EBioMedicine最新文献

{"title":"Computational modelling of CAR T-cell therapy: from cellular kinetics to patient-level predictions.","authors":"Adrià Murias-Closas, Clara Prats, Gonzalo Calvo, Daniel López-Codina, Eulàlia Olesti","doi":"10.1016/j.ebiom.2025.105597","DOIUrl":"10.1016/j.ebiom.2025.105597","url":null,"abstract":"<p><p>Chimeric Antigen Receptor (CAR) T-cell therapy is characterised by the heterogeneous cellular kinetic profile seen across patients. Unlike traditional chemotherapy, which displays predictable dose-exposure relationships resulting from well-understood pharmacokinetic processes, CAR T-cell dynamics rely on complex biologic factors that condition treatment response. Computational approaches hold potential to explore the intricate cellular dynamics arising from CAR T therapy, yet their ability to improve cancer treatment remains elusive. Here we present a comprehensive framework through which to understand, construct, and classify CAR T-cell kinetics models. Current approaches often rely on adapted empirical pharmacokinetic methods that overlook dynamics emerging from cellular interactions, or intricate theoretical multi-population models with limited clinical applicability. Our review shows that the utility of a model does not depend on the complexity of its design but on the strategic selection of its biological constituents, implementation of suitable mathematical tools, and the availability of biological measures from which to fit the model.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105597"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying chronic obstructive pulmonary disease subtypes using multi-trait genetics.","authors":"Andrey Ziyatdinov, Brian D Hobbs, Samir Kanaan-Izquierdo, Matthew Moll, Phuwanat Sakornsakolpat, Nick Shrine, Jing Chen, Kijoung Song, Russell P Bowler, Peter J Castaldi, Martin D Tobin, Peter Kraft, Edwin K Silverman, Hanna Julienne, Michael H Cho, Hugues Aschard","doi":"10.1016/j.ebiom.2025.105609","DOIUrl":"10.1016/j.ebiom.2025.105609","url":null,"abstract":"<p><strong>Background: </strong>Chronic Obstructive Pulmonary Disease (COPD) has a broad spectrum of clinical characteristics. The aetiology of these differences is not well understood. The objective of this study is to assess whether respiratory genetic variants cluster by phenotype and associate with COPD heterogeneity.</p><p><strong>Methods: </strong>We clustered genome-wide association studies of COPD, lung function, and asthma and phenotypes from the UK Biobank using non-negative matrix factorization. We constructed cluster-specific genetic risk scores and tested these scores for association with phenotypes in non-Hispanic white subjects in the COPDGene study.</p><p><strong>Findings: </strong>We identified three clusters from 482 variants and 44 traits from genetic associations in 379,337 UK Biobank participants. Variants from asthma, COPD, and lung function were found in all three clusters. Clusters displayed varying effects on white blood cell counts, height, and body mass index (BMI)-related phenotypes in the UK Biobank. In the COPDGene cohort, cluster-specific genetic risk scores were associated with differences in steroid use, BMI, lymphocyte counts, and chronic bronchitis, as well as variations in gene and protein expression.</p><p><strong>Interpretation: </strong>Our results suggest that multi-phenotype analysis of obstructive lung disease-related risk variants may identify genetically driven phenotypic patterns in COPD.</p><p><strong>Funding: </strong>MHC was supported by R01HL149861, R01HL135142, R01HL137927, R01HL147148, and R01HL089856. HA and HJ were supported by ANR-20-CE36-0009-02 and ANR-16-CONV-0005. The COPDGene study (NCT00608764) is supported by grants from the NHLBI (U01HL089897 and U01HL089856), by NIH contract 75N92023D00011, and by the COPD Foundation through contributions made to an Industry Advisory Committee that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer and Sunovion.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105609"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urgent need for scaling up vaccine research on WHO priority fungal pathogens, authors' reply.","authors":"Mateusz Hasso-Agopsowicz, Angela Hwang, Maria-Graciela Hollm-Delgado, Isis Umbelino-Walker, Ruth A Karron, Raman Rao, Kwaku Poku Asante, Meru Sheel, Erin Sparrow, Birgitte Giersing","doi":"10.1016/j.ebiom.2025.105621","DOIUrl":"10.1016/j.ebiom.2025.105621","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105621"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning detection of heteroresistance in Escherichia coli.","authors":"Andrei Guliaev, Karin Hjort, Michele Rossi, Sofia Jonsson, Hervé Nicoloff, Lionel Guy, Dan I Andersson","doi":"10.1016/j.ebiom.2025.105618","DOIUrl":"10.1016/j.ebiom.2025.105618","url":null,"abstract":"<p><strong>Background: </strong>Heteroresistance (HR) is a significant type of antibiotic resistance observed for several bacterial species and antibiotic classes where a susceptible main population contains small subpopulations of resistant cells. Mathematical models, animal experiments and clinical studies associate HR with treatment failure. Currently used susceptibility tests do not detect heteroresistance reliably, which can result in misclassification of heteroresistant isolates as susceptible which might lead to treatment failure. Here we examined if whole genome sequence (WGS) data and machine learning (ML) can be used to detect bacterial HR.</p><p><strong>Methods: </strong>We classified 467 Escherichia coli clinical isolates as HR or non-HR to the often used β-lactam/inhibitor combination piperacillin-tazobactam using pre-screening and Population Analysis Profiling tests. We sequenced the isolates, assembled the whole genomes and created a set of predictors based on current knowledge of HR mechanisms. Then we trained several machine learning models on 80% of this data set aiming to detect HR isolates. We compared performance of the best ML models on the remaining 20% of the data set with a baseline model based solely on the presence of β-lactamase genes. Furthermore, we sequenced the resistant sub-populations in order to analyse the genetic mechanisms underlying HR.</p><p><strong>Findings: </strong>The best ML model achieved 100% sensitivity and 84.6% specificity, outperforming the baseline model. The strongest predictors of HR were the total number of β-lactamase genes, β-lactamase gene variants and presence of IS elements flanking them. Genetic analysis of HR strains confirmed that HR is caused by an increased copy number of resistance genes via gene amplification or plasmid copy number increase. This aligns with the ML model's findings, reinforcing the hypothesis that this mechanism underlies HR in Gram-negative bacteria.</p><p><strong>Interpretation: </strong>We demonstrate that a combination of WGS and ML can identify HR in bacteria with perfect sensitivity and high specificity. This improved detection would allow for better-informed treatment decisions and potentially reduce the occurrence of treatment failures associated with HR.</p><p><strong>Funding: </strong>Funding provided to DIA from the Swedish Research Council (2021-02091) and NIH (1U19AI158080-01).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105618"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linking epidemiology and genomics of maternal smoking during pregnancy in utero and in ageing: a population-based study using human foetuses and the UK Biobank cohort.","authors":"Mihail Mihov, Hannah Shoctor, Alex Douglas, David C Hay, Peter J O'Shaughnessy, John P Iredale, Sophie Shaw, Paul A Fowler, Felix Grassmann","doi":"10.1016/j.ebiom.2025.105590","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105590","url":null,"abstract":"<p><strong>Background: </strong>Maternal smoking and foetal exposure to nicotine and other harmful chemicals in utero remains a serious public health issue with little knowledge about the underlying genetics and consequences of maternal smoking in ageing individuals. Here, we investigated the epidemiology and genomic architecture of maternal smoking in a middle-aged population and compare the results to effects observed in the developing foetus.</p><p><strong>Methods: </strong>In the current project, we included 351,562 participants from the UK Biobank (UKB) and estimated exposure to maternal smoking status during pregnancy through self-reporting from the UKB participants about the mother's smoking status around their birth. In addition, we analysed 64 foetal liver transcriptomic expression datasets collected from women seeking elective pregnancy terminations. Foetal maternal smoking exposure was confirmed through measurement of foetal plasma cotinine levels.</p><p><strong>Findings: </strong>Foetal exposure to maternal smoking had a greater impact on males than females, with more differentially expressed genes in liver tissue (3313 vs. 1163) and higher liver pathway activation. In the UKB, maternal smoking exposure was linked to an unhealthy lifestyle, lower education, and liver damage. In a genome-wide analysis in the UKB, we leveraged the shared genetic basis between affected offspring and their mothers and identified five genome-wide significant regions. We found a low heritability of the trait (∼4%) and implicated several disease-related genes in a transcriptome-wide association study. Maternal smoking increased all-cause mortality risk (Hazard ratio and 95% CI: 1.10 [1.04; 1.16], P = 4.04 × 10^-4), which was attenuated in non-smoking males.</p><p><strong>Interpretation: </strong>Although male foetuses are more affected than females by maternal smoking in pregnancy, this effect was largely reduced in middle-aged individuals. Importantly, our results highlight that the overall 10% increased mortality due to maternal smoking in pregnancy was greatly attenuated in non-smokers. This study demonstrates the importance of campaigns promoting offspring smoking prevention in families where the parent(s) smoke.</p><p><strong>Funding: </strong>Funding for this project was provided by the University of Aberdeen, the Science Initiative Panel of the Institute of Medical Science, the UK Medical Research Council, the Seventh Framework Programme of the European Union under Grant Agreement 212885 (REEF) and by NHS Grampian Endowments grants.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":" ","pages":"105590"},"PeriodicalIF":9.7,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613993","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}

{"title":"The impact of oral cannabis consumption during pregnancy on maternal spiral artery remodelling, fetal growth and offspring behaviour in mice.","authors":"Tyrah M Ritchie, Emily Feng, Fatemeh Vahedi, Sofya Ermolina, Christian J Bellissimo, Erica De Jong, Ana L Portillo, Sophie M Poznanski, Lauren Chan, Sara M Ettehadieh, Deborah M Sloboda, Dawn M E Bowdish, Ali A Ashkar","doi":"10.1016/j.ebiom.2025.105572","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105572","url":null,"abstract":"<p><strong>Background: </strong>The use of cannabis during pregnancy is rising following its widespread legalization. Cannabidiol (CBD) is gaining popularity due to the public perception that it is safer than the psychoactive cannabis component Δ9-tetrahydrocannabinol (THC). However, while evidence underpins the harm of THC and cannabis smoke on fetal development, there is minimal research on the safety of CBD and oral cannabis. The current study aims to decipher the safety of oral CBD and THC use during pregnancy.</p><p><strong>Methods: </strong>Using a mouse model, we directly compared the effects of oral CBD and THC oil exposure (20 mg/kg body weight) from early to mid-gestation on implantation site remodelling and fetal growth. We examined offspring behaviour and metabolic activity using both traditional and automated cage systems. Lastly, using human and mouse immune cells we assessed how CBD and THC influence angiogenic factor production.</p><p><strong>Findings: </strong>We observed impaired maternal spiral artery remodelling in cannabis exposed mice and found that CBD and THC disrupt immune cell angiogenic factor production. Oral consumption of THC or CBD oil also resulted in significant fetal growth impairment and led to long-lasting sex-dependent consequences as male offspring exhibited altered aggression and metabolic activity while females had impaired spatial learning.</p><p><strong>Interpretation: </strong>Our results show that oral consumption of either CBD or THC oil during pregnancy in mice results in harm to the developing fetus and causes behavioural changes after birth.</p><p><strong>Funding: </strong>The Michael G. DeGroote Centre for Medicinal Cancer Research, the Canadian Institutes of Health Research, and the Canadian Foundation for Innovation.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":" ","pages":"105572"},"PeriodicalIF":9.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364032","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}

{"title":"Comparison of autism domains across thirty rare variant genotypes.","authors":"Nabila M H Ali, Samuel J R A Chawner, Leila Kushan-Wells, Carrie E Bearden, Jennifer Gladys Mulle, Rebecca M Pollak, Raquel E Gur, Wendy K Chung, Michael J Owen, Marianne B M van den Bree","doi":"10.1016/j.ebiom.2024.105521","DOIUrl":"10.1016/j.ebiom.2024.105521","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;A number of Neurodevelopmental risk Copy Number Variants (ND-CNVs) and Single Gene Variants (SGVs) are strongly linked to elevated likelihood of autism. However, few studies have examined the impact on autism phenotypes across a wide range of rare variant genotypes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This study compared Social Communication Questionnaire (SCQ) scores (total and subdomains: social, communication, repetitive behaviour) in 1314 young people with one of thirty rare variant genotypes (15 ND-CNVs; n = 1005, 9.2 ± 3.5 years and 15 SGVs; n = 309, 8.3 ± 4.0 years). Comparisons were also conducted with young people without known genetic conditions (controls; n = 460, 10.6 ± 3.4 years) and with idiopathic autism (n = 480, 8.6 ± 3.2 years).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;The prevalence of indicative autism (SCQ ≥ 22) was higher in those with a rare variant genotype compared to controls (32% vs 2%; OR = 43.1, CI = 6.6-282.2, p &lt; 0.001) and in those with SGVs compared to ND-CNVs (53% vs 25%; OR = 4.00, CI = 2.2-7.3, p = 0.002). The prevalence of indicative autism varied considerably across the 30 rare variant genotypes (range 10-85%). SGVs were associated with greater impairment in total, social, communication and repetitive behaviour subdomains than ND-CNVs. However, genotype explained limited variation in these scores (η&lt;sup&gt;2&lt;/sup&gt; between 11.8 and 21.4%), indicating more convergence than divergence in autism phenotype across rare variant genotypes. Comparisons with young people with idiopathic autism indicated no differences compared to those with ND-CNVs, whereas those with SGVs showed greater communication and less repetitive behaviour.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;The likelihood of autism was higher across all rare variant genotypes, with individuals with SGVs showing higher prevalence and greater impairment compared to those with ND-CNVs. Despite subdomain-specific patterns, there was no strong evidence for specific genotype-phenotype associations. This suggests that rare variant genotypes alone may have limited predictive value for autism phenotypes and that other factors like polygenic risk and the environment are likely to play a role. Further research is needed in order to understand these influences, improve risk prediction and inform genetic counselling and interventions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Funding: &lt;/strong&gt;This work was funded by the Tackling Multimorbidity at Scale Strategic Priorities Fund programme (MR/W014416/1) (van den Bree) delivered by the Medical Research Council and the National Institute for Health Research in partnership with the Economic and Social Research Council and in collaboration with the Engineering and Physical Sciences Research Council. NIMH U01 MH119738-01 (van den Bree), IMAGINE study (Medical Research Council UK: MR/T033045/1; MR/N022572/1; and MR/L011166/1) (van den Bree) and Medical Research Council UK Centre Grant (MR/L010305/1) (Owen). SJRAC is funded by a Medical","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105521"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11835590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interpretation of indoor air surveillance for respiratory infections: a prospective longitudinal observational study in a childcare setting.","authors":"Caspar Geenen, Steven Traets, Sarah Gorissen, Michiel Happaerts, Kurt Beuselinck, Lies Laenen, Jens Swinnen, Sien Ombelet, Joren Raymenants, Els Keyaerts, Emmanuel André","doi":"10.1016/j.ebiom.2024.105512","DOIUrl":"10.1016/j.ebiom.2024.105512","url":null,"abstract":"<p><strong>Background: </strong>Sampling the air in indoor congregate settings, where respiratory pathogens are ubiquitous, may constitute a valuable yet underutilised data source for community-wide surveillance of respiratory infections. However, there is a lack of research comparing air sampling and individual sampling of attendees. Therefore, it remains unclear how air sampling results should be interpreted for the purpose of surveillance.</p><p><strong>Methods: </strong>In this prospective observational study, we compared the presence and concentration of several respiratory pathogens in the air with the number of attendees with infections and the pathogen load in their nasal mucus. Weekly for 22 consecutive weeks, we sampled the air in a single childcare setting in Belgium. Concurrently, we collected the paper tissues used to wipe the noses of 23 regular attendees: children aged zero to three and childcare workers. All samples were tested for 29 respiratory pathogens using PCR.</p><p><strong>Findings: </strong>Air sampling sensitively detected most respiratory pathogens found in nasal mucus. Some pathogens (SARS-CoV-2, Pneumocystis jirovecii) were found repeatedly in the air, but rarely in nasal mucus, whilst the opposite was true for others (Human coronavirus NL63). All three pathogens with a clear outbreak pattern (Human coronavirus HKU-1, human parainfluenza virus 3 and 4) were found in the air one week before or concurrent with the first detection in paper tissue samples. The presence and concentration of pathogens in the air was best predicted by the pathogen load of the most infectious case. However, air pathogen concentrations also correlated with the number of attendees with infections. Detection and concentration in the air were associated with CO₂ concentration, a marker of ventilation and occupancy.</p><p><strong>Interpretation: </strong>Our results suggest that air sampling could provide sensitive, responsive epidemiological indicators for the surveillance of respiratory pathogens. Using air CO₂ concentrations to normalise such signals emerges as a promising approach.</p><p><strong>Funding: </strong>KU Leuven; DURABLE project, under the EU4Health Programme of the European Commission; Thermo Fisher Scientific.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105512"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11830284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"homeRNA self-blood collection enables high-frequency temporal profiling of presymptomatic host immune kinetics to respiratory viral infection: a prospective cohort study.","authors":"Fang Yun Lim, Hannah G Lea, Ashley M Dostie, Soo-Young Kim, Tammi L van Neel, Grant W Hassan, Meg G Takezawa, Lea M Starita, Karen N Adams, Michael Boeckh, Joshua T Schiffer, Ollivier Hyrien, Alpana Waghmare, Erwin Berthier, Ashleigh B Theberge","doi":"10.1016/j.ebiom.2024.105531","DOIUrl":"10.1016/j.ebiom.2024.105531","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Early host immunity to acute respiratory infections (ARIs) is heterogenous, dynamic, and critical to an individual's infection outcome. Due to limitations in sampling frequency/timepoints, kinetics of early immune dynamics in natural human infections remain poorly understood. In this nationwide prospective cohort study, we leveraged a Tasso-SST based self-blood collection and stabilization tool (homeRNA) to profile detailed kinetics of the presymptomatic to convalescence host immunity to contemporaneous respiratory pathogens.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We enrolled non-symptomatic adults with recent exposure to ARIs who subsequently tested negative (exposed-uninfected) or positive for respiratory pathogens. Participants self-collected blood and nasal swabs daily for seven consecutive days followed by weekly blood collection for up to seven additional weeks. Symptom burden was assessed during each collection. Nasal swabs were tested for SARS-CoV-2 and common respiratory pathogens. 92 longitudinal blood samples spanning the presymptomatic to convalescence phase of eight participants with SARS-CoV-2 infection and 40 interval-matched samples from four exposed-uninfected participants were subjected to high-frequency longitudinal profiling of 785 immune genes. Generalized additive mixed models (GAMM) were used to identify temporally dynamic genes from the longitudinal samples and linear mixed models (LMM) were used to identify baseline differences between exposed-infected (n = 8), exposed-uninfected (n = 4), and uninfected (n = 13) participant groups.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;Between June 2021 and April 2022, 68 participants across 26 U.S. states completed the study and self-collected a total of 691 and 466 longitudinal blood and nasal swab samples along with 688 symptom surveys. SARS-CoV-2 was detected in 17 out of 22 individuals with study-confirmed respiratory infection, of which five were still presymptomatic or pre-shedding, enabling us to profile detailed expression kinetics of the earliest blood transcriptional response to contemporaneous variants of concern. 51% of the genes assessed were found to be temporally dynamic during COVID-19 infection. During the pre-shedding phase, a robust but transient response consisting of genes involved in cell migration, stress response, and T cell activation were observed. This is followed by a rapid induction of many interferon-stimulated genes (ISGs), concurrent to onset of viral shedding and increase in nasal viral load and symptom burden. Finally, elevated baseline expression of antimicrobial peptides was observed in exposed-uninfected individuals.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;We demonstrated that unsupervised self-collection and stabilization of capillary blood can be applied to natural infection studies to characterize detailed early host immune kinetics at a temporal resolution comparable to that of human challenge studies. The remote (decentralized)","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105531"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Experimental medicine study with stabilised native-like HIV-1 Env immunogens drives long-term antibody responses, but lacks neutralising breadth.","authors":"Katrina M Pollock, Hannah M Cheeseman, Leon R McFarlane, Suzanne Day, Monica Tolazzi, Hannah L Turner, Jennifer Joypooranachandran, Katsiaryna Shramko, Stefania Dispinseri, Philipp Mundsperger, Ilja Bontjer, Nana-Marie Lemm, Sofia Coelho, Maniola Tanaka, Tom Cole, Bette Korber, Dietmar Katinger, Quentin J Sattentau, Andrew B Ward, Gabriella Scarlatti, Rogier W Sanders, Robin J Shattock","doi":"10.1016/j.ebiom.2024.105544","DOIUrl":"10.1016/j.ebiom.2024.105544","url":null,"abstract":"<p><strong>Background: </strong>We report findings from an experimental medicine study of rationally designed prefusion stabilised native-like HIV envelope glycoprotein (Env) immunogens, representative of global circulating strains, delivered by sequential intramuscular injection.</p><p><strong>Methods: </strong>Healthy adult volunteers were enrolled into one of five groups (A to E) each receiving a different schedule of one of two consensus Env immunogens (ConM SOSIP, ConS UFO, either unmodified or stabilised by chemical cross-linking, followed by a boost with two mosaic Env immunogens (Mos3.1 and Mos3.2). All immunogens were co-formulated with liposomal Monophosphoryl-Lipid A (MPLA) adjuvant, and volunteers were followed up for 28 days post final Mosaic booster injection. Participants gave written informed consent to join the study. The study is registered on ClinicalTrials.gov ID NCT03816137.</p><p><strong>Findings: </strong>Fifty-one participants (men n = 23 and women n = 28) aged 18-55 were enrolled. The seroconversion rate against Env was 100% with all participants having measurable anti-Env IgG antibodies after their second injection and throughout the study. Neutralisation was detected against the ConM pseudovirus in sera of those who had received both ConM and ConS immunogens. However, this activity was limited in breadth and was neither boosted nor broadened in those receiving the Mos3.1 and Mos3.2 immunogens. Neutralising antibody function correlated with binding to V1/V3 and V5 epitopes and peaked after the third injection.</p><p><strong>Interpretation: </strong>Rationally designed prefusion-stabilised native-like Env trimers are robustly immunogenic in a prime-boost schedule. When given alone they are insufficient to induce neutralising antibody titres of significant breadth, but they represent potentially valuable polishing immunogens after germline-targeting.</p><p><strong>Funding: </strong>European Aids Vaccine initiative (EAVI2020) received funding from EU Horizon 2020, grant number 681137. Structural studies were supported by the Bill and Melinda Gates Foundation (INV-002916).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"112 ","pages":"105544"},"PeriodicalIF":9.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11753977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}