Pub Date : 2026-03-10DOI: 10.1016/j.lanmic.2026.101373
Linda S Klavinskis, Edward P Rybicki
{"title":"Report on the 2025 International Society for Vaccines Annual Congress.","authors":"Linda S Klavinskis, Edward P Rybicki","doi":"10.1016/j.lanmic.2026.101373","DOIUrl":"https://doi.org/10.1016/j.lanmic.2026.101373","url":null,"abstract":"","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":" ","pages":"101373"},"PeriodicalIF":20.4,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147460501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-07DOI: 10.1016/j.lanmic.2026.101394
Stuart D Blacksell, Sandhya Dhawan
{"title":"Biosafety without borders: bridging the capacity gap in resource-limited laboratory settings.","authors":"Stuart D Blacksell, Sandhya Dhawan","doi":"10.1016/j.lanmic.2026.101394","DOIUrl":"https://doi.org/10.1016/j.lanmic.2026.101394","url":null,"abstract":"","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":" ","pages":"101394"},"PeriodicalIF":20.4,"publicationDate":"2026-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147436634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-06DOI: 10.1016/j.lanmic.2026.101391
Shengshan Xu, Zhichao Lin, Zhuming Lu
{"title":"HIV drug resistance in the era of antiretroviral therapy expansion: the hidden cost of success.","authors":"Shengshan Xu, Zhichao Lin, Zhuming Lu","doi":"10.1016/j.lanmic.2026.101391","DOIUrl":"https://doi.org/10.1016/j.lanmic.2026.101391","url":null,"abstract":"","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":" ","pages":"101391"},"PeriodicalIF":20.4,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147391279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-05DOI: 10.1016/j.lanmic.2025.101274
Sebastian T Tandar, Laura B Zwep, Sjoukje H S Woudt, Annelot F Schoffelen, Wiep Klaas Smits, Linda B S Aulin, Apostolos Liakopoulos, J G Coen van Hasselt
Background: Collateral effects arise when resistance to one antibiotic alters the susceptibility of a bacterial strain to another antibiotic, resulting in either increased (collateral sensitivity) or decreased (collateral resistance) susceptibility. Collateral sensitivity-based antibiotic treatment offers a promising strategy against antibiotic resistance. To date, the clinical occurrence of collateral sensitivity between bacterial strains and species remains to be further evaluated. Our study aims to evaluate the occurrence patterns of collateral sensitivity in clinical settings.
Methods: For this systematic exploration of multicentre antimicrobial surveillance data, we analysed large-scale antimicrobial resistance surveillance data from three datasets, covering over 5 million minimum inhibitory concentration (MIC) measurements across 86 antibiotics and 30 pathogen species, to identify collateral effect interactions. Pairwise and three-way collateral effects were quantified to assess species-wide trends in both collateral sensitivity and collateral resistance within individual pathogen species. Additionally, we compared the prevalence of collateral sensitivity between and within antibiotic classes. By comparing collateral sensitivity occurrence across species, we identified collateral sensitivity interactions conserved across several pathogens.
Findings: We found a low occurrence of collateral sensitivity in clinical strains, with 364 of 12 024 species-antibiotic pairs (3·0%) affected, compared to 5044 cases (42·0%) of collateral resistance. Most collateral sensitivity interactions involved antibiotics from different classes, except for β-lactams, which showed 41 (34·2%) of 120 occurrences of intraclass collateral sensitivity. We identified six collateral sensitivity pairs that were conserved across four bacterial species, including several highly virulent pathogens belonging to the ESKAPEE group. Three of these conserved collateral sensitivity pairs were associated with a higher MIC towards colistin. Only one three-way collateral sensitivity interaction was shared across four pathogen species. The collateral effect network generated in this study is available via a web application, enabling further data exploration and supporting future research on antibiotic collateral effects.
Interpretation: Several collateral sensitivity interactions were conserved across several clinically relevant pathogens. The identified collateral sensitivity pairs can be considered for the development and application of collateral sensitivity-based antibiotic therapies to prevent and reverse antimicrobial resistance.
Funding: The Longfonds foundation and the Dutch Ministry of Health, Welfare, and Sport.
{"title":"Clinical prevalence of collateral sensitivity: a systematic exploration of multicentre antimicrobial surveillance data.","authors":"Sebastian T Tandar, Laura B Zwep, Sjoukje H S Woudt, Annelot F Schoffelen, Wiep Klaas Smits, Linda B S Aulin, Apostolos Liakopoulos, J G Coen van Hasselt","doi":"10.1016/j.lanmic.2025.101274","DOIUrl":"https://doi.org/10.1016/j.lanmic.2025.101274","url":null,"abstract":"<p><strong>Background: </strong>Collateral effects arise when resistance to one antibiotic alters the susceptibility of a bacterial strain to another antibiotic, resulting in either increased (collateral sensitivity) or decreased (collateral resistance) susceptibility. Collateral sensitivity-based antibiotic treatment offers a promising strategy against antibiotic resistance. To date, the clinical occurrence of collateral sensitivity between bacterial strains and species remains to be further evaluated. Our study aims to evaluate the occurrence patterns of collateral sensitivity in clinical settings.</p><p><strong>Methods: </strong>For this systematic exploration of multicentre antimicrobial surveillance data, we analysed large-scale antimicrobial resistance surveillance data from three datasets, covering over 5 million minimum inhibitory concentration (MIC) measurements across 86 antibiotics and 30 pathogen species, to identify collateral effect interactions. Pairwise and three-way collateral effects were quantified to assess species-wide trends in both collateral sensitivity and collateral resistance within individual pathogen species. Additionally, we compared the prevalence of collateral sensitivity between and within antibiotic classes. By comparing collateral sensitivity occurrence across species, we identified collateral sensitivity interactions conserved across several pathogens.</p><p><strong>Findings: </strong>We found a low occurrence of collateral sensitivity in clinical strains, with 364 of 12 024 species-antibiotic pairs (3·0%) affected, compared to 5044 cases (42·0%) of collateral resistance. Most collateral sensitivity interactions involved antibiotics from different classes, except for β-lactams, which showed 41 (34·2%) of 120 occurrences of intraclass collateral sensitivity. We identified six collateral sensitivity pairs that were conserved across four bacterial species, including several highly virulent pathogens belonging to the ESKAPEE group. Three of these conserved collateral sensitivity pairs were associated with a higher MIC towards colistin. Only one three-way collateral sensitivity interaction was shared across four pathogen species. The collateral effect network generated in this study is available via a web application, enabling further data exploration and supporting future research on antibiotic collateral effects.</p><p><strong>Interpretation: </strong>Several collateral sensitivity interactions were conserved across several clinically relevant pathogens. The identified collateral sensitivity pairs can be considered for the development and application of collateral sensitivity-based antibiotic therapies to prevent and reverse antimicrobial resistance.</p><p><strong>Funding: </strong>The Longfonds foundation and the Dutch Ministry of Health, Welfare, and Sport.</p>","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":" ","pages":"101274"},"PeriodicalIF":20.4,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147379028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-04DOI: 10.1016/j.lanmic.2026.101372
Tess Johnson, Lewis C E Mason, Hayley J Wilson, James R Price, Katie L Hopkins, Marie Anne Chattaway, Alistair Leanord, Olga Francino Marti, Rivie Mayele-Tamina, Stephanie Johnson, Paul Flowers, Willem van Schaik, Kate S Baker
Antimicrobial resistance (AMR) is a major threat to human and animal health, in addition to environmental resilience. Countries set the agenda on their national action against AMR in the form of National Action Plans (NAPs), with the UK's latest NAP released in May, 2024. Advances in genomics have strengthened our ability to work towards NAP priorities; however, to date, no mapping of the role genomics plays in contributing to specific goals within the NAP has been undertaken. The UK Research and Innovation-funded Transdisciplinary Antimicrobial Resistance Genomics Network brought together a range of stakeholders to discuss the role of genomics for action on AMR and to deliver policy priority-led research, as outlined in the UK NAP 2024-29. We report our discussions in this Personal View, with key roles for genomics, including informing targeted stewardship in health-care settings, supporting AMR literacy, and supporting effective antimicrobial innovation. However, changes in infrastructure, communication, and cross-sector coordination are needed to support implementation.
{"title":"The role of microbial genomics in delivering the UK's national action plan for confronting antimicrobial resistance 2024-29.","authors":"Tess Johnson, Lewis C E Mason, Hayley J Wilson, James R Price, Katie L Hopkins, Marie Anne Chattaway, Alistair Leanord, Olga Francino Marti, Rivie Mayele-Tamina, Stephanie Johnson, Paul Flowers, Willem van Schaik, Kate S Baker","doi":"10.1016/j.lanmic.2026.101372","DOIUrl":"https://doi.org/10.1016/j.lanmic.2026.101372","url":null,"abstract":"<p><p>Antimicrobial resistance (AMR) is a major threat to human and animal health, in addition to environmental resilience. Countries set the agenda on their national action against AMR in the form of National Action Plans (NAPs), with the UK's latest NAP released in May, 2024. Advances in genomics have strengthened our ability to work towards NAP priorities; however, to date, no mapping of the role genomics plays in contributing to specific goals within the NAP has been undertaken. The UK Research and Innovation-funded Transdisciplinary Antimicrobial Resistance Genomics Network brought together a range of stakeholders to discuss the role of genomics for action on AMR and to deliver policy priority-led research, as outlined in the UK NAP 2024-29. We report our discussions in this Personal View, with key roles for genomics, including informing targeted stewardship in health-care settings, supporting AMR literacy, and supporting effective antimicrobial innovation. However, changes in infrastructure, communication, and cross-sector coordination are needed to support implementation.</p>","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":" ","pages":"101372"},"PeriodicalIF":20.4,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147373303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-03DOI: 10.1016/j.lanmic.2025.101341
Koen Bartholomeeusen, Pieter Monsieurs, Jan Van Den Abbeele, Pieter Moris, Odin Goovaerts, Wim Pinxten, Jef Verellen, Oren Tzfadia, Kristien Verdonck, Raffaella Ravinetto
In genomic research primarily targeting microorganisms (or pathogens), a substantial risk exists that the presence of human genetic bycatch is not sufficiently recognised, and that the potential harm of unwarranted analysis, access, or sharing of human genetic bystander data is also insufficiently acknowledged or mitigated. In this Personal View, we contend that mandatory risk mitigation measures are necessary, more so in view of the likely increase of sharing of materials and pathogen sequence information under the WHO Pandemic Agreement and the related Pathogen Access and Benefit Sharing framework. Based on a joint reflection of the Institutional Review Board and individual researchers at the Institute of Tropical Medicine in Antwerp, Belgium, we propose a four-step approach to mitigate such risks: prevention or early removal of human genetic sequences, secure storage of samples and data, adaptation of informed consent, and targeted ethics review. This approach should contribute to maintaining ethical integrity, protect the rights of individuals and communities, and bolster public trust in the expanding use of untargeted sequencing in global health research.
{"title":"Research on the genome of microorganisms: ethical considerations and recommendations regarding the incidental bystander sequencing of human genetic material.","authors":"Koen Bartholomeeusen, Pieter Monsieurs, Jan Van Den Abbeele, Pieter Moris, Odin Goovaerts, Wim Pinxten, Jef Verellen, Oren Tzfadia, Kristien Verdonck, Raffaella Ravinetto","doi":"10.1016/j.lanmic.2025.101341","DOIUrl":"https://doi.org/10.1016/j.lanmic.2025.101341","url":null,"abstract":"<p><p>In genomic research primarily targeting microorganisms (or pathogens), a substantial risk exists that the presence of human genetic bycatch is not sufficiently recognised, and that the potential harm of unwarranted analysis, access, or sharing of human genetic bystander data is also insufficiently acknowledged or mitigated. In this Personal View, we contend that mandatory risk mitigation measures are necessary, more so in view of the likely increase of sharing of materials and pathogen sequence information under the WHO Pandemic Agreement and the related Pathogen Access and Benefit Sharing framework. Based on a joint reflection of the Institutional Review Board and individual researchers at the Institute of Tropical Medicine in Antwerp, Belgium, we propose a four-step approach to mitigate such risks: prevention or early removal of human genetic sequences, secure storage of samples and data, adaptation of informed consent, and targeted ethics review. This approach should contribute to maintaining ethical integrity, protect the rights of individuals and communities, and bolster public trust in the expanding use of untargeted sequencing in global health research.</p>","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":" ","pages":"101341"},"PeriodicalIF":20.4,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147370224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-02DOI: 10.1016/j.lanmic.2025.101289
Soo Jen Low, Matthew T O'Neill, Janath A Fernando, William J Kerry, Jacqueline Prestedge, Natasha Wild, Simran Chahal, Georgina L Pollock, Georgina Papadakis, Marcelina Krysiak, Eloise Williams, Francesca Azzato, Thomas Tran, Christopher Fairley, Catriona Bradshaw, Marcus Y Chen, Chuan K Lim, Deborah A Williamson, Shivani Pasricha
<p><strong>Background: </strong>Timely, point-of-care diagnosis of sexually transmitted infections (STIs) is crucial for enabling prompt treatment and reducing transmission. We aimed to develop a portable, multiplexed, CRISPR-based assay panel for the detection of Neisseria gonorrhoeae (including the ciprofloxacin resistance marker gyrA S91F), Chlamydia trachomatis, Treponema pallidum, and herpes simplex virus (HSV).</p><p><strong>Methods: </strong>In this laboratory development and evaluation study, we developed and optimised four multiplexed, CRISPR-based, diagnostic STI assays for point-of-care use. The complete assay panel comprised a CRISPR TP-HSV (cTP-HSV) panel for the detection of T pallidum and pan-HSV, with reflex testing to distinguish HSV-1 from HSV-2, and a CRISPR NG-CT (cNG-CT) panel for the detection of N gonorrhoeae and C trachomatis, with reflex testing to detect N gonorrhoeae using two additional genome regions and to identify the gyrA S91F mutation. Each pathogen was targeted at two independent genomic regions by isothermal amplification and CRISPR-Cas reaction using Cas12a and Cas13a, each with distinct fluorescent reporters. Analytical specificity and limits of detection (LODs) were determined, and a retrospective, masked concordance study was conducted on genomic DNA from 900 clinical samples (400 for cTP-HSV and reflex testing and 500 for cNG-CT and reflex testing), using quantitative PCR as the reference standard. The diagnostic accuracy of the test was assessed by analysis of receiver operating characteristic curves.</p><p><strong>Findings: </strong>The overall sensitivity of the TP-HSV CRISPR assay was 82·5% (95% CI 74·0-88·7) for T pallidum and 94·4% (90·2-97·0) for pan-HSV; LODs were 6·2 copies per μL for T pallidum and 7·8 copies per μL for HSV. Reflex testing gave sensitivities of 97·0% (91·1-99·3) for HSV-1 and 96·0% (89·7-98·7) for HSV-2. The NG-CT CRISPR assay had an overall sensitivity of 80·0% (74·0-84·9) for N gonorrhoeae and 73·0% (65·5-79·3) for C trachomatis, with a LOD of 3·9 copies per μL for both pathogens. Reflex testing for the detection of the gyrA S91F mutation in N gonorrhoeae showed an overall sensitivity of 63·1% (55·1-70·4); however, this was dependent on sample type, with a sensitivity of 85·7% (46·7-99·5) in genital samples and 61·2% (52·8-68·9) in extragenital samples. For all pathogens, assay sensitivity was positively correlated with pathogen load. Area under the curve (AUC) values were 0·90 for T pallidum and 0·99 for pan-HSV in the TP-HSV assay, with values of 0·99 for HSV-1 and 0·97 for HSV-2 obtained in the reflex HSV-1-HSV-2 assay. For the cNG-CT assay, AUC values were 0·90 for N gonorrhoeae and 0·85 for C trachomatis, with a value of 0·72 obtained for gyrA S91F in the reflex cNG-gyrA assay.</p><p><strong>Interpretation: </strong>Our multiplexed, CRISPR-based, point-of-care platform achieved performance consistent with WHO target product profiles for N gonorrhoeae and T pallidum. Proof-o
{"title":"CRISPR-Cas-based diagnostics for point-of-care detection of sexually transmitted infections: a laboratory development and evaluation study.","authors":"Soo Jen Low, Matthew T O'Neill, Janath A Fernando, William J Kerry, Jacqueline Prestedge, Natasha Wild, Simran Chahal, Georgina L Pollock, Georgina Papadakis, Marcelina Krysiak, Eloise Williams, Francesca Azzato, Thomas Tran, Christopher Fairley, Catriona Bradshaw, Marcus Y Chen, Chuan K Lim, Deborah A Williamson, Shivani Pasricha","doi":"10.1016/j.lanmic.2025.101289","DOIUrl":"https://doi.org/10.1016/j.lanmic.2025.101289","url":null,"abstract":"<p><strong>Background: </strong>Timely, point-of-care diagnosis of sexually transmitted infections (STIs) is crucial for enabling prompt treatment and reducing transmission. We aimed to develop a portable, multiplexed, CRISPR-based assay panel for the detection of Neisseria gonorrhoeae (including the ciprofloxacin resistance marker gyrA S91F), Chlamydia trachomatis, Treponema pallidum, and herpes simplex virus (HSV).</p><p><strong>Methods: </strong>In this laboratory development and evaluation study, we developed and optimised four multiplexed, CRISPR-based, diagnostic STI assays for point-of-care use. The complete assay panel comprised a CRISPR TP-HSV (cTP-HSV) panel for the detection of T pallidum and pan-HSV, with reflex testing to distinguish HSV-1 from HSV-2, and a CRISPR NG-CT (cNG-CT) panel for the detection of N gonorrhoeae and C trachomatis, with reflex testing to detect N gonorrhoeae using two additional genome regions and to identify the gyrA S91F mutation. Each pathogen was targeted at two independent genomic regions by isothermal amplification and CRISPR-Cas reaction using Cas12a and Cas13a, each with distinct fluorescent reporters. Analytical specificity and limits of detection (LODs) were determined, and a retrospective, masked concordance study was conducted on genomic DNA from 900 clinical samples (400 for cTP-HSV and reflex testing and 500 for cNG-CT and reflex testing), using quantitative PCR as the reference standard. The diagnostic accuracy of the test was assessed by analysis of receiver operating characteristic curves.</p><p><strong>Findings: </strong>The overall sensitivity of the TP-HSV CRISPR assay was 82·5% (95% CI 74·0-88·7) for T pallidum and 94·4% (90·2-97·0) for pan-HSV; LODs were 6·2 copies per μL for T pallidum and 7·8 copies per μL for HSV. Reflex testing gave sensitivities of 97·0% (91·1-99·3) for HSV-1 and 96·0% (89·7-98·7) for HSV-2. The NG-CT CRISPR assay had an overall sensitivity of 80·0% (74·0-84·9) for N gonorrhoeae and 73·0% (65·5-79·3) for C trachomatis, with a LOD of 3·9 copies per μL for both pathogens. Reflex testing for the detection of the gyrA S91F mutation in N gonorrhoeae showed an overall sensitivity of 63·1% (55·1-70·4); however, this was dependent on sample type, with a sensitivity of 85·7% (46·7-99·5) in genital samples and 61·2% (52·8-68·9) in extragenital samples. For all pathogens, assay sensitivity was positively correlated with pathogen load. Area under the curve (AUC) values were 0·90 for T pallidum and 0·99 for pan-HSV in the TP-HSV assay, with values of 0·99 for HSV-1 and 0·97 for HSV-2 obtained in the reflex HSV-1-HSV-2 assay. For the cNG-CT assay, AUC values were 0·90 for N gonorrhoeae and 0·85 for C trachomatis, with a value of 0·72 obtained for gyrA S91F in the reflex cNG-gyrA assay.</p><p><strong>Interpretation: </strong>Our multiplexed, CRISPR-based, point-of-care platform achieved performance consistent with WHO target product profiles for N gonorrhoeae and T pallidum. Proof-o","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":" ","pages":"101289"},"PeriodicalIF":20.4,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147370203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-02DOI: 10.1016/j.lanmic.2025.101257
Anders Østergaard Petersen, Birgitte Damholt, Mette Grove, Jonas Hink, Tamara Marotte-Hurbon, Johan Söderqvist, Alice Troy, Milan Zdravkovic, Lone Bayer, Katja Brunner, Tina Bryde, Jasper Clube, Yilmaz Emre Gencay, Aurelie Gram, Jakob Krause Haaber, Björn Hallström, Džiuginta Jasinskytė, Ricardo Pascal, Marianne Petersen, Szabolcs Semsey, Ana de Santiago Torio, Iszabela Cristiana Turcu, Frenk Smrekar, Ying Taur, Michael J Satlin, Morten Otto Alexander Sommer, Eric van der Helm, Christian Grøndahl
<p><strong>Background: </strong>Patients with haematological cancer who receive stem-cell transplantation are at risk of bloodstream infections, often caused by multidrug resistant gut pathogens such as Escherichia coli. SNIPR001 is a cocktail of four CRISPR-Cas-armed bacteriophages that reduce colonisation of E coli in the gastrointestinal tract in animal models and is designed to not affect other members of the commensal microbiota. We aimed to investigate the safety and tolerability of SNIPR001 in healthy participants.</p><p><strong>Methods: </strong>In this randomised, placebo-controlled, double-blind, first-in-human, dose-escalation trial conducted at a single centre (Medpace Clinical Pharmacology Unit; Cincinnati, OH, USA), we sequentially enrolled healthy participants (aged 18-65 years) with more than 10<sup>7</sup>E coli colony-forming units per gram of stool into cohorts 1, 2, and 3, pending a safety review of the previous enrolment group where applicable. Participants in each cohort were randomly assigned to treatment or placebo using a unique three-digit participant identification number. Participants were orally administered 10<sup>8</sup> plaque-forming units (PFU) per dose (cohort 1), 10<sup>10</sup> PFU per dose (cohort 2), and 10<sup>12</sup> PFU per dose (cohort 3) of SNIPR001 or placebo (phosphate-buffered saline buffer), twice daily for 7 days. All personnel, except for a pharmacy staff member who prepared both SNIPR001 and placebo vials, were masked to the administered dose and assignment; masking was ensured by fully covering the surface of each vial. Participants were followed up to day 187. The primary outcome was the incidence and severity of adverse events and medically attended adverse events from the first administration of the study drug until 4 weeks after the last dose administration on day 35 of the study. Recovery and biodistribution of SNIPR001 in faeces, blood, and urine; pharmacodynamics, including the ability of SNIPR001 to reduce E coli levels in stool (assessed using a linear mixed-effects model); and microbiome composition (using Bray-Curtis dissimilarity) were secondary outcomes. Primary safety analyses were assessed per-protocol (ie, all enrolled participants who received at least one administration of the study drug). This trial was conducted under an Investigational New Drug application from the US Food and Drug Administration, is registered with ClinicalTrials.gov (NCT05277350), and is closed to new participants.</p><p><strong>Findings: </strong>The trial was carried out between March 24, 2022, and Nov 30, 2022. 36 eligible participants were randomly assigned to receive SNIPR001 or placebo in cohorts 1 (six assigned to 10<sup>8</sup> PFU per dose and two assigned to placebo), 2 (six to 10<sup>10</sup> PFU per dose and two to placebo), and 3 (12 to 10<sup>12</sup> PFU per dose and eight to placebo). The mean age of participants was 42·1 years (SD 13·8), with 14 (39%) female participants and 22 (61%) male
{"title":"Safety, recovery, and pharmacodynamics of CRISPR-Cas therapeutic SNIPR001: a phase 1, randomised, double-blind, first-in-human, dose-escalation study.","authors":"Anders Østergaard Petersen, Birgitte Damholt, Mette Grove, Jonas Hink, Tamara Marotte-Hurbon, Johan Söderqvist, Alice Troy, Milan Zdravkovic, Lone Bayer, Katja Brunner, Tina Bryde, Jasper Clube, Yilmaz Emre Gencay, Aurelie Gram, Jakob Krause Haaber, Björn Hallström, Džiuginta Jasinskytė, Ricardo Pascal, Marianne Petersen, Szabolcs Semsey, Ana de Santiago Torio, Iszabela Cristiana Turcu, Frenk Smrekar, Ying Taur, Michael J Satlin, Morten Otto Alexander Sommer, Eric van der Helm, Christian Grøndahl","doi":"10.1016/j.lanmic.2025.101257","DOIUrl":"https://doi.org/10.1016/j.lanmic.2025.101257","url":null,"abstract":"<p><strong>Background: </strong>Patients with haematological cancer who receive stem-cell transplantation are at risk of bloodstream infections, often caused by multidrug resistant gut pathogens such as Escherichia coli. SNIPR001 is a cocktail of four CRISPR-Cas-armed bacteriophages that reduce colonisation of E coli in the gastrointestinal tract in animal models and is designed to not affect other members of the commensal microbiota. We aimed to investigate the safety and tolerability of SNIPR001 in healthy participants.</p><p><strong>Methods: </strong>In this randomised, placebo-controlled, double-blind, first-in-human, dose-escalation trial conducted at a single centre (Medpace Clinical Pharmacology Unit; Cincinnati, OH, USA), we sequentially enrolled healthy participants (aged 18-65 years) with more than 10<sup>7</sup>E coli colony-forming units per gram of stool into cohorts 1, 2, and 3, pending a safety review of the previous enrolment group where applicable. Participants in each cohort were randomly assigned to treatment or placebo using a unique three-digit participant identification number. Participants were orally administered 10<sup>8</sup> plaque-forming units (PFU) per dose (cohort 1), 10<sup>10</sup> PFU per dose (cohort 2), and 10<sup>12</sup> PFU per dose (cohort 3) of SNIPR001 or placebo (phosphate-buffered saline buffer), twice daily for 7 days. All personnel, except for a pharmacy staff member who prepared both SNIPR001 and placebo vials, were masked to the administered dose and assignment; masking was ensured by fully covering the surface of each vial. Participants were followed up to day 187. The primary outcome was the incidence and severity of adverse events and medically attended adverse events from the first administration of the study drug until 4 weeks after the last dose administration on day 35 of the study. Recovery and biodistribution of SNIPR001 in faeces, blood, and urine; pharmacodynamics, including the ability of SNIPR001 to reduce E coli levels in stool (assessed using a linear mixed-effects model); and microbiome composition (using Bray-Curtis dissimilarity) were secondary outcomes. Primary safety analyses were assessed per-protocol (ie, all enrolled participants who received at least one administration of the study drug). This trial was conducted under an Investigational New Drug application from the US Food and Drug Administration, is registered with ClinicalTrials.gov (NCT05277350), and is closed to new participants.</p><p><strong>Findings: </strong>The trial was carried out between March 24, 2022, and Nov 30, 2022. 36 eligible participants were randomly assigned to receive SNIPR001 or placebo in cohorts 1 (six assigned to 10<sup>8</sup> PFU per dose and two assigned to placebo), 2 (six to 10<sup>10</sup> PFU per dose and two to placebo), and 3 (12 to 10<sup>12</sup> PFU per dose and eight to placebo). The mean age of participants was 42·1 years (SD 13·8), with 14 (39%) female participants and 22 (61%) male","PeriodicalId":46633,"journal":{"name":"Lancet Microbe","volume":" ","pages":"101257"},"PeriodicalIF":20.4,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147366872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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