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]

NCT03742804

/ Withdrawn临床2期IIT

Pilot Phase 2 Study of Intratumoral G100 in Patients With Cutaneous T Cell Lymphoma

The overall goal of this study is to evaluate the safety and immunogenicity of repeat-dose intratumoral G100 administration in patients with Cutaneous T Cell Lymphoma (CTCL) alone (Part 1) and following standard local radiation therapy or topical nitrogen mustard application (Part 2). Plaque, patch, or tumor lesions of CTCL may be injected. Disease will be assessed in all sites, including skin, nodes, and blood.

开始日期2019-06-01

申办/合作机构

Yale University

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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项与 Glucopyranosyl lipid A 相关的文献（医药）

2024-12-01·VETERINARY JOURNAL

Dose titration of intravenously administered gamma-hydroxybutyric acid for sedation in Holstein-Friesian calves

Article

作者: Alonso, B. ; Cuypers, C ; Devreese, M ; Schauvliege, S. ; Devreese, M. ; Cuypers, C. ; Alonso, B ; Schauvliege, S

Gamma-hydroxybutyric acid (GHB) is a short-chain fatty acid that can potentially provide safe, prolonged sedation with minimal cardiorespiratory effects. This preliminary trial, performed in 10 three-week-old male Holstein-Friesian calves, investigated the effects of GHB administered intravenously over 5 min at a dose of 100 (G100, n=2), 150 (G150, n=4) or 200 mg/kg (G200, n=4). Once lateral recumbency was achieved, scores for sedation depth (range: 0 = no sedation to 3 = marked) and response to noxious stimulation (range: 0 = strong to 3 = absent), heart rate (HR), respiratory rate (RR), mean arterial pressure (MAP) and arterial blood gases were monitored every 15 min until sternal recumbency. Times from end of administration to lateral recumbency and return to sternal/standing positions were recorded. Dose G100 resulted in mild sedation and ataxia without decubitus. Doses G150 and G200 respectively resulted in time to lateral recumbency 8 ± 2 and 9 ± 3 min, lasting 189 ± 41 and 283 ± 29 min, while overall median (range) scores for sedation were 3 (1-3) and 3 (2-3) respectively and response to noxious stimulation 0 (0-3) and 0 (0-3) respectively. The mean ± SD for HR was 110 ± 10 and 106 ± 11 bpm respectively; for MAP 87±9 and 94±5 mmHg respectively; and for RR 28 ± 5 and 26 ± 5 bpm respectively. The mean ± SD for arterial partial pressure of oxygen (PaO2) at these two dose rates was 74 ± 6 and 74 ± 2 mmHg respectively, while the arterial partial pressure of carbon dioxide oxygen (PaCO₂) was 53 ± 3 and 47 ± 0.8 mmHg respectively. Based on these preliminary results we conclude that GHB has the potential to be used as a long-acting sedative in calves. Further studies are needed to confirm this.

2024-07-01·The Lancet. Infectious diseases

Safety and immunogenicity of the co-administered Na-APR-1 and Na-GST-1 hookworm vaccines in school-aged children in Gabon: a randomised, controlled, observer-blind, phase 1, dose-escalation trial

Article

作者: Dejon-Agobé, Jean Claude ; Bikangui, Rodrigue ; Honkpehedji, Yabo Josiane ; Grobusch, Martin P ; Bottazzi, Maria Elena ; Bethony, Jeffrey M ; Massinga Loembe, Marguerite ; Li, Guangzhao ; Diemert, David J ; Kremsner, Peter G ; Zinsou, Jeannot F ; Edoa, Jean Ronald ; Vodonou, Kafui G ; van Leeuwen, Remko ; Yazdanbakhsh, Maria ; Adegnika, Ayola A ; Adégbité, Bayodé R ; Hotez, Peter J

BACKGROUND:

A human hookworm vaccine is being developed to protect children against iron deficiency and anaemia associated with chronic infection with hookworms. Necator americanus aspartic protease-1 (Na-APR-1) and N americanus glutathione S-transferase-1 (Na-GST-1) are components of the blood digestion pathway critical to hookworm survival in the host. Recombinant Na-GST-1 and catalytically inactive Na-APR-1 (Na-APR-1[M74]) adsorbed to Alhydrogel were safe and immunogenic when delivered separately or co-administered to adults in phase 1 trials in non-endemic and endemic areas. We aimed to investigate the safety and immunogenicity of these antigens in healthy children in a hookworm-endemic area.

METHODS:

This was a randomised, controlled, observer-blind, phase 1, dose-escalation trial, conducted in a clinical research centre, in 60 children aged six to ten years in Lambaréné, a hookworm-endemic region of Gabon. Healthy children (determined by clinical examination and safety laboratory testing) were randomised 4:1 to receive co-administered Na-GST-1 on Alhydrogel plus Na-APR-1(M74) on Alhydrogel and glucopyranosyl lipid A in aqueous formulation (GLA-AF), or co-administered ENGERIX-B hepatitis B vaccine (HBV) and saline placebo, injected into the deltoid of each arm. Allocation to vaccine groups was observer-masked. In each vaccine group, children were randomised 1:1 to receive intramuscular injections into each deltoid on two vaccine schedules, one at months 0, 2, and 4 or at months 0, 2, and 6. 10 μg, 30 μg, and 100 μg of each antigen were administered in the first, second, and third cohorts, respectively. The intention-to-treat population was used for safety analyses; while for immunogenicity analyses, the per-protocol population was used (children who received all scheduled vaccinations). The primary outcome was to evaluate the vaccines' safety and reactogenicity in healthy children aged between six and ten years. The secondary outcome was to measure antigen-specific serum IgG antibody levels at pre-vaccination and post-vaccination timepoints by qualified ELISAs. The trial is registered with ClinicalTrials.gov, NCT02839161, and is completed.

FINDINGS:

Between Jan 23 and Oct 3, 2017, 137 children were screened, of whom 76 were eligible for this trial. 60 children were recruited, and allocated to either 10 μg of the co-administered antigens (n=8 for each injection schedule), 30 μg (n=8 for each schedule), 100 μg (n=8 for each schedule), or HBV and placebo (n=6 for each schedule) in three sequential cohorts. Co-administration of the vaccines was well tolerated; the most frequent solicited adverse events were mild-to-moderate injection-site pain, observed in up to 12 (75%) of 16 participants per vaccine group, and mild headache (12 [25%] of 48) and fever (11 [23%] of 48). No vaccine-related serious adverse events were observed. Significant anti-Na-APR-1(M74) and anti-Na-GST-1 IgG levels were induced in a dose-dependent manner, with peaks seen 14 days after the third vaccinations, regardless of dose (for Na-APR-1[M74], geometric mean levels [GML]=2295·97 arbitrary units [AU] and 726·89 AU, while for Na-GST-1, GMLs=331·2 AU and 21·4 AU for the month 0, 2, and 6 and month 0, 2, and 4 schedules, respectively). The month 0, 2, and 6 schedule induced significantly higher IgG responses to both antigens (p=0·01 and p=0·04 for Na-APR-1[M74] and Na-GST-1, respectively).

INTERPRETATION:

Co-administration of recombinant Na-APR-1(M74) and Na-GST-1 to school-aged Gabonese children was well tolerated and induced significant IgG responses. These results justify further evaluation of this antigen combination in proof-of-concept controlled-infection and efficacy studies in hookworm-endemic areas.

FUNDING:

European Union Seventh Framework Programme.

2024-03-01·EFSA journal. European Food Safety Authority

Safety and efficacy of a feed additive consisting of narasin (Monteban® G100) for chickens for fattening (Elanco GmbH)

Article

作者: López‐Alonso, Marta ; Petkova, Mariana ; Holczknecht, Orsolya ; Ramos, Fernando ; Durjava, Mojca ; Villa, Roberto Edoardo ; Gropp, Jürgen ; Marcon, Francesca ; Rossi, Barbara ; Navarro‐Villa, Alberto ; Christensen, Henrik ; Mayo, Baltasar ; Rychen, Guido ; Woutersen, Ruud ; Vettori, Maria Vittoria ; Dusemund, Birgit ; Azimonti, Giovanna ; Finizio, Antonio ; Galobart, Jaume ; Pechová, Alena ; Bampidis, Vasileios ; Kouba, Maryline ; López Puente, Secundino ; Pettenati, Elisa ; Teodorovic, Ivana ; Bastos, Maria de Lourdes

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of the coccidiostat narasin (Monteban® G100) for chickens for fattening. In a previous opinion, uncertainties remained on the identification and characterisation of the non-genetically modified production strain of the active substance narasin. The Panel could not conclude either on the safety of Monteban® G100 for chickens for fattening or on the efficacy of the additive at the minimum applied concentration. The FEEDAP Panel excluded risks for environment but the risk for sediment compartment could not be assessed. The applicant provided supplementary information to cover the data gaps and substituted the narasin production strain from Streptomyces spp. NRRL 8092 to Streptomyces spp. NRRL B-67771. The information submitted to taxonomically identify the production strain did not allow to assign it to any described microbial species. Based on the information provided, the Panel concluded that the use of Monteban® G100 did not raise safety concerns as regards the production strain for the target animal, consumer, user and environment. The Panel concluded that 70 mg narasin/kg complete feed was safe for chickens for fattening with a margin of safety of 1.4; narasin from Monteban® G100 was unlikely to increase shedding of Salmonella Enteritidis, Salmonella Typhimurium and Campylobacter jejuni. Narasin, when used in chickens for fattening at 70 mg/kg feed, was not expected to pose a risk to the aquatic compartment and to sediment, while a risk for the terrestrial compartment could not be excluded. No risk for groundwater was expected, nor for secondary poisoning via the terrestrial food chain, but the risk of secondary poisoning via the aquatic food chain could not be excluded. The Panel concluded that 60 mg narasin/kg feed was efficacious in controlling coccidiosis in chickens for fattening.

项与 Glucopyranosyl lipid A 相关的新闻（医药）

2024-09-09

·生物制品圈

结核病蛋白亚单位疫苗佐剂研究进展

结核病是由结核分枝杆菌感染引起的全球传染病，是导致人类死亡的十大主要原因之一。卡介苗(BCG)是目前唯一临床应用的结核病疫苗，但其对成人结核病的保护作用不明确。在结核病新型疫苗中，蛋白亚单位疫苗因其成分明确、安全性高的特点，且具有强化BCG效应的优势，近年来备受关注。然而，亚单位结核病疫苗中的蛋白抗原所诱导的免疫应答较弱，通常需要佐剂辅助以增强其免疫效果。本综述旨在关注结核病疫苗新制剂中使用的各类佐剂(包括已进入临床试验阶段和尚处于临床前开发阶段的佐剂)，对各类佐剂的优缺点及可应用性进行客观评价，并指出目前佐剂研究中存在的问题及未来的研究方向。 NEXT 结核病(tuberculosis, TB)是由结核分枝杆菌(Mycobacterium tuberculosis, Mtb)感染引起的慢性传染病，目前仍是人类健康的巨大威胁。据WHO的最新统计，2022年全球约有1 060万结核病病例以及130万死亡病例[1]。卡介苗(Bacillus Calmette-Guerin, BCG)是唯一在临床应用的结核病疫苗，其对儿童重症结核病的预防效果较好，但是对成人肺结核的预防效果不佳[2]。因此，结核病新型疫苗的研究尤为重要。目前，已经有多种新型结核病疫苗处于临床或临床前研究阶段，包括重组BCG、减毒活疫苗、病毒载体疫苗、重组蛋白亚单位疫苗和DNA疫苗等[3]。其中，蛋白亚单位疫苗成分明确、安全性好，且具有强化BCG的免疫保护效应，被认为是非常有应用前景的疫苗类型[4] ，特别是在人群广泛接受BCG接种的国家和地区。佐剂(adjuvant)又称免疫调节剂或免疫增强剂(immunepotentiator)，是蛋白亚单位疫苗不可或缺的组分之一，具有增强机体对蛋白抗原的免疫原性并提高其保护效果、减少疫苗抗原剂量的作用[5,6]，其研究现状备受关注。本文对结核病蛋白亚单位疫苗佐剂的研究现状进行综述，以期为新型结核病疫苗的研究提供参考。一、进入临床试验阶段的佐剂在结核亚单位疫苗佐剂的研究中，AS01E、IC31、GLA-SE、CpG-ODN和BC02已经进入临床试验阶段[7]。基于它们构建的结核病疫苗分别有M72/AS01E、H1/IC31、H4/IC31、H56/IC31、ID93/GLA-SE、GamTBVac和AEC/BC02(表1)。表1 进入临床阶段结核亚单位疫苗的佐剂 AS01E佐剂系统是一种油包水型乳剂，含有QS-21(quillaja saponaria)和单磷酸脂质A(monophosphoryl lipid A，MPLA)两种关键组分[8]。 QS-21：是从皂荚树皮中分离纯化得到的一种水溶性三萜糖苷，它包括两种异构体分子QA-21Apiose和QS-21木糖，能够刺激CD4＋T细胞产生多种免疫调节因子，并促进高水平的IgG2a和IgG3生成[9]。 MPLA：是明尼苏达沙门菌(Salmonella minnesota)脂多糖的一种灭毒衍生物，作为Toll样受体4(TLR4)受体激动剂，可以直接激活表达TLR4的抗原提呈细胞(APCs)，从而增强抗原提呈功能并提高免疫应答的效果[10,11,12] 。已有研究发现，AS01E能提高单核细胞和树突状细胞的募集能力[13]，并促进抗原特异性抗体和T细胞的生成，辅助疫苗产生持久且广泛的免疫应答[8]。在人群中，M72/AS01E疫苗可刺激产生高水平的细胞因子和自然杀伤细胞[14]。 Ⅱb阶段的临床试验结果显示，接种M72/AS01E疫苗的HIV阴性成人，在接种后3年内肺结核发病率降低50%，提示AS01E辅助构建的疫苗具有良好的抗结核保护效果[15]。虽然该临床试验显示基于AS01E佐剂的疫苗在人群中具有良好的保护效果，但其研究人群单一，因此仍需开展更多的临床试验(比如更广泛的人群和更长期的试验阶段)进行进一步验证。目前，基于AS01佐剂的疟疾疫苗(Mosquirix)已经在欧洲药品管理局和世界卫生组织的批准下上市销售[16]，且含有AS01佐剂的疱疹疫苗也可显著刺激机体产生高水平的抗体，并增强细胞免疫应答[17]。这些研究结果提示，AS01E佐剂具有普适性，是一种非常有前景的佐剂。但是皂苷可以通过特异性地与胆固醇结合并在红细胞等细胞的脂质双层膜上打孔而发挥毒性。尽管在AS01E佐剂系统开发中，通过加入胆固醇(cholesterol)使佐剂形成脂质体，中和了QS-21和MPLA的毒性[18,19]，但该佐剂在人群(尤其是婴幼儿等特殊群体)应用的安全性仍需继续关注并进行系统性临床评价。 IC31佐剂由天然的阳离子抗菌肽KLKL(5)KLK和人工合成的带有胞嘧啶-磷酸-鸟嘌呤(unmethylated cytosine-phosphate-guanine, CpG)基序的寡脱氧核苷酸(oligodeoxyribonucleotide containing CpG-motifs, CpG-ODN1a)组成，通过启动TLR9/MyD88信号通路发挥免疫辅助作用[20]。 KLKL(5)KLK能够促进抗原与APCs的结合，从而辅助疫苗激发持久的适应性免疫应答[21]。 CpG-ODN1a是一种带有负电荷的DNA序列，通过与TLR9结合并招募多个下游信号分子来实现免疫激活作用[22,23]，从而诱导抗原特异性Th1或Th17型免疫应答[21] ，进而增强疫苗的免疫保护效果。 KLKL(5)KLK和CpG-ODN1a的联合应用，促进了CpG-ODN1a的摄取和递送，从而促进树突状细胞内化抗原并将其提呈给幼稚T细胞[24]。据报道，IC31佐剂能够辅助疫苗诱导免疫细胞产生多种Th1型细胞因子，如IFN-α、IFN-γ、IL-2和TNF-α，诱导产生更多的细胞毒性T淋巴细胞[25]。基于IC31佐剂构建的H1(Ag85B-ESAT6)/IC31、H4(Ag85B-TB10.4)/IC31、H56(Ag85B-ESAT6-Rv2660c)/IC31疫苗均已进入不同的临床试验阶段[26,27,28]。近期备受关注的H56/IC31疫苗已完成Ⅱa期临床试验[29]，结果显示接种H56/IC31疫苗的Mtb感染和未感染的成年人均能够产生持久的CD4＋T细胞免疫应答[28]。然而，CpG-ODN可能有潜在的副作用，比如诱导释放促炎因子、抗核酸酶的硫代磷酸酯骨架的非特异性免疫刺激活性等[30,31,32]。最近的研究表明，阳离子聚氨基酸聚-L-精氨酸(the cationic polyamino acid poly-L-arginine)与CpG-ODN结合可阻止CpG-ODN诱导的促炎因子的全身释放[33] 。因此，如何巧妙地将阳离子聚氨基酸聚-L-精氨酸添加到IC31佐剂系统中，是一个有意义且值得关注的科学问题。 CpG-ODN单一组分佐剂基于CpG-ODN单一组分佐剂的疫苗也已经进入临床试验研究中，比如GamTBVac疫苗。该疫苗所包含的蛋白抗原有Ag85a单抗原和肠膜明串珠菌(Leuconostoc mesenteroides)右旋糖酐结合域(dextran-binding domain, DBD)修饰的ESAT6-CFP10融合抗原，佐剂是一种由DEAE-右旋糖酐(500 kDa)核心和覆盖CpG-ODN组成的混合物[34]。该疫苗已经完成了Ⅱa期临床试验，结果显示在接种卡介苗的健康成年人中，显示出较好的免疫保护作用[35]。但是，该疫苗中佐剂与抗原构建方式复杂，可能增加了生产和评估的难度，需要在未来的研究和临床实践中进一步评估其可行性和效果。 GLA-SE 由葡糖吡喃糖脂A(glycopyranosyl lipid A, GLA)和含角鲨烯的稳定乳剂(stable emulsion, SE)构成。GLA可以激活TLR4，可诱导免疫细胞释放趋化因子和促炎细胞因子、促进DC成熟，从而发挥辅助疫苗激活免疫应答作用[36]。 GLA被广泛用于多种疾病疫苗的研发，并在动物实验中显示出良好的免疫应答和安全性[37,38]。因此，GLA被认为是一种有着极高临床应用潜力的新型佐剂组分。 SE由角鲨烯和表面活性剂组成的乳剂，可以稳定疫苗中的抗原和佐剂组分，从而增强免疫细胞对抗原的响应，提高疫苗的稳定性和免疫保护效果[39]。此外，SE乳液佐剂具有很好的生物相容性和生物降解性，具有作为佐剂组分的良好安全性。据报道，GLA-SE可辅助ID93(Rv1813-Rv2608-Rv3619-Rv3620)疫苗产生持久的Th1型免疫应答和抗体IgG的产生，并提高疫苗的保护效果[40,41]。基于GLA-SE的ID93疫苗已经在多人群(接受4个月结核病治疗的结核病患者和健康成人)完成Ⅱa期临床试验[42,43,44]，该疫苗能够诱导机体有效的免疫应答，但受试者出现了轻微的不良反应，如硬结和红斑等[43]。这些不良反应是否与佐剂有关还有待证实。此外，GLA-SE也被应用在H5N1流感疫苗和肿瘤疫苗等其他疾病疫苗的研制中[45]。 BC02 是一种基于BCG的未甲基化CpG DNA片段和铝盐两种组分的佐剂[46]。CpG可以激活免疫细胞，诱导强烈的Th1和Th2免疫应答，而铝盐则通过缓释抗原发挥佐剂作用，两者组合可以协同提升疫苗的免疫保护效果[47]。基于该佐剂和Ag85B、ESAT6、CFP10复合抗原的AEC/BC02疫苗，是中国食品药品检定研究院自主研发的结核亚单位疫苗。目前，该疫苗正在湖南省疾病预防控制中心开展Ⅱa期临床研究(CTR20220240)。前期的临床试验结果显示该疫苗在接种者体内能够诱导强烈的体液和细胞免疫应答，具有用于潜伏感染治疗的潜力[48]。另外，基于BC02佐剂的重组带状疱疹疫苗也正在申报临床研究[49] 。二、处于临床前研究阶段的佐剂除上述进入临床阶段的佐剂外，还有很多尚处于临床前研究阶段。按照其作用机制的不同分为免疫刺激类、免疫递送类和复合系统类佐剂。 1．免疫刺激类佐剂 (1)核苷酸类佐剂环二核苷酸(cyclodinucleotides, CDN) 是一类常见的微生物信使分子，广泛存在于细菌和真菌中，主要参与细菌的次级信号传导[50]。CDN具有病原相关分子模式(pathogen associated molecular pattern, PAMP)，可通过与胞质受体STING结合，刺激细胞释放多种细胞因子，如Ⅰ型干扰素、IL-6、IL-12和TNF-α等，同时还可以通过激活NF-κB和INK等典型炎症途径调节免疫应答[51]。在结核病亚单位疫苗的研究中，CDN作为佐剂能够诱发长寿命的免疫记忆性T细胞，并降低小鼠结核病的发病率[52]。环二腺苷酸(cyclic diadenosine monophosphate, c-di-AMP) 是一种存在于微生物中的环状核苷酸分子，通过与宿主细胞表面的模式识别受体结合调节宿主免疫应答[53]。据报道，c-di-GMP佐剂不仅能促进Mtb抗原诱导的IgG抗体的生成，还能促进淋巴细胞的增殖并增加细胞因子的分泌，从而显著增强免疫应答[54]。多聚肌胞苷酸(polyinosinic：polycytidylic acid, Poly I∶C) 是一种合成的双链RNA分子，它通过与TLR3受体特异性相互作用，可以激活机体的免疫应答，并诱导IL-12和Ⅰ型干扰素的释放。我们前期的研究发现，基于Poly I∶C的复合佐剂DDA-Poly I∶C-Cholesterol(DPC)，能显著增强LT70融合蛋白所诱导的Th1型免疫应答及抗结核菌的保护作用[55]。此外，基于Poly I∶C的纳米佐剂PLGA-PEG-Poly I∶C同样能增强Mtb蛋白抗原所诱导的Th1型免疫应答和体液免疫应答[56]。在临床实践中，Poly I∶C注射液通常被用作免疫调节剂，辅助治疗多种病毒感染[57,58]，提示其具有临床应用的安全性。除上述免疫增强效应外，核苷酸类佐剂还具有易溶于水、性质稳定、可量产等优势，因此具有较好的应用开发前景。 (2)菊糖类佐剂菊糖是由D-果糖通过β-1，2糖苷键连接而形成的天然果糖聚合物。 Advax™ 是一种基于菊粉微粒的新型佐剂，可通过调节免疫细胞活性诱导多效应性T细胞反应，产生IFN-γ、TNF-α和IL-2等细胞因子[59]。在小鼠感染模型中，该佐剂可增强小鼠对流感病毒感染的防御能力[60]。Advax™在增强机体免疫应答的同时具有致炎作用小的优点，已进入临床评价研究阶段。据报道，菊糖佐剂联合Mtb抗原ESAT-CFP10(EC)，能够刺激脾脏淋巴细胞分泌更多的TNF-α[61]。 AdvaxCpG 是在Advax™的基础上添加了TLR9激动剂CpG的复合佐剂，研究发现其同样具有增强Mtb抗原Ag85B (Rv1886c)和CysD (Rv1285)免疫原性的作用[59]。鉴于其在人群应用中显示的良好安全性和耐受性，我们认为菊粉是进行疫苗佐剂开发的理想候选组分。 (3)细菌组分类佐剂可以模拟细菌感染的特征，刺激免疫系统产生针对特定细菌的免疫应答，从而提高疫苗的保护效果。从惰性枯草芽孢杆菌分离的芽孢据报道，其具有促进树突状细胞成熟并提高固有免疫应答的能力[62]。将该组分与Mtb抗原MPT64和Acr-Ag85B结合后，该疫苗可刺激机体产生高水平的IgG1和IgG2a并且促进Th2/Th1谱系的分化平衡[63]。海藻糖-6，6-二分枝杆菌酸酯(trehalose dimycolate, TDM)及其类似物海藻糖-6，6-二山嵛酸酯(trehalose-6，6-dibehenate，TDB) 是Mtb细胞壁的组成成分，可通过激活CARD9途径诱导Th1和Th17细胞应答发挥免疫效应[64]。TDB还具有激活C型凝集素受体2(C-type lectin receptor 2)，从而激活NLRP3炎症小体，诱导IL-1β产生的作用[65] 。目前，基于TDM和TDB已构建多款结核亚单位疫苗用复合佐剂，比如CAF01等，在本文复合佐剂部分进行详述。我们团队前期也基于TDM和融合蛋白Mtb10.4-HspX构建了结核病亚单位疫苗MH，结果显示该疫苗具有很好的免疫原性和保护效果[66]。 TDM和TDB都是Mtb菌体表面的糖脂分子，具有肺部黏膜免疫的黏附优势[67]，因此在黏膜疫苗的研发中具有较好的前景。但是这些糖脂分子合成困难，从菌体分离纯化成本高且产量低，在临床应用规模化制备方面具有缺点。我们前期还评价了经热酚法提取的卡介苗多糖核酸对结核病亚单位疫苗的佐剂效应，结果显示其具有辅助疫苗减轻毒株攻击后免疫病理损伤的作用[68]。但是具体的机制和保护效应仍需进一步验证。 (4)金属类佐剂铝盐与抗原混合后注射到豚鼠体内，能够诱导比单独施用抗原更多的抗体产生，这一发现可以追溯到1926年，由亚历山大·格伦尼(Alexander Glenny)首次发现。随后，在1932年，铝佐剂首次被批准用于人用疫苗[69]。铝佐剂通过形成稳定沉淀来延长抗原作用时间，从而促进持续的免疫应答[70]。然而，由于其诱导Th1细胞免疫和CD8＋细胞毒性反应的能力不足，使其在结核病疫苗中的应用受到限制。锰离子北京大学的蒋争凡教授报道了另外一种具有佐剂效应的金属元素锰[71]。据报道，锰离子可以促进抗原摄取以及呈递，并可通过激活cGAS-STING和NLRP3途径改善免疫应答[72]，其佐剂效应已经在狂犬病、流感等疫苗中得到验证[73]。我们前期验证了锰离子对结核蛋白亚单位疫苗BrfB-GrpE(BG)的佐剂效应，结果显示其具有增强抗原诱导的长寿记忆T细胞产生和抗分枝杆菌感染的免疫保护作用[74]。锰佐剂不仅成本低、易获取，还有良好的生物相容性，可以作为理想的佐剂用于开发。 2．免疫递送类佐剂 (1)纳米颗粒(nanoparticles, NPs)佐剂是指粒径小于100/1 000 nm的微小颗粒佐剂，通过将疫苗抗原封装在纳米颗粒内部或修饰到表面上，使抗原以完整的形式运送至淋巴细胞或者抗原提呈细胞。纳米佐剂具有缓慢释放的特点，可以促进抗原的提呈以及产生持久且高效的记忆性免疫应答[75]。聚乳酸-羟基乙酸共聚物(poly-lactic-co-glycolic acid, PLGA) 是一种在生物医学领域广泛应用的聚合物材料，由于其出色的安全性，已获得FDA批准用于疫苗和药物递送[76]。研究表明，基于PLGA佐剂的结核病疫苗，包封结核抗原Ag85B-ESAT6融合蛋白后，不仅能提高血清抗体水平，还能引发强烈的Th1细胞免疫应答[77]。此外，PLGA微粒不仅可以包封疫苗抗原，还可以包封模式识别受体的各种配体[78,79] ，以增强疫苗抗原提呈。 PLGA颗粒作为递送载体已在乙型肝炎、疟疾、利什曼病等疾病疫苗研究中得到广泛证实[80,81]。但PLGA微环境的酸性特性以及颗粒制备过程中的苛刻参数可能会影响蛋白抗原的完整性和免疫原性[82]。因此，在实际应用中需合理设计和优化制备过程，以充分发挥其作用。壳聚糖是一种来源于甲壳类生物外壳的高分子多糖聚合物，其具有出色的生物相容性和安全性[83]。研究显示，其带正电荷的特性可以针对性地影响树突状细胞，刺激NLRP3炎症小体，随后激活Th1、Th2和Th17反应[84,85]。在动物模型中，基于壳聚糖递送系统的结核病亚单位疫苗能够促进抗原提呈细胞摄取，并有效诱导体液和细胞免疫应答[86,87]。然而，壳聚糖在生理条件下具有低溶解度的局限性，需要在构建疫苗时合理设计。总之，纳米佐剂已在临床前试验和临床试验中取得显著进展，具有广泛的应用前景。 (2)脂质体佐剂是一种具有磷脂层的球状结构，该佐剂不仅能够包裹抗原还能增强巨噬细胞对抗原的处理能力[88]。阳离子脂质体二甲基双十八烷基铵(dimethyldioctadecylammonium, DDA) 具有净正电荷的特性，不仅能够将抗原引导入抗原提呈细胞，还可以将内吞的抗原直接递送至细胞质，以提高CD8＋T细胞对提呈抗原的反应[89,90,91]。 CAF01 是一种基于该佐剂和TDB组成的双组分脂质体佐剂，该佐剂在注射部位显示出持久的储存效应，并能够诱导产生强烈的体液和细胞免疫应答[92]。基于CAF01制备的多款结核亚单位候选疫苗在临床前和临床试验中得到评价，比如：H1/CAF01疫苗能够诱导显著的免疫应答，并且这种反应可持续3年[93]。同样，H56/CA01在接种疫苗的动物中可诱导产生高水平的IL-2、IL-17及Th1/Th17偏倚并显著降低细菌负荷[94]。这些发现表明，CAF01是一种高效的佐剂递送系统，可以与不同的抗原组合使用，并且可以引发强烈的免疫应答。但是，CAF01在临床试验中存在一些全身不良反应，包括头痛、疲劳、不适和发烧[92]，因此其安全性仍待进一步评价。此外，DDA脂质体的溶解性很差，制备需要经过高温水浴加热等复杂过程，且颗粒均一性欠佳，该过程限制了其规模化的制备和应用。 (3)免疫刺激复合物(immunostimulating complex, ISCOMS)佐剂是一种由皂苷、胆固醇和磷脂相互作用形成的笼状结构。该佐剂通过将自然杀伤细胞、淋巴细胞等募集到淋巴结提高Th1和Th2型免疫应答[95]，已广泛应用于疫苗抗原递送[96]。将其与Mtb融合蛋白Ag85B-ESAT6组合制备的亚单位疫苗，能够显著增强蛋白抗原在小鼠体内的体液和细胞免疫应答，诱导产生高水平的IFN-γ并降低肺部细菌负荷量[97]。 ISCOMS佐剂在提升疫苗效果方面显示出巨大潜力，且已获批应用于兽用疫苗，期待该佐剂进一步人用疫苗的临床试验和安全性评估。 3．复合系统类佐剂随着时代不断进步和新型疫苗技术的迅猛发展，研究人员在佐剂研发方面开始追求更创新、更高效的策略。单一佐剂已经无法满足理想的免疫应答要求，因此复合系统类佐剂成为疫苗研究的前沿趋势。复合系统类佐剂由两种或两种以上的佐剂组合而成，旨在通过协同作用最大程度地调节或增强免疫应答效果[98]。目前，已有多种对结核病亚单位疫苗的复合系统类佐剂正在开发中(表2)，这些新的研究结果为疫苗佐剂的研发带来新的希望。表2 复合系统类佐剂三、中药组分佐剂在结核病亚单位疫苗研究中的潜在应用中药组分佐剂被认为是一类具有广泛潜力的疫苗佐剂，因为其含有多种生物活性成分、具有多方面的免疫活性。此外，相比传统佐剂，中药类佐剂的毒副作用较小，通常不易产生依赖性，被认为是理想的生物反应调节剂[99]。中药组分佐剂在疫苗研究领域已得到广泛验证(表3)，主要是多糖类和皂苷类成分，比如：黄芪多糖在乙型肝炎亚单位疫苗的研究中，从黄芪根部提取的黄芪多糖显著增强疫苗的免疫原性[100] ；枸杞多糖作为一种增强免疫功能的中药成分[101] ，在甲型肝炎疫苗研究中展现出卓越的效果，并与传统铝佐剂具有协同作用[102] ；合欢皂苷在禽流感疫苗中，能够促进小鼠脾细胞产生Th1和Th2型细胞因子的基因表达水平，进而增强了疫苗的免疫应答能力[103]。含有中药多糖类的Advax™和中药皂苷类的QS-21佐剂在结核病疫苗研究中具有显著潜力，可有效提高免疫应答水平和保护效果[9,104]，进一步证实中药组分佐剂在结核病亚单位疫苗研究中应用的可行性。中药组分在疫苗佐剂研究中具有较大的开发空间，其应用价值和效果值得进一步深入挖掘。表3 中药组分佐剂四、总结和展望佐剂在亚单位疫苗的研制与应用中发挥着举足轻重的作用。但是，除了广泛应用的铝盐佐剂外，临床获批使用的佐剂数量非常有限。在我国，由于高效、安全佐剂的欠缺，严重限制亚单位疫苗、RNA疫苗等的开发应用，成为疫苗行业的"卡脖子"问题。最近几年，疫苗佐剂的开发研究在国际上进展迅速。本文深入探讨了佐剂的分类、作用机制及其在结核亚单位疫苗开发中的应用现状，旨在为结核亚单位疫苗的研发提供参考。理想的佐剂不仅应该能够增强免疫应答，使机体获得最佳的保护性免疫，而且应该能实现工艺放大。此外，佐剂的安全性和经济性也是不可忽视的重要因素。在新型疫苗佐剂的开发中，我们认为核苷酸类和菊糖类免疫刺激物具有很好的应用开发前景。与传统铝佐剂激活体液免疫应答相比，锰离子佐剂能够激活更全面的包括细胞免疫在内的免疫应答，值得在结核病疫苗中进行进一步的探索研究。为了激活更全面的免疫应答，复合佐剂是理想的疫苗形式，尤其是基于纳米颗粒的类型。近年来，随着分子动力学模拟、量子化学计算等高端技术的发展，使纳米颗粒的结构稳定性和相互作用机制的预测成为可能。随着更多具有免疫刺激活性物质的发现，及其作用机制的阐明，都将为新型佐剂的开发提供理论基础。尤其是近年来，更多中药提取物免疫活性的发现和研究，使得疫苗佐剂的开发有更多组分的选择。新型佐剂的开发意义重大，但是其临床前开发和临床试验的成本高且周期很长，因此政府机构和企业应该加大对疫苗佐剂开发的持续投入和支持。来源：中华微生物学和免疫学杂志识别微信二维码，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。

疫苗临床研究

2018-01-19

·BioSpace

Why This Seattle Biotech Could be an M&A Target

Investor Immune Design is a clinical-stage immunotherapy company. With the recent tax reform bill cutting corporate tax rates and providing an even lower amnesty rate for off-shored funds, most investors are expecting a boom in mergers and acquisitions. Oliver Reiche, writing for Seeking Alpha, takes a look at a Seattle-based biotech company, Immune Design , and why he thinks it’s a leading takeover target for 2018. Immune Design is a clinical-stage immunotherapy company. It focuses on oncology, although the company notes its approaches have broad potential across multiple areas. Its lead product candidates are CMB305 and G100. CMB305 is in Phase II clinical trials and is targeting soft tissue sarcoma and other NY-ESO-1 tumors. G100 is also in Phase II, and leverages endogenous and neo-antigens follicular non-Hodgkin’s lymphoma. The company also has LA51, in preclinical development for various cancers, and has a pipeline of vaccines for RSV, peanut allergy and HSV-2. On Dec. 10, 2017, the company reported data from its Phase II trial of G100 plus low-dose radiation with or without Keytruda, Merck ’ s anti-PD-1 therapy, in follicular non-Hodgkin’s lymphoma. The G100 monotherapy and Keytruda combination showed a 39 percent objective response (ORR) rate with a 57 percent ORR in patients who expressed a potential predictive biomarker. The data was presented at the American Society of Hematology Annual meeting. “We have been developing two immuno-oncology platforms in parallel: an intratumoral immunization approach with G100 as the lead therapeutic candidate, and novel cancer vaccines from the Dendritic cell-targeting RNA vector platform, ZVex,” said Carlos Paya, president and chief executive officer of Immune Design, in a statement. “We believe these data presented at ASH confirm that G100 is an active and safe agent that results in systemic tumor responses, which are further enhanced in combination with Keytruda. In light of the fact that some inhibitors of the anti-PD-1 class are viewed to have limited activity in this type of hematological malignancy, these positive data support further investigation of the potential synergy of G100 with ananti-PD-1/L1 agents and the use of TLR4 expression as a potential predictive biomarker.” Reiche writes, “Driven by a very bullish market environment in 2014, the company sold shares into a bubble and its share price began to crash, especially in the weeks after its lock-up periods ended. During the bearish market phase, the company conducted its first post-IPO offering in April 2015, followed by a second post-IPO offering in September 2016, all of them mainly being used to fund clinical development of its Antigen Specific and Antigen Agnostic approaches, including among other things GMB305, G100 and its working capital. Because of this, its share price plummeted by more than 84 percent from an all-time high at $36.19 in December 2014 to the lowest at $5.50 in December 2016.” The company’s financial earnings reports suggest it has less than two years of cash, which partially explains a third post-IPO offering of 19.5 million shares in October 2017. The net proceeds of about $90 million are planned to fund a Phase III for CMB305 in synovial sarcoma, continued development of CA21, working capital and general corporate activities. Reiche writes, “To me this product pipeline and its entire timeline are looking very solid, especially with the most recent cash situation and, for instance, its latest data update from its randomized Phase II trial of its investigational intratumoral TLR4 agonist G100. Assuming, however, that the operating expenses will increase in the next quarters and the company will keep on having operating loss, management might initiate another offering in the second half of 2019, if all of its cash will be burnt again.” He argues that Immune Design is an attractive takeover target because of the corporate tax breaks and the company’s solid pipeline. “Big pharma companies could start buying out smaller but listed biotech companies in the U.S. with a strong product pipeline, a solid management, an adequate cash position and a positive working capital instead of paying higher dividends or performing share buyback programs. That’s why I believe that Immune Design could be an attractive target for big pharma companies in 2018 with its low market capitalization of $180.2 million based on the last price ($3.75) from Wednesday, January 17, 2018.”

临床2期免疫疗法临床结果IPO疫苗

100 项与 Glucopyranosyl lipid A 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
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	Immune Design Corp.	2015-02-28
粘液样脂肪肉瘤	临床1期	美国	Immune Design Corp.	2015-02-28
非小细胞肺癌	临床1期	美国	Immune Design Corp.	2015-02-28
卵巢癌	临床1期	美国	Immune Design Corp.	2015-02-28
软组织肉瘤	临床1期	美国	Immune Design Corp.	2015-02-28
滑膜肉瘤	临床1期	美国	Immune Design Corp.	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 (Pubmed \| Leuk Lymphoma)	临床1/2期	滤泡性淋巴瘤	-	Intratumoral G100	鬱願鬱糧簾蓋築餘願網(夢獵範衊壓顧簾鑰齋膚) = 齋衊糧網鹹繭顧鏇鑰構範鏇鹹壓夢構鏇繭襯繭 (積網構繭膚壓齋鬱夢壓 ) 更多	-	2022-03-21
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)	製繭襯壓衊顧製衊繭衊 = 遞製鹽艱窪襯廠網製積餘選膚顧選構鏇醖襯襯 (夢鏇願淵淵齋鹹衊遞夢, 範鏇艱餘積壓糧艱構繭 ~ 顧夢鹹窪遞衊艱鏇範夢) 更多	-	2020-09-09
				G100 (Part 1: Local Radiation + G100 10μg/Tumor)	製繭襯壓衊顧製衊繭衊 = 襯窪壓積壓鬱廠齋選願餘選膚顧選構鏇醖襯襯 (夢鏇願淵淵齋鹹衊遞夢, 憲獵糧獵餘築鬱壓壓鑰 ~ 憲構簾艱製夢簾積獵壓) 更多
NCT02501473 (P367, SITC2018)	临床1/2期	肿瘤	-	G100	築鏇繭鏇夢齋鏇鹽顧顧(廠觸窪網觸選願壓壓淵) = 築願艱襯網憲鏇願製衊繭醖膚鏇製糧鬱鏇鬱鹹 (願壓鏇鹹齋餘鑰蓋網淵 )	积极	2018-11-06
				Anti-OX40 antibody	築鏇繭鏇夢齋鏇鹽顧顧(廠觸窪網觸選願壓壓淵) = 遞醖鏇餘鬱獵齋醖糧簾繭醖膚鏇製糧鬱鏇鬱鹹 (願壓鏇鹹齋餘鑰蓋網淵 )
SITC2018	N/A	-	-	G100 (Transfer-pull regimen)	襯壓鬱衊鑰憲鏇製窪餘(選積夢鑰鏇憲選膚簾窪) = 醖遞憲衊顧壓顧構構鏇膚窪艱齋築窪積網壓選 (夢壓鑰願鹹衊構網積壓 )	积极	2018-11-06
NCT02501473 (P327, SITC2018)	临床1/2期	滤泡性淋巴瘤 TLR4 expression \| CD8 TILs	27	G100 10Î¼g	鬱糧鑰繭淵繭糧築遞艱(觸選選簾製襯築範膚廠) = greater reduction of CD20+ tumor cells 選繭襯積糧鑰築獵蓋鬱 (鬱糧淵夢繭壓鑰鹹網醖 ) 更多	积极	2018-11-06
				G100 20Î¼g
AACR2017	N/A	肉瘤	15	IT G100	鏇簾網獵積鑰衊壓選淵(衊衊衊廠觸廠糧餘築鬱) = 憲膚鹽憲獵鬱獵艱鬱糧簾糧夢壓鑰廠淵淵夢積 (範選醖觸繭蓋鹹顧鏇鬱 ) 更多	-	2017-07-01
				G100 (Radiation)	鏇鑰觸壓淵網繭構選鏇(糧膚糧憲簾遞壓窪餘廠) = 憲構淵獵遞鹽壓艱窪襯構窪鑰憲鏇襯鑰淵淵鹽 (膚願淵觸襯築鑰獵衊膚 )
NCT02501473 (3475-174 \| IMDZ-G142 \| MK-3475-174, ASCO 12017 \| ASCO 22017) 人工标引	临床1/2期	滤泡性淋巴瘤	-	Glucopyranosyl lipid A	衊醖積積製醖艱夢襯築(選艱築製糧蓋蓋餘顧鏇) = none 鏇醖願獵淵餘窪齋艱鏇 (餘網顧獵膚艱衊獵醖簾 ) 更多	积极	2017-06-05