A Phase 2, Randomized, Placebo-Controlled, Double-Blind, Study of the Prevention of Infection With Mycobacterium Tuberculosis Among Adolescents Who Have Previously Received BCG

DAR-901 booster vaccine or placebo will be administered to adolescents in Tanzania primed with BCG to determine if immunization reduces the risk of TB infection

开始日期2016-03-01

申办/合作机构

Dartmouth-Hitchcock Medical Center

[+1]

NCT02063555 / Completed临床1期IIT

A Phase 1, Randomized, Placebo-Controlled, Double-Blind, Multiple-Dose, Dose-Ranging Study of the Safety and Immunogenicity of DAR-901, a Killed, Non-Tuberculous Mycobacterial Vaccine, in HIV-negative and HIV-positive Adults Who Have Previously Received BCG

This is a Phase 1, randomized, controlled, double-blind, multiple-dose, dose-ranging study of DAR 901, (an inactivated whole cell mycobacterial vaccine) to be conducted in HIV negative and HIV positive adults previously vaccinated with BCG. The goals of the trial are to determine the safety, tolerability, and immunogenicity of multiple doses of the vaccine at different dose levels, ranging from 0.1 to 1 mg.

开始日期2014-02-01

申办/合作机构

Dartmouth-Hitchcock Medical Center

[+1]

NCT00052195 / Completed临床2/3期IIT

DARDAR Health Project (Disseminated Tuberculosis and HIV Infection)

A significant number of HIV infected patients in Africa also have disseminated tuberculosis (infection throughout multiple organs). This type of tuberculosis is a significant cause of mortality in these patients. The purpose of this study is to evaluate the safety and effectiveness of a vaccine designed to prevent disseminated tuberculosis.

开始日期2001-09-01

申办/合作机构

Dartmouth-Hitchcock Medical Center

[+1]

100 项与 IMM-201 相关的临床结果

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100 项与 IMM-201 相关的转化医学

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100 项与 IMM-201 相关的专利（医药）

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项与 IMM-201 相关的文献（医药）

2020-12-01·BMC Infectious Diseases3区 · 医学

The potential of CBC-derived ratios (monocyte-to-lymphocyte, neutrophil-to-lymphocyte, and platelet-to-lymphocyte) to predict or diagnose incident TB infection in Tanzanian adolescents

3区 · 医学

ArticleOA

作者: von Reyn, C Fordham ; Amour, Maryam ; Pallangyo, Kisali ; Rees, Christiaan A ; Matee, Mecky ; Munseri, Patricia ; Said, Jamila ; Pineros, Dwan B ; Magohe, Albert

AbstractBackgroundRatios of different immune cell populations (i.e., monocyte-to-lymphocyte, neutrophil-to-lymphocyte, and platelet-to-lymphocyte ratios) have been studied as a means of predicting future tuberculosis (TB) disease risk or to assist in the diagnosis of incident TB disease. No studies to-date, however, have evaluated the potential of these ratios to predict or assist in the diagnosis of incident TB infection - the first step in the natural history of TB disease.MethodsIn this prospective study, we evaluated the complete blood count (CBC)-derived metrics of monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) as predictors of future TB infection risk or aids in the diagnosis of TB infection among 145 Tanzanian adolescents enrolled in the DAR-901 vaccine trial, using paired CBCs and interferon-gamma release assays (IGRAs) obtained at 0, 60 and 720 days after study enrollment.ResultsAt baseline, there were no significant differences between study participants who remained persistently IGRA negative throughout the study period and those who subsequently converted to IGRA positive with respect to MLR (0.18 vs 0.17, p = 0.10), NLR (0.88 vs 1.02, p = 0.08), or PLR (115 vs 120, p = 0.28). Similarly, no significant differences were noted with respect to MLR, NLR, and PLR between IGRA converters and time-matched negative controls at the time of IGRA conversion. With respect to other blood cell measures, however, there were modest but significant differences between IGRA negatives and IGRA converters with respect to red blood cell count (4.8 vs 4.6 × 106 cells/mcL, p = 0.008), hemoglobin (12.6 vs 12.3 g/dL, p = 0.01), and hematocrit (38.8 vs 37.8%, p = 0.005).ConclusionsIn contrast to prior studies that have suggested that the ratios of different immune cell populations are associated with development of TB disease, our present findings do not demonstrate an association between these ratios and the development of TB infection. However, decreased red blood cell measures were associated with the subsequent development of TB infection, suggesting either that dysregulation of iron metabolism may play a role in TB pathogenesis or that following TB infection, iron dysregulation may precede IGRA positivity.Trial registrationClinicaltrials.gov NCT02712424. Date of registration: March 14, 2016.

2020-10-01·Vaccine3区 · 医学

DAR-901 vaccine for the prevention of infection with Mycobacterium tuberculosis among BCG-immunized adolescents in Tanzania: A randomized controlled, double-blind phase 2b trial

3区 · 医学

Article

作者: Arbeit, Robert D ; Adams, Lisa V ; Bailey-Kellogg, Chris ; von Reyn, C Fordham ; Wieland-Alter, Wendy ; Mackenzie, Todd ; Amour, Maryam ; Pallangyo, Kisali ; Rees, Christiaan A ; Magohe, Albert ; Horsburgh, C Robert ; Nakamura, Keiko ; Munseri, Patricia ; Matee, Mecky ; Maro, Isaac ; Said, Jamila ; Tvaroha, Susan

BACKGROUNDSRL172 prevented disease due to Mycobacterium tuberculosis in a Phase 3 trial. DAR-901 represents a scalable manufacturing process for SRL172. We sought to determine if DAR-901 would prevent infection with M. tuberculosis among BCG-primed adolescents age 13-15 years in Tanzania.METHODSAdolescents with a negative T- SPOT.TB^R interferon gamma release assay (IGRA) were randomized 1:1 to three intradermal injections of DAR-901 or saline placebo at 0, 2 and 4 months. Repeat IGRAs were performed at 2 months, and at 1, 2, and 3 years. The primary efficacy outcome was time to new TB infection (IGRA conversion to positive); the secondary outcome was time to persistent TB infection (IGRA conversion with repeat positive IGRA).RESULTSAmong 936 participants screened 667 were eligible and randomized to their first dose of vaccine or placebo (safety cohort). At 2 months, 625 participants remained IGRA-negative and were scheduled for the additional two doses (efficacy cohort). DAR-901 was safe and well-tolerated. One DAR-901 recipient developed a vaccine site abscess. Neither the primary nor secondary endpoints differed between the two treatment arms (p = 0.90 and p = 0.20, respectively). DAR-901 IGRA converters had median responses to ESAT-6 of 50.1 spot-forming cells (SFCs) vs. 19.6 SFCs in placebo IGRA converters (p = 0.03).CONCLUSIONSA three-dose series of 1 mg DAR-901 was safe and well-tolerated but did not prevent initial or persistent IGRA conversion. DAR-901 recipients with IGRA conversion demonstrated enhanced immune responses to ESAT-6. Since protection against disease may require different immunologic responses than protection against infection a trial of DAR-901 to prevent TB disease is warranted.TRIAL REGISTRATIONThe trial is registered at ClinicalTrials.gov as NCT02712424.

2018-12-01·BMC Public Health3区 · 医学

Altruism, Scepticism, and collective decision-making in foreign-born U.S. residents in a tuberculosis vaccine trial

3区 · 医学

ArticleOA

作者: Fordham von Reyn, C ; Dixit, Apoorva ; Lahey, Timothy ; Craig, Sienna R

BACKGROUNDThe current vaccine against tuberculosis, BCG, is effective when given in most TB-endemic countries at birth but has diminished efficacy against pulmonary TB after 15-20 years. As a result, new booster vaccines for adolescents and adults are being developed to realize the World Health Organization target of global elimination of TB by 2035. Multiple TB candidates thus are in active clinical development.METHODSOne of these, DAR-901, is advancing in human clinical trials. These clinical trials are conducted in BCG immunized adults with and without HIV infection in order to assess safety and efficacy among the people most in need of a new vaccine. A Phase I dose escalation trial of DAR-901 in BCG-immunized adults with or without HIV infection was conducted between 2014 and 2016. This offered an unusual opportunity to qualitatively examine why foreign-born adults living in the United States - a poorly studied population - decide to participate, or not, in clinical trials.RESULTSWe conducted a qualitative study of individuals who were recruited to participate in this Phase I vaccine trial, interviewing those who agreed and declined to participate. We found diverse motivations for participation or refusal; varied understandings of tuberculosis and vaccines; and complex views about how 'informed consent' can be at odds with cultural understandings of power, authority, and medical decision-making. These dynamics included: knowledge (direct or indirect) of tuberculosis, a desire to be altruistic and simultaneous hopes for personal gain as well as concerns over what remuneration for participation could mean, the importance of personal relationships with care providers in shaping volunteerism, concerns over privacy, and evidence of how culture and history shape medical decision-making.CONCLUSIONSThis US-based trial, aimed at addressing a crucible global health issue, raises productive questions about the interface between altruism and scepticism regarding clinical research participation.TRIAL REGISTRATIONNCT02063555 .

项与 IMM-201 相关的新闻（医药）

2024-02-15

·生物制品圈

全球结核病疫苗研究进展概述

目前，用于预防结核病的疫苗只有近100年前研制出来的卡介苗(BCG)，至今仍在世界各地广泛使用。其对脑膜炎和播散性结核病等几种侵袭性儿童结核病的疗效已得到公认，但在所有年龄段对肺结核(PTB)的疗效差异很大，仍然是一个主要问题，开发更有效的结核疫苗是终止结核病流行的关键。结核疫苗保护机制接种疫苗的主要目的是建立长期有效的免疫记忆，以便迅速控制结核分枝杆菌感染。结核疫苗涉及CD4 + T细胞、CD8 + T细胞、B细胞和其他免疫细胞(如NK细胞和非常规T细胞)的免疫反应。疫苗的功效在很大程度上取决于记忆性T细胞介导的免疫记忆，CD4+ T细胞通常被认为对控制结核病至关重要，为了预防结核病，CD4+ T细胞分化为四个主要特征:1T 中央记忆细胞(TCM) 主要存在于淋巴器官中，并保持较高的增殖能力；2T 效应记忆细胞(TEM) 主要存在于循环和外周部位，抗原再暴露后与TCM细胞分化；3T 组织常驻记忆细胞(TRM) 一部分TEM细胞随后留在肺中；4T 效应细胞(TEFF) 感染后新招募的免疫细胞。T干细胞记忆(TSCM)细胞和TCM细胞，在慢性结核杆菌感染的免疫应答中发挥了核心作用，反应性记忆是由TCM介导的，TCM存在于次级淋巴器官的T细胞区域，几乎没有效应功能。然而，当暴露于外来抗原时，这些细胞能够增殖并迅速分化为效应细胞。因此，TCM可以为宿主提供针对病原体入侵的长期保护，而TEM细胞只能提供短期保护。TRM驻留在外周组织（例如肺）中，提供局部保护以防止再次感染。目前有17种候选疫苗处于临床试验阶段，它们包括预防结核病感染和结核病的候选药物，以及帮助改善结核病治疗结果的候选药物。根据其设计路线可分为减毒分枝杆菌活疫苗、灭活分枝杆菌疫苗、佐剂亚单位疫苗、病毒载体疫苗和信使RNA (mRNA)疫苗。减毒分枝杆菌活疫苗卡介苗是牛结核的减毒株，由于细胞内感染的细胞生物学相似，卡介苗和结核分枝杆菌都能引起CD4和CD8 T细胞反应并刺激抗体产生。在其衰减过程中，基因组区域的缺失使其主要毒力因子消失，因此，卡介苗在免疫能力强的宿主中是安全的。然而，近30年来，BCG呈现部分人群失效和不稳定状态，仅对最多60%的成人肺结核有免疫作用。而结核分枝杆菌多耐药菌株的流行和大量潜伏感染人群的存在，使得取代BCG的新型结核疫苗的研发十分迫切和关键。目前，开发重组卡介苗(rBCG)候选疫苗作为卡介苗的潜在替代品备受关注，因为活疫苗可引起更多样化的免疫反应，提高rBCG疗效的策略包括从卡介苗中删除基因和将分枝杆菌编码基因插入卡介苗基因组中。VPM1002是目前临床试验中唯一的rBCG疫苗，它是通过删除BCG DNA中的脲酶亚基编码基因，同时添加李斯特菌溶素基因而设计的。一项针对VPM1002与卡介苗在南非HIV暴露和HIV未暴露新生儿中的安全性和免疫原性的2期试验表明，与卡介苗相比，其安全性更好，目前正在进行一系列3期试验，以评估VPM1002预防结核病、结核病复发、结核分枝杆菌感染或持续感染的效果。除此之外，进入临床试验3期的活疫苗还有MTBVAC疫苗和BCG单克隆，MTBVAC是从MT103临床分离物发展而来，是目前唯一的减毒分枝杆菌候选活疫苗，缺失了两个毒力基因phoP和fadD26。灭活分枝杆菌疫苗微卡（Mycobacterium Vaccae）是一种特定的溶菌产物，用母牛分枝杆菌培养后收集的菌体，经高压均质、灭活后加入稳定剂冻干制成，主要有效成份为母牛分枝杆菌菌体蛋白，经药效学研究显示，其具有双向免疫调节功能，作为预防性结核病疫苗开展的3期临床研究已完成。2021年6月获得国家食品药品监督管理局批准，但是目前该生物制品未被纳入疫苗范畴，属于治疗性生物制品。多项研究结果显示，注射微卡并接受抗结核治疗的初治、复治和耐多药肺结核患者，痰涂片阴转率和痰培养阴转率均高于对照组，且能够促进肺部病灶吸收和空洞闭合。分枝杆菌灭活疫苗进入临床试验阶段的还有DAR-901、RUTI和MIP。DAR-901是Mycobacterium kyogaense sp.nov的灭活制剂，在一项2期试验表明，在BCG免疫的青少年中具有良好的安全性和耐受性；有研究表明，皮内注射3~12次DAR-901联合抗结核药物治疗可提高痰菌阴转率，促进病变吸收，增强Th1细胞反应。RUTI是一种基于细胞壁碎片化的结核分枝杆菌的非活性多抗原疫苗，其用途是作为治疗性疫苗，可联合短疗程、高强度抗生素治疗使用。一项针对健康志愿者的1期研究和一项针对潜伏结核感染人群的2期研究已经证实了此疫苗具有良好的安全特性，且在所有的研究剂量下都能产生免疫反应。MIP是由Mycobacterium obuense组成的灭活疫苗，最初被许可作为麻风病患者化疗的辅助药物，随后MIP先后完成了对复发结核病患者进行免疫治疗的1-3期临床试验。这表明MIP对结核分枝杆菌有明显的疗效，但另一项3期临床试验发现MIP作为结核性心包炎患者抗结核治疗的辅助治疗无效。佐剂亚单位疫苗佐剂亚单位结核疫苗的开发在很大程度上依赖于鉴定参与保护性免疫的新型结核抗原和选择合适的佐剂系统。大多数亚单位结核病疫苗针对的是结核分枝杆菌的某些蛋白质，因此免疫反应的广度通常要窄得多，抗原靶标的选择尤为重要。目前正在进行临床试验的亚单位疫苗有M72/AS01E、H56:IC31、ID93+GLA-SE、GamTBvac和AEC/BC02，这些疫苗以不同的组合和配方使用了11种分枝杆菌抗原。M72/AS01E是正在开发的最有希望的候选疫苗之一，它通过将高免疫原性结核分枝杆菌蛋白Rv1196和Rv0125与佐剂AS01融合而成。在印度、南非和其他地区完成的一系列2期临床试验，在2b期临床试验中，M72/AS01E显著降低了HIV阴性、潜伏性结核感染成人患者的TB发病率，在接种后3年内的疫苗效力为50%。3期临床试验将由比尔及梅琳达·盖茨医学研究所组织开展，以评估候选疫苗在预防潜伏性结核感染发展为肺结核方面的有效性。AEC/BC02疫苗是由结核分枝杆菌抗原Ag85B、ESAT-6、CFP-10蛋白与佐剂BC02组成，用于预防结核分枝杆菌潜伏感染人群结核病发病。一项评估预防结核分枝杆菌潜伏感染人群结核病发病的安全性和免疫原性的1b期研究已经完成，初步结果显示该疫苗具有良好的安全性和耐受性，目前2a期临床研究已启动，以研究在18岁及以上LTBI患者中的安全性、耐受性和免疫原性。病毒载体疫苗病毒载体疫苗能够模拟病原菌入侵机体并诱导免疫应答的过程，具备形成长效免疫记忆的能力。除此之外，重组活疫苗载体通常具备以下优点：（1）能够容纳较长的抗原片段；（2）外源基因表达效率稳定；（3）能够同时诱导高水平T细胞免疫应答和体液免疫反应；（4）载体本身诱导的固有免疫反应能够在一定程度上增强适应性免疫应答；（5）不需使用佐剂；（6）易于操作制备，扩大培养和生产方式成熟；（7）使用感染机制明确的减毒或复制缺陷型病毒，安全性较强；（8）一般单次免疫即可诱导强烈的免疫记忆，不需反复接种或接种次数少。对于结核疫苗而言，由于结核分枝杆菌能够感染细胞并在胞内长期生存，因此，活病毒载体诱导高水平细胞毒性T淋巴细胞应答的特殊能力有助于机体对于胞内结核菌的清除。目前临床试验中的三种候选病毒载体疫苗，包括ChAdOx185A +MVA85A、AdHu5Ag85A和TB/Flu-05E。MVA85A是第一个获准用于临床评估的病毒载体疫苗，在早期试验中在不同人群中具有良好的安全性和免疫原性，但在2b期临床试验中被证明无效。在南非进行的第一项临床试验表明，在接种过BCG的婴儿中，与卡介苗相比，增强MVA85A不能显著提高预防结核病感染或结核病发病的能力。在HIV感染者中进行的第二次疗效试验中，MVA85A也没有显示出保护作用，尽管它增强了Ag85A特异性Th1应答。MVA85A受挫有多种原因，包括使用单一抗原、HIV感染者的免疫抑制以及结核感染后Ag85A表达降低。然而，研究人员仍然没有放弃。他们将MVA85A与猴腺病毒疫苗ChAdOx185A结合，两者都表达Ag85A，目前处于Ⅱa期临床研究。mRNA疫苗受COVID-19 mRNA疫苗巨大成功的启发，针对猴痘(Mpox)和结核病等其他传染病的mRNA疫苗的开发受到了前所未有的关注。2004年，证实了RNA疫苗对结核病的保护作用，但其保护作用不如卡介苗。2023年，BioNTech与比尔及梅琳达·盖茨基金会合作，启动了BNT164的1期临床试验，这是首个针对结核病的mRNA候选疫苗。临床试验将评估BNT164a1和BNT164b1抗结核病的安全性、反应原性和免疫原性。参考资料[1]Mark F Cotton,et al.Safety and immunogenicity of VPM1002 versus BCG in South African newborn babies: a randomised, phase 2 non-inferiority double-blind controlled trial.Lancet Infect Dis,2022 ,22(10):1472-1483.[2]Fangbin Zhou and Dongmei Zhang.Recent advance in the development of tuberculosis vaccines in clinical trials and virus-like particle-based vaccine candidates.Frontiers in immunology,2023,14:1238649.[3]张梦娴，等.中国结核病疫苗研发现状及展望.中国防痨杂志，2023，45（2）：125-129.识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

疫苗信使RNA临床研究

100 项与 IMM-201 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
HIV感染	临床3期	-	Immodulon Therapeutics Ltd.	-
HIV感染	临床3期	-	Silence Therapeutics Plc	-
HIV感染	临床3期	-	Aeras Technologies LLC	-
HIV感染	临床3期	-	Geisel School of Medicine	-
结核	临床1期	赞比亚	-	-
结核	临床1期	马拉维	-	-
结核	临床前	南非	-	-
结核	药物发现	南非	-	-
结核	药物发现	马拉维	-	-
结核	药物发现	赞比亚	-	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02712424 (CTgov)	临床2期	结核	625	DAR-901 (DAR-901)	觸選獵餘顧遞廠製網廠(顧膚襯鏇鑰壓憲糧糧壓) = 鬱艱齋壓構夢築觸構衊衊憲選襯鏇夢製範衊觸 (鏇憲簾憲築膚觸壓壓糧, 膚醖鑰淵醖製鬱繭廠壓 ~ 憲獵膚壓築糧鏇構築顧) 更多	-	2021-05-11
				Sterile saline placebo (Placebo)	觸選獵餘顧遞廠製網廠(顧膚襯鏇鑰壓憲糧糧壓) = 齋窪積膚鏇製襯願顧鏇衊憲選襯鏇夢製範衊觸 (鏇憲簾憲築膚觸壓壓糧, 繭醖憲鏇繭範廠淵顧醖 ~ 製壓蓋壓淵夢衊糧獵膚) 更多
NCT02712424 (Pubmed) 人工标引	临床2期	结核	667	DAR-901 vaccine	-	不佳	2020-10-27
				Placebo
NCT02063555 (Pubmed \| J Biol Chem)	临床1期	-	59	DAR-901	遞壓窪窪構鹹鹽鏇構積(範製鬱壓鑰鹹淵壓廠艱) = 鬱製範鹹構襯鹽襯廠淵鹹顧廠鹹遞醖簾鹹醖製 (餘壓繭醖壓衊憲憲積願 ) 更多	-	2017-01-01
				DAR-901 (BCG)	遞壓窪窪構鹹鹽鏇構積(範製鬱壓鑰鹹淵壓廠艱) = 糧艱鑰衊廠鹽簾構壓觸鹹顧廠鹹遞醖簾鹹醖製 (餘壓繭醖壓衊憲憲積願 ) 更多