Marcus Mumme, Anke Wixmerten, Alan Ivkovic, Giuseppe M. Peretti, Tayfun Yilmaz, Stephan Reppenhagen, Oliver Pullig, Sylvie Miot, Kaywan Izadpanah, Marcel Jakob, Laura Mangiavini, Corrado Sosio, Filip Vuletić, Oliver Bieri, Stefano Biguzzi, Brigitta Gahl, Gyözö Lehoczky, Rudolf Vukojevic, Sebastian Häusner, Anna Gryadunova, Martin Haug, Andrea Barbero, Ivan Martin
Cartilage lesions do not heal spontaneously and predispose to osteoarthritis. Functional cartilage tissues, engineered using autologous chondrocytes, have a therapeutic advantage over conventional cellular therapies in preclinical studies. Here, we tested whether ex vivo maturation of engineered grafts for cartilage repair leads to improved patient benefit. Using autologous nasal chondrocytes (NCs), we tested whether implantation of in vitro–matured NC-tissue-engineered cartilage (N-TEC) versus undifferentiated NC-cell-activated matrices (N-CAM) in focal cartilage lesions would result in a superior clinical outcome. The prospective, randomized, parallel, open-label phase-2 trial (ClinicalTrials.gov, NCT02673905) enrolled 108 patients in five hospitals from four countries. Patients ranging in age from 30 to 46 years with full-thickness knee cartilage defects (size, 2.7 to 6.0 square centimeters) were equally randomized and treated with N-TEC or N-CAM. The primary preregistered outcome was the overall Knee Injury Osteoarthritis Outcome Score (KOOS) at 24 months. N-TEC, which underwent a longer NC culture time, was phenotypically, structurally, and functionally more like hyaline cartilage than N-CAM. The overall KOOS increased with clinical relevance in both groups compared with preoperative values. KOOS was higher at 24 months for N-TEC [85; interquartile range (IQR), 74 to 91] than for N-CAM (79; IQR, 65 to 85). N-TEC, but not N-CAM, was similarly effective in patients with larger defects or revision surgery. Radiologically, N-TEC resulted in a superior composition of both repair tissue and surrounding cartilage, whereas structural scores were similar. This trial validates the clinical efficacy of NC-based grafts for articular cartilage repair and supports the clinical relevance of engineering mature tissues, even for patients with more challenging cartilage defects.
{"title":"Clinical relevance of engineered cartilage maturation in a randomized multicenter trial for articular cartilage repair","authors":"Marcus Mumme, Anke Wixmerten, Alan Ivkovic, Giuseppe M. Peretti, Tayfun Yilmaz, Stephan Reppenhagen, Oliver Pullig, Sylvie Miot, Kaywan Izadpanah, Marcel Jakob, Laura Mangiavini, Corrado Sosio, Filip Vuletić, Oliver Bieri, Stefano Biguzzi, Brigitta Gahl, Gyözö Lehoczky, Rudolf Vukojevic, Sebastian Häusner, Anna Gryadunova, Martin Haug, Andrea Barbero, Ivan Martin","doi":"","DOIUrl":"","url":null,"abstract":"<div >Cartilage lesions do not heal spontaneously and predispose to osteoarthritis. Functional cartilage tissues, engineered using autologous chondrocytes, have a therapeutic advantage over conventional cellular therapies in preclinical studies. Here, we tested whether ex vivo maturation of engineered grafts for cartilage repair leads to improved patient benefit. Using autologous nasal chondrocytes (NCs), we tested whether implantation of in vitro–matured NC-tissue-engineered cartilage (N-TEC) versus undifferentiated NC-cell-activated matrices (N-CAM) in focal cartilage lesions would result in a superior clinical outcome. The prospective, randomized, parallel, open-label phase-2 trial (ClinicalTrials.gov, NCT02673905) enrolled 108 patients in five hospitals from four countries. Patients ranging in age from 30 to 46 years with full-thickness knee cartilage defects (size, 2.7 to 6.0 square centimeters) were equally randomized and treated with N-TEC or N-CAM. The primary preregistered outcome was the overall Knee Injury Osteoarthritis Outcome Score (KOOS) at 24 months. N-TEC, which underwent a longer NC culture time, was phenotypically, structurally, and functionally more like hyaline cartilage than N-CAM. The overall KOOS increased with clinical relevance in both groups compared with preoperative values. KOOS was higher at 24 months for N-TEC [85; interquartile range (IQR), 74 to 91] than for N-CAM (79; IQR, 65 to 85). N-TEC, but not N-CAM, was similarly effective in patients with larger defects or revision surgery. Radiologically, N-TEC resulted in a superior composition of both repair tissue and surrounding cartilage, whereas structural scores were similar. This trial validates the clinical efficacy of NC-based grafts for articular cartilage repair and supports the clinical relevance of engineering mature tissues, even for patients with more challenging cartilage defects.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 788","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-05DOI: 10.1126/scitranslmed.ado0020
Shuo Sun, Shiyu Qian, Ran Wang, Mengya Zhao, Ran Li, Wei Gu, Mengjie Zhao, Chunfa Qian, Liang Liu, Xianglong Tang, Yangyang Li, Hui Shi, Yunsong Pan, Hong Xiao, Kun Yang, Chupeng Hu, Yedi Huang, Liangnian Wei, Yuhan Zhang, Jing Ji, Yun Chen, Hongyi Liu
Radiotherapy (RT) has been the standard-of-care treatment for patients with glioblastoma (GBM); however, the clinical effectiveness is hindered by therapeutic resistance. Here, we demonstrated that the tumor immune microenvironment (TIME) exhibited immunosuppressive properties and high expression of Golgi phosphoprotein 3 like (GOLPH3L) in RT-resistant GBM. Our study showed that GOLPH3L interacted with stimulator of interferon genes (STING) at the aspartic acid residue 184 in Golgi after RT, leading to coat protein complex II–mediated retrograde transport of STING from Golgi to endoplasmic reticulum. This suppressed the STING–NOD-like receptor thermal protein domain associated protein 3 (NLRP3)–mediated pyroptosis, resulting in suppressive TIME, driving GBM resistance to RT. Genetic GOLPH3L ablation in RT-resistant GBM cells augmented antitumor immunity and overcame tumor resistance to RT. Moreover, we have identified a small molecular inhibitor of GOLPH3L, vitamin B5 calcium (VB5), which improved the therapeutic efficacy of RT and immune checkpoint blockade by inducing a robust antitumor immune response in mouse models. Clinically, patients with GBM treated with VB5 exhibited improved responses to RT. Thus, reprogramming the TIME by targeting GOLPH3L may offer a potential opportunity to improve RT in GBM.
{"title":"Targeting GOLPH3L improves glioblastoma radiotherapy by regulating STING-NLRP3–mediated tumor immune microenvironment reprogramming","authors":"Shuo Sun, Shiyu Qian, Ran Wang, Mengya Zhao, Ran Li, Wei Gu, Mengjie Zhao, Chunfa Qian, Liang Liu, Xianglong Tang, Yangyang Li, Hui Shi, Yunsong Pan, Hong Xiao, Kun Yang, Chupeng Hu, Yedi Huang, Liangnian Wei, Yuhan Zhang, Jing Ji, Yun Chen, Hongyi Liu","doi":"10.1126/scitranslmed.ado0020","DOIUrl":"https://doi.org/10.1126/scitranslmed.ado0020","url":null,"abstract":"Radiotherapy (RT) has been the standard-of-care treatment for patients with glioblastoma (GBM); however, the clinical effectiveness is hindered by therapeutic resistance. Here, we demonstrated that the tumor immune microenvironment (TIME) exhibited immunosuppressive properties and high expression of Golgi phosphoprotein 3 like (GOLPH3L) in RT-resistant GBM. Our study showed that GOLPH3L interacted with stimulator of interferon genes (STING) at the aspartic acid residue 184 in Golgi after RT, leading to coat protein complex II–mediated retrograde transport of STING from Golgi to endoplasmic reticulum. This suppressed the STING–NOD-like receptor thermal protein domain associated protein 3 (NLRP3)–mediated pyroptosis, resulting in suppressive TIME, driving GBM resistance to RT. Genetic GOLPH3L ablation in RT-resistant GBM cells augmented antitumor immunity and overcame tumor resistance to RT. Moreover, we have identified a small molecular inhibitor of GOLPH3L, vitamin B5 calcium (VB5), which improved the therapeutic efficacy of RT and immune checkpoint blockade by inducing a robust antitumor immune response in mouse models. Clinically, patients with GBM treated with VB5 exhibited improved responses to RT. Thus, reprogramming the TIME by targeting GOLPH3L may offer a potential opportunity to improve RT in GBM.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"7 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-05DOI: 10.1126/scitranslmed.adr0942
Oluwabunmi Olaloye, Weihong Gu, Arne Gehlhaar, Burhanuddin Sabuwala, Chino K. Eke, Yujia Li, Tessa Kehoe, Rohit Farmer, Gisela Gabernet, Carrie L. Lucas, John S. Tsang, Saquib A. Lakhani, Sarah N. Taylor, George Tseng, Steven H. Kleinstein, Liza Konnikova
Extremely premature infants (EPIs) who are born before 30 weeks of gestation are susceptible to infection; however, the trajectory of their peripheral immunity is poorly understood. Here, we undertook longitudinal analyses of immune cells from 250 μl of whole blood at 1 week, 1 month, and 2 months from 10 EPIs and compared these with samples from healthy adults and with preterm and full-term cord blood samples. Single-cell suspensions from individual samples were split to perform single-cell RNA sequencing, T and B cell receptor sequencing, and phosphoprotein mass cytometry. The trajectories of circulating T, B, myeloid, and natural killer cells in EPIs over the first 2 months of life were distinct from those of full-term infants. In EPIs, peripheral T cell development rapidly progressed over the first month of life, with an increase in the proportion of naïve CD4 + , regulatory, and cycling T cells, accompanied by greater STAT5 (signal transducer and activator of transcription 5) signaling. EPI memory CD4 + T cells showed a T helper 1 (T H 1) predominance compared with T H 2 skewing of central memory–like T cells in full-term infants, and B cells from 2-month-old EPIs exhibited increased signatures of activation and differentiation. Both B and T cells from 2-month-old EPIs displayed increased interferon signatures compared with cells from full-term infants. In conclusion, we demonstrated the feasibility of longitudinal multiomic analyses in EPIs using minute amounts of blood and developed a resource describing peripheral immune development in EPIs that suggested ongoing activation in early life.
{"title":"A single-cell atlas of circulating immune cells over the first 2 months of age in extremely premature infants","authors":"Oluwabunmi Olaloye, Weihong Gu, Arne Gehlhaar, Burhanuddin Sabuwala, Chino K. Eke, Yujia Li, Tessa Kehoe, Rohit Farmer, Gisela Gabernet, Carrie L. Lucas, John S. Tsang, Saquib A. Lakhani, Sarah N. Taylor, George Tseng, Steven H. Kleinstein, Liza Konnikova","doi":"10.1126/scitranslmed.adr0942","DOIUrl":"https://doi.org/10.1126/scitranslmed.adr0942","url":null,"abstract":"Extremely premature infants (EPIs) who are born before 30 weeks of gestation are susceptible to infection; however, the trajectory of their peripheral immunity is poorly understood. Here, we undertook longitudinal analyses of immune cells from 250 μl of whole blood at 1 week, 1 month, and 2 months from 10 EPIs and compared these with samples from healthy adults and with preterm and full-term cord blood samples. Single-cell suspensions from individual samples were split to perform single-cell RNA sequencing, T and B cell receptor sequencing, and phosphoprotein mass cytometry. The trajectories of circulating T, B, myeloid, and natural killer cells in EPIs over the first 2 months of life were distinct from those of full-term infants. In EPIs, peripheral T cell development rapidly progressed over the first month of life, with an increase in the proportion of naïve CD4 <jats:sup>+</jats:sup> , regulatory, and cycling T cells, accompanied by greater STAT5 (signal transducer and activator of transcription 5) signaling. EPI memory CD4 <jats:sup>+</jats:sup> T cells showed a T helper 1 (T <jats:sub>H</jats:sub> 1) predominance compared with T <jats:sub>H</jats:sub> 2 skewing of central memory–like T cells in full-term infants, and B cells from 2-month-old EPIs exhibited increased signatures of activation and differentiation. Both B and T cells from 2-month-old EPIs displayed increased interferon signatures compared with cells from full-term infants. In conclusion, we demonstrated the feasibility of longitudinal multiomic analyses in EPIs using minute amounts of blood and developed a resource describing peripheral immune development in EPIs that suggested ongoing activation in early life.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"14 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shuo Sun, Shiyu Qian, Ran Wang, Mengya Zhao, Ran Li, Wei Gu, Mengjie Zhao, Chunfa Qian, Liang Liu, Xianglong Tang, Yangyang Li, Hui Shi, Yunsong Pan, Hong Xiao, Kun Yang, Chupeng Hu, Yedi Huang, Liangnian Wei, Yuhan Zhang, Jing Ji, Yun Chen, Hongyi Liu
Radiotherapy (RT) has been the standard-of-care treatment for patients with glioblastoma (GBM); however, the clinical effectiveness is hindered by therapeutic resistance. Here, we demonstrated that the tumor immune microenvironment (TIME) exhibited immunosuppressive properties and high expression of Golgi phosphoprotein 3 like (GOLPH3L) in RT-resistant GBM. Our study showed that GOLPH3L interacted with stimulator of interferon genes (STING) at the aspartic acid residue 184 in Golgi after RT, leading to coat protein complex II–mediated retrograde transport of STING from Golgi to endoplasmic reticulum. This suppressed the STING–NOD-like receptor thermal protein domain associated protein 3 (NLRP3)–mediated pyroptosis, resulting in suppressive TIME, driving GBM resistance to RT. Genetic GOLPH3L ablation in RT-resistant GBM cells augmented antitumor immunity and overcame tumor resistance to RT. Moreover, we have identified a small molecular inhibitor of GOLPH3L, vitamin B5 calcium (VB5), which improved the therapeutic efficacy of RT and immune checkpoint blockade by inducing a robust antitumor immune response in mouse models. Clinically, patients with GBM treated with VB5 exhibited improved responses to RT. Thus, reprogramming the TIME by targeting GOLPH3L may offer a potential opportunity to improve RT in GBM.
{"title":"Targeting GOLPH3L improves glioblastoma radiotherapy by regulating STING-NLRP3–mediated tumor immune microenvironment reprogramming","authors":"Shuo Sun, Shiyu Qian, Ran Wang, Mengya Zhao, Ran Li, Wei Gu, Mengjie Zhao, Chunfa Qian, Liang Liu, Xianglong Tang, Yangyang Li, Hui Shi, Yunsong Pan, Hong Xiao, Kun Yang, Chupeng Hu, Yedi Huang, Liangnian Wei, Yuhan Zhang, Jing Ji, Yun Chen, Hongyi Liu","doi":"","DOIUrl":"","url":null,"abstract":"<div >Radiotherapy (RT) has been the standard-of-care treatment for patients with glioblastoma (GBM); however, the clinical effectiveness is hindered by therapeutic resistance. Here, we demonstrated that the tumor immune microenvironment (TIME) exhibited immunosuppressive properties and high expression of Golgi phosphoprotein 3 like (GOLPH3L) in RT-resistant GBM. Our study showed that GOLPH3L interacted with stimulator of interferon genes (STING) at the aspartic acid residue 184 in Golgi after RT, leading to coat protein complex II–mediated retrograde transport of STING from Golgi to endoplasmic reticulum. This suppressed the STING–NOD-like receptor thermal protein domain associated protein 3 (NLRP3)–mediated pyroptosis, resulting in suppressive TIME, driving GBM resistance to RT. Genetic GOLPH3L ablation in RT-resistant GBM cells augmented antitumor immunity and overcame tumor resistance to RT. Moreover, we have identified a small molecular inhibitor of GOLPH3L, vitamin B5 calcium (VB5), which improved the therapeutic efficacy of RT and immune checkpoint blockade by inducing a robust antitumor immune response in mouse models. Clinically, patients with GBM treated with VB5 exhibited improved responses to RT. Thus, reprogramming the TIME by targeting GOLPH3L may offer a potential opportunity to improve RT in GBM.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 788","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Juyeon Park, Lisa C. Lindesmith, Adam S. Olia, Veronica P. Costantini, Paul D. Brewer-Jensen, Michael L. Mallory, Cynthia E. Kelley, Ed Satterwhite, Victoria Longo, Yaroslav Tsybovsky, Tyler Stephens, Jeffrey Marchioni, Christina A. Martins, Yimin Huang, Ridhi Chaudhary, Mark Zweigart, Samantha R. May, Yaoska Reyes, Becca Flitter, Jan Vinjé, Sean N. Tucker, Gregory C. Ippolito, Jason J. Lavinder, Joost Snijder, Peter D. Kwong, George Georgiou, Ralph S. Baric
Human norovirus causes more than 700 million illnesses annually. Extensive genetic diversity and a paucity of information on conserved neutralizing epitopes pose major obstacles to the design of broadly protective norovirus immunogens. Here, we used high-resolution liquid chromatography–tandem mass spectrometry (LC-MS/MS)–driven proteomics to quantitatively characterize the circulating serum IgG repertoire before and after immunization with an experimental monovalent norovirus GII.4 VP1 capsid–encoding adenoviral vaccine. Two participants were specifically selected on the basis of the breadth of serum neutralization responses either across GII.4 variants (participant A) or across GII genotypes (participant B). In participant A, vaccination back-boosted highly abundant serum antibody clonotypes targeting epitopes conserved among rapidly evolving GII.4 variants spanning from a strain identified in 1987 to a strain identified in 2019. In participant B, we identified a recall response consisting of broadly neutralizing monoclonal antibodies with remarkable cross-GII ligand-binding blockade (blocking ≥ seven GII genotypes) and virus neutralization breadth. The cocrystal structure of one of these antibodies, VX22, in complex with the VP1 capsid protruding (P) domain revealed a highly conserved epitope (residues 479 to 484 and 509 to 513) within two lateral loops of the P1 subdomain. Antibody evolutionary trajectory analysis further revealed that VX22 had originally evolved from an early heterologous infection, likely by a GII.12 strain. Together, our study demonstrates that norovirus human monoclonal antibodies with broad GII.4 potency and cross-GII breadth can be boosted in serum after immunization with an adenoviral vector–based vaccine, findings that may guide the design of immunogens for broadly protective norovirus vaccines.
{"title":"Broadly neutralizing antibodies targeting pandemic GII.4 variants or seven GII genotypes of human norovirus","authors":"Juyeon Park, Lisa C. Lindesmith, Adam S. Olia, Veronica P. Costantini, Paul D. Brewer-Jensen, Michael L. Mallory, Cynthia E. Kelley, Ed Satterwhite, Victoria Longo, Yaroslav Tsybovsky, Tyler Stephens, Jeffrey Marchioni, Christina A. Martins, Yimin Huang, Ridhi Chaudhary, Mark Zweigart, Samantha R. May, Yaoska Reyes, Becca Flitter, Jan Vinjé, Sean N. Tucker, Gregory C. Ippolito, Jason J. Lavinder, Joost Snijder, Peter D. Kwong, George Georgiou, Ralph S. Baric","doi":"","DOIUrl":"","url":null,"abstract":"<div >Human norovirus causes more than 700 million illnesses annually. Extensive genetic diversity and a paucity of information on conserved neutralizing epitopes pose major obstacles to the design of broadly protective norovirus immunogens. Here, we used high-resolution liquid chromatography–tandem mass spectrometry (LC-MS/MS)–driven proteomics to quantitatively characterize the circulating serum IgG repertoire before and after immunization with an experimental monovalent norovirus GII.4 VP1 capsid–encoding adenoviral vaccine. Two participants were specifically selected on the basis of the breadth of serum neutralization responses either across GII.4 variants (participant A) or across GII genotypes (participant B). In participant A, vaccination back-boosted highly abundant serum antibody clonotypes targeting epitopes conserved among rapidly evolving GII.4 variants spanning from a strain identified in 1987 to a strain identified in 2019. In participant B, we identified a recall response consisting of broadly neutralizing monoclonal antibodies with remarkable cross-GII ligand-binding blockade (blocking ≥ seven GII genotypes) and virus neutralization breadth. The cocrystal structure of one of these antibodies, VX22, in complex with the VP1 capsid protruding (P) domain revealed a highly conserved epitope (residues 479 to 484 and 509 to 513) within two lateral loops of the P1 subdomain. Antibody evolutionary trajectory analysis further revealed that VX22 had originally evolved from an early heterologous infection, likely by a GII.12 strain. Together, our study demonstrates that norovirus human monoclonal antibodies with broad GII.4 potency and cross-GII breadth can be boosted in serum after immunization with an adenoviral vector–based vaccine, findings that may guide the design of immunogens for broadly protective norovirus vaccines.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 788","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Becca A. Flitter, Susan N. Greco, Colin A. Lester, Elena D. Neuhaus, Sarah N. Tedjakusuma, Mallory Shriver, Esmeralda Cuevas-Juárez, Samanta Gutierrez, Molly R. Braun, Marcela F. Pasetti, Sean N. Tucker, James F. Cummings
Norovirus is a leading cause of acute gastroenteritis globally, with infections in older adults associated with heightened severity and increased risk of mortality. Currently, no licensed vaccines are available to prevent norovirus infection. We developed an orally administered vaccine tablet (VXA-G1.1-NN) that delivers a nonreplicating adenoviral vector expressing norovirus GI.1 major capsid protein VP1 to the small intestine. Here, we report safety and immunogenicity results of a randomized, double-blind, placebo-controlled clinical trial (NCT04854746) that investigated the oral administration of VXA-G1.1-NN in two groups of healthy older adults aged 55 to 65 and 66 to 80 years. VXA-G1.1-NN was administered orally at three dose levels by prime and boost, 28 days apart. Immunization was well tolerated regardless of dose, with mild to moderate reported solicited symptoms and no related serious or grade 3 adverse events. Oral delivery of VXA-G1.1-NN elicited VP1-specific serum immunoglobulin G (IgG) and IgA and functional antibodies in a dose-dependent manner 28 days postvaccination and remained above baseline for 210 days. Moreover, robust circulating VP1-specific IgA antibody-secreting cells were detected 1 week postvaccination along with IgA+ plasmablasts expressing the mucosal-homing marker α4β7. VP1-specific IgA increased in saliva and nasal lining fluid 28 days postvaccination in both age groups and remained above baseline concentrations through 210 days, demonstrating durable mucosal responses. This clinical trial established that oral administration of VXA-G1.1-NN is safe, well tolerated, and induces robust systemic and mucosal immune responses in adults up to 80 years old.
{"title":"An oral norovirus vaccine tablet was safe and elicited mucosal immunity in older adults in a phase 1b clinical trial","authors":"Becca A. Flitter, Susan N. Greco, Colin A. Lester, Elena D. Neuhaus, Sarah N. Tedjakusuma, Mallory Shriver, Esmeralda Cuevas-Juárez, Samanta Gutierrez, Molly R. Braun, Marcela F. Pasetti, Sean N. Tucker, James F. Cummings","doi":"","DOIUrl":"","url":null,"abstract":"<div >Norovirus is a leading cause of acute gastroenteritis globally, with infections in older adults associated with heightened severity and increased risk of mortality. Currently, no licensed vaccines are available to prevent norovirus infection. We developed an orally administered vaccine tablet (VXA-G1.1-NN) that delivers a nonreplicating adenoviral vector expressing norovirus GI.1 major capsid protein VP1 to the small intestine. Here, we report safety and immunogenicity results of a randomized, double-blind, placebo-controlled clinical trial (NCT04854746) that investigated the oral administration of VXA-G1.1-NN in two groups of healthy older adults aged 55 to 65 and 66 to 80 years. VXA-G1.1-NN was administered orally at three dose levels by prime and boost, 28 days apart. Immunization was well tolerated regardless of dose, with mild to moderate reported solicited symptoms and no related serious or grade 3 adverse events. Oral delivery of VXA-G1.1-NN elicited VP1-specific serum immunoglobulin G (IgG) and IgA and functional antibodies in a dose-dependent manner 28 days postvaccination and remained above baseline for 210 days. Moreover, robust circulating VP1-specific IgA antibody-secreting cells were detected 1 week postvaccination along with IgA<sup>+</sup> plasmablasts expressing the mucosal-homing marker α4β7. VP1-specific IgA increased in saliva and nasal lining fluid 28 days postvaccination in both age groups and remained above baseline concentrations through 210 days, demonstrating durable mucosal responses. This clinical trial established that oral administration of VXA-G1.1-NN is safe, well tolerated, and induces robust systemic and mucosal immune responses in adults up to 80 years old.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 788","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-05DOI: 10.1126/scitranslmed.ads0556
Becca A. Flitter, Susan N. Greco, Colin A. Lester, Elena D. Neuhaus, Sarah N. Tedjakusuma, Mallory Shriver, Esmeralda Cuevas-Juárez, Samanta Gutierrez, Molly R. Braun, Marcela F. Pasetti, Sean N. Tucker, James F. Cummings
Norovirus is a leading cause of acute gastroenteritis globally, with infections in older adults associated with heightened severity and increased risk of mortality. Currently, no licensed vaccines are available to prevent norovirus infection. We developed an orally administered vaccine tablet (VXA-G1.1-NN) that delivers a nonreplicating adenoviral vector expressing norovirus GI.1 major capsid protein VP1 to the small intestine. Here, we report safety and immunogenicity results of a randomized, double-blind, placebo-controlled clinical trial (NCT04854746) that investigated the oral administration of VXA-G1.1-NN in two groups of healthy older adults aged 55 to 65 and 66 to 80 years. VXA-G1.1-NN was administered orally at three dose levels by prime and boost, 28 days apart. Immunization was well tolerated regardless of dose, with mild to moderate reported solicited symptoms and no related serious or grade 3 adverse events. Oral delivery of VXA-G1.1-NN elicited VP1-specific serum immunoglobulin G (IgG) and IgA and functional antibodies in a dose-dependent manner 28 days postvaccination and remained above baseline for 210 days. Moreover, robust circulating VP1-specific IgA antibody-secreting cells were detected 1 week postvaccination along with IgA + plasmablasts expressing the mucosal-homing marker α4β7. VP1-specific IgA increased in saliva and nasal lining fluid 28 days postvaccination in both age groups and remained above baseline concentrations through 210 days, demonstrating durable mucosal responses. This clinical trial established that oral administration of VXA-G1.1-NN is safe, well tolerated, and induces robust systemic and mucosal immune responses in adults up to 80 years old.
{"title":"An oral norovirus vaccine tablet was safe and elicited mucosal immunity in older adults in a phase 1b clinical trial","authors":"Becca A. Flitter, Susan N. Greco, Colin A. Lester, Elena D. Neuhaus, Sarah N. Tedjakusuma, Mallory Shriver, Esmeralda Cuevas-Juárez, Samanta Gutierrez, Molly R. Braun, Marcela F. Pasetti, Sean N. Tucker, James F. Cummings","doi":"10.1126/scitranslmed.ads0556","DOIUrl":"https://doi.org/10.1126/scitranslmed.ads0556","url":null,"abstract":"Norovirus is a leading cause of acute gastroenteritis globally, with infections in older adults associated with heightened severity and increased risk of mortality. Currently, no licensed vaccines are available to prevent norovirus infection. We developed an orally administered vaccine tablet (VXA-G1.1-NN) that delivers a nonreplicating adenoviral vector expressing norovirus GI.1 major capsid protein VP1 to the small intestine. Here, we report safety and immunogenicity results of a randomized, double-blind, placebo-controlled clinical trial (NCT04854746) that investigated the oral administration of VXA-G1.1-NN in two groups of healthy older adults aged 55 to 65 and 66 to 80 years. VXA-G1.1-NN was administered orally at three dose levels by prime and boost, 28 days apart. Immunization was well tolerated regardless of dose, with mild to moderate reported solicited symptoms and no related serious or grade 3 adverse events. Oral delivery of VXA-G1.1-NN elicited VP1-specific serum immunoglobulin G (IgG) and IgA and functional antibodies in a dose-dependent manner 28 days postvaccination and remained above baseline for 210 days. Moreover, robust circulating VP1-specific IgA antibody-secreting cells were detected 1 week postvaccination along with IgA <jats:sup>+</jats:sup> plasmablasts expressing the mucosal-homing marker α4β7. VP1-specific IgA increased in saliva and nasal lining fluid 28 days postvaccination in both age groups and remained above baseline concentrations through 210 days, demonstrating durable mucosal responses. This clinical trial established that oral administration of VXA-G1.1-NN is safe, well tolerated, and induces robust systemic and mucosal immune responses in adults up to 80 years old.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"53 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-05DOI: 10.1126/scitranslmed.adq5720
Adonis A. Rubio, Viren A. Baharani, Bernadeta Dadonaite, Megan Parada, Morgan E. Abernathy, Zijun Wang, Yu E. Lee, Michael R. Eso, Jennie Phung, Israel Ramos, Teresia Chen, Gina El Nesr, Jesse D. Bloom, Paul D. Bieniasz, Michel C. Nussenzweig, Christopher O. Barnes
The ongoing emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized amino-terminal domain (NTD)– and receptor binding domain (RBD)–specific monoclonal antibodies previously isolated from coronavirus disease 2019 (COVID-19) convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo–electron microscopy structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596’s favorable binding profile, we designed a series of bispecific antibodies (bsAbs), termed CoV2-biRNs, that featured both NTD and RBD specificities. Two of the C1596-inclusive bsAbs, CoV2-biRN5 and CoV2-biRN7, retained potent in vitro neutralization activity against all Omicron variants tested, including XBB.1.5, BA.2.86, and JN.1, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 reduced the viral load within the lungs of K18-hACE2 mice after challenge with SARS-CoV-2 XBB.1.5. In conclusion, NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs.
{"title":"Bispecific antibodies targeting the N-terminal and receptor binding domains potently neutralize SARS-CoV-2 variants of concern","authors":"Adonis A. Rubio, Viren A. Baharani, Bernadeta Dadonaite, Megan Parada, Morgan E. Abernathy, Zijun Wang, Yu E. Lee, Michael R. Eso, Jennie Phung, Israel Ramos, Teresia Chen, Gina El Nesr, Jesse D. Bloom, Paul D. Bieniasz, Michel C. Nussenzweig, Christopher O. Barnes","doi":"10.1126/scitranslmed.adq5720","DOIUrl":"https://doi.org/10.1126/scitranslmed.adq5720","url":null,"abstract":"The ongoing emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized amino-terminal domain (NTD)– and receptor binding domain (RBD)–specific monoclonal antibodies previously isolated from coronavirus disease 2019 (COVID-19) convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo–electron microscopy structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596’s favorable binding profile, we designed a series of bispecific antibodies (bsAbs), termed CoV2-biRNs, that featured both NTD and RBD specificities. Two of the C1596-inclusive bsAbs, CoV2-biRN5 and CoV2-biRN7, retained potent in vitro neutralization activity against all Omicron variants tested, including XBB.1.5, BA.2.86, and JN.1, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 reduced the viral load within the lungs of K18-hACE2 mice after challenge with SARS-CoV-2 XBB.1.5. In conclusion, NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"76 5 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Oluwabunmi Olaloye, Weihong Gu, Arne Gehlhaar, Burhanuddin Sabuwala, Chino K. Eke, Yujia Li, Tessa Kehoe, Rohit Farmer, Gisela Gabernet, Carrie L. Lucas, John S. Tsang, Saquib A. Lakhani, Sarah N. Taylor, George Tseng, Steven H. Kleinstein, Liza Konnikova
Extremely premature infants (EPIs) who are born before 30 weeks of gestation are susceptible to infection; however, the trajectory of their peripheral immunity is poorly understood. Here, we undertook longitudinal analyses of immune cells from 250 μl of whole blood at 1 week, 1 month, and 2 months from 10 EPIs and compared these with samples from healthy adults and with preterm and full-term cord blood samples. Single-cell suspensions from individual samples were split to perform single-cell RNA sequencing, T and B cell receptor sequencing, and phosphoprotein mass cytometry. The trajectories of circulating T, B, myeloid, and natural killer cells in EPIs over the first 2 months of life were distinct from those of full-term infants. In EPIs, peripheral T cell development rapidly progressed over the first month of life, with an increase in the proportion of naïve CD4+, regulatory, and cycling T cells, accompanied by greater STAT5 (signal transducer and activator of transcription 5) signaling. EPI memory CD4+ T cells showed a T helper 1 (TH1) predominance compared with TH2 skewing of central memory–like T cells in full-term infants, and B cells from 2-month-old EPIs exhibited increased signatures of activation and differentiation. Both B and T cells from 2-month-old EPIs displayed increased interferon signatures compared with cells from full-term infants. In conclusion, we demonstrated the feasibility of longitudinal multiomic analyses in EPIs using minute amounts of blood and developed a resource describing peripheral immune development in EPIs that suggested ongoing activation in early life.
{"title":"A single-cell atlas of circulating immune cells over the first 2 months of age in extremely premature infants","authors":"Oluwabunmi Olaloye, Weihong Gu, Arne Gehlhaar, Burhanuddin Sabuwala, Chino K. Eke, Yujia Li, Tessa Kehoe, Rohit Farmer, Gisela Gabernet, Carrie L. Lucas, John S. Tsang, Saquib A. Lakhani, Sarah N. Taylor, George Tseng, Steven H. Kleinstein, Liza Konnikova","doi":"","DOIUrl":"","url":null,"abstract":"<div >Extremely premature infants (EPIs) who are born before 30 weeks of gestation are susceptible to infection; however, the trajectory of their peripheral immunity is poorly understood. Here, we undertook longitudinal analyses of immune cells from 250 μl of whole blood at 1 week, 1 month, and 2 months from 10 EPIs and compared these with samples from healthy adults and with preterm and full-term cord blood samples. Single-cell suspensions from individual samples were split to perform single-cell RNA sequencing, T and B cell receptor sequencing, and phosphoprotein mass cytometry. The trajectories of circulating T, B, myeloid, and natural killer cells in EPIs over the first 2 months of life were distinct from those of full-term infants. In EPIs, peripheral T cell development rapidly progressed over the first month of life, with an increase in the proportion of naïve CD4<sup>+</sup>, regulatory, and cycling T cells, accompanied by greater STAT5 (signal transducer and activator of transcription 5) signaling. EPI memory CD4<sup>+</sup> T cells showed a T helper 1 (T<sub>H</sub>1) predominance compared with T<sub>H</sub>2 skewing of central memory–like T cells in full-term infants, and B cells from 2-month-old EPIs exhibited increased signatures of activation and differentiation. Both B and T cells from 2-month-old EPIs displayed increased interferon signatures compared with cells from full-term infants. In conclusion, we demonstrated the feasibility of longitudinal multiomic analyses in EPIs using minute amounts of blood and developed a resource describing peripheral immune development in EPIs that suggested ongoing activation in early life.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 788","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-26DOI: 10.1126/scitranslmed.adk3922
Chih-Chun Lin, Ke-Chu Fang, Ilaria Balbo, Ting-Yu Liang, Chia-Wei Liu, Wen-Chuan Liu, Yi-Mei Wang, Yen-Ling Hung, Kai-Chien Yang, Scott Kun Geng, Chun-Lun Ni, Christopher P. Driscoll, David S. Ruff, Ami Kumar, Nadia Amokrane, Natasha Desai, Phyllis L. Faust, Elan D. Louis, Sheng-Han Kuo, Ming-Kai Pan
Cerebellar ataxia results from various genetic and nongenetic disorders and is characterized by involuntary movements that impair precision and motor rhythm. Here, we report that climbing fiber (CF) denervation is a common pathophysiology underlying motor rhythm loss in cerebellar ataxia. By examining cerebellar pathology in patients with spinocerebellar ataxia (SCA) types 1, 2, and 6 and multiple system atrophy, we identified CF degeneration with synaptic loss as a shared pathophysiology. Optogenetic silencing of CF synaptic activity in mice induced ataxia-like motor dysfunctions and loss of motor precision. In addition, CF silencing resulted in cerebellar and motor rhythm loss, another core feature of ataxia. This rhythm loss was predominantly CF dependent and resistant to Purkinje cell–specific lesioning by diphtheria toxin. Correspondingly, two patients with inferior olive pathology, the brain site that provides CFs to Purkinje cells, presented with ataxia and cerebellar rhythm loss. Patients with genetic or nongenetic cerebellar ataxia exhibited cerebellar rhythm loss that correlated with the Scale for the Assessment and Rating of Ataxia. Chemogenetic stimulation of CFs improved cerebellar and motor rhythms as well as motor performance in the SCA type 1 mouse model of ataxia. These results suggest that CF-dependent cerebellar rhythm loss occurs across different types of cerebellar ataxia, contributing to motor imprecision and motor rhythm loss, two defining features of ataxia.
{"title":"Reduced cerebellar rhythm by climbing fiber denervation is linked to motor rhythm deficits in mice and ataxia severity in patients","authors":"Chih-Chun Lin, Ke-Chu Fang, Ilaria Balbo, Ting-Yu Liang, Chia-Wei Liu, Wen-Chuan Liu, Yi-Mei Wang, Yen-Ling Hung, Kai-Chien Yang, Scott Kun Geng, Chun-Lun Ni, Christopher P. Driscoll, David S. Ruff, Ami Kumar, Nadia Amokrane, Natasha Desai, Phyllis L. Faust, Elan D. Louis, Sheng-Han Kuo, Ming-Kai Pan","doi":"10.1126/scitranslmed.adk3922","DOIUrl":"https://doi.org/10.1126/scitranslmed.adk3922","url":null,"abstract":"Cerebellar ataxia results from various genetic and nongenetic disorders and is characterized by involuntary movements that impair precision and motor rhythm. Here, we report that climbing fiber (CF) denervation is a common pathophysiology underlying motor rhythm loss in cerebellar ataxia. By examining cerebellar pathology in patients with spinocerebellar ataxia (SCA) types 1, 2, and 6 and multiple system atrophy, we identified CF degeneration with synaptic loss as a shared pathophysiology. Optogenetic silencing of CF synaptic activity in mice induced ataxia-like motor dysfunctions and loss of motor precision. In addition, CF silencing resulted in cerebellar and motor rhythm loss, another core feature of ataxia. This rhythm loss was predominantly CF dependent and resistant to Purkinje cell–specific lesioning by diphtheria toxin. Correspondingly, two patients with inferior olive pathology, the brain site that provides CFs to Purkinje cells, presented with ataxia and cerebellar rhythm loss. Patients with genetic or nongenetic cerebellar ataxia exhibited cerebellar rhythm loss that correlated with the Scale for the Assessment and Rating of Ataxia. Chemogenetic stimulation of CFs improved cerebellar and motor rhythms as well as motor performance in the SCA type 1 mouse model of ataxia. These results suggest that CF-dependent cerebellar rhythm loss occurs across different types of cerebellar ataxia, contributing to motor imprecision and motor rhythm loss, two defining features of ataxia.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"25 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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