Mucosal antibodies are critical for protection against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection by limiting viral replication and transmission.While systemic immunity to SARS-CoV-2 is well-...Mucosal antibodies are critical for protection against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection by limiting viral replication and transmission.While systemic immunity to SARS-CoV-2 is well-characterized,the durability and protective efficacy of mucosal vaccines,especially during the recent JN.1 wave,are less understood.In this study,we conducted a longitudinal assessment of systemic and nasal immune responses in 34 individuals who had received the inhaled Ad5-XBB.1.5 vaccination at days 0,7,14,28,90,and 180 post-vaccination,using neutralization assays,immunoglobulin A/G(IgA/IgG)enzyme-linked immunosorbent assay(ELISA),T-cell staining,and Fc-effector function assays.Our results showed that mucosal vaccination preferentially induces IgA responses in both nasal mucosa and systemic circulation,with nasal IgA showing stronger correlation with neutralizing titers than IgG.However,nasal antibody responses declined significantly by 6 months post-vaccination,with most participants experiencing breakthrough infections during the JN.1 wave.Individuals with high pre-existing anti-Ad5 antibodies exhibited reduced vaccine-induced neutralizing responses.The Ad5-XBB.1.5 mucosal vaccine enhanced antigen-specific CD8^(+)T cell responses with a slight increase in Fc-mediated antibody-dependent cellular phagocytosis(ADCP),but failed to induce detectable CD4^(+)T cell responses.Collectively,our findings elucidate the limited durability of mucosal immunity post-vaccination and highlight the need for improved mucosal vaccine strategies that sustain and optimize nasal IgA responses.展开更多
We have previously reported that AD5-10, a novel agonistic monoclonal antibody against DRS, possessed a strong cytotoxic activity in various tumor cells, via induction of caspase-dependent and -independent signaling p...We have previously reported that AD5-10, a novel agonistic monoclonal antibody against DRS, possessed a strong cytotoxic activity in various tumor cells, via induction of caspase-dependent and -independent signaling pathways. The present study further demonstrates that reactive oxygen species （ROS） were generated in abundance in Jurkat leukemia cells upon AD5-10 stimulation and that ROS accumulation subsequently evoked sustained activation of c-Jun N-terminal kinase （JNK）, loss of mitochondrial membrane potential, and release of endonuclease G （Endo G） from mitochondria into the cytosol. The reducing agent, N-acetylcysteine （NAC）, effectively inhibited the sustained activation of JNK, release of Endo G, and cell death in Jurkat cells treated by AD5-10. Moreover, a dominant-negative form of JNK （but not of p38） enhanced NF-κB activation, suppressed caspase-8 recruitment in death-inducing signaling complexes （DISCs）, and reduced adverse effects on mitochondria, thereby inhibiting AD5-10-induced cell death in Jnrkat leukemia cells. These data provide novel information on the DR5-mediated ceil death-signaling path- way and may shed new light on effective strategies for leukemia and solid tumor therapies.展开更多
Homologous booster,heterologous booster,and Omicron variants breakthrough infection(OBI)could improve the humoral immunity against Omicron variants.Questions concerning about memory B cells(MBCs)and T cells immunity a...Homologous booster,heterologous booster,and Omicron variants breakthrough infection(OBI)could improve the humoral immunity against Omicron variants.Questions concerning about memory B cells(MBCs)and T cells immunity against Omicron variants,features of long-term immunity,after booster and OBI,needs to be explored.Here,comparative analysis demonstrate antibody and T cell immunity against ancestral strain,Delta and Omicron variants in Omicron breakthrough infected patients(OBIPs)are comparable to that in Ad5-nCoV boosted healthy volunteers(HVs),higher than that in inactivated vaccine(InV)boosted HVs.However,memory B cells(MBCs)immunity against Omicron variants was highest in OBIPs,followed by Ad5-nCoV boosted and InV boosted HVs.OBIPs and Ad5-nCoV boosted HVs have higher classical MBCs and activated MBCs,and lower naïve MBCs and atypical MBCs relative to both vaccine boosted HVs.Collectively,these data indicate Omicron breakthrough infection elicit higher MBCs and T cells against SARS-CoV-2 especially Omicron variants relative to homologous InV booster and heterologous Ad5-nCoV booster.展开更多
基金supported by grants from the National Key Research and Development Program of China(grant number 2024YFA0920001 to Y.W.)the National Natural Science Foundation of China(grant numbers 82025001,82495200,and 82495203 to J.Z.,92369113 and 82172240 to Y.W.)+5 种基金Guangzhou National Laboratory and State Key Laboratory of Respiratory Disease(grant number GZNL2024B01001 to Y.W.)Selfsupporting Program of Guangzhou National Laboratory(grant number SRPG22-001 to Y.W.)Guangdong Basic and Applied Research Projects(grant number 2023B1515020040 to Y.W.)State Key Laboratory of Respiratory Disease(grant number SKLRD-Z-202411 to L.Z.)Science and Technology Planning Project of Guangzhou City(grant numbers 2023A04J1279 to L.Z.and 2024A03J1230 to J.Z.)the Science and Technology Project of General Administration of Customs,P.R.China(grant number 2023HK065 to L.Z.).
文摘Mucosal antibodies are critical for protection against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection by limiting viral replication and transmission.While systemic immunity to SARS-CoV-2 is well-characterized,the durability and protective efficacy of mucosal vaccines,especially during the recent JN.1 wave,are less understood.In this study,we conducted a longitudinal assessment of systemic and nasal immune responses in 34 individuals who had received the inhaled Ad5-XBB.1.5 vaccination at days 0,7,14,28,90,and 180 post-vaccination,using neutralization assays,immunoglobulin A/G(IgA/IgG)enzyme-linked immunosorbent assay(ELISA),T-cell staining,and Fc-effector function assays.Our results showed that mucosal vaccination preferentially induces IgA responses in both nasal mucosa and systemic circulation,with nasal IgA showing stronger correlation with neutralizing titers than IgG.However,nasal antibody responses declined significantly by 6 months post-vaccination,with most participants experiencing breakthrough infections during the JN.1 wave.Individuals with high pre-existing anti-Ad5 antibodies exhibited reduced vaccine-induced neutralizing responses.The Ad5-XBB.1.5 mucosal vaccine enhanced antigen-specific CD8^(+)T cell responses with a slight increase in Fc-mediated antibody-dependent cellular phagocytosis(ADCP),but failed to induce detectable CD4^(+)T cell responses.Collectively,our findings elucidate the limited durability of mucosal immunity post-vaccination and highlight the need for improved mucosal vaccine strategies that sustain and optimize nasal IgA responses.
基金Acknowledgments We thank Dr Shimin Hu for his generous gifts of constructs. This work was partially supported by National Natural Science Foundation of China （Grant Nos. 30571687 and 30721063） and by State Key Basic Research Program of China （Grant No. 2007CB507404）.
文摘We have previously reported that AD5-10, a novel agonistic monoclonal antibody against DRS, possessed a strong cytotoxic activity in various tumor cells, via induction of caspase-dependent and -independent signaling pathways. The present study further demonstrates that reactive oxygen species （ROS） were generated in abundance in Jurkat leukemia cells upon AD5-10 stimulation and that ROS accumulation subsequently evoked sustained activation of c-Jun N-terminal kinase （JNK）, loss of mitochondrial membrane potential, and release of endonuclease G （Endo G） from mitochondria into the cytosol. The reducing agent, N-acetylcysteine （NAC）, effectively inhibited the sustained activation of JNK, release of Endo G, and cell death in Jurkat cells treated by AD5-10. Moreover, a dominant-negative form of JNK （but not of p38） enhanced NF-κB activation, suppressed caspase-8 recruitment in death-inducing signaling complexes （DISCs）, and reduced adverse effects on mitochondria, thereby inhibiting AD5-10-induced cell death in Jnrkat leukemia cells. These data provide novel information on the DR5-mediated ceil death-signaling path- way and may shed new light on effective strategies for leukemia and solid tumor therapies.
基金Guangzhou Health Science and Technology Project(20201A011078)Guangzhou Science and Technology Project(202102010094)+5 种基金Guangdong Basic and Applied Basic Research Foundation(2021A1515012550)Clinical research project of Guangzhou Medical University Second Affiliated Hospital(2021-LCYJ-05)Guangdong Medical Research Fund(A2022255)Key Clinical Specialty of Guangzhou Medical University(0F03031)Guangzhou Laboratory(EKPG21-30-3)Guangzhou key discipline of urology.The funding sources had no role in the study design,data collection,analysis,interpretation,or writing of the report.
文摘Homologous booster,heterologous booster,and Omicron variants breakthrough infection(OBI)could improve the humoral immunity against Omicron variants.Questions concerning about memory B cells(MBCs)and T cells immunity against Omicron variants,features of long-term immunity,after booster and OBI,needs to be explored.Here,comparative analysis demonstrate antibody and T cell immunity against ancestral strain,Delta and Omicron variants in Omicron breakthrough infected patients(OBIPs)are comparable to that in Ad5-nCoV boosted healthy volunteers(HVs),higher than that in inactivated vaccine(InV)boosted HVs.However,memory B cells(MBCs)immunity against Omicron variants was highest in OBIPs,followed by Ad5-nCoV boosted and InV boosted HVs.OBIPs and Ad5-nCoV boosted HVs have higher classical MBCs and activated MBCs,and lower naïve MBCs and atypical MBCs relative to both vaccine boosted HVs.Collectively,these data indicate Omicron breakthrough infection elicit higher MBCs and T cells against SARS-CoV-2 especially Omicron variants relative to homologous InV booster and heterologous Ad5-nCoV booster.
