A Phase 1 Clinical Trial to Evaluate the Safety and Immunogenicity of HIV-1 Vaccines Based on Chimpanzee Serotypes of Adenovirus Expressing Clade C gp140 and a CH505TF gp120 Protein Boost in Healthy, HIV- Uninfected Adult Participants

The purpose of this study is to evaluate the safety and immunogenicity of HIV-1 vaccines based on chimpanzee serotypes of adenovirus expressing clade C gp140 and a CH505TF gp120 protein boost in healthy, HIV- uninfected adult participants.

开始日期2021-11-25

申办/合作机构

HIV Vaccine Trials Network

[+3]

NCT04607408 / Completed临床1期

A Phase 1 Clinical Trial to Evaluate the Safety and Immunogenicity of the HIV-1 CH505 Transmitted/Founder gp120 Adjuvanted With GLA-SE in Healthy, HIV-exposed Uninfected Infants

This study will evaluate the safety and immune response in healthy HIV-exposed and uninfected infants to the protein vaccine, CH505TF gp120, adjuvanted with GLA-SE.

开始日期2020-11-10

申办/合作机构

HIV Vaccine Trials Network

[+1]

100 项与 Glucopyranosyl lipid A 相关的临床结果

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100 项与 Glucopyranosyl lipid A 相关的转化医学

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100 项与 Glucopyranosyl lipid A 相关的专利（医药）

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1,283

项与 Glucopyranosyl lipid A 相关的文献（医药）

2024-02-01·The Journal of thoracic and cardiovascular surgery

Surgical ablation for atrial fibrillation is efficacious in patients with giant left atria

Article

作者: Melby, Spencer J ; Kelly, Meghan O ; Zemlin, Christian W ; Yates, Tari-Ann E ; Sinn, Laurie A ; Bakir, Nadia H ; McGilvray, Martha M O ; Damiano, Ralph J

OBJECTIVE:

The Cox-Maze IV procedure (CMP-IV) is the most effective treatment for atrial fibrillation. Increased left atrial (LA) size has been identified as a risk factor for failure to restore sinus rhythm. This has biased many surgeons against ablation in patients with giant left atrium (GLA), defined as LA diameter >6.5 cm. In this study we aimed to define the efficacy of the CMP-IV in patients with GLA.

METHODS:

From April 2004 through March 2020, 786 patients with a documented LA diameter underwent elective CMP-IV, 72 of whom had GLA. Median follow-up duration was 4 years (interquartile range, 1-7 years). Recurrence was defined as any documented atrial tachyarrhythmia (ATA) lasting 30 seconds. ATA recurrence and survival were analyzed across GLA versus non-GLA groups.

RESULTS:

Median age at surgery was 65 (interquartile range, 56-73) years. Median LA diameter within the GLA group was 7.0 (range, 6.6-10.0) cm. There were no differences in rates of postoperative complications for the 2 groups, including rate of postoperative stroke and pacemaker placement (GLA 14%; non-GLA 12%; P = .682). A trend toward increased 30-day mortality in the GLA group did not reach statistical significance (GLA 6%; non-GLA 2%; P = .051). Freedom from ATAs at 5 years postoperatively was comparable for the 2 groups (GLA 82%; non-GLA 84%).

CONCLUSIONS:

The CMP-IV had good efficacy in patients with GLA. Our results suggest that LA diameter >6.5 cm should not preclude a patient from undergoing surgical ablation for atrial fibrillation.

2024-01-18·The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale

What Makes the Gut-Lung Axis Working? From the Perspective of Microbiota and Traditional Chinese Medicine

Review

作者: Wang, Ying ; Wang, Hui

Background. An increasing number of studies have proved that gut microbiota is involved in the occurrence and development of various lung diseases and can interact with the diseased lung. The concept of the gut-lung axis (GLA) provides a new idea for the subsequent clinical treatment of lung diseases through human microbiota. This review aims to summarize the microbiota in the lung and gut and the interaction between them from the perspectives of traditional Chinese medicine and modern medicine. Method. We conducted a literature search by using the search terms “GLA,” “gut microbiota,” “spleen,” and “Chinese medicine” in the databases PubMed, Web of Science, and CNKI. We then explored the mechanism of action of the gut-lung axis from traditional Chinese medicine and modern medicine. Results. The lung and gut microbiota enable the GLA to function through immune regulation, while metabolites of the gut microbiota also play an important role. The spleen can improve the gut microbiota to achieve the regulation of the GLA. Conclusion. Improving the gut microbiota through qi supplementation and spleen fortification provides a new approach to the clinical treatment of lung diseases by regulating the GLA. Currently, our understanding of the GLA is limited, and more research is needed to explain its working principle.

2024-01-01·Environmental toxicology

Glufosinate‐ammonium causes liver injury in zebrafish by blocking the Nrf2 pathway

Article

作者: Wang, Hui ; Fan, Honggang ; Zhao, Shuping ; Sun, Ning ; Chen, Luomeng ; Feng, Guofeng ; Jiao, Wenjing ; Chen, Yongping ; Yang, Tianyuan ; Kou, Yuhong ; Feng, Tongtong ; Zhao, Yuan

Abstract:

Glufosinate‐ammonium (GLA) is a widely used herbicide, but less research has been done on its harmful effects on non‐target organisms, especially aquatic organisms. In this study, 600 adult zebrafish were exposed to different concentration of GLA (0, 1.25, 2.5, 5, 10, and 20 mg/L) for 7 days, and the livers were dissected on the eighth day to examine the changes in liver structure, function, oxidative stress, inflammation, apoptosis, and Nrf2 pathway, and finally to clarify the mechanism of GLA induced liver injury in zebrafish. The levels of alanine aminotransferase, aspartate aminotransferase, reactive oxygen species, malondialdehyde, inflammatory factors (IL‐6 and TNF‐α), and caspase‐3 gradually increased, while the levels of superoxide dismutase, catalase, glutathione, and glutathione peroxidase gradually decreased with the increase of GLA concentration. The Nrf2 pathway was activated at low concentrations (1.25–5 mg/L) and significantly inhibited at high concentrations (10 and 20 mg/L). These results suggested that GLA could cause oxidative stress, inflammation, and apoptosis in zebrafish liver. Therefore, GLA can cause liver injury in zebrafish, and at high concentrations, the inhibition of Nrf2 pathway is one of the important causes of liver injury.

项与 Glucopyranosyl lipid A 相关的新闻（医药）

2023-07-25

·药创客

收藏！现有在研佐剂平台详细汇总，魏于全院士团队解析疫苗佐剂作用机制。

点击上方图片链接可报名疫苗佐剂（Vaccine adjuvants）被定义为与疫苗抗原联合给药时能够增强疫苗免疫反应的强度、广度和持久性的各种成分，被广泛用于疫苗开发，是大部分疫苗产品不可缺少的组成部分。佐剂的范围可以涵盖从合成小分子化合物到复杂的天然提取物和纳米颗粒材料。常见的有矿物盐，微生物产物，乳液，皂苷，合成小分子激动剂，聚合物，纳米颗粒和脂质体。尽管佐剂长期以来一直广泛用于疫苗中，但它们增强免疫反应的机制尚未得到很好的表征，因此对佐剂的作用机制几乎没有系统的概括和总结。此外，现已有或正处于研发阶段的佐剂平台，业内普遍对机制、特性、免疫有效性和应用场景缺乏系统和深入的了解，难以匹配和设计适合特定疫苗的佐剂。这些原因导致目前的疫苗产品在临床实践与应用中渐显颓势，如无法提供长期保护性免疫，无法为老年、易感人群提供有效的免疫保护。2023年7月19日，来自四川大学华西医院的研究团队在Signal Transduction and Targeted Therapy上发表了题为“Vaccine adjuvants: mechanisms and platforms”的综述文章，在本文中详细解读了疫苗佐剂增强疫苗效力的作用机制，并对当前已有的佐剂平台（含在研）进行了分析汇总。疫苗佐剂的作用机制根据作用机制，佐剂通常被分为免疫刺激剂（Immunostimulants）和递送系统（Delivery Systems）两大类，但核心概念不外乎通过直接或间接帮助疫苗成分激活APC，促进抗原呈递信号（图1，①）和共刺激信号（图1，②）产生。抗原呈递信号的产生，首先由抗原被摄取和处理后呈递在APC表面的抗原肽-主要组织相容性复合体（MHC）上，并与naive T细胞表面TCR受体结合诱导T细胞的激活。共刺激信号包括表达在APC表面的共刺激分子（例如 CD40、CD80、CD86）和分泌的炎性细胞因子（例如 IL-6、IL-10、IL-12 和 TNF-α），通过与naive T细胞表面共刺激受体（CD28或细胞因子受体）结合，诱导T细胞激活，增强适应性免疫反应。图1. 佐剂的作用机制示意图免疫刺激剂免疫刺激剂通常为危险信号分子(Danger signal molecules)，以化学合成的小分子激动剂充当PAMP，DAMP，通过靶向APC上的模式识别受体(PRR)，触发先天免疫反应并诱导APC的激活和成熟。APC成熟后终止抗原吞噬活性，并增强其抗原呈递和表达高水平共刺激信号和细胞因子的能力，启动并增强适应性免疫反应。需要注意的是，不同类型的免疫刺激剂会通过不同PRR发出信号并导致不同的细胞因子分泌。目前所使用的免疫刺激剂主要按靶向受体的不同分为4类（图2）。图2. 免疫刺激剂作用机制靶向TLRs免疫刺激剂通过靶向激活TLRs（Toll 样受体），可以增强抗原呈递并上调共刺激信号和细胞因子表达（图2a）。TLR1，TLR2，TLR4，TLR5和TLR6通常在细胞表面表达，主要识别生物膜成分，包含脂质，脂蛋白和蛋白质。作用于该类TLRs的相应免疫刺激剂将促进促炎细胞因子，如IL-1β，TNF-α和IL-6的产生，并最终激活Th1或Th2型免疫应答。TLR3、TLR7、TLR8和TLR9是在细胞囊泡中表达并与核酸反应的细胞内TLRs。相应类型的免疫刺激剂激活这些细胞内TLR通常会导致I型干扰素的产生。27I型干扰素可促进Th1细胞分化并调节其功能。此外，I型干扰素通过常规树突状细胞（DC）促进抗原交叉呈递到CD8 T细胞，并直接刺激CD8 T细胞的增殖。靶向cGAS-STING通路cGAS-STING全称为环鸟苷单磷酸-腺苷单磷酸合酶-干扰素基因刺激因子，该通路在协调先天免疫和适应性免疫方面具有独特的作用，受到佐剂研发科学家们的广泛青睐（图2b）。cGAS是一种细胞质DNA受体，被双链DNA激活后将促进胞质单磷酸腺苷(Adenosine monophosphate, AMP)和鸟苷单磷酸(guanosine monophosphate, GMP)环化形成环鸟苷酸-腺苷酸(cGAMP)。随后cGAMP将与STING二聚体的V形结合域结合，引起STING的构象变化，聚集和活化，并激活NF-κB和IRF3，促进促炎细胞因子和I型干扰素表达。靶向CLRsC型凝集素受体（CLR）是一个超家族，包括Dectin-1，Dectin-2，MINCLE，DC-SIGN，CD206，CD205等，主要位于细胞膜上，作为抗原受体参与抗原捕获和抗原呈递（图2c）。具有碳水化合物结构的免疫刺激剂通常会激活CLR，随后诱导APC启动抗原的内化，加工和呈递，以增强适应性免疫应答。此外，一部分免疫刺激剂激活CLRs后可激活不同信号通路，诱导特定细胞因子的表达，控制naive T细胞的极化方向。如β-葡聚糖通过激活Dectin-1诱导Syk激酶磷酸化，进而激活NF-κB通路，促进促炎细胞因子IL12，IL-1β，IL6和IL23的表达，诱导naive T细胞分化为Th1和Th17细胞。Th1细胞诱导强烈的CTLs（细胞毒性T淋巴细胞）反应，并驱动B细胞中免疫球蛋白转化为IgG2a。Th17效应细胞的特征在于产生IL-17，IL-17F和IL-22，并通过募集中性粒细胞引发大量炎症反应。靶向其他PRRs 除上述机制外，免疫激动剂还可激活其他PRRs，主要分为核苷酸结合寡聚结构域样受体(Nucleotide-binding oligomerization domain-like receptors, NLRs) 和视黄酸诱导基因I样受体(Retinoic acid-inducible gene I-like receptors, RLRs)。核苷酸结合寡聚化结构域1(NOD1)、核苷酸结合寡聚化结构域2(NOD2)和NOD样受体热蛋白结构域相关蛋白3(NLRP3)是NLRs家族的主要成员。免疫刺激剂通过激活该类受体可诱导APC上调MHC II，增强抗原呈递。此外，该类受体的激活将导致促炎细胞因子如IL-1β和IL-18的表达，驱动naive T细胞偏向极化为Th2型细胞，产生Th2细胞免疫反应。视黄酸诱导基因I(RIG-I)和黑色素瘤分化相关基因5(MDA5)是RLRs家族的主要成员，主要识别RNA。激活RIG-I和MDA5将导致IRF3和IRF7的激活，进而诱导I型干扰素的表达。靶向这两种受体的免疫刺激剂最终偏向于导致Th1细胞和CTL的产生。递送系统递送系统通常被定义为搭载抗原以增加APCs对抗原摄取和呈递的载体材料。主要促进抗原的呈递，包括APCs对抗原的识别、摄取和内化。因此，递送系统通常可以以一种或多种方式增强抗原呈递信号（图3）。图3. 递送系统作用机制延长抗原生物利用度目前延长抗原生物利用度的策略主要有（1）允许抗原持续释放；（2）形成免疫生态位；（3）为抗原载物提供保护延长生物利用度，使APCs有足够抗原促进MHC抗原肽信号产生。抗原持续释放目前已被证实可实现抗原持续释放的递送系统，包括纳米乳液递送系统(MF59, AS03)，可注射水凝胶以及可生物降解的PLGA或聚酐聚合物制成的固体聚合物颗粒。此外，具有大孔结构的自组装支架也具有缓慢释放抗原的能力，且还可同时搭载免疫刺激剂来释放炎症信号，提高血清抗体水平和CTL水平。形成免疫生态位一些递送系统可以通过在注射部位形成抗原库/免疫生态位来实现更高效的免疫活化。除了延长抗原在免疫系统中的作用时间，还可招募更多的免疫细胞浸润注射部位，这将增加抗原的摄取并提供局部炎症线索来激活随后的适应性免疫反应。先天免疫细胞的浸润会进一步使得生态位形成递送材料比常规递送材料具有更强大的免疫激活能力，并可掺入细胞因子，增加细胞迁移。可注射聚己内酯-聚乙二醇-聚己内酯热敏水凝胶可同时包封GM-CSF和卵清蛋白，增加注射部位DCs的募集，并提高抗原摄取效率。介孔二氧化硅棒是一种具有自佐剂效应的递送材料，可以激活NLRP3先天免疫路径。当注射到小鼠体内时，它会增加先天免疫细胞对注射部位的浸润并增强免疫反应。为抗原载物提供保护递送系统可以通过保护以DNA和mRNA为主的抗原免受体内酶的分解来延长抗原的生物利用度，从而保持其生物活性。mRNA抗原容易被细胞外血清中的RNA酶降解。LNP是一种经过验证的有效mRNA递送系统，其基本功能之一是封装mRNA并保护其免受降解RNA酶的影响。增强APCs靶向性递送系统可通过两种主要方式增强APCs靶向性。第一种方法是通过模拟病原体的大小、维度和空间结构，利用微尺度或纳米级材料来促进APC摄取抗原。与可溶性抗原相比，用脂质体纳米颗粒包封抗原可改善APC对抗原的识别和内吞作用，从而增加抗原呈递和诱导更高幅度和更高亲和力的抗体。此外，免疫系统会以高度敏感的方式识别和响应病原体固有的高度有序和重复的空间结构，自组装蛋白质纳米颗粒和其他多价颗粒递送系统通过模拟病原体的这类结构可有效增加APCs抗原摄取率。值得注意的是，即使没有补充其他免疫刺激剂，这些递送系统也能引起强烈的体液和细胞免疫反应。递送系统高度有序和重复的空间结构也有利于B细胞受体（BCR）的共聚集，导致B细胞的强激活。第二种方法是通过直接靶向APCs表面特定受体（Fc受体，CLR）增加抗原摄取。纳米颗粒递送系统的表面可以被特异性修饰以主动靶向特定的细胞群。使用CLRs配体（通常是碳水化合物，如甘露糖）来修饰递送系统将导致抗原更直接地靶向特异性DC，从而增强抗原摄取。淋巴结递送由于淋巴结是初始免疫反应的部位，聚集大量先天免疫细胞和淋巴细胞，因此成为递送系统的关键靶点。常用方法通过设计合适尺寸和表面特性（如电荷和疏水性）可以使递送载体通过被动扩散进入淋巴管和淋巴结。据报道，最佳尺寸在通常在5到100 nm之间，若过小就会进入毛细血管而太大就难以通过淋巴管内皮细胞间隙。在该种方法中，递送材料通常设计为携带负电荷，避免与淋巴管间质基质中带负电荷的糖胺聚糖相互作用降低通过效率。另一种方式被称为内源性白蛋白“搭便车”机制。内源性白蛋白是脂肪酸分子的转运蛋白，利用其在淋巴系统中的循环特性，将抗原与内源性白蛋白结合，可实现淋巴结的靶向。早前报道的一项具有亲脂性尾巴的肿瘤肽疫苗通过结合白蛋白在淋巴结中大量积累，小鼠注射后使T细胞产量增加30倍，抗肿瘤功效显著增强。抗原的交叉呈递抗原的交叉呈递是外源性抗原通过MHC I分子呈递给CD8 T细胞的过程，也是抗病毒感染疫苗和癌症疫苗设计中的重要一步。在正常情况下，外源性抗原大多仅由APC单独内化，并由MHC II分子呈递给CD4 T细胞，不会发生任何交叉呈递。研究已报道三种主要方式：质子海绵效应当具有质子胺基团的阳离子聚合物或脂质递送载体被APC内化后将缓冲内涵体/溶酶体的酸性环境，导致大量氯离子和细胞质的水流入使得内涵体/溶酶体肿胀破裂，释放抗原并促进MHC I分子抗原的交叉呈递。内涵体/溶酶体膜融合一些递送系统通过融合或结合内涵体/溶酶体膜来破坏稳定性，促进抗原释放。颗粒化乳液(PAPE)就可通过结合内涵体/溶酶体膜，破环其稳定性，使抗原释放到细胞质中并交叉呈递给CD8 T细胞。光化学内化释放技术将光敏剂掺入递送系统中和抗原一起递送，光敏剂暴露于特定光源后会被激发形成单线态氧(singlet oxygen)，导致脂质过氧化和内涵体膜破坏，使抗原释放到细胞质中，增强CD8 T细胞介导的免疫应答。经典佐剂平台铝佐剂，MF59，AS01，AS03，AS04和CpG ODN 1018是经典的人用疫苗佐剂。它们已被广泛批准用于各种疫苗，并用于增加疫苗抗体滴度和增强细胞免疫反应。铝佐剂铝佐剂是第一类获准用于人用疫苗的佐剂，上市疫苗中常用的两种铝基佐剂是氢氧化铝和磷酸铝，具有广泛认可的安全性和可靠性。铝佐剂通过促进Th1细胞反应来增强IgG2和IgE抗体的产生。然而，铝助剂的作用机制很复杂，学术界仍在争论，但已在延长抗原的生物利用度和激活先天免疫途径的PRR这两个机制上得到了充分的认识。铝佐剂可以充当与抗原紧密结合并持续释放抗原的递送系统延长抗原的生物利用度并增加抗原呈递。此外，铝佐剂也可作为免疫刺激剂诱导DAMPs的产生，从而激活先天免疫途径的PRR，从而产生IL-1β和Th2型免疫应答等细胞因子。有研究表明，铝佐剂可在注射部位诱导宿主细胞死亡并释放宿主DNA或尿酸充当内源性危险信号，作为DAMPs诱导先天免疫途径的激活。目前学术界的争论点在于铝佐剂靶向的PRR，但并不影响铝佐剂成为疫苗行业的首选佐剂。含铝佐剂广泛用于预防和治疗各种疾病，包括白喉、破伤风、脑膜炎和乙型肝炎病毒（HBV）疫苗，已获得美国食品药品监督管理局（FDA）的批准。然而，铝佐剂也有一些缺点，包括难以诱导强烈的细胞免疫反应和引起不良反应（红斑，过敏反应）的可能性。目前佐剂研究科学家致力于改进配方和开发纳米铝佐剂来克服现有的缺点。图4. 铝佐剂激活的信号通路乳佐剂MF59由角鲨烯、吐温80和司盘85组成。MF59于1997年获准作为流感疫苗佐剂，成为第一个获准用于人用疫苗的非铝佐剂。MF59乳剂具有抗原递送和免疫刺激的双重功能。MF59可用作乳液递送系统，当与抗原共同递送时，它可以延长抗原与免疫系统的相互作用，并通过在淋巴结中缓慢释放抗原来增加抗原呈递，可激活更多的APC抗原信号呈递。此外，MF59还充当免疫刺激剂。MF59可以靶向特定的PRR，并通过诱导产生内源性危险信号激活先天免疫细胞。在肌肉中施用MF59可激活先天免疫细胞，如巨噬细胞和DC，并促进趋化因子如CC-趋化因子配体2（CCL2），CCL4，CCL5和CXC-趋化因子配体8（CXCL8）的产生。这些趋化因子又可以将更多的先天免疫细胞募集到注射部位以进一步放大免疫反应，并促进这些招募的先天免疫细胞迁移到引流淋巴结以激活B细胞和T细胞。然而，MF59的确切靶向PRR尚不清楚，一般认为MF59可能通过NLRP3非依赖性ASC激活途径和TLR非依赖性MyD88激活途径起作用。简而言之，接种MF59佐剂会导致Th2偏向的免疫反应和体内Th1反应的弱诱导。目前，MF59已广泛应用于多种人用疫苗中，并显示出良好的安全性和有效性。AS03由α-生育酚、角鲨烯和吐温80组成，和MF59佐剂作用相似。与MF59一样，AS03通过NLRP3非依赖性ASC激活途径和TLR非依赖性MyD88激活途径发挥免疫刺激作用。此外，AS03还含有α-生育酚作为额外的免疫刺激剂成分。研究表明，α-生育酚参与调节某些趋化因子和细胞因子的表达，如CCL2、CCL3、白细胞介素6和CXCL1，可增强APC的抗原摄取，增加募集到引流淋巴结的先天免疫细胞的数量。一般来说，AS03也主要诱导Th2偏向的免疫反应，对Th1反应的诱导较弱。AS03主要用于多种流感疫苗中，以增加抗体的滴度和持久性。最近，AS03在COVID-19疫苗（NCT04450004，NCT04405908）的开发中也显示出良好的临床益处。基于TLR激动剂分子的佐剂AS04是通过铝吸附TLR4激动剂分子制备的，含有铝佐剂，因此还具有免疫刺激和传递抗原的功能。但AS04的免疫刺激功能强于铝佐剂，这是因为AS04含有一种更有效的免疫刺激分子，称为单磷酰脂质A（MPLA）。MPLA是从LPS中分离出的低毒性衍生物，可以特异性激活APC上的TLR4，导致NK-κB的激活和促炎细胞因子的表达，从而产生更强的Th1细胞反应。此外，当将补充AS04的疫苗与仅补充铝佐剂的疫苗进行比较时，发现补充AS04的疫苗诱导了更高水平的抗体。这证明了TLR4激动剂MPLA在AS04中起到重要作用。总体而言，AS04可以诱导比铝佐剂更强的抗体反应和Th1细胞反应，并诱导更平衡的Th1 / Th2免疫反应。目前被批准主要用于人瘤病毒（HPV）疫苗（Cervarix）和HBV疫苗（Fendrix），增加抗体产生和抗原特异性T细胞的活化。CpG ODN 1018是一种人工合成的单链DNA分子，作为TLR激动剂已被广泛研究。CpG ODN 1018特异性激活TLR9，并导致TRF7的激活，进而导致促炎细胞因子和I型干扰素的表达，最终引起强烈的Th1型细胞反应和细胞毒性T细胞产生。CpG ODN 1018最初被批准用于HBV疫苗，目前正在临床试验中作为COVID-19疫苗（NCT04450004，NCT04405908）的潜在疫苗佐剂进行评估。三叶草生物SCB-2019的CpG ODN 1018佐剂COVID-19疫苗已经在国内获紧急使用授权。微粒佐剂系统AS01是一种经典的脂质体微粒佐剂系统，含有免疫刺激剂MPLA和从Quillaja Saponaria(QS)树皮中提取的称为QS-21的活性成分，具有抗原呈递和免疫刺激的双重功能。该脂质体是一种中空磷脂双层人造膜，可用于抗原的包封和递送，保护抗原不被降解并延长其生物利用度，从而使APC能够捕获更多的抗原信号。AS01的MPLA通过TLR4激活先天免疫系统，促进Th1型反应增加。QS-21激活APC中的NLRP3，随后激活半胱天冬酶1以促进活性细胞因子IL1β，IL18和IL33的表达。此外，还发现QS-21可促进内涵体逃逸并促进交叉呈递。总体而言，这两种免疫刺激剂成分协同作用，使AS01诱导以Th1为主的免疫反应并促进CTL的产生。AS01是已获得许可的疟疾和带状疱疹疫苗的一部分。最近，AS01还被应用于开发针对结核病的新型肽疫苗（M72 / AS01E），并显示出在健康成人中预防结核病的安全性和有效性前景（NCT01755598，NCT01755598）。研究中的佐剂平台目前被广泛使用的佐剂在增强疫苗效力的同时也暴露了一些问题。例如，它们增强疫苗免疫力的能力较弱，不提供长期保护性免疫力，对老年人群效果较差。此外，这些批准的佐剂大多只能诱导抗体反应，诱导CD8 T细胞介导的细胞免疫能力较弱，这对于针对病毒感染性疾病和癌症疫苗至关重要。大多数许可佐剂的作用机制在很大程度上仍不清楚，这可能导致这些佐剂的不当使用和无法控制的副作用。因此，需要新型佐剂来解决这些问题。双链核糖核酸（dsRNA）人工体外合成的双链RNA（dsRNA）可以靶向并激活APC上的TLR3和MDA5，导致促炎细胞因子如IL-12和I型干扰素的产生，并促进强Th1极化免疫反应和CTL的产生。Poly-I：C及其修饰的变体Poly-ICLC是研究最多的合成dsRNA免疫刺激剂。在体外实验中，poly-I：C和poly-ICLC诱导人外周血单核细胞来源DC的成熟，促进IFN-β和促炎细胞因子IL-6和IL-12的分泌，使外源性抗原与CD8 T细胞发生交叉呈递并触发Th1极化免疫反应。poly-I：C和poly-ICLC在临床上多用于肽疫苗，DC疫苗和全细胞疫苗，主要用于多种癌症疫苗的开发。在癌症疫苗中添加poly-I：C或poly-ICLC可增强疫苗诱导的抗肿瘤T细胞和NK细胞反应，从而有助于肿瘤消退或根除。然而，值得注意的是，poly-I：C/poly-ICLC 除了具有触发强大免疫反应的功能外，还可能具有剂量依赖性全身发热和凝血异常等副作用。因此，应考虑合理的给药系统以保护其免受降解，在剂量上需要确保激活APCs并减少副作用。图5. 目前用于癌症疫苗开发的poly-I：C/poly-ICLCGLA及其衍生物吡喃葡萄糖脂质A（GLA）是一种人工合成的LPS模拟物，是MPLA的替代品，通过激活APC上的TLR4在体内诱导Th1型免疫反应。GLA通常制备为吡喃葡萄糖基脂质A-水性纳米悬浮液（GLA-AF），吡喃葡萄糖基脂质A-稳定乳液（GLA-SE），吡喃葡萄糖脂质A-脂质体（GLA-LS）和吡喃葡萄糖脂质A-氢氧化铝（GLA-明矾），以GLA-SE在临床前和临床研究中研究最多。在几项临床试验中，当GLA-SE被用作结核病疫苗的佐剂并针对ID93重组蛋白进行测试时，发现该疫苗可诱导高滴度抗原特异性抗体产生和CD4 T反应，在接种疫苗的人群中显示出良好的安全性和免疫原性（NCT01599897，NCT02465216，NCT02508376，NCT01927159）。咪唑喹啉咪唑喹啉能够激活TLR 7/8通路，激活NF-κB和IRF7，促进促炎细胞因子和I型干扰素的表达，引起强大的Th1细胞免疫反应和CTLs产生。咪喹莫特（R837）、瑞西莫特（R848）和3M-052（也称为替拉莫德）是临床前和临床环境中研究最多的咪唑喹啉佐剂。大量证据表明，R837在黑色素瘤、HPV、乳腺癌和T细胞淋巴瘤疫苗中表现出很强的佐剂作用。病毒疫苗和肿瘤疫苗与R848相结合已被证明可诱导更强的体液反应和CD8 T细胞免疫反应。然而，咪唑喹啉作为疫苗佐剂仍存在一些缺点。具体而言，它们经常从注射部位扩散至全身，从而远离抗原，降低疗效并诱发全身副作用。因此，这些咪唑喹啉佐剂需要与合成聚合物支架、纳米凝胶、脂质基纳米颗粒或其他递送材料偶联，以增强其免疫作用并减少其副作用。环状二核苷酸（CDN）CDN可以靶向并激活cGAS-STING途径，导致IRF3和NF-κB的激活，诱导I型干扰素和促炎细胞因子的产生，刺激抗原交叉呈递并产生强烈的Th1型细胞响应和CTL响应。目前还未有使用这些合成CDN作为疫苗佐剂的具体例子。由于这些合成CDN在临床前和临床试验中已显示出显着增强人体免疫反应的能力，我们相信使用这些合成CDN作为疫苗佐剂的愿望将很快实现（NCT03172936，NCT03010176，NCT03010176，NCT04096638，NCT04020185），利用纳米颗粒包封CDNs被视为提高CDNs体内利用效率的策略。代谢佐剂一些靶向代谢途径的小分子调节剂被发现可用作新型疫苗佐剂。靶向甲羟戊酸途径的小分子抑制剂在增加小鼠和食蟹猴的抗体滴度和增强细胞免疫反应方面显示出佐剂作用，延长抗原保留从而增强了抗原呈递。许多研究结果表明，细胞代谢途径的酶或调节因子可能是设计和开发新型佐剂的潜在靶标。锰佐剂及其衍生物锰（Mn）及其衍生物被发现具有潜在的佐剂活性，可充当cGAS的激活剂，诱导2'3'-cGAMP的非规范催化合成，并通过这种方式激活cGAS-STING的先天免疫途径，诱导I型干扰素的产生。研究人员开发了一系列基于Mn纳米助剂，例如纳米级锰凝胶（MnJ）。它不仅具有激活cGAS-STING通路作为免疫刺激剂诱导I型干扰素产生的能力，而且还具有携带抗原的递送系统作用。研究中的递送系统平台脂质纳米颗粒LNP 是非病毒纳米脂质囊泡递送系统，由可电离脂质、磷脂、胆固醇和聚乙二醇修饰脂质组成。可电离脂质是LNPs的主要成分，磷脂和胆固醇有助于LNPs的结构完整性，聚乙二醇改性有助于维持LNPs的稳定性。LNP的作用机制主要包括（1）为抗原提供有效的货物保护，延长其生物利用度;（2）增加抗原的粒径以靶向APCs并促进APCs吸收;（3）通过膜融合促进抗原从内体逃逸，引起CD8 T细胞免疫应答。LNP已被用于各种疫苗的递送，也被认为是目前最适合mRNA疫苗的递送系统聚合物颗粒聚合物颗粒一般分为天然聚合物颗粒和合成聚合物颗粒，主要实现抗原的缓慢释放。疫苗递送中最常用的天然聚合物是壳聚糖。壳聚糖具有高阳离子电荷和生物粘附特性。因此，壳聚糖可以通过静电相互作用与阴离子核酸形成紧密的络合物。此外，壳聚糖的生物粘附特性使其能够长时间与粘膜表面保持接触，促使抗原持续刺激免疫细胞，表明壳聚糖可能是核酸疫苗和粘膜疫苗的有前途的递送系统。此外，壳聚糖最近还被发现通过激活cGAS-STING通路诱导CD8 T细胞免疫的I型干扰素产生。与天然聚合物相比，合成聚合物颗粒通常具有更高的重现性和更可控的缓释速率。PLGA是一种合成聚合物颗粒材料，现在被广泛用作疫苗递送的载体。目前，PLGA颗粒作为癌症疫苗的输送系统已经经过临床测试（NCT01753089，NCT04751786）。此外，PLGA已被FDA批准用于兽用药物递送。因此，相信基于PLGA的疫苗递送系统将在不久的将来被批准用于人类疫苗。病毒样颗粒（VLP）VLP来源于病毒衣壳的外壳蛋白，由蛋白质单体的自组装形成，其出色的粒径和几何形状使其成为递送疫苗抗原的有效平台，使疫苗很容易进入淋巴管，靶向淋巴结。由于VLPs的高度有序和重复的空间结构，非常有利于交联BCR，即使在没有T辅助（Th）细胞的情况下也能强烈激活B细胞。目前，基于VLP的疫苗已经取得成功，并且已经在市场上广泛使用，例如用于HPV的Cervarix®和Gardasil®，用于肝炎病毒的Sci-B-Vac™以及RTS,S VLP疫苗。蛋白质纳米颗粒笼（Caged protein nanoparticles）笼状蛋白质纳米颗粒通常由一系列重复的基序组成，这些基序允许抗原表位或抗原掺入其亚基结构中，从而使这些掺入的抗原表位或抗原显示在组装颗粒的表面上。与VLP类似，笼养蛋白质纳米颗粒具有高度有序和重复的空间结构以及淋巴结运输的最佳大小等特性。然而与VLP不同，笼状蛋白质纳米颗粒是非病毒来源的。蛋白质纳米颗粒中，铁蛋白应用最频繁。铁蛋白是一种具有八面体对称结构的蛋白质，由24个亚基自组装形成，每个亚基由四个α-螺旋束组成。无机纳米材料金纳米颗粒是常用的无机纳米材料输送系统之一。由于金纳米颗粒的大小、形态、疏水性、表面电荷、均匀性和分布等理化性质可以通过材料合成和表面化学修饰来精确调节，以形成特定的免疫类型，因此近年来金纳米粒子作为一种有前途的抗原递送系统获得了广泛关注。金纳米颗粒通过（1）保护抗原免受降解和（2）形成合理粒径的纳米疫苗以促进抗原直接转运到淋巴结来促进抗原呈递并增强适应性免疫反应。有研究报道，金纳米颗粒可以通过激活NLRP3炎症小体和促进Th2型细胞因子的产生来增强抗原特异性抗体的产生。与金纳米颗粒类似，介孔二氧化硅纳米颗粒（MSN）也具有负载能力强和易于表面改性的特点。改良的MSN已被研究为有效的疫苗递送系统，当用作癌症疫苗递送系统时，它增加了抗原特异性CTL的产生，抑制了小鼠的肿瘤生长，提高了荷瘤小鼠的存活率。总结选择合适的佐剂来辅助抗原呈递和改善免疫反应是开发新疫苗的重要问题。在佐剂的选择上，除了需要考虑给药途径，病原体类型，抗原类型和疾病阶段外，还需要重视接种者的生物学特征，如种族、年龄、病史和遗传因素。此外，在作为疫苗产品研究时，还需要考虑佐剂的安全性和经济性。最终这些因素都将或多或少影响疫苗佐剂的有效性。撰文：三姐夫来源：RNAScript识别微信二维码，添加小编，符合条件者即可申请加入微信群！请注明：姓名+研究方向！声明：本文旨在传递更多信息，版权归原作者所有。原创文章转载均需经过授权并注明来源，如涉及内容、版权或其他问题请时联系小编删除！文章仅代表作者个人观点，并不代表公众号立场。本公众号拥有对此声明的最终解释权！投稿邮箱：yck19876@163.com

疫苗

2023-03-24

·佰傲谷BioValley

甲贝视野 | 越了解，越无畏，这一份结核病手册请查收

导语2023年3月24日是第28个世界防治结核病日。世界卫生组织（WHO）发布的主题为：“是的！我们可以终止结核病（YES! WE CAN END TB）！”，旨在呼吁各国广泛参与，共同终结结核病的流行。我国疾病预防控制局最新发布的宣传主题“你我共同努力，终止结核流行”。正文感染结核病的人大多脸色苍白，身形消瘦，咳嗽严重，故西方称之为“白色瘟疫”。历史上三国著名军事家诸葛亮就是脊椎结核，所以年纪轻轻就是扶杖而行，最后死于吐血。红楼梦中的女主角林黛玉是肺结核，最后吐血而亡。波兰著名作曲家肖邦，俄国批判现实主义作家契诃夫，德国著名文学家席勒，美国诗人梭罗，以及英国诗人雪莱——他曾向世人呼喊“冬天来了，春天还会远吗”，自己却未能看到人类战胜肺结核的春天。中国近代文学大家鲁迅先生，也是身患肺结核最后早逝。今天，我们一起来了解下什么是结核病，如何预防、诊断和治疗这种疾病，以及关于它的最新研究进展。1.结核病和结核杆菌结核杆菌(Mycobacterium Tuberculosis,MTB))是德国细菌学家Robert Koch于1882年3月24日发现的，它是引起人和动物结核病的病原菌。并将其分为人型、牛型、鸟型和鼠型4型，其中人型菌是人类结核病的主要病原体。图1.结核病常见临床表现肺结核(Tuberculosis，TB)就是主要由人型结核杆菌侵入肺脏后引起的一种具有强烈传染性的慢性消耗性疾病。常见临床表现为咳嗽、咯痰、咯血、胸痛、发热、乏力、食欲减退等局部及全身症状。肺结核90％以上是通过呼吸道传染的，病人通过咳嗽、打喷嚏、高声喧哗等将带菌液体喷出体外，健康人吸入后就会被感染。据WHO的《2022年全球结核病报告》显示：2021年全球约有1060万结核病患者，比2020年增加4.5%；有160万人死于结核病，我国2021年估算的结核病新发患者数为78.0万。受新冠肺炎疫情的影响，预计2020年和2021年结核病作为单一传染源的死亡原因将降至第2位。2.结核杆菌与宿主免疫系统MTB是一种非常成功的细胞内病原体，与宿主共同进化。宿主免疫细胞被触发成不杀灭MTB，导致MTB的潜伏感染，其通过形成肉芽肿在宿主和病原体之间保持平衡。患者体内的潜伏期肺结核的再激活率从5到10%。宿主细胞不能抑制MTB生长导致肉芽肿病变，坏死的巨噬细胞死亡和炎性细胞募集增。这种宿主免疫力的退避反映了致病性分枝杆菌在宿主细胞内存活、存留的高度进化和多因子能力。MTB开发的逃避宿主天然免疫的复杂机制包括细胞溶质逃逸，抗菌肽的限制性生成，吞噬体成熟的阻断，细胞凋亡，炎性体激活和自噬的调节。3.结核病的预防图2.如何预防结核病1.控制传染源。早期发现传染源和彻底治愈涂阳肺结核病人是控制传染源的关键。对确诊的结核病人，应及时转至结核病防治机构，进行统一管理，并实行全程督导短程化学治疗(DOTS)。2.切断传播途径。结核菌主要通过呼吸道传播，患者和家属应佩戴一次性外科口罩；开窗通风，保持空气新鲜，可有效降低结核病传播；餐具煮沸消毒或用消毒液浸泡毒，同桌共餐时使用公筷；衣物、寝具、书籍等污染物可在烈日下暴晒进行杀菌。3.保护易感人群。进行卡介苗(BCG)接种：可使未受过结核菌感染者获得对结核病的特异免疫力；化学药物预防：对于高危人群，可以遵医嘱预防服用抗结核的化学药物；生活有规律：避免长期过劳和精神紧张，戒烟、饮食均衡，适当进行锻炼，增强抵抗力。4. 结核病的诊断及治疗1.体外诊断IVD世界卫生组织(WHO)推荐使用快速分子检测技术作为结核病的初始诊断方法，分子检测技术准确可靠，在早期发现结核病和耐药结核病方面发挥着重要作用，是终止结核病流行（END TB）策略中加强结核病实验室工作的重要内容。2021年，WHO推荐分子诊断技术的原则由特定技术类型推荐改为基于类别进行推荐，依据操作复杂程度和自动化水平对诊断技术进行分类，共批准6项用于结核病诊断和抗结核药物耐药性检测的分子诊断技术：l 低复杂程度自动化检测平台：赛沛Xpert MTB/XDRl 中等复杂程度自动化检测平台：雅培Abbott RealTime MTB &MTB RIF/INH、碧迪BD Max MDR-TB、罗氏cobas MTB & MTB-RIF/INH、海恩/布鲁克FluroType MTB & MTBDRl 高复杂程度尼：普洛Genoscholar PZA-TB检测 2.化学药物治疗临床上针对敏感结核分歧杆菌广泛采用的标准治疗方案由利福平、异烟肼、吡嗪酰胺和乙胺丁醇组成，其机理为杀菌和抑菌作用，具有较好的治疗效果。但目前，耐多药和广泛耐药结核分枝杆菌感染在世界范围内广泛流行。针对这一现象，WHO推荐用药不断推陈出新，从以往的注射药物治疗转为短程口服治疗，以缩短药物疗程，防止细菌耐药。此外，结核新药研发也取得很大的进展。抗结核新药(贝达喹啉、普瑞玛尼、德拉马尼等)已进入临床使用，对于耐药结核治疗及缩短疗程具有良好的效果。包括 TBA-7371、 GSK-656、 OPC-167832、Telacebec、Delpazolid、Sutezolid、SQ-109等候选药物已经进入Ⅱ期临床试验。3.免疫治疗耐药结核病的治疗，除了开发新型抗结核药物外，提高宿主免疫应答水平和减轻宿主免疫炎性损伤的免疫治疗逐渐受到重视。● 细胞因子治疗通过注射或者雾化吸入的方式提高宿主体内特定细胞因子的含量，对宿主进行免疫干预来激发宿主的抗结核免疫应答。例如γ－干扰素、粒细胞－巨噬细胞集落刺激因子、、白细胞介素１/2等。● 免疫细胞治疗通过体内激活自体免疫效应细胞，或体外扩增自体或异体免疫效应细胞，然后回输给患者纠正免疫失衡和改善免疫功能，提高宿主抗感染应答水平。例如Ｖγ２Ｖδ２Ｔ细胞、固有自然杀伤Ｔ细胞等。4.治疗性疫苗实验性疫苗ID93+GLA-SE是由西雅图的Christopher B. Fox博士和Access to Advanced Health Institute（前身为传染病研究所）的科学家开发的。它是一种重组亚单位疫苗，由结核分枝杆菌的4种蛋白质与GLA-SE（一种免疫刺激佐剂）结合而成。这种冻干配方不需要冷藏，在注射前与无菌水混合。对于偏远地区来说，不需要冷链运输的高效疫苗将成为结束这一流行病的重要工具。5. 最新研究进展自新型冠状病毒全球大流行以来，结核分枝杆菌已成为仅次于SARS-CoV-2的第二大单一感染致死病原，同时感染结核分枝杆菌和艾滋病病毒的患者更是高危人群。近期，北京协和医院医院李永哲教授、石家庄市第五医院戴二黑教授团队发表于《感染杂志》（Journal of Infection）一项横断面研究，对成年结核病患者新冠灭活疫苗加强针的安全性和免疫原性进行分析。临床数据表明：尽管灭活疫苗加强针提高了结核病患者的SARS-CoV-2特异性抗体水平和中和活性，但结核病患者的体液免疫差于健康人群，可进行动态血清抗体监测以推断接种加强针的最佳时机，从而发挥疫苗的最大优势。同时，相对于第2剂灭活疫苗，加强接种可实现结核病患者广泛的体液免疫，尽管仍低于健康人群。而相对于野生毒株，Omicron BA.4/5的中和活性仍然较低，虽然两组人群均已接种第3剂COVID-19疫苗。Omicron亚变种的刺突蛋白RBD突变使其获得了突破性感染，并且能够逃避由COVID-19疫苗构建的免疫保护。因此，为Omicron变异株定制疫苗必不可少。让我们一起努力，对抗结核，守护健康!❒ 第七届宁波生物产业论坛暨BioDeveloper药研者大会大会名称丨第七届宁波生物产业论坛暨BioDeveloper药研者大会大会主题丨潮起甬南 · 破浪笃行大会时间丨2023年4月26-27日大会地点 | 浙江 · 宁海（喜来登酒店-桃源街道天明中路108号）大会规模 | 200+主办单位 | 中共宁海县委组织部、宁海县生物产业园管理中心承办单位 | 甲贝医药支持单位 | 中国生物工程学会、宁波市经信局、宁波市科技局、宁波市投资促进署、中共宁海县委统战部、宁波市医药行业协会、宁波体外诊断联盟、宁波股权交易中心、“科创中国”生物医药产业科技服务团、美国华人生物医药科技协会(CBA)媒体支持 | 佰傲谷BioValley、动脉网扫码报名（免费参会需审核）▽邀请辞本届论坛将以“潮起甬南，破浪笃行”为主题，汇聚政产学研等各路行业领袖专家。于暮春日，游宁海，凭栏远眺，闲谈些许求药故事。第七届宁波生物产业论坛暨BioDeveloper药研者大会将于4月26日-27日在浙江宁海举办。我们期待药物研发者们暂时放下严肃的“奋斗者”姿态，换一种风格、换一种情绪，在严谨的工作之余，重新认识一下并肩作战的朋友们，好好的交流一下当前与未来？风景几许？岂不美哉？推荐阅读：最新议程发布 | 第七届宁波生物产业论坛4月宁海召开！点击“阅读原文”，立即报名~

临床研究

2023-03-24

·Pharmaceutical Technology

Pharma Fix: The quest for the next tuberculosis vaccine

Credit: Shutterstock/ Helena Nechaeva Since the first human administration of the Bacillus Calmette-Guérin vaccine in 1921, no one has been able to successfully follow the vaccine’s path to become the next approved vaccine to tackle tuberculosis (TB). However, as the TB-related death toll remains high, the global need for another vaccine is steadily rising. Free Report How is the Biopharmaceutical industry evolving? 2021 was a year of continued innovation and change in the Biopharmaceutical industry. As the COVID-19 pandemic continues to take its toll on businesses worldwide, it’s time to look for new ways to create value, prepare for the future, and remain competitive in the ever-changing landscape. GlobalData’s expansive report examines the business environment and trends that shape the Biopharmaceutical industry. We highlight the most impactful emerging technologies, as well as the industry, regulatory, and macroeconomic factors that influence growth prospects. Access the report to: Benchmark the impact of major themes on the Biopharmaceutical industry. Gain a deeper "on the ground" perspective through exclusive opinions and analysis from industry respondents. Evaluate the effects of COVID-19 on the sector. Download the full report to understand what to expect and how to align your strategies for success. 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Visit our privacy policy for more information about our services, how we may use, process and share your personal data, including information on your rights in respect of your personal data and how you can unsubscribe from future marketing communications. Our services are intended for corporate subscribers and you warrant that the email address submitted is your corporate email address. Thank you. Please check your email to download the Report. TB is caused by the bacillus Mycobacterium tuberculosis and is transmitted when infected individuals expel bacteria into the air (e.g., by coughing). According to the World Health Organization (WHO), despite a reduction in TB cases during the Covid-19 pandemic, the incidence has risen again with 6.4 million new cases reported worldwide. Researchers expect TB to soon return to its pre-2020 position as the deadliest infectious disease globally. In light of World TB day on March 24, the field hopes to overcome some major barriers to the drug development landscape. Unfortunately, lack of funding and resources remain an obstacle within the TB field for developing new vaccines. The BCG vaccine is a live-attenuated virus vaccine. This vaccine is also being used in cancer therapies, studied as a Covid-19 prophylactic and is also being considered as a vaccine for Alzheimer’s . However, the vaccine is less effective in those who already have viral antibodies present in their blood, leaving out a large proportion of people. The vaccine also only has an efficacy of 22%.“When children reach adolescence and adult age group, [the BCG vaccine] really does not have an impact on TB disease. Thus, new vaccine approaches are needed,” says Christopher Fox, PhD, an associate professor of Global Health at the University of Washington, Seattle. This is important as TB is mostly spread by adults. Despite the dearth of options, researchers are cautiously optimistic about the having new vaccines in the pipeline. Helen McShane, PhD, a professor of vaccinology at the University of Oxford, says, “Twenty-three years ago, there were no new TB vaccines being tested in clinical trials. We now have 12 vaccines being tested in clinical trials at different stages of development.” New Developments for TB In a recent Phase I clinical trial (NCT03722472), researchers have been able to test the first thermostable TB vaccine in patients. In this trial, patients were given a thermostable version of the vaccine or a non-thermostable vaccine in two treatment regimens. The results showed that participants’ antibody responses remained elevated through six months after the last vaccination in both regimens. The ID93 vaccine is being developed by the Infectious Disease Research Institute (IDRI). The trial, led by IDRI in collaboration with the National Institutes of Health (NIH), investigated a thermostable formulation of the previously tested ID93 + GLA-SEDr adjuvant subunit vaccine. The results showed that participants’ antibody responses remained elevated through six months after the last vaccination for the thermostable version of the vaccine and a non-thermostable vaccine formulation. Fox, the principal scientist behind the trial, says this is an important development in TB vaccine research as the current BCG vaccine must be refrigerated. He explains that this new vaccine could be stored at 37 degree s Celsius for up to three months and may allow easier vaccine storage in more rural locations with a high prevalence of TB. Fox says adjuvant protein subunit vaccines can be a safer approach compared to live attenuated virus vaccines as there is a minimized risk of developing side effects. Using an adjuvant with an antigen can give specific tailored and potent immune responses, he adds. “There are a handful of vaccine candidates now that are using this approach and marching towards that efficacy testing stage in Phase II trials,” says Fox. The National Institutes of Health (NIH) is sponsoring a Phase II trial (trial ID?) of the ID93 + GLA-SEDr adjuvant subunit vaccine in South Africa. Copenhagen-based Statens Serum institut is also developing an adjuvant subunit vaccine called SSIH-56IC31 for the prevention of TB. McShane predicts the new pipeline vaccines could also address the issue of drug-resistance in TB. “We expect that all the [investigational] vaccines will work as well against drug resistant strains as they will against drug sensitive strains”. The Bill and Melinda Gates Medical Research Institute is also sponsoring an extensive, 26,000 participant-Phase III trial studying M72 (AS01E) , a protein adjuvant vaccine. Initially, GSK was studying the M72 TB vaccine but stopped funding the development after a successful Phase IIb study. News on this Phase III trial could be released in the next few months, says Dr. Alex Schmidt, Head of Vaccine Development at the Bill and Melinda Gates Medical Research Institute (MRI). The Phase IIb (NCT01755598) study found the vaccine to be 54% effective, making it a landmark in the field. However, McShane urges for the field not to become complacent. “We should not forget that we would not have accepted the Covid-19 vaccine that was only 50% effective. The Covid vaccines that we have are more than 90% effective, so it’s fantastic news… but we should not stop there,” she says. According to GlobalData, there are six TB vaccines in Phase III clinical trials right now. The Gamaleya Federal Research Center of Epidemiology and Microbiology is developing a protein subunit vaccine called GamTBvac for respiratory TB. GC Biopharma is also running a Phase III trial for its live-attenuated vaccine GC-3107A to replace BCG. Furthermore, the Serum Institute of India is also developing its own live-attenuated vaccine to replace BCG for infants, that can also be used by adults. GlobalData is the parent company of Pharmaceutical Technology. Stagnation in TB research Until approximately two decades ago, the field of TB vaccine development was stagnated due to the complexity of the virus and a lack of interest and funding. “As opposed to most viruses which often have 10 or 15 genes, MTB has 3,500 or so and we don’t understand the virulence factors. We also don’t understand why when 20 people are infected with MTB, only one gets ill and that’s a huge problem,” says Schmidt. Dr. Keertan Dheda, a professor of Mycobacteriology and Global Health at the University of Cape Town says, “We don’t know what biomarker identifies with successful immunity in TB…That has been a real challenge for TB vaccine development for decades now and we still don’t have a good idea”. The complexity of the virus and these unknown factors can also pose some challenges for clinical trials as larger patient cohorts are needed. McShane explains that TB vaccine efficacy trials involve 1,000s to 10,000s of subjects, cost tens of millions of dollars and can take more than five years to complete. With minimal funding, researchers have to carefully select which drug candidates are worth the “massive undertaking” needed for these studies, she adds. Dheda says “The one factor that has retarded development is money.” Schmidt adds, “There is no market and there’s no big disease burden in high income countries… Typically, policy people make money available for diseases that they feel close to.”. A lack of funding also slowed the development of the M72 vaccine. We need a Phase III study, but it’s been five years and the Phase III study for M72 hasn’t started yet,” says Dheda. Results from the Phase II trial were released for the vaccine in September 2018. Accounting for the time needed to complete the trial, publish results and manufacture the vaccine, if successful, market access to TB vaccines may be 10 years away. Clinical trials for TB are mostly funded through philanthropic means, but McShane says funding has seen fair improvement over the years, which has allowed for the recent progress in the field. Poverty and overcrowding, key factors leading to TB spreads, are challenging to tackle on a global level. “If we really want to impact TB our only hope is to have a good vaccine that can control TB, because better diagnostics and drugs , which we do have, aren’t doing the trick,” says Dheda. Free Report How is the Biopharmaceutical industry evolving? 2021 was a year of continued innovation and change in the Biopharmaceutical industry. As the COVID-19 pandemic continues to take its toll on businesses worldwide, it’s time to look for new ways to create value, prepare for the future, and remain competitive in the ever-changing landscape. GlobalData’s expansive report examines the business environment and trends that shape the Biopharmaceutical industry. We highlight the most impactful emerging technologies, as well as the industry, regulatory, and macroeconomic factors that influence growth prospects. 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临床2期疫苗临床3期临床1期临床结果

100 项与 Glucopyranosyl lipid A 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
滤泡性淋巴瘤	临床2期	-	-	2016-02-03
流感病毒感染	临床2期	美国	Protein Sciences Corp.	2010-06-01
非霍奇金淋巴瘤	临床2期	-	Merck & Co., Inc.	-
黑色素瘤	临床1期	美国	-	2015-02-28
非小细胞肺癌	临床1期	美国	-	2015-02-28
卵巢癌	临床1期	美国	-	2015-02-28
肉瘤	临床1期	美国	-	2015-02-28
梅克尔细胞癌	临床1期	-	Merck & Co., Inc.	-

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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


NCT02501473 (P367 \| 3475-174 \| P327 \| IMDZ-G142 \| MK-3475-174, CTgov)	临床1/2期	滤泡性淋巴瘤	52	G100 (Part 1: Local Radiation + G100 5μg/Tumor)	構築觸襯鏇膚鏇襯積鏇(築廠獵觸窪醖範膚築蓋) = 觸積憲選鹹繭鏇築壓願顧顧鬱遞範獵鹹範顧積 (顧構鑰繭遞艱鏇鏇顧鬱, 醖鑰醖鹽糧蓋獵衊繭窪 ~ 襯艱願膚製襯廠餘糧積) 更多	-	2020-09-09
				G100 (Part 1: Local Radiation + G100 10μg/Tumor)	構築觸襯鏇膚鏇襯積鏇(築廠獵觸窪醖範膚築蓋) = 憲衊觸範鹹蓋築膚鹽蓋顧顧鬱遞範獵鹹範顧積 (顧構鑰繭遞艱鏇鏇顧鬱, 構齋廠蓋選鹽鏇蓋鹽鏇 ~ 餘壓廠願廠願窪遞淵鏇) 更多
NCT02501473 (P367, SITC2018)	临床1/2期	癌症	-	G100	鏇艱獵繭淵膚艱鹽齋製(製壓構淵積餘憲夢鹽選) = 膚衊網積衊構繭顧壓積膚夢觸鹹膚廠獵簾範夢 (範膚憲構積夢鹽鹽衊憲 )	积极	2018-11-06
				Anti-OX40 antibody	鏇艱獵繭淵膚艱鹽齋製(製壓構淵積餘憲夢鹽選) = 選艱膚獵簾鏇廠製築憲膚夢觸鹹膚廠獵簾範夢 (範膚憲構積夢鹽鹽衊憲 )
NCT02501473 (P327, SITC2018)	临床1/2期	滤泡性淋巴瘤 TLR4 expression \| CD8 TILs	27	G100 10Î¼g	艱繭窪觸獵築構顧窪範(鹹淵衊獵網鏇簾糧廠遞) = greater reduction of CD20+ tumor cells 觸鹹顧憲衊餘襯製簾淵 (簾鹹壓製廠觸壓繭壓艱 ) 更多	积极	2018-11-06
				G100 20Î¼g
SITC2018	N/A	-	-	G100 (Transfer-pull regimen)	蓋衊築鏇遞夢淵醖築積(構範製淵顧鬱夢淵鬱製) = 網蓋鏇築窪廠願憲壓淵遞夢窪餘製製鬱選壓鹽 (鬱糧繭鑰蓋衊獵衊觸鬱 )	积极	2018-11-06
AACR2017	N/A	肉瘤	15	IT G100	襯襯獵繭積願築壓製襯(築觸構積簾衊遞鹽鹹鏇) = 觸繭窪蓋願網選範遞顧構願廠衊衊鬱醖網築積 (顧鑰鏇齋艱繭夢鑰製獵 ) 更多	-	2017-07-01
				G100 (Radiation)	觸繭鹹遞衊廠廠獵鹹構(遞餘網餘糧簾餘糧膚獵) = 鑰獵膚製築鏇繭壓衊選繭鬱築淵鹹觸網顧鬱憲 (鏇壓顧廠廠範齋範壓簾 )
NCT02501473 (3475-174 \| IMDZ-G142 \| MK-3475-174, ASCO2017) 人工标引	临床1/2期	滤泡性淋巴瘤	-	Glucopyranosyl lipid A	窪糧鑰壓壓廠獵艱鏇獵(衊夢窪鑰顧遞鏇糧網鹹) = none 網選餘襯憲壓觸膚顧範 (鬱顧壓願網衊衊淵糧憲 ) 更多	积极	2017-06-05