Rajiv S Jumani, Bryanna Thomas, Jay Lakshman, Christian Ostermeier, Natko Nuber, Juergen Hubert Blusch, Sofia Braud-Perez, Dean Wetty, Lizhuo Nouaime, Juergen Dederichs, Joseph Etse, Slobodan Grubesic, Suresh B Lakshminarayana, Lucy C Watson, Johanne Blais, Zachary Thompson, Tareq Z Jaber, Mark R Jones, Deborah A Schaefer, Michael W Riggs, Christopher D Huston, Thierry T Diagana, Ujjini H Manjunatha
Background Cryptosporidiosis is a leading cause of severe diarrhea and mortality in young children with no vaccine or effective treatment. Cryptosporidium controlled human infection model (CHIM) in healthy adults provides an opportunity to evaluate the safety and efficacy of novel chemical entities prior to testing in young pediatric patients. However, CHIM development has been hindered by the lack of current good manufacturing practice (cGMP)-compliant Cryptosporidium parvum oocysts, which are required for filing an Investigational New Drug Application (IND) with the U.S. Food and Drug Administration. Methods To overcome this barrier, we developed a cGMP-compliant process for producing C. parvum oocysts. The approach involved sourcing well-characterized oocysts purified from neonatal calves under controlled non-GMP conditions, followed by cGMP processing that included peracetic acid–based surface sanitization, comprehensive microbial testing and release as a non-sterile oral product for human use. Results Peracetic acid (0.5% for 20 minutes) treated C. parvum oocysts demonstrated acceptable microbial safety and preserved viability. Viability was assessed through oocyst excystation, HCT-8 cell infection and mouse infectivity studies. The cGMP produced C. parvum oocysts with stringent batch-release test criteria for quantity, purity, identity, potency and bioburden was released as ABO809 for clinical use under an IND. ABO809 was successfully used in human challenge studies, producing reliable infection and characteristic clinical symptoms in healthy adult volunteers. Conclusions We describe a robust cGMP-compliant and qualification process for C. parvum oocysts that enables CHIM studies in healthy adults. Thereby opening avenues to evaluate efficacy of novel therapeutics and vaccines to treat cryptosporidiosis.
{"title":"Development of a current Good Manufacturing Practice-compliant Process for Producing Cryptosporidium parvum oocysts for Clinical Use","authors":"Rajiv S Jumani, Bryanna Thomas, Jay Lakshman, Christian Ostermeier, Natko Nuber, Juergen Hubert Blusch, Sofia Braud-Perez, Dean Wetty, Lizhuo Nouaime, Juergen Dederichs, Joseph Etse, Slobodan Grubesic, Suresh B Lakshminarayana, Lucy C Watson, Johanne Blais, Zachary Thompson, Tareq Z Jaber, Mark R Jones, Deborah A Schaefer, Michael W Riggs, Christopher D Huston, Thierry T Diagana, Ujjini H Manjunatha","doi":"10.1093/infdis/jiag107","DOIUrl":"https://doi.org/10.1093/infdis/jiag107","url":null,"abstract":"Background Cryptosporidiosis is a leading cause of severe diarrhea and mortality in young children with no vaccine or effective treatment. Cryptosporidium controlled human infection model (CHIM) in healthy adults provides an opportunity to evaluate the safety and efficacy of novel chemical entities prior to testing in young pediatric patients. However, CHIM development has been hindered by the lack of current good manufacturing practice (cGMP)-compliant Cryptosporidium parvum oocysts, which are required for filing an Investigational New Drug Application (IND) with the U.S. Food and Drug Administration. Methods To overcome this barrier, we developed a cGMP-compliant process for producing C. parvum oocysts. The approach involved sourcing well-characterized oocysts purified from neonatal calves under controlled non-GMP conditions, followed by cGMP processing that included peracetic acid–based surface sanitization, comprehensive microbial testing and release as a non-sterile oral product for human use. Results Peracetic acid (0.5% for 20 minutes) treated C. parvum oocysts demonstrated acceptable microbial safety and preserved viability. Viability was assessed through oocyst excystation, HCT-8 cell infection and mouse infectivity studies. The cGMP produced C. parvum oocysts with stringent batch-release test criteria for quantity, purity, identity, potency and bioburden was released as ABO809 for clinical use under an IND. ABO809 was successfully used in human challenge studies, producing reliable infection and characteristic clinical symptoms in healthy adult volunteers. Conclusions We describe a robust cGMP-compliant and qualification process for C. parvum oocysts that enables CHIM studies in healthy adults. Thereby opening avenues to evaluate efficacy of novel therapeutics and vaccines to treat cryptosporidiosis.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"132 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Giuseppe Sangiorgio, Grace Chamberlin, Riccardo Castagnoli, Brianna Wachter, Kerry A Dobbs, Danielle Fink, Gina A Montealegre Sanchez, Karyl Barron, Helen C Su, Douglas Kuhns, Peter D Burbelo, Luigi D Notarangelo, Esther Freeman, Ottavia M Delmonte
Most pandemic-associated chilblains (PAC) resolve spontaneously, but a subset of patients develops persistent or recurrent disease. We analyzed peripheral cytokine profiles in 17 patients with prolonged PAC and identified elevated IFN-γ, CXCL10, CX3CL1, IL-16, CCL22, and S100A8. In contrast to the transient type I interferon response described in acute PAC, prolonged disease was characterized by a type II interferon–skewed inflammatory signature with T cell activation and endothelial involvement. Frequent autoimmune comorbidities suggest baseline immune dysregulation contributing to chronicity. These findings highlight potential therapeutic targets, including JAK inhibition and IFN-γ–directed therapies.
{"title":"Immune-Based Cytokine Signatures of Prolonged Pandemic-Associated Chilblains","authors":"Giuseppe Sangiorgio, Grace Chamberlin, Riccardo Castagnoli, Brianna Wachter, Kerry A Dobbs, Danielle Fink, Gina A Montealegre Sanchez, Karyl Barron, Helen C Su, Douglas Kuhns, Peter D Burbelo, Luigi D Notarangelo, Esther Freeman, Ottavia M Delmonte","doi":"10.1093/infdis/jiag103","DOIUrl":"https://doi.org/10.1093/infdis/jiag103","url":null,"abstract":"Most pandemic-associated chilblains (PAC) resolve spontaneously, but a subset of patients develops persistent or recurrent disease. We analyzed peripheral cytokine profiles in 17 patients with prolonged PAC and identified elevated IFN-γ, CXCL10, CX3CL1, IL-16, CCL22, and S100A8. In contrast to the transient type I interferon response described in acute PAC, prolonged disease was characterized by a type II interferon–skewed inflammatory signature with T cell activation and endothelial involvement. Frequent autoimmune comorbidities suggest baseline immune dysregulation contributing to chronicity. These findings highlight potential therapeutic targets, including JAK inhibition and IFN-γ–directed therapies.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146222868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Julien Gras, Marie Laure Nere, Julien Robert, Kevin Louis, Marie Noëlle Peraldi, Linda Feghoul, Jérôme Verine, Ali Amara, Carmen Lefaucheur, Jean Michel Molina, Constance Delaugerre, Maud Salmona
Background Among kidney transplant recipients (KTR) with BKPyV associated nephropathy (BKPyVN), the dynamics of BKPyV replication are not well established. We aim to investigate BKPyV genetic diversity and evolution following kidney transplantation. Methods We retrospectively analyzed 32 KTR with a biopsy-proven diagnosis of BKPyVN. Stored plasma and kidney biopsies were tested for BKPyV viral load, and BKPyV whole genome sequencing (WGS) performed on BKPyV-positive samples. Results A total of 104 samples positive for BKPyV DNA detection were sequenced, among which 83 were included in the analysis. BKPyV-I was the most frequent genotype detected, followed by BKPyV-IVc2 and BKPyV-II. At BKPyVN diagnosis (median time: 12 [8-17] months post-transplant), WGS identified the same BKPyV-subtype in the plasma and kidney biopsy for all patients but one. Alignment of BKPyV consensus sequences between the two compartments at the time of BKPyVN showed similarity > 99%, but identified single nucleotide polymorphisms in 13/23 of the cases, including 25% APOBEC-associated mutations. Among the 16 KTR with ≥ 2 consecutive BKPyV-positive samples available for analysis, consensus sequence showed a different BKPyV subtype in pre-BKPyVN kidney biopsies compared to BKPyVN in 9 patients. Before BKPyVN diagnosis, minority variants on VP1 sequence were identified in 10/11 kidney biopsy and 5/10 plasma samples. Conclusions Among KTR with BKPyVN, we show that BKPyV viral populations change over time, with the coexistence of several viral populations in early samples compared to BKPyVN, as a result of both APOBEC-mediated editing and replication-driven diversification within the kidney allograft.
{"title":"BK Polyomavirus Genetic Diversity and Evolution in Kidney Transplant Recipients with Viral Nephropathy Using Whole Genome Sequencing","authors":"Julien Gras, Marie Laure Nere, Julien Robert, Kevin Louis, Marie Noëlle Peraldi, Linda Feghoul, Jérôme Verine, Ali Amara, Carmen Lefaucheur, Jean Michel Molina, Constance Delaugerre, Maud Salmona","doi":"10.1093/infdis/jiag108","DOIUrl":"https://doi.org/10.1093/infdis/jiag108","url":null,"abstract":"Background Among kidney transplant recipients (KTR) with BKPyV associated nephropathy (BKPyVN), the dynamics of BKPyV replication are not well established. We aim to investigate BKPyV genetic diversity and evolution following kidney transplantation. Methods We retrospectively analyzed 32 KTR with a biopsy-proven diagnosis of BKPyVN. Stored plasma and kidney biopsies were tested for BKPyV viral load, and BKPyV whole genome sequencing (WGS) performed on BKPyV-positive samples. Results A total of 104 samples positive for BKPyV DNA detection were sequenced, among which 83 were included in the analysis. BKPyV-I was the most frequent genotype detected, followed by BKPyV-IVc2 and BKPyV-II. At BKPyVN diagnosis (median time: 12 [8-17] months post-transplant), WGS identified the same BKPyV-subtype in the plasma and kidney biopsy for all patients but one. Alignment of BKPyV consensus sequences between the two compartments at the time of BKPyVN showed similarity > 99%, but identified single nucleotide polymorphisms in 13/23 of the cases, including 25% APOBEC-associated mutations. Among the 16 KTR with ≥ 2 consecutive BKPyV-positive samples available for analysis, consensus sequence showed a different BKPyV subtype in pre-BKPyVN kidney biopsies compared to BKPyVN in 9 patients. Before BKPyVN diagnosis, minority variants on VP1 sequence were identified in 10/11 kidney biopsy and 5/10 plasma samples. Conclusions Among KTR with BKPyVN, we show that BKPyV viral populations change over time, with the coexistence of several viral populations in early samples compared to BKPyVN, as a result of both APOBEC-mediated editing and replication-driven diversification within the kidney allograft.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"95 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrew P Platt, Viviane Callier, Alison Grazioli, Zonghui Hu, Sydney R Stein, Megan G Anders, Seth Warner, Emily Ricotta, Trevor M Stantliff, Jocelyn Wu, Nicole Hays, Katherine Raja, Ryan Curto, Madeleine Purcell, Shreya Singireddy, Douglas Tran, Raymond Rector, Sabrina Cho, Katelyn Wagner, Sabrina C Ramelli, Marcos J Ramos-Benitez, James Dickey, Jeffrey R Strich, Kevin M Vannella, Miranda Gibbons, Peter Rock, Ali Tabatabai, Michael T McCurdy, Thomas Scalea, Robert Christenson, Mohammad M Sajadi, Daniel Herr, Bradley Taylor, Kapil Saharia, Ronson J Madathil, Joseph Rabin, Dean Follmann, Daniel S Chertow
Background Critical illness in COVID-19 may require support with Extracorporeal Membrane Oxygenation (ECMO). As immunothrombosis contributes to pathogenesis of critical illness we quantified immunothrombotic markers in patients with COVID-19 on ECMO and evaluated the predictive capacity of these markers for death. Methods We performed a retrospective analysis of 74 consecutive patients with COVID-19 on ECMO at a single academic medical center between March 2020 and February 2021. SARS-CoV-2 nucleocapsid RNA and 16 immunothrombotic biomarkers were longitudinally quantified. Biomarker trajectories were assessed with univariate and multivariate models and used to predict death and decannulation across multiple models. Results Male sex, smoking status, high serum bilirubin level, and low partial pressure of oxygen in arterial blood to the fraction of inspired oxygen (P/F) ratio were associated with an increased risk of death. Plasma levels of 10 immunothrombotic markers were significantly elevated in fatal cases. Elevated IL-8 and von Willebrand factor (VWF) were associated with an increased hazard of death and elevated angiopoietin-2, IL-1β, IL-6, IL-8, IL-18, ICAM, p-selectin, syndecan-1, and VWF were associated with a decreased hazard for decannulation when adjusting for sex, smoking status, and time to cannulation. Predictive models incorporating biomarkers were superior to demographics alone and equivalent to models including clinical information. Conclusions We found increased immunothrombotic markers, male sex, and history of smoking were risk factors in patients with COVID-19 on ECMO who died as compared to those who were decannulated. These findings are important for understanding the pathogenesis of severe COVID-19 and prognostication.
{"title":"Plasma biomarkers of immunothrombosis are independently associated with death in patients with COVID-19 on ECMO","authors":"Andrew P Platt, Viviane Callier, Alison Grazioli, Zonghui Hu, Sydney R Stein, Megan G Anders, Seth Warner, Emily Ricotta, Trevor M Stantliff, Jocelyn Wu, Nicole Hays, Katherine Raja, Ryan Curto, Madeleine Purcell, Shreya Singireddy, Douglas Tran, Raymond Rector, Sabrina Cho, Katelyn Wagner, Sabrina C Ramelli, Marcos J Ramos-Benitez, James Dickey, Jeffrey R Strich, Kevin M Vannella, Miranda Gibbons, Peter Rock, Ali Tabatabai, Michael T McCurdy, Thomas Scalea, Robert Christenson, Mohammad M Sajadi, Daniel Herr, Bradley Taylor, Kapil Saharia, Ronson J Madathil, Joseph Rabin, Dean Follmann, Daniel S Chertow","doi":"10.1093/infdis/jiag106","DOIUrl":"https://doi.org/10.1093/infdis/jiag106","url":null,"abstract":"Background Critical illness in COVID-19 may require support with Extracorporeal Membrane Oxygenation (ECMO). As immunothrombosis contributes to pathogenesis of critical illness we quantified immunothrombotic markers in patients with COVID-19 on ECMO and evaluated the predictive capacity of these markers for death. Methods We performed a retrospective analysis of 74 consecutive patients with COVID-19 on ECMO at a single academic medical center between March 2020 and February 2021. SARS-CoV-2 nucleocapsid RNA and 16 immunothrombotic biomarkers were longitudinally quantified. Biomarker trajectories were assessed with univariate and multivariate models and used to predict death and decannulation across multiple models. Results Male sex, smoking status, high serum bilirubin level, and low partial pressure of oxygen in arterial blood to the fraction of inspired oxygen (P/F) ratio were associated with an increased risk of death. Plasma levels of 10 immunothrombotic markers were significantly elevated in fatal cases. Elevated IL-8 and von Willebrand factor (VWF) were associated with an increased hazard of death and elevated angiopoietin-2, IL-1β, IL-6, IL-8, IL-18, ICAM, p-selectin, syndecan-1, and VWF were associated with a decreased hazard for decannulation when adjusting for sex, smoking status, and time to cannulation. Predictive models incorporating biomarkers were superior to demographics alone and equivalent to models including clinical information. Conclusions We found increased immunothrombotic markers, male sex, and history of smoking were risk factors in patients with COVID-19 on ECMO who died as compared to those who were decannulated. These findings are important for understanding the pathogenesis of severe COVID-19 and prognostication.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kiran Bosco, Aleksandra Petrovic Fabijan, Jonathan Iredell, Krystyna Dabrowska, Ameneh Khatami
This review explores mammalian immune responses to phages with a particular emphasis on human immune responses to therapeutic phages and their potential implications for the outcomes of phage therapy. Despite the ubiquity of phages in the human microbiome, particularly in the gut (the phageome), research on immunological mechanisms governing immune responses to both endogenous and therapeutic phages are still in their infancy. We highlight key components of the immune system that contribute to clearance of phages in vivo and examine how various factors– including patient-specific variables, treatment regimens and phage characteristics can influence immune responses and, consequently, phage pharmacokinetics during therapy. A clearer understanding of human immune responses to phages is urgently needed to inform the development of more targeted and effective personalised phage therapies – an essential step in combating the escalating threat of antimicrobial resistance.
{"title":"Immune responses to phage therapy in humans: A review","authors":"Kiran Bosco, Aleksandra Petrovic Fabijan, Jonathan Iredell, Krystyna Dabrowska, Ameneh Khatami","doi":"10.1093/infdis/jiag096","DOIUrl":"https://doi.org/10.1093/infdis/jiag096","url":null,"abstract":"This review explores mammalian immune responses to phages with a particular emphasis on human immune responses to therapeutic phages and their potential implications for the outcomes of phage therapy. Despite the ubiquity of phages in the human microbiome, particularly in the gut (the phageome), research on immunological mechanisms governing immune responses to both endogenous and therapeutic phages are still in their infancy. We highlight key components of the immune system that contribute to clearance of phages in vivo and examine how various factors– including patient-specific variables, treatment regimens and phage characteristics can influence immune responses and, consequently, phage pharmacokinetics during therapy. A clearer understanding of human immune responses to phages is urgently needed to inform the development of more targeted and effective personalised phage therapies – an essential step in combating the escalating threat of antimicrobial resistance.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"299 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146169721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jimmy Kizza, Thomas Katairo, Abel Kakuru, Bienvenu Nsengimaana, Trevor Esilu, Innocent Wiringilimaana, Francis D Semakuba, Inna Gerlovina, Nicholas Hathaway, Jessica Briggs, Stephen Tukwasibwe, Steven M Kiwuwa, Moses R Kamya, Joaniter I Nankabirwa, Grant Dorsey, Philip J Rosenthal
Background Intermittent preventive treatment with monthly sulfadoxine-pyrimethamine (IPTp-SP) is recommended during pregnancy in malaria-endemic countries. However, widespread resistance of Plasmodium falciparum to SP has compromised its efficacy, and the alternative dihydroartemisinin-piperaquine (DP) is under study. Potential selection of drug resistance is important. Methods We sequenced 1377 samples collected from pregnant women enrolled in a trial comparing monthly SP, DP, and DP+SP for IPTp in Busia, Uganda and with asymptomatic parasitemia at the time of IPTp administration. We characterized known markers of drug resistance and assessed the 28-day cumulative risk of recurrent parasitemia, with genotyping to distinguish recrudescence from new infections. Results Among 771 samples collected on the day IPTp was initiated, the prevalences of 5 resistance mutations in P. falciparum dihydrofolate reductase (PfDHFR) and dihydropteroate synthase (PfDHPS) were nearly 100%, and the PfDHFR I164L and PfDHPS A581G mutations, associated with high-level resistance, had combined prevalence of 26.5%. The cumulative risks of recurrent parasitemia (SP 57.8%, DP 4.1%, DP+SP 3.9%), symptomatic malaria (SP 9.3%, DP 1.1%, DP+SP 0.3%), and recrudescent parasitemia (SP 40.1%, DP 2.0%, DP+SP 0.8%) were all significantly greater in the SP arm, with risks greatest in primigravidae. In the IPT-SP arm, the combined prevalence of the PfDHFR I164L and PfDHPS A581G mutations increased significantly from 24.9% at initiation of IPTp to 35.2% after receipt of IPTp-SP. Infection with mutant parasites was associated with non-significant increases in risks of recrudescence. Conclusions IPTp-SP had poor antimalarial preventive efficacy and selected for increased drug resistance, questioning the value of this intervention.
{"title":"Recurrent Plasmodium falciparum parasitemia and drug resistance mutations during intermittent preventive treatment of malaria in pregnancy in Uganda","authors":"Jimmy Kizza, Thomas Katairo, Abel Kakuru, Bienvenu Nsengimaana, Trevor Esilu, Innocent Wiringilimaana, Francis D Semakuba, Inna Gerlovina, Nicholas Hathaway, Jessica Briggs, Stephen Tukwasibwe, Steven M Kiwuwa, Moses R Kamya, Joaniter I Nankabirwa, Grant Dorsey, Philip J Rosenthal","doi":"10.1093/infdis/jiag074","DOIUrl":"https://doi.org/10.1093/infdis/jiag074","url":null,"abstract":"Background Intermittent preventive treatment with monthly sulfadoxine-pyrimethamine (IPTp-SP) is recommended during pregnancy in malaria-endemic countries. However, widespread resistance of Plasmodium falciparum to SP has compromised its efficacy, and the alternative dihydroartemisinin-piperaquine (DP) is under study. Potential selection of drug resistance is important. Methods We sequenced 1377 samples collected from pregnant women enrolled in a trial comparing monthly SP, DP, and DP+SP for IPTp in Busia, Uganda and with asymptomatic parasitemia at the time of IPTp administration. We characterized known markers of drug resistance and assessed the 28-day cumulative risk of recurrent parasitemia, with genotyping to distinguish recrudescence from new infections. Results Among 771 samples collected on the day IPTp was initiated, the prevalences of 5 resistance mutations in P. falciparum dihydrofolate reductase (PfDHFR) and dihydropteroate synthase (PfDHPS) were nearly 100%, and the PfDHFR I164L and PfDHPS A581G mutations, associated with high-level resistance, had combined prevalence of 26.5%. The cumulative risks of recurrent parasitemia (SP 57.8%, DP 4.1%, DP+SP 3.9%), symptomatic malaria (SP 9.3%, DP 1.1%, DP+SP 0.3%), and recrudescent parasitemia (SP 40.1%, DP 2.0%, DP+SP 0.8%) were all significantly greater in the SP arm, with risks greatest in primigravidae. In the IPT-SP arm, the combined prevalence of the PfDHFR I164L and PfDHPS A581G mutations increased significantly from 24.9% at initiation of IPTp to 35.2% after receipt of IPTp-SP. Infection with mutant parasites was associated with non-significant increases in risks of recrudescence. Conclusions IPTp-SP had poor antimalarial preventive efficacy and selected for increased drug resistance, questioning the value of this intervention.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146169722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rosa C Coldbeck-Shackley, Erin Flynn, Arshdeep Kaur Mudhar, Mona L Taouk, George Taiaroa, Charlotte Bell, Trisha J Rogers, Caitlin A Selway, Lito Papanicolas, Mark Turra, Lex E X Leong
Background National and international travel drives the spread of antimicrobial resistance in high-priority pathogens, including Neisseria gonorrhoeae. Border closures and travel restrictions in response to the COVID-19 pandemic had wide-reaching impacts on infectious disease epidemiology, including the transmission and genomic diversity of N. gonorrhoeae. However, less is known about N. gonorrhoeae population structures in the years following lifting of pandemic restrictions. Methods This study analysed N. gonorrhoeae genomic data collected for routine public health surveillance in South Australia, Australia, and contextual sequences from Victoria, Australia, before and after the cessation of COVID-19 interstate and international travel restrictions. Results N. gonorrhoeae was highly clonal during periods with restricted travel, and genomic diversity markedly increased after restrictions were removed, possibly driven by increased transmission and the introduction of new strains. Conclusions Routine genomic surveillance is an important public health tool for the monitoring of N. gonorrhoeae, especially the introduction and spread of antimicrobial resistant strains.
{"title":"Increased diversity and introduction of multi-drug resistant strains of Neisseria gonorrhoeae following cessation of COVID-19 pandemic-related travel restrictions: an observational genomic epidemiological study","authors":"Rosa C Coldbeck-Shackley, Erin Flynn, Arshdeep Kaur Mudhar, Mona L Taouk, George Taiaroa, Charlotte Bell, Trisha J Rogers, Caitlin A Selway, Lito Papanicolas, Mark Turra, Lex E X Leong","doi":"10.1093/infdis/jiag097","DOIUrl":"https://doi.org/10.1093/infdis/jiag097","url":null,"abstract":"Background National and international travel drives the spread of antimicrobial resistance in high-priority pathogens, including Neisseria gonorrhoeae. Border closures and travel restrictions in response to the COVID-19 pandemic had wide-reaching impacts on infectious disease epidemiology, including the transmission and genomic diversity of N. gonorrhoeae. However, less is known about N. gonorrhoeae population structures in the years following lifting of pandemic restrictions. Methods This study analysed N. gonorrhoeae genomic data collected for routine public health surveillance in South Australia, Australia, and contextual sequences from Victoria, Australia, before and after the cessation of COVID-19 interstate and international travel restrictions. Results N. gonorrhoeae was highly clonal during periods with restricted travel, and genomic diversity markedly increased after restrictions were removed, possibly driven by increased transmission and the introduction of new strains. Conclusions Routine genomic surveillance is an important public health tool for the monitoring of N. gonorrhoeae, especially the introduction and spread of antimicrobial resistant strains.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146160438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Niranjana Nair, Julia Friese, Paul J Wichgers Schreur, Albert D M E Osterhaus, Guus F Rimmelzwaan, Chittappen Kandiyil Prajeeth
The live-attenuated RVFV-4s vaccine against Rift Valley Fever has demonstrated safety and efficacy across multiple animal models and in a phase-I clinical trial. In this study, we examined its impact on innate immune responses and found that RVFV-4s enhances the expression of costimulatory molecules critical for T cell activation, while also triggering proinflammatory responses in primary human monocytes.
{"title":"Efficient sensing of a four-segmented Rift Valley fever virus vaccine candidate by human monocytes","authors":"Niranjana Nair, Julia Friese, Paul J Wichgers Schreur, Albert D M E Osterhaus, Guus F Rimmelzwaan, Chittappen Kandiyil Prajeeth","doi":"10.1093/infdis/jiag085","DOIUrl":"https://doi.org/10.1093/infdis/jiag085","url":null,"abstract":"The live-attenuated RVFV-4s vaccine against Rift Valley Fever has demonstrated safety and efficacy across multiple animal models and in a phase-I clinical trial. In this study, we examined its impact on innate immune responses and found that RVFV-4s enhances the expression of costimulatory molecules critical for T cell activation, while also triggering proinflammatory responses in primary human monocytes.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"59 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146169725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDHigh-dose dual therapy (HDDT) is a promising first-line treatment option for Helicobacter pylori infection. In this study, we aimed to compare the efficacy and safety of different HDDT regimens.METHODSThis multicenter retrospective study included data from 10 centers between January 2022 and January 2025. Inverse probability of treatment-weighted (IPTW) adjustment was used to address the imbalance in variables across groups. The outcomes included the eradication rate, adverse events and adherence.RESULTSA total of 1,665 patients were included, with a full analysis set (FAS) eradication rate of 88.6% and a per-protocol (PP) eradication rate of 89.5% for HDDT. After IPTW adjustment, the eradication rate of vonoprazan-amoxicillin (VA) 14-day based on FAS analysis was 95.1%, which was significantly higher than VA-10 day (88.7%) (P = 0.001), esomeprazole-amoxicillin (EA) (85.1%) (P < 0.001), and tegoprazan-amoxicillin (TA) (87.3%) (P < 0.001). The incidence of adverse events for VA-14 was 8.1%, which was comparable to VA-10 (11.1%) but lower than TA (14.4%) and EA (15.3%) (P = 0.002). Adherence showed no significant difference across groups. High body surface area (BSA) (≥1.80 m²) (OR 1.594, 95% confidence interval [CI], 1.018-2.495, P = 0.041), poor adherence (OR 4.975, 95% CI, 2.753-8.992, P < 0.001), and non-VA-14 treatment regimen were independent risk factors for eradication failure. Factors varied across regimens.CONCLUSIONSHDDT, particularly VA-14, is a competitive first-line option for H. pylori eradication. High BSA and low adherence were risk factors for eradication failure but varied across regimens, highlighting the necessity of personalized adjustment.
{"title":"Comparative Analysis of High-Dose Dual Therapies in First-Line Helicobacter pylori Eradication: An Inverse Probability of Treatment-Weighted Multicenter Study.","authors":"Qingzhou Kong,Baobao Wang,Bengang Zhou,Hong Lu,Tianlian Yan,Yingying Han,Yanbing Ding,Peiyuan Li,Miao Duan,Kunping Ju,Wenrong Geng,Yuting Guo,Hongyu Zhao,Xiaohui Song,Xiaowei Li,Xin Long,Xiuli Zuo,Yanqing Li,Yueyue Li","doi":"10.1093/infdis/jiag059","DOIUrl":"https://doi.org/10.1093/infdis/jiag059","url":null,"abstract":"BACKGROUNDHigh-dose dual therapy (HDDT) is a promising first-line treatment option for Helicobacter pylori infection. In this study, we aimed to compare the efficacy and safety of different HDDT regimens.METHODSThis multicenter retrospective study included data from 10 centers between January 2022 and January 2025. Inverse probability of treatment-weighted (IPTW) adjustment was used to address the imbalance in variables across groups. The outcomes included the eradication rate, adverse events and adherence.RESULTSA total of 1,665 patients were included, with a full analysis set (FAS) eradication rate of 88.6% and a per-protocol (PP) eradication rate of 89.5% for HDDT. After IPTW adjustment, the eradication rate of vonoprazan-amoxicillin (VA) 14-day based on FAS analysis was 95.1%, which was significantly higher than VA-10 day (88.7%) (P = 0.001), esomeprazole-amoxicillin (EA) (85.1%) (P < 0.001), and tegoprazan-amoxicillin (TA) (87.3%) (P < 0.001). The incidence of adverse events for VA-14 was 8.1%, which was comparable to VA-10 (11.1%) but lower than TA (14.4%) and EA (15.3%) (P = 0.002). Adherence showed no significant difference across groups. High body surface area (BSA) (≥1.80 m²) (OR 1.594, 95% confidence interval [CI], 1.018-2.495, P = 0.041), poor adherence (OR 4.975, 95% CI, 2.753-8.992, P < 0.001), and non-VA-14 treatment regimen were independent risk factors for eradication failure. Factors varied across regimens.CONCLUSIONSHDDT, particularly VA-14, is a competitive first-line option for H. pylori eradication. High BSA and low adherence were risk factors for eradication failure but varied across regimens, highlighting the necessity of personalized adjustment.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Priya Khetan,Kunjal Patel,Wendy Yu,Joseph Szewczyk,Adit Dhummakupt,Sandra Burchett,Russell B Van Dyke,Deborah Persaud
BACKGROUNDUnderstanding HIV-1 reservoir dynamics during long-term antiretroviral therapy (ART) in youth with perinatal HIV-1 is essential for ART-free remission strategies.METHODSWe quantified intact and defective HIV-1 proviruses in 201 peripheral blood mononuclear cell samples (PBMCs) from participants ages 17.6-21.2 years in the Pediatric HIV/AIDS Cohort Study (PHACS) Adolescent Master Protocol. Participants were classified as early-suppressed (ES, <1 year of age at virologic suppression (VS)) or late-suppressed (LS, 1-5 years of age at VS) and had maintained VS for up to 20 years. We compared proviral dynamics based on age at and duration of suppression, and sex.RESULTSTwenty-six participants (11 ES and 15 LS) were evaluated. ES participants exhibited significantly lower intact HIV-1 reservoirs compared with LS participants, with 67% of ES samples below detection limits (2.0 copies/106 PBMCs), By 5 years of VS, the ES participants had significantly lower mean intact proviral load (2.0 vs 6.6 copies/106 PBMCs) than LS participants, largely driven by faster clearance of intact proviruses in the first 5 years of VS. Among LS- participants, females had larger intact reservoirs than males (mean: 12.5 vs 4.1 intact copies/106 PBMCs) and exhibited greater increases in defective proviruses over time.CONCLUSIONSAchieving VS by 1 year of age in perinatal HIV-1 infection results in substantially smaller HIV-1 intact reservoirs by age 5, with effects sustained through young adulthood. Additionally, sex-based differences, larger intact reservoirs and increases in defective proviruses in females, underscore the need for tailored ART-free remission and cure strategies for this population.
背景：了解围产期HIV-1青少年长期抗逆转录病毒治疗（ART）期间HIV-1病毒库的动态对于制定无ART缓解策略至关重要。方法：我们对来自儿童HIV/AIDS队列研究（PHACS）青少年主方案中17.6-21.2岁参与者的201个外周血单个核细胞样本（PBMCs）中的完整和缺陷HIV-1前病毒进行了定量分析。参与者被分为早期抑制（ES，病毒学抑制时<1岁）或晚期抑制（LS，病毒学抑制时1-5岁），并维持了长达20年的VS。我们比较了基于年龄和抑制持续时间以及性别的前病毒动态。结果共对26例患者进行了评估，其中11例为中西医结合，15例为中西医结合。与LS参与者相比，ES参与者表现出更低的完整HIV-1库，67%的ES样本低于检测限（2.0拷贝/106 PBMCs），到VS的5年，ES参与者的平均完整前病毒载量（2.0拷贝/106 PBMCs）显著低于LS参与者，这主要是由于在VS的前5年，完整前病毒的清除速度更快。12.5 vs 4.1完整拷贝/106 pbmc)，并且随着时间的推移，缺陷原病毒的增加幅度更大。结论围产期HIV-1感染在1岁时达到VS，可导致5岁时HIV-1完整库的显著缩小，其影响持续到青年期。此外，基于性别的差异，更大的完整储存库和女性中缺陷原病毒的增加，强调了针对这一人群量身定制的无art缓解和治愈策略的必要性。
{"title":"Dynamics of Intact and Defective HIV-1 Proviruses during Decades of Suppressive Antiretroviral Treatment in Young Adults with Perinatal HIV-1.","authors":"Priya Khetan,Kunjal Patel,Wendy Yu,Joseph Szewczyk,Adit Dhummakupt,Sandra Burchett,Russell B Van Dyke,Deborah Persaud","doi":"10.1093/infdis/jiag045","DOIUrl":"https://doi.org/10.1093/infdis/jiag045","url":null,"abstract":"BACKGROUNDUnderstanding HIV-1 reservoir dynamics during long-term antiretroviral therapy (ART) in youth with perinatal HIV-1 is essential for ART-free remission strategies.METHODSWe quantified intact and defective HIV-1 proviruses in 201 peripheral blood mononuclear cell samples (PBMCs) from participants ages 17.6-21.2 years in the Pediatric HIV/AIDS Cohort Study (PHACS) Adolescent Master Protocol. Participants were classified as early-suppressed (ES, <1 year of age at virologic suppression (VS)) or late-suppressed (LS, 1-5 years of age at VS) and had maintained VS for up to 20 years. We compared proviral dynamics based on age at and duration of suppression, and sex.RESULTSTwenty-six participants (11 ES and 15 LS) were evaluated. ES participants exhibited significantly lower intact HIV-1 reservoirs compared with LS participants, with 67% of ES samples below detection limits (2.0 copies/106 PBMCs), By 5 years of VS, the ES participants had significantly lower mean intact proviral load (2.0 vs 6.6 copies/106 PBMCs) than LS participants, largely driven by faster clearance of intact proviruses in the first 5 years of VS. Among LS- participants, females had larger intact reservoirs than males (mean: 12.5 vs 4.1 intact copies/106 PBMCs) and exhibited greater increases in defective proviruses over time.CONCLUSIONSAchieving VS by 1 year of age in perinatal HIV-1 infection results in substantially smaller HIV-1 intact reservoirs by age 5, with effects sustained through young adulthood. Additionally, sex-based differences, larger intact reservoirs and increases in defective proviruses in females, underscore the need for tailored ART-free remission and cure strategies for this population.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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