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Targeting the Host针对主机
Recovery from acute HBV infection is associated with robust innate and adaptive immune responses. Innate immune response is the first line of defense against viral infections and results in production of type I IFN, which leads to suppression of viral replication, mediation of NK cell-mediated killing of viral infected cells, and supports the efficient maturation and site recruitment of adaptive immunity through production of proinflammatory cytokines and chemokines.[59,106] These IFN enhance the first defense against viral infections and modulate both innate and adaptive immune cells.[77,107] The principal producers of type I IFN are the plasmacytoid dendritic cells (pDC) that respond to viruses and other pathogens primarily through the recognition of pathogen-associated molecular patterns by two intracellular TLRs: TLR7 and TLR9.[77,108] Triggering of TLR leads to activation of pDC and production of high levels of type I IFNs, along with the release of other cytokines, including TNF-α, IL-6 and cell surface costimulatory molecules. pDC also activate NK cells and T lymphocytes, allowing further priming and regulation of antiviral immunity.[107,109–110] Efficient priming of the adaptive immune system causes functional maturation and expansion of distinct B- and T-cell clones, which are able to specifically recognize the infectious agents. This process leads to control of infection and generates a memory response that increases the host ability to block subsequent infections with the same pathogens.[59]
恢复从急性HBV感染与鲁棒先天和适应性免疫反应相关联。先天免疫应答是抵御病毒感染,并导致生产的I型IFN,这导致抑制病毒复制,NK细胞介导的杀伤病毒感染细胞的调解的第一行,并且支持高效的成熟和现场招聘通过促炎性细胞因子和趋化因子的适应性免疫。[59106]这些干扰素增强抗病毒感染的第一道防线,并调节这两个先天和适应性免疫细胞。[77107]式的主要生产者I型IFN是浆细胞样树突细胞(PDC),该主要是通过由两个胞内的TLR识别病原体相关的分子模式响应病毒和其他病原体:TLR7和TLR9[77108]触发的TLR导致活化的pDC和生产高水平予IFN的类型,随着释放的其他细胞因子,包括TNF-α,IL-6和细胞表面的共刺激分子。的pDC也激活NK细胞和T淋巴细胞,从而进一步引发和抗病毒免疫的调节[107,109-110]适应性免疫系统的高效引发导致功能性成熟和扩张的鲜明的B和T细胞克隆,其能够特异性识别该传染性病原体。这个过程导致感染的控制,并产生记忆反应,增加阻止继发性感染具有相同的病原体的宿主的能力。[59]
In CHB patients, HBV is associated with blunting of innate and adaptive immune responses. Hence, strategies that would augment innate immune responses may also enhance adaptive anti-HBV immunity. Several studies have demonstrated that expressions of TLRs (TLR 2, TLR 3, TLR4, TLR7 and TLR9) were decreased in CHB patients.[111–114] In this regard, HBV interferes with TLR2, 7 and 9 signaling, which are considered to play an important role in the control of infection and elimination of virally infected cells.
慢性乙型肝炎患者,乙肝病毒与钝化的先天免疫和适应性免疫反应有关。因此,战略,将增强先天免疫反应也可增强自适应抗乙肝病毒的免疫力。几项研究已经表明,Toll样受体的表达(TLR2,TLR3,TLR4,TLR7和TLR9)分别降低慢性乙型肝炎患者[111-114]在这方面,HBV干扰TLR2,7,9信令,这被认为是玩在感染的病毒感染的细胞的控制和消灭具有重要作用。
TLR Agonists. Studies have shown that when HBV transgenic mice were injected with ligands specific for TLR 2–9, liver of these HBV transgenic mice produce IFN-α, -β and -γ to inhibit HBV replication, suggesting that HBV replication can be controlled by the activation of innate immune response in the liver.[115] The inhibition of HBV replication was accomplished at a post-transcriptional level by suppressing the assembly or stability of HBV RNA-containing capsids.[115,116] These provide evidence that TLR activation directly inhibits HBV replication.[117,118] However, HBV somehow evades innate recognition by TLRs as a strategy to escape innate immune response by its ability to disrupt TLR expression and inhibit TLR signaling cascades.[117,118] It has been reported that the expression of TLRs in hepatocytes and other cells is downregulated in the presence of various HBV viral products.[112,119–123] Although HBV circumvents endogenous type I IFN pathways, it is plausible that the use of exogenous IFN induction using the TLR7 agonist may reinstate the IFN-α response. When combined with a strategy that results in maximal suppression of HBV replication in vivo using NAs, exogenous IFN stimulation via TLR agonists may result in development of protective immunity. Several studies have shown that long-term suppression of HBV using NA results in partial reconstitution of adaptive immunity. In this regard, an adjuvant therapy using TLR agonist may able to accelerate this process of immune reconstitution and HBV clearance. First, TLR agonists are available as oral compounds enabling rapid uptake by the liver. Second, they may allow being combined along with other NAs as a single pill. Finally, similar to injected IFN, TLR agonists induce IFN production, triggering the production of cytokines to facilitate intracellular communication and cellular trafficking. However, through the use of TLR agonists this antiviral state can be induced at the liver, eliminating the adverse events associated with systemic innate immune activation.
Toll样受体激动剂。研究表明,当HBV转基因小鼠注射特异性针对TLR2-9配位体,这些HBV转基因小鼠的肝脏中产生的IFN-α,-β和-γ抑制乙型肝炎病毒复制,这表明HBV复制可以通过激活控制在肝脏中的先天免疫应答。[115] HBV复制的抑制是通过抑制HBV RNA的含衣壳的组装或稳定性来实现在转录后水平。[115116]这些提供的证据表明,TLR活化直接抑制HBV复制[117118]然而,HBV某种方式通过TLR的逃避先天识别作为一个策略,以逃避通过其扰乱TLR表达和抑制TLR信号传导级联的能力先天免疫应答[117118]已经报道了Toll样受体在肝细胞和其他的表达细胞被下调中的各种B型肝炎病毒的产品的存在。[112,119-123]尽管HBV绕过内源I型IFN途径,它是合理的,使用用TLR7激动剂外源性干扰素的诱导可能恢复的IFN-α应答。当与一种策略使用NAS其导致HBV复制的最大值抑制在体内结合,经由TLR激动剂外源性IFN刺激可导致保护性免疫的发展。几项研究已经表明,HBV的使用NA长期抑制导致获得性免疫的部分重构。在这方面,使用的TLR激动剂佐剂疗法可能能够加速免疫重建和HBV间隙的这一过程。首先,Toll样受体激动剂可作为口服化合物由肝脏能够快速吸收。其次,他们可能会被允许与其他NAS,作为一个单一的药丸结合一起。最后,类似于注射干扰素,TLR激动剂诱导干扰素的产生,引发细胞因子的产生,以促进胞内通信和细胞运输。然而,通过使用的TLR激动剂此抗病毒状态,可在肝脏引起的,消除了与全身先天性免疫的激活相关的不良事件。
Lanford et al., investigated the effects of immune activation with GS-9620, an orally administered agonist of TLR-7, in chimpanzees chronically infected with HBV. GS-9620 was administered to chimpanzees every other day for 4 weeks at 1 mg/kg and, after a 1-week rest, for a second cycle of 4 weeks at 2 mg/kg. TLR-7 agonists induced prolonged suppression of HBV DNA in both the serum and liver.[124] GS-9620 administration induced the production of IFN-α and various cytokines and chemokines. In addition, it activated all lymphocyte subsets to induce interferon stimulated genes (ISGs).[124] HBV DNA was reduced, in addition to serum levels of HBsAg, HBeAg and HBV antigen positive hepatocytes. However, an increase in liver enzymes and immune cell infiltration was observed during the period of decrease in both intrahepatic and serum viral load.
兰福德等人,研究了免疫激活作用和GS-9620,TLR-7的口服给药的激动剂,在慢性感染HBV的黑猩猩。 GS-9620在1毫克/公斤为2毫克/千克给予黑猩猩隔日4周,后1周的休息,为4周的第二轮。 TLR-7激动剂诱导的HBV DNA在血清和肝脏两者的延长抑制[124] GS-9620施用诱导产生IFN-α和各种细胞因子和趋化因子。此外,激活的所有淋巴细胞亚群诱导干扰素刺激基因(的ISG)[124]的HBV DNA的减少,除了对HBsAg,HBeAg和HBV抗原阳性肝细胞中的血清水平。然而,在减少在肝内和血清病毒载量的期间观察到的增加的肝酶和免疫细胞浸润。
In early studies to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of oral GS-9620 in healthy volunteers, oral doses (single dose of 0.3, 1, 2, 3, 4, 6, 8 or 12 mg) were well absorbed and well tolerated. Adverse events associated with IFN treatment were seen in subjects who received the 8 or 12 mg dose and serum IFN-α was only detected at these doses although activation or ISGs were seen at doses ≥2 mg.[125] Two Phase I clinical trials of GS-9620 on CHB patients are completed. One in virologically suppressed subjects with CHB, and other treatment naive subjects with CHB.[126,127] It will be interesting to know the results of these trials.
在早期的研究中,调查了安全性,耐受性,药代动力学和口服GS-9620在健康志愿者中的药效学,口服剂量(0.3,1,2,3,4,6,8或12毫克单一剂量)被很好地吸收和良好容忍。与干扰素治疗相关的不良事件主要出现在谁收到的8或12毫克的剂量,血清IFN-α仅在这些剂量检测,虽然激活的ISG或者被发现在剂量≥2毫克。[125]两个I期临床试验受试者GS-9620对慢性乙肝患者完成。一位在病毒学抑制受试者慢性乙型肝炎和慢性乙肝等治疗天真的科目。[126127]这将是有趣的知道这些试验的结果。
Cytokines. The use of cytokines as immunomodulatory therapy for the treatment of chronic viral infections has been extensively studied. Most promising candidates that may be beneficial in CHB patients are IL-7 and IL-21.[128–130]
细胞因子。使用细胞因子作为免疫调节治疗慢性病毒感染的治疗中已被广泛研究。最有希望的候选人,可能在慢性乙型肝炎患者是有益的,IL-7和IL-21。[128-130]
IL-7. IL-7 is absolutely essential for primary T-cell development and probably has an important role in the normal B-cell development process. IL-7 also plays a role in the development of some dendritic cell (DC) subsets. IL-7-mediated signaling in DCs has been shown to regulate peripheral CD4+ T-cell homeostasis.[131] IL-7 therapy for CHB patients would be to enhance, rejuvenate and restore immune response to HBV. Preclinical data generated from numerous model systems have shown that IL-7 has potent immunorestorative effects, as well as vaccine adjuvant effects and beneficial effects in the setting of adoptive cell therapy. CYT107 is a second-generation recombinant human IL-7 product made by Cytheris SA via a recombinant mammalian cell culture system.[132] A Phase I/II randomized, open labeled, controlled, dose-escalation study of repeated administration of recombinant human IL-7 (CYT107), in combination with standard antiviral treatment and vaccination in HBeAg-negative CHB patients is ongoing.[133]
IL-7。 IL-7是用于初级T-细胞的发展是绝对必要的,可能具有在正常B细胞发育过程中起重要作用。 IL-7也起着一些树突状细胞(DC)的子集的发展中的作用。 DC中的IL-7介导的信号已被证明是调节外周血CD4 + T细胞稳态。[131]的IL-7治疗慢性乙型肝炎患者会提升,恢复活力和恢复对HBV的免疫应答。从众多的模型系统中产生的临床前数据表明,IL-7具有强效immunorestorative效果,以及疫苗的佐剂效应,在过继性细胞治疗的设定的有益作用。 CYT107是第二代重组人IL-7产品通过重组哺乳动物细胞培养系统,通过Cytheris SA进行。[132]一个I / II期随机,开放标记,对照,剂量递增的重组人白细胞介素重复给药的研究-7(CYT107),符合标准的抗病毒治疗和疫苗接种HBeAg阴性CHB患者结合正在进行中。[133]
IL-21. IL-21 mediates an important function in the induction and maintenance of effector CD8+ T cells. Several studies done on chronic lymphocytic choriomeningitis virus (LCMV) infection in mice have shown that IL-21 signaling is required to maintain a functional pool of effector CD8+ T cells. Mice deficient in IL-21 or IL-21R show a progressive decline in the number of virus-specific polyfunctional effector CD8+ T cells, which correlates with poor viral control.[134–136] In CHB infection, IL-21 was shown to be critical in promoting immune responses that can control infection in mice.[137]
IL-21。 IL-21介导的诱导和维持效应CD8 + T细胞的重要功能。在小鼠上进行的慢性淋巴细胞性脉络丛脑膜炎病毒(LCMV)感染的几项研究表明,IL-21信号传导是必需的,以保持效应CD8 + T细胞的功能池。缺陷的小鼠中,IL-21或IL-21R示出了病毒特异的多官能效应CD8 + T细胞的数量,这与病毒对照差逐渐下降。[134-136]在慢性乙型肝炎感染,IL-21被证实为促进免疫反应,可以在小鼠中控制感染的关键。[137]
In a longitudinal study of CHB patients, it was demonstrated that patients treated with antivirals with complete suppression had significantly higher levels of serum IL-21 than those who did not.[138] High serum IL-21 concentrations were also predictive of HBeAg seroconversion, a clinically important outcome associated with control of HBV infection.[138] Recombinant IL-21 is a new immune modulator currently undergoing Phase I and II testing in cancer patients.[139] Use of recombinant IL-21 for CHB might be a promising approach as a combination therapy for CHB patients receiving NAs.
慢性乙型肝炎患者的纵向研究中,我们证实了抗病毒药物完全抑制治疗的患者血清中IL-21的显著更高水平比那些谁没有。[138]高血清中IL-21浓度也预测HBeAg血清学转换的,与HBV感染控制相关的重要的临床结果。[138]重组IL-21是一种新型的免疫调节剂目前正在进行一期和二期试验的癌症患者。[139]用重组IL-21对慢性乙型肝炎可能是一种很有前途的方法作为联合治疗用于接收新来港慢性乙型肝炎患者。
Programmed Death-1/Programmed Death Ligand-1. Chronic and persistent HBV infection is associated with weak and functionally impaired immune response. The persistent exposure to viral antigens leads to virus-specific CD4 and CD8 cell dysfunction or deletion, and with prolonged exposure leads to exhaustion of T-cell response.
程序性死亡1/程序性死亡配体1。慢性HBV持续感染与弱,功能受损的免疫反应有关。持续暴露于病毒抗原导致病毒特异性的CD4和CD8细胞的功能障碍或缺失,并且与长期暴露导致的T细胞应答的疲劳。
Recent data suggest these virus specific T cells hyperexpress the PD-1 molecule and interaction between programmed death-1 (PD-1) receptor on lymphocytes and its ligand programmed death ligand-1 (PD-L1)/2 plays an important role in T-cell exhaustion.[140–145] In vitro and in vivo data suggest that inhibition of PD-1/PD-L1/2 ligand, which blocks the engagement of PD-1 with its ligand (PD-L1/2), has shown improvement in the antiviral functions of these T cells.[146–152] Studies have shown that HBV-specific T cells express PD-1 at a higher level than other T cells and exhibit exhaustive functionality as determined by cytokine secretion.[140–141,143–144] Attempts have been made to reverse the PD-1–PD-L interaction in vitro to rejuvenate HBV-specific immunity. In this regard, in vitro blockade of PD-1/PDL1 in a woodchuck hepatitis model with chronically infected WHV showed restoration of T-cell function.[153] Moreover, in vivo blockade of PD1/PD-L1 along with therapeutic vaccination and antiviral NA treatment in persistently WHV-infected woodchucks showed that this combination resulted in potent antiviral effect and improved function of woodchuck hepatitis core antigen-specific CD8 T cells.[154]
最近的数据表明这些病毒特异性T细胞hyperexpress对PD-1分子和程序性死亡-1(PD-1)受体之间相互作用对淋巴细胞和其配体程序性死亡配体-1(PD-L1)/ 2起着T中起重要作用β细胞衰竭。[140-145]在体外和体内数据表明,抑制PD-1/ PD-L1/ 2的配体,其阻断PD-1与其配体(PD-L1/ 2)的卡合,具有在这些T细胞的抗病毒功能的明显的改善。[146-152]研究表明,HBV特异性T细胞表达的PD-1在较高的水平比其它的T细胞,并表现出如通过细胞因子的分泌来确定详尽的功能[140- 141,143-144]已经尝试扭转体外对PD-1-PD-L相互作用,以恢复HBV特异性免疫。在这方面,在土拨鼠肝炎模型与慢性感染WHV体外阻断PD-1 / PDL1的显示恢复的T细胞的功能。[153]此外,在体内阻断PD1 / PD-L1的同时治疗性疫苗和抗病毒NA治疗坚持不懈WHV感染的土拨鼠表明,这种组合导致了有效的抗病毒效果,并改善土拨鼠肝炎核心抗原特异性CD8 T细胞的功能。[154]
Fisicaro et al. examined the role of T-cell exhaustion in the pathogenesis of chronic HBV infection in patients with CHB. They compared phenotype and function of intrahepatic and circulating HBV-specific T cells, and effect of PD-1/PD-L1 blockade. Results showed that intrahepatic HBV-specific CD8 cells express higher PD-1 and lower IL-7 receptor, CD127 levels. PD-1/PD-L1 blockade led to T-cell restoration, both in the periphery and in the liver, with better functional improvement among intrahepatic T cells.[155]
Fisicaro等。研究了T细胞耗竭的作用在慢性HBV感染患者的慢性乙肝的发病机制。他们比较了表型和肝内和循环HBV特异性T细胞的功能,和PD-1 / PD-L1阻断的效果。结果表明,肝内HBV特异性CD8细胞表达更高的PD-1和下部的IL-7受体,CD127的水平。 PD-1/ PD-L1阻断导致T细胞的修复,无论是在周边和在肝脏,肝内T细胞之间更好的功能改善。[155]
Intravenous PD-1 and PD-L1 antibodies have been tested on patients with advanced cancer. Antibody-mediated blockade of PD-L1 induced durable tumor regression and prolonged stabilization of disease in patients with advanced cancers.[156] However, use of anti-PD-1 antibody was associated with a relatively high frequency of grade 3 or 4 adverse events (adverse events occurred in 14% of patients including three deaths from pulmonary toxicity).[157] Utilization of PD-1 blockade as a therapeutic modality for CHB patients is being investigated. This approach is unique and offers an excellent opportunity to revive exhausted T cells in CHB, thereby allowing restoration of adaptive immunity against HBV and offers a fair chance of achieving sustained virologic remission. Utilizing any approach to block central immunoregulatory mechanisms is associated with unsuspected complications. These constitute a risk profile that may not be acceptable to otherwise healthy CHB patients as compared with terminally ill cancer patients. Use of anti-PD-1 antibodies offers the best hope of blocking PD-1/L12 interaction, as PD-L1 block would still allow PD-1–PDL2 interaction, however, anti-PD-1 antibodies have been associated with most adverse events and may require further studies prior to application as a therapeutic agent for CHB.
静脉注射,PD-1和PD-L1的抗体已经过测试,在晚期癌症患者。 PD-L1的抗体介导的封锁引起的耐用肿瘤消退和疾病治疗晚期癌症的长期稳定。[156]然而,使用抗PD-1抗体为3级比较高的频率或4级不良事件有关(发生在患者包括肺毒性三人死亡14%的不良事件)的PD-1阻断的治疗方法对慢性乙型肝炎患者[157]利用正在调查中。这种方法是独一无二的,并提供恢复慢性乙型肝炎疲惫的T细胞,从而使恢复对乙肝病毒适应性免疫的一个极好的机会,并提供实现持续病毒学缓解一个公平的机会。使用任何方法来阻止免疫调节中心机制与没有料到的并发症。这些构成与身患绝症的癌症患者相比,可能无法接受,原本健康的慢性乙型肝炎患者的风险状况。用抗PD-1抗体的提供阻断PD-1/ L12相互作用,如PD-L1块将仍然允许PD-1-PDL2相互作用,然而,抗PD-1抗体已与最不利的相关联的最大希望事件,并且可能需要在应用之前作为治疗剂慢性乙型肝炎进一步研究。
Tregs. Tregs consist of different T-cell subpopulations, including naturally occurring CD4+ CD25+ Tregs, induced Tregs (IL-10 producing CD4+ type I Tregs (Tr1) and T helper type 3 (Th3) cells), and CD4+ CD25+ T cells that develop in the periphery by conversion of CD4+ CD25− T cells. Experimental data suggest that circulating CD+ CD25+ Tregs may suppress HBV-specific T-cell responses in CHB patients resulting in persistence of HBV.[158]
调节性T细胞。调节性T细胞包括不同的T细胞亚群,包括天然存在的CD4 + CD25 +调节性T细胞,诱导调节性T细胞(IL-10的CD4+ I型调节性T细胞(Tr1的)和T辅助细胞类型3(Th3的)细胞)和CD4 + CD25 + T细胞的发展中的周由转换的CD4 + CD25 - T细胞。实验数据表明,循环CD+ CD25 +调节性T细胞可以抑制产生HBV的持续性慢性乙型肝炎患者HBV特异性T细胞应答。[158]
Despite all the above observations, a study on WHV-infected woodchucks, treated with IL-12 in combination with a TGF-β inhibitory peptide or Treg depletion showed that TGF-β inhibition or Treg depletion had no antiviral effect, instead an enhancement of the intrahepatic tolerogenic environment was observed.[159] Since there are no distinct phenotypic characteristics of Tregs available to target, it will be a difficult task to interfere with the function of Tregs in vivo.
尽管所有的上述意见,对WHV感染的土拨鼠,与IL-12与TGF-β抑制肽或调节性T细胞耗竭结合治疗的研究表明,TGF-β抑制或调节性T细胞耗竭没有抗病毒的作用,的而不是增强肝内致耐受环境进行了观察。[159]由于存在调节性T细胞没有明显的表型特征可用于靶向,这将是一项困难的任务干扰Treg细胞在体内的功能。
Therapeutic Vaccinations. Therapeutic vaccination presents a promising strategy in approach towards HBV eradication. As discussed before, HBV-specific T-cell exhaustion due to persistent antigen stimulation is considered a major determinant of HBV persistence or chronicity. A therapeutic vaccine, which could induce a potent CD4+ T-cell response, counteract immune tolerance, activate humoral immune response and stimulate CD8+ T cells directed against one or more HBV antigens, could achieve sustained control of CHB. During the past several years, different therapeutic vaccines have been developed and investigated in CHB patients with different clinical outcomes.
治疗性疫苗。治疗性疫苗在呈现对乙肝病毒消灭的办法有前途的战略。如之前所讨论的,HBV特异性T细胞耗竭由于持续的抗原刺激被认为是乙型肝炎病毒的持久性或慢性的主要决定因素。一种治疗性疫苗,其可以诱导一种强的CD4 + T细胞应答,抵消免疫耐受,激活的体液免疫反应和刺激的CD8 + T细胞针对一种或多种HBV抗原,可以实现CHB的持续控制。在过去的几年中,不同的治疗性疫苗已经开发和研究了慢性乙型肝炎患者具有不同的临床结果。
Several categories of therapeutic vaccines are being developed for CHB infection, which includes: vaccines based on recombinant HBV proteins, HBV-envelope subviral particles, naked DNA eventually combined with viral vectors and vaccines based on T-cell peptide epitopes derived from different HBV proteins.[160–162]
正在开发用于慢性乙型肝炎感染,其中包括几种类型的治疗性疫苗:基于重组HBV蛋白疫苗,乙肝病毒包膜亚病毒颗粒,裸DNA,最终基于从不同的HBV蛋白的T细胞肽表位的病毒载体和疫苗的组合。 [160-162]
Early classical therapeutic vaccines were based on the HBsAg protein that proved to be excellent in terms of its prophylactic potential, however, use of these vaccines have failed to reach expectations in terms of therapeutic efficacy. Antiviral effect of conventional prophylactic HBsAg-based vaccines were only transient and did not result in sustained viral suppression.[163] This is probably because most patients with CHB have diminished HBV responses due to exhaustive T-cell response and do not respond to classical immunizations.
早期的经典治疗性疫苗,是根据乙肝表面抗原蛋白,其被证明是优异的预防潜在的术语,但是,使用这些疫苗都未能达到在治疗功效方面的期望。常规预防的HBsAg为基础的疫苗的抗病毒效果只有短暂的,并没有导致持续的病毒抑制[163]这可能是因为大多数慢性乙型肝炎患者已经减少由于详尽的T-细胞应答的HBV反应和不经典的免疫反应。
Therapeutic Vaccination Based on Recombinant HBV Proteins or HBV-envelope Sub-viral Particles.
治疗性疫苗接种。基于重组乙型肝炎病毒蛋白或乙型肝炎病毒包膜亚病毒颗粒。
Immunogenic – Complexes: A double-blind placebo-controlled Phase IIb trial of a therapeutic HBV vaccine based on antigen–antibody immune complexes (HBsAg with antiHBs immunoglobulin) has been conducted in 242 patients with CHB presenting some initial evidence of clinical and virological efficacy.[164] These patients received antigen–antibody immune complexes with alum as adjuvant with the aim of targeting DCs. The rationale of this combination was based on the hypothesis that immune complex-loaded DCs were superior in efficiently priming HBV-specific CD8+ cytotoxic T cells responses in vivo compared with naturally occurring immune complexes.[165]
免疫原性 - 配合:基于抗原 - 抗体免疫复合物治疗性乙肝疫苗的双盲安慰剂对照的IIb期临床试验(乙肝表面抗原与免疫球蛋白antiHBs)已在242例进行了介绍慢性乙型肝炎的临床和病毒学疗效一些初步的证据。 [164]这些患者接受抗原 - 抗体免疫复合物用明矾为佐剂并靶向DC的目的。这个组合的基本原理是基于这一假设的免疫复合物负载的DC是在有效地吸HBV特异性CD8 +细胞毒性T细胞在体内的反应与天然存在的免疫复合物进行比较优越。[165]
However, the results of Phase III clinical trial failed to show the therapeutic efficacy of immune complex-based vaccination.[166]
然而,III期临床试验的结果没有显示出的免疫复合物为基础的疫苗接种的治疗效果。[166]
HBsAg & HBcAg Combination: Another approach involves the nasal HBV vaccine candidate, comprising HBsAg and core (HBcAg) as vaccine antigens. The nasal HBV vaccine candidate is based on the results of preclinical studies that have demonstrated a good immunogenicity and safety profile. Recombinant HBcAg can act as a potent Th1 adjuvant to HBsAg, as well as a strong immunogen.[167,168] This was tested in a Phase I double-blinded, placebo-controlled randomized clinical trial in healthy volunteers that demonstrated the safety and immunologic efficacy of this combination approach.[169] At present, a Phase III clinical trial is ongoing with HBsAg/HBcAg-based combined vaccine through the nasal and subcutaneous route in CHB patients and results are awaited.[170]
的HBsAg和HBcAg的组合:另一种方法涉及到鼻乙肝疫苗候选,包括乙肝表面抗原和核心(核心抗原)作为疫苗抗原。鼻乙肝疫苗的候选是基于临床前研究已经表现出了良好的免疫原性和安全性的结果。重组核心抗原可以作为一种有效的Th1佐剂乙肝表面抗原,以及强大的免疫原。[167168]这是在I期双盲,安慰剂对照的随机临床试验,在证明的安全性和免疫效果的健康志愿者进行测试这种组合方式。[169]目前,III期临床试验正在进行用HBsAg / HBcAg的基础,通过慢性乙型肝炎患者和结果期待已久的鼻腔,皮下途径联合疫苗。[170]
Whole Recombinant Yeast-based Therapeutic Vaccine: A yeast-based immunotherapy platform, Tarmogens (targeted molecular immunogen), is currently under development. Tarmogen incorporates multiple viral antigens, expressing HBV X, surface (S), and core Ags (X-S-core) and has been shown to induce both CD4+ and CD8+ T-cell responses in healthy and CHB patients ex vivo. TheGS-4774 is a tarmogen that consists of whole, heat-killed, recombinant Saccharomyces cerevisiae yeast, which is genetically modified to express HBV antigens. Use of entire yeast results in preferential uptake/processing by dendritic cells rather than B cells to present HBV antigens to T cells, theoretically resulting in a more efficacious cellular immunity compared with a predominantly humoral immunity with the use of subunit vaccines.
整体重组酵母为基础的治疗性疫苗:酵母为基础的免疫治疗平台,Tarmogens(分子靶向免疫),目前正在开发中。 Tarmogen结合多种病毒抗原,表达HBV X,表面(S),以及核心AGS(XS芯),并已显示出诱导CD4 +和CD8 + T细胞应答在健康和慢性乙型肝炎患者体外。在GS-4774是一种tarmogen,由全,热灭活的重组酿酒酵母的酵母,其是通过基因修饰以表达HBV抗原。使用的整个酵母导致优先摄取/加工由树突状细胞而不是B细胞呈现HBV抗原给T细胞,理论上产生更有效的细胞免疫由于主要是体液免疫与使用亚单位疫苗进行比较。
Guo et al. demonstrated antigen-specific T-cell responses generated in mice immunized with two candidate vaccines mentioned above.[171] In addition, the data showed that GS 4774 (X-S core) significantly protected mice from tumors engineered to express HBV antigens. In a second study by Kemmler et al., both tarmogens elicited HBV-specific T-cell responses ex vivo in samples collected from healthy individuals and donors with CHB.[172]
Guo等。证实在免疫的上述两个候选疫苗的小鼠中产生的抗原特异性T细胞应答。[171]此外,该数据表明,GS4774(XS芯)从肿瘤显著保护小鼠改造以表达HBV抗原。在第二项研究由KEMMLER等,均tarmogens引起HBV特异性T细胞反应离体健康者和捐助者与慢性乙肝收集的样本。[172]
Recently, murine and human immunogenicity models were used to evaluate the type and magnitude of HBV-Ag specific T-cell responses elicited by the vaccine. Mice immunized with yeast expressing X-S-core showed T-cell responses to X, S and core. Both CD4+ and CD8+ T-cell responses were observed. Human T cells transduced with HBc18–27 and HBs183–91 specific T-cell receptors (TCRs) produced IFN-γ following incubation with X-S-core-pulsed DCs. Furthermore, stimulation of peripheral blood mononuclear cells isolated from CHB patients or from HBV vaccine recipients with autologous DCs pulsed with X-S-core or a related product (S-core) resulted in pronounced expansions of HBV Ag-specific T cells possessing a cytolytic phenotype. These data indicate that X-S-core-expressing yeast elicits functional adaptive immune responses. This therapeutic vaccine seems promising in inducing HBV-specific T-cell responses in patients with CHB [KING TH ET AL . UNPUBLISHED DATA].
最近,小鼠和人的免疫原性的模型,用于评估的类型和由疫苗引起的HBV-银特异性T细胞应答的量级。免疫小鼠酵母表达XS核表明T细胞反应,以X,S和核心。 CD4 +和CD8 + T细胞应答的变化。人类T细胞转导的HBc18-27和HBs183-91特异性T细胞受体(TCR)产生的IFN-γ孵育后用XS-核 - 脉冲的DC。此外,外周血单个核细胞慢性乙肝患者或乙肝疫苗接种者有脉冲与XS核或相关产品(第芯)自体DC隔离的刺激导致乙肝病毒抗原特异性T细胞具有溶细胞表型的显着扩张。这些数据表明,XS核表达酵母引发功能性免疫应答。这种治疗性疫苗似乎有希望在诱导HBV特异性T细胞应答在慢性乙型肝炎患者[KING TH等。未发表的数据。
Tarmogen, GS-4774 is being tested in combination with direct-acting antivirals in CHB patients to determine if the combination can increase rates of HBsAg seroconversion. A Phase I trial on GS-4774 has been completed and a Phase II, randomized, open-label study to evaluate the safety and efficacy of GS-4774 for the treatment of virally suppressed subjects with CHB is currently ongoing. Ongoing Phase II studies will determine whether yeast-based vaccines would result in unexpected allergic adverse reactions to common yeast infections in these patients.
Tarmogen,GS-4774正与慢性乙型肝炎患者直接作用的抗病毒药物的组合进行测试,以确定该组合可以提高HBsAg的血清转化率。对GS-4774 I期临床试验已经完成,第二阶段,随机,开放标签研究,以评估GS-4774的安全性和有效性的病毒抑制者与慢性乙肝的治疗是目前正在进行中。正在进行的II期研究中,将决定基于酵母的疫苗是否会导致意想不到的过敏性不良反应在这些患者中常见的真菌感染。
Adeno-virus-based Therapeutic Vaccination: TG1050 is a therapeutic vaccination based on a recombinant nonreplicative human adenovirus serotype 5, expressing multiple specific HBV antigens (truncated core, modified polymerase and HBsAg domains). The product has been designed to prime de novo and/or stimulate functional T cells expected to control the HBV replication and to clear HBV. In an experiment by Perrine Martin et al, TG1050 was found to induce high levels of T cells targeting core, polymerase and HBsAg domains in naive mice. In the Adeno-associated virus (AAV) tolerant mouse model, a single injection of TG1050 was shown to induce functional and long lasting T cells producing IFN-γ, TNF-α and IL-2, which were detected in spleen and liver without elevation of ALT. Experiments are ongoing to analyze immunological and virological effects of multiple injections of TG1050 as well as longer follow-ups.[173] t of CHB patients.
腺病毒为基础的治疗性疫苗:TG1050是基于一个非复制性重组人腺病毒血清型5治疗性疫苗,多表达乙肝病毒特异性抗原(截断核心,修改聚合酶和乙肝表面抗原域)。该产品已被设计成素从头和/或刺激预期来控制病毒复制和清除HBV的功能性T细胞。在实验中通过珀赖恩Martin等,TG1050,发现诱导高水平靶向芯,聚合酶和HBsAg的结构域在幼稚小鼠的T细胞。在腺相关病毒(AAV)耐受小鼠模型中,单次注射TG1050的结果显示,诱导产生IFN-γ,TNF-α和IL-2,这是在脾脏和肝脏中检测到不抬高功能和持久性T细胞的ALT键。实验正在进行中,分析免疫学和TG1050多次注射的病毒学效果以及较长的后续行动。[173] T,慢性乙肝患者
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