV-2infection.Seven compounds reduced weight loss and promoted weight regain of hamsters infected not only with the original strain but also the D614G variant.Except for cisatracurium,six compounds reduced hamster pulmonary viral load,and IL-6 and TNF-αm RNAwhen assayed at 4 d postinfection.In particular,sertraline,salinomycin,and gilteritinib showed similar protective effects as remdesivir in vivo and did not induce antiviral drug resistance after 10 serial passages of SARS-CoV-2 in vitro,suggesting promising application for COVID-19 treatment.展开更多
基金supported by the National Key Research&Development Program of China(2022YFC2304100)the Major Research Plan of the National Natural Science Foundation of China(92169206).
文摘Immune imprinting,or original antigenic sin,challenges the control of evolving severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).How the quantity and quality of pre-existing immunity modulate the recall antibody response upon re-exposure remains poorly understood.We immunized hamsters with a recombinant ancestral spike protein(S-2P)formulated with one of four distinct adjuvants to assess the impact of adjuvant-induced immunity on protective efficacy.Furthermore,we analyzed the modulatory effect of the adjuvant on the potency,breadth,and evolution of antibody responses after homologous viral challenge.We found that vaccination with Montanide ISA720-adjuvanted S-2P(S-2P:ISA720)not only induced higher initial neutralizing antibody titers and conferred stronger protection but also established a pre-existing immune state capable of cross-neutralizing the antigenically distant Omicron BA.1 variant.In contrast,aluminum hydroxide adjuvanted S-2P(S-2P:Al)elicited comparatively lower neutralizing titers and showed no cross-neutralization against BA.1.Following viral challenge,the S-2P:ISA720 group exhibited significant affinity maturation toward conserved epitopes,which markedly enhanced cross-neutralization against BA.1 without increasing neutralizing titers or affinity against the homologous strain or the antigenically related Delta variant.Conversely,the S-2P:Al group mounted a narrow,imprinting-facilitated response,characterized by boosting of strain-specific antibodies without substantial improvement in BA.1 neutralization.These findings suggest that in S-2P:ISA720-immunized animals,high-affinity antibodies mediate epitope masking of immunodominant sites,thereby redirecting responses toward subdominant conserved epitopes with cross-neutralizing potential.In conclusion,our study demonstrates that adjuvants can critically guide recall immune responses toward breadth and affinity maturation,offering a rational strategy for developing next-generation vaccines against SARS-CoV-2 and other variable pathogens.
基金supported by the National Natural Science Foundation of China(31570170)the National Key Research and Development Program of China(2016YFC1200401)。
文摘The coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARSCoV-2)is a global crisis.Clinical candidates with high efficacy,ready availability,and that do not develop resistance are in urgent need.Despite that screening to repurpose clinically approved drugs has provided a variety of hits shown to be effective against SARS-CoV-2 infection in cell culture,there are few confirmed antiviral candidates in vivo.In this study,94 compounds showing high antiviral activity against SARS-CoV-2 in Vero E6 cells were identified from 2,580 FDA-approved small-molecule drugs.Among them,24 compounds with low cytotoxicity were selected,and of these,17 compounds also effectively suppressed SARS-CoV-2 infection in He La cells transduced with human ACE2.Six compounds disturb multiple processes of the SARSCoV-2 life cycle.Their prophylactic efficacies were determined in vivo using Syrian hamsters challenged with SARS-CoV-2infection.Seven compounds reduced weight loss and promoted weight regain of hamsters infected not only with the original strain but also the D614G variant.Except for cisatracurium,six compounds reduced hamster pulmonary viral load,and IL-6 and TNF-αm RNAwhen assayed at 4 d postinfection.In particular,sertraline,salinomycin,and gilteritinib showed similar protective effects as remdesivir in vivo and did not induce antiviral drug resistance after 10 serial passages of SARS-CoV-2 in vitro,suggesting promising application for COVID-19 treatment.
