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Safety and Immunogenicity of an Adjuvanted Clostridioides difficile Vaccine Candidate in Healthy Adults: A Randomized Placebo-Controlled Phase 1 Study 健康成年人接种艰难梭菌佐剂疫苗的安全性和免疫原性:随机安慰剂对照 1 期研究
Pub Date : 2024-10-24 DOI: 10.1093/infdis/jiae466
Isabel Leroux-Roels, Azhar Alhatemi, Magalie Caubet, Fien De Boever, Bertrand de Wergifosse, Mohamed El Idrissi, Guilherme S Ferreira, Bart Jacobs, Axel Lambert, Sandra Morel, Charlotte Servais, Juan Pablo Yarzabal
Background This study investigated the safety, reactogenicity, and immunogenicity in healthy subjects of a Clostridioides difficile vaccine candidate with/without adjuvant, targeting toxins A and B. Methods In this first-in-human, phase 1, observer-blind study, subjects aged 18–45 years were randomized to receive F2 antigen (n = 10) or placebo (n = 10), and subjects aged 50–70 years to receive F2 antigen plus AS01 adjuvant (n = 45), F2 antigen (n = 45), or placebo (n = 30) in 2 doses 1 month apart. A subcohort (n = 40) received a third dose 15 months later. Solicited adverse events (AEs) were recorded for 7 days and unsolicited AEs for 30 days after each dose. Immunogenicity was assessed at baseline and after each dose. Results Solicited AEs were transient and most frequent in subjects receiving F2 antigen plus AS01. No serious AEs were considered related to study vaccine. Immunogenicity was substantially higher in subjects receiving F2 antigen plus AS01 than subjects receiving F2 antigen alone. A third dose increased the immune response in subjects with baseline neutralization titers below the assay lower limit of quantitation. Conclusions The GSK C. difficile vaccine candidate was immunogenic, especially when given with AS01, and was well tolerated with an acceptable safety profile. Clinical Trial Registration NCT04026009.
背景 本研究调查了针对毒素 A 和毒素 B 的含/不含佐剂的艰难梭菌候选疫苗在健康受试者中的安全性、致反应性和免疫原性。方法 在这项首次人体1期观察盲法研究中,18-45岁的受试者随机接受F2抗原(n = 10)或安慰剂(n = 10),50-70岁的受试者随机接受F2抗原加AS01佐剂(n = 45)、F2抗原(n = 45)或安慰剂(n = 30),分2次接种,每次间隔1个月。一个亚群(n = 40)在 15 个月后接受第三剂治疗。每次用药后 7 天内记录主动发生的不良事件 (AE),30 天内记录非主动发生的不良事件 (AE)。免疫原性在基线和每次用药后进行评估。结果 在接受 F2 抗原加 AS01 治疗的受试者中,主动出现的不良反应是短暂的,且最为常见。没有发现与研究疫苗相关的严重不良反应。接种F2抗原加AS01的受试者的免疫原性大大高于单独接种F2抗原的受试者。在基线中和滴度低于检测定量下限的受试者中,第三剂可提高免疫反应。结论 葛兰素史克艰难梭菌候选疫苗具有免疫原性,尤其是在与AS01一起接种时,耐受性良好,安全性可接受。临床试验注册 NCT04026009。
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引用次数: 0
An Expression Quantitative Trait Locus of Fc Gamma Receptor Genes is Associated with Anti-Malarial IgG Responses and Infection Levels in Burkinabe Families Fc Gamma 受体基因的表达量性状基因座与布基纳法索家庭的抗疟疾 IgG 反应和感染水平有关
Pub Date : 2024-10-23 DOI: 10.1093/infdis/jiae528
Christelle Dieppois, Mathieu Adjemout, Jules Cretin, Frederic Gallardo, Magali Torres, Christophe Picard, Serge Aimé Sawadogo, Pascal Rihet, Pascale Paul
Background The interaction between antibodies and Fc gamma receptors (FcγRs) plays a critical role in regulating immune responses to Plasmodium falciparum. Polymorphisms in genes encoding FcγRs influence the host's capacity to control parasite infection. This study investigates whether non-coding variants influencing FcγR expression are associated with anti-malarial immunization and infection traits. Methods We utilized eQTL databases and functional annotations to identify non-coding variants, specifically rs1771575, rs2099684, and rs6700241, within the FCGR gene cluster. In addition, we examined the coding variants rs1801274 (p.His167Arg) and rs1050501 (p.Ile231Thr), which affect the affinity of FcγRIIa and FcγRIIb for IgG. These variants were genotyped in 163 individuals from Burkinabe families. Family-based linear mixed regression and Quantitative Transmission Disequilibrium Tests (QTDT) analyses were performed to assess associations with IgG levels and malaria infection, accounting for relevant covariates. Results Linear mixed models identified rs1771575 as associated with total IgG levels, while both rs1771575 and rs1801274 were linked to IgG2, and rs1050501 to IgG1 levels. A haplotype combining rs2099684 and rs6700241 was positively associated with IgG1. The rs1771575-CC and rs1050501-TT genotypes correlated with higher infection levels in children. QTDT models confirmed the association of rs1771575 with IgG2 and infection in children. Conclusions Our findings suggest that the intergenic variant rs1771575 serves as an independent marker for IgG levels and blood infection in children. This highlights the interplay between regulatory variants and coding mutations in FCGR, which may influence immune function and antibody production. These results underscore the potential for personalized strategies to monitor humoral responses in malaria-endemic regions.
背景 抗体与 FcγRs 受体(FcγRs)之间的相互作用在调节对恶性疟原虫的免疫反应中起着至关重要的作用。FcγRs 编码基因的多态性会影响宿主控制寄生虫感染的能力。本研究探讨了影响 FcγR 表达的非编码变异是否与抗疟免疫和感染特征有关。方法 我们利用 eQTL 数据库和功能注释来鉴定 FCGR 基因簇中的非编码变异,特别是 rs1771575、rs2099684 和 rs6700241。此外,我们还研究了编码变异 rs1801274(p.His167Arg)和 rs1050501(p.Ile231Thr),它们会影响 FcγRIIa 和 FcγRIIb 对 IgG 的亲和力。这些变异在 163 个布基纳法索家庭中进行了基因分型。在考虑相关协变量的情况下,进行了基于家族的线性混合回归和定量传播失衡检验(QTDT)分析,以评估与 IgG 水平和疟疾感染的关系。结果 线性混合模型确定 rs1771575 与总 IgG 水平相关,而 rs1771575 和 rs1801274 与 IgG2 相关,rs1050501 与 IgG1 水平相关。结合了 rs2099684 和 rs6700241 的单倍型与 IgG1 呈正相关。rs1771575-CC 和 rs1050501-TT 基因型与儿童较高的感染水平相关。QTDT 模型证实了 rs1771575 与儿童 IgG2 和感染的相关性。结论 我们的研究结果表明,基因间变异 rs1771575 是儿童 IgG 水平和血液感染的独立标记。这突显了 FCGR 中调节变异和编码突变之间的相互作用,它们可能会影响免疫功能和抗体的产生。这些结果强调了在疟疾流行地区监测体液反应的个性化策略的潜力。
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引用次数: 0
Evaluation and real-world experience of a neutralization susceptibility screening assay for broadly neutralizing anti-HIV-1 antibodies. 广泛中和抗 HIV-1 抗体的中和敏感性筛选试验的评估和实际经验。
Pub Date : 2024-10-23 DOI: 10.1093/infdis/jiae486
Marie Høst Pahus,Yu Zheng,Maxine Olefsky,Jesper Damsgaard Gunst,Pablo Tebas,Babafemi Taiwo,Ole S Søgaard,Michael J Peluso,Yolanda Lie,Jacqueline D Reeves,Christos J Petropoulos,Marina Caskey,Katharine J Bar
BACKGROUNDDevelopment of a screening assay for the clinical use of broadly neutralizing antibodies (bnAbs) is a priority for HIV therapy and cure initiatives.METHODSWe assessed the PhenoSense Monoclonal Antibody (mAb) Assay (Labcorp-Monogram Biosciences) which is CLIA-validated and has been used prospectively and retrospectively in multiple recent bnAb clinical trials.RESULTSWhen performed on pre-ART plasma and on-ART longitudinal PBMC samples sourced from a recent clinical trial, the PhenoSense mAb Assay produced robust reproducibility, concordance across sample types, and expected ranges in the susceptibility measures of bnAbs in clinical development. PhenoSense mAb applied retrospectively to baseline samples from three recent studies correlated with published laboratory-based study evaluations, but baseline bnAb susceptibility was not consistently predictive of durable virus suppression. Assessment of the feasibility of the assay in four recent clinical studies provides estimates of assay success rate and processing time.CONCLUSIONSThe PhenoSense mAb Assay provides reproducible bnAb susceptibility measurements across relevant sample types yet was not consistently predictive of virus suppression. Logistical and operational assay requirements can impact timely clinical trial conduct. These results inform bnAb studies in development.
方法我们评估了 PhenoSense 单克隆抗体(mAb)检测试剂盒(Labcorp-Monogram Biosciences),该试剂盒已通过 CLIA 认证,并已在最近的多个 bnAb 临床试验中进行了前瞻性和回顾性使用。结果PhenoSense mAb 检测试剂盒对来自近期临床试验的抗逆转录病毒治疗前血浆和抗逆转录病毒治疗期间纵向 PBMC 样本进行检测时,在临床开发中的 bnAbs 易感性测量中,PhenoSense mAb 检测试剂盒的重现性、跨样本类型的一致性和预期范围都很好。将 PhenoSense mAb 回溯应用于最近三项研究的基线样本与已发表的基于实验室的研究评估结果相关联,但基线 bnAb 药敏性并不能持续预测病毒的持久抑制。结论:PhenoSense mAb 检测法可对相关样本类型进行可重复的 bnAb 药敏测定,但不能持续预测病毒抑制效果。后勤和操作测定要求会影响临床试验的及时进行。这些结果为开发中的 bnAb 研究提供了参考。
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引用次数: 0
Review: Diagnostic Potential for Collaborative Pharyngitis Biomarkers. 评论:咽炎合作生物标志物的诊断潜力。
Pub Date : 2024-10-23 DOI: 10.1093/infdis/jiae416
Nathan A Ledeboer,Jane M Caldwell,Bobby L Boyanton
Pharyngitis is an inflammatory condition of the pharynx and/or tonsils commonly seen in both children and adults. Viruses and bacteria represent the most common encountered etiologic agents-yeast/fungi and parasites are infrequently implicated. Some of these are predominantly observed in unique populations (eg, immunocompromised or unvaccinated individuals). This manuscript (part 3 of 3) summarizes the current state of biomarker diagnostic testing and highlights the expanding role they will likely play in the expedited diagnosis and management of patients with acute pharyngitis. Biomarkers, in conjunction with rapid antigen and/or nucleic acid amplification testing, will likely become the standard of care to accurately diagnose the etiologic agent(s) of pharyngitis. This novel testing paradigm has the potential to guide appropriate patient management and antibiotic stewardship by accurately determining if the cause of pharyngitis is due to a viral or bacterial etiology.
咽炎是儿童和成人常见的咽部和/或扁桃体炎症。病毒和细菌是最常见的病原体,而酵母菌/真菌和寄生虫则不常见。其中一些病原体主要见于特殊人群(如免疫力低下或未接种疫苗者)。本手稿(共 3 部分中的第 3 部分)概述了生物标记诊断检测的现状,并强调了生物标记诊断检测在急性咽炎患者的快速诊断和管理中可能发挥的越来越大的作用。生物标记物与快速抗原和/或核酸扩增检测相结合,很可能成为准确诊断咽炎病原体的标准方法。这种新的检测模式可以准确判断咽炎的病因是病毒还是细菌,从而指导适当的患者管理和抗生素管理。
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引用次数: 0
Review: Current Laboratory and Point-of-Care Pharyngitis Diagnostic Testing and Knowledge Gaps. 回顾:当前实验室和护理点咽炎诊断测试及知识差距。
Pub Date : 2024-10-23 DOI: 10.1093/infdis/jiae415
Bobby L Boyanton,Jane M Caldwell,Nathan A Ledeboer
Pharyngitis is an inflammatory condition of the pharynx and/or tonsils commonly seen in both children and adults. Viruses and bacteria represent the most common encountered etiologic agents-yeast/fungi and parasites are infrequently implicated. Some of these are predominantly observed in unique populations (eg, immunocompromised or unvaccinated individuals). This manuscript (part 2 of 3) summarizes the current state of laboratory and point-of-care diagnostic testing and highlights the expanding role of nucleic acid amplification in the expedited diagnosis and management of patients with acute pharyngitis. It discusses preanalytical, analytical, and postanalytical variables that impact the performance of culture, rapid antigen, and nucleic acid amplification testing. Finally, it sets the stage for part 3, which discusses the emerging role of biomarkers in the management of individuals with acute pharyngitis.
咽炎是儿童和成人常见的咽部和/或扁桃体炎症。病毒和细菌是最常见的致病因子,而酵母菌/真菌和寄生虫则不常见。其中一些病原体主要见于特殊人群(如免疫力低下或未接种疫苗者)。本手稿(3 部曲中的第 2 部曲)概述了实验室和护理点诊断检测的现状,并强调了核酸扩增技术在急性咽炎患者的快速诊断和管理中不断扩大的作用。它讨论了影响培养、快速抗原和核酸扩增检测性能的分析前、分析中和分析后变量。最后,它为第三部分做了铺垫,第三部分将讨论生物标记物在急性咽炎患者管理中的新作用。
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引用次数: 0
EDP-938 Has a High Barrier to Resistance in Healthy Adults Experimentally Infected with Respiratory Syncytial Virus. EDP-938 在实验性感染呼吸道合胞病毒的健康成人中具有很高的抗性屏障。
Pub Date : 2024-10-23 DOI: 10.1093/infdis/jiae471
Rachel Emily Levene,John DeVincenzo,Annie L Conery,Alaa Ahmed,Yat Sun Or,Michael H J Rhodin
BACKGROUNDEDP-938 is an oral once-daily RSV nucleoprotein (N) inhibitor with potent antiviral activity. In a human RSV challenge trial, EDP-938 significantly reduced viral load and symptom severity. During antiviral development, it is critical to understand the propensity for resistance to develop. In vitro studies of EDP-938 suggest a higher barrier to resistance as compared to RSV fusion inhibitors. We evaluated the development of viral resistance to EDP-938 in a human challenge trial.METHODSA subset of the 124 participants with RSV infection were chosen for genetic analysis; 159 nasal wash samples from 48 participants were analyzed using next-generation sequencing of the N gene of RSV. Of the 48 participant sampled, 37 were from EDP-938-treated and 11 were placebo-treated participants, representing 45% and 26% of the participants, respectively. The effects of treatment-emergent mutations on viral load, EDP-938 efficacy, and viral fitness were evaluated.RESULTSTwo of the 37 EDP-938-treated participants with samples sequenced had treatment-emergent mutations: N:L139I and N:E112G. From in vitro analysis, N:L139I reduced sensitivity to EDP-938 by approximately 10-fold, while N:E112G had no effect. However, N:L139I was associated with a reduction in viral fitness, suggesting clinical resistance is associated with fitness costs. Neither of these variants were associated with reduced viral clearance.CONCLUSIONSIn human RSV infections treated with EDP-938, emergence of RSV variants with reduced sensitivity to EDP-938 occurred in only 1 participant and was associated with reduced viral fitness. EDP-938's high barrier to resistance highlights its robust mechanism of action.CLINICAL TRIALS REGISTRATIONNCT03691623.
背景EDP-938是一种每日口服一次的RSV核蛋白(N)抑制剂,具有很强的抗病毒活性。在一项人类 RSV 挑战试验中,EDP-938 能显著降低病毒载量和症状严重程度。在抗病毒药物研发过程中,了解耐药性的产生倾向至关重要。EDP-938 的体外研究表明,与 RSV 融合抑制剂相比,EDP-938 的抗药性屏障更高。我们在一项人体挑战试验中评估了病毒对 EDP-938 的耐药性发展情况。在 48 名参与者样本中,37 名来自接受过 EDP-938 治疗的参与者,11 名来自接受过安慰剂治疗的参与者,分别占参与者总数的 45% 和 26%。结果37名接受过EDP-938治疗的参与者中,有2人的样本测序出现了治疗突变:N:L139I 和 N:E112G。体外分析显示,N:L139I 使患者对 EDP-938 的敏感性降低了约 10 倍,而 N:E112G 则没有影响。然而,N:L139I 与病毒适应性的降低有关,这表明临床耐药性与适应性成本有关。结论 在接受 EDP-938 治疗的人类 RSV 感染中,仅有 1 名参与者出现了对 EDP-938 敏感性降低的 RSV 变异,并且与病毒适应性降低有关。EDP-938的高抗性屏障凸显了其强大的作用机制。
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引用次数: 0
COVID-19 lineages in a minimally vaccinated island population: Genomic epidemiology of SARS-CoV-2 in Haiti. 接种疫苗最少的岛屿人口中的 COVID-19 世系:海地 SARS-CoV-2 基因组流行病学。
Pub Date : 2024-10-23 DOI: 10.1093/infdis/jiae520
Carla N Mavian,Massimiliano S Tagliamonte,Maclean Bassett,Meer Alam,Melanie N Cash,Matt Hitchings,Rigan Louis,Alberto Riva,Kayvan Zainabadi,Marie Marcelle Deschamps,Bernard Liautaud,Vanessa Rouzier,Daniel W Fitzgerald,Jean William Pape,J Glenn Morris,Marco Salemi
We monitored SARS-CoV-2 variants in Haiti from 2020-2023. Despite Haitian COVID-19 travel restrictions and in the setting of a vaccination rate of 2.7%, the timing and lineage evolution of the Haiti epidemic mirrored what was occurring in the rest of the world. Sources for importation of lineages into Haiti were the United States (US), the Dominican Republic (DR), Europe, and Brazil, with exportation of lineages to the US, DR, Europe, and Asia. Viral load in patients infected by the Delta and Omicron BA.1 were correlated along the phylogenies, suggesting that higher viral loads have facilitated strain transmission and evolution.
我们在 2020-2023 年期间对海地的 SARS-CoV-2 变种进行了监测。尽管海地对 COVID-19 实施了旅行限制,而且疫苗接种率仅为 2.7%,但海地疫情的发生时间和变异株的演变与世界其他地区的情况如出一辙。向海地输入病毒株的来源地包括美国、多米尼加共和国、欧洲和巴西,病毒株则向美国、多米尼加共和国、欧洲和亚洲输出。受德尔塔型和奥米克隆型 BA.1 感染的患者的病毒载量与系统发育相关,这表明较高的病毒载量促进了病毒株的传播和进化。
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引用次数: 0
Review: Known, Emerging, and Remerging Pharyngitis Pathogens. 回顾:已知、新出现和再次出现的咽炎病原体。
Pub Date : 2024-10-23 DOI: 10.1093/infdis/jiae391
Jane M Caldwell,Nathan A Ledeboer,Bobby L Boyanton
Pharyngitis is an inflammatory condition of the pharynx and/or tonsils commonly seen in both children and adults. Viruses and bacteria represent the most common encountered etiologic agents-yeast/fungi and parasites are infrequently implicated. Some of these are predominantly observed in unique populations (eg, immunocompromised or unvaccinated individuals). This article (part 1 of 3) summarizes the impact of acute pharyngitis on the health care system and reviews the etiologic agents of acute pharyngitis, including both emerging and reemerging pathogens that health care providers should consider when evaluating their patients. Finally, it sets the stage for parts 2 and 3, which discuss the current and evolving state of diagnostic testing for acute pharyngitis.
咽炎是儿童和成人常见的咽部和/或扁桃体炎症。病毒和细菌是最常见的病原体,而酵母菌/真菌和寄生虫则不常见。其中一些病原体主要见于特殊人群(如免疫力低下或未接种疫苗者)。本文(3 部分中的第 1 部分)概述了急性咽炎对医疗保健系统的影响,并回顾了急性咽炎的病原体,包括医疗保健提供者在评估患者时应考虑的新出现和再次出现的病原体。最后,它为第二部分和第三部分做了铺垫,这两部分讨论了急性咽炎诊断检测的现状和发展。
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引用次数: 0
Neutralizing Antibody Responses to Chlamydia trachomatis in Women and Associations with Chlamydia Outcomes 女性沙眼衣原体中和抗体反应及其与衣原体感染结果的关系
Pub Date : 2024-10-22 DOI: 10.1093/infdis/jiae519
Hong Yu, William M Geisler, Chuanbin Dai, Kanupriya Gupta, Gary Cutter, Robert C Brunham
We assessed neutralizing antibody responses in a well-characterized cohort of 60 women with different Chlamydia trachomatis infection outcomes noted at a treatment visit and 3-month follow-up. We found varying rates of neutralization (inhibition of C. trachomatis) in sera at different dilution levels and varying neutralizing antibody titers across outcomes. Median neutralization rates were significantly higher in sera at high dilutions (1:320-1:1280) from women with spontaneous resolution versus persisting infection before treatment (all P< .05). These findings suggest that neutralizing antibody responses may contribute to protective immunity against chlamydia.
我们对 60 名妇女的中和抗体反应进行了评估,这些妇女在接受治疗和 3 个月随访时,沙眼衣原体感染的结果各不相同。我们发现,不同稀释水平的血清中的中和率(对沙眼衣原体的抑制作用)不同,不同结果的中和抗体滴度也不同。在高稀释度(1:320-1:1280)的血清中,中和率的中位数明显高于治疗前自发缓解和持续感染的女性(所有 P< .05)。这些研究结果表明,中和抗体反应可能有助于对衣原体产生保护性免疫。
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引用次数: 0
Systems Vaccinology: Navigating the Future of Personalized Immunity and Next Generation Vaccines 系统疫苗学:引领个性化免疫和下一代疫苗的未来
Pub Date : 2024-10-19 DOI: 10.1093/infdis/jiae505
Serena Maria Dib, Sonia Tandon Wimalasena, Daniel S Graciaa, Nadine Rouphael
Systems vaccinology integrates a range of "omics" technologies to identify key immune signatures and enhance vaccine development. This approach aids in understanding variations in immune responses, driven by genetics, health status, and microbiome. Consequently, systems vaccinology helps pave the way for personalized vaccination strategies, essential for addressing diverse populations.
系统疫苗学整合了一系列 "omics "技术,以确定关键的免疫特征并加强疫苗开发。这种方法有助于了解由遗传、健康状况和微生物组驱动的免疫反应变化。因此,系统疫苗学有助于为个性化疫苗接种策略铺平道路,这对解决不同人群的问题至关重要。
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引用次数: 0
期刊
The Journal of Infectious Diseases
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