疫苗佐剂研究进展

在疫苗生产过程中，使用适当的佐剂，不再是单纯地提高机体对抗原的免疫应答水平，而更着重于选择性地诱导产生有效防御相应病原体感染的特异性应答的类型。本文从辅助性Ｔ（Ｔｈ）淋巴细胞亚型及特异性免疫应答类型角度，对新近研究开发的重要选择性佐剂（油性乳剂、脂多糖、皂苷、脂质体以及细胞因子）作一介绍。     

疫苗佐剂的研究进展

新一代疫苗，尤其是重组蛋白或DNA，比传统疫苗反应性弱，免疫原性也小。因此，迫切需要开展和改进疫苗佐剂。根据佐剂的主要作用机制可以将其分为两大类：疫苗输送系统及免疫刺激性佐剂。疫苗输送系统通常为微粒，功能主要是使相关抗原进入抗原提呈细胞。免疫刺激佐剂主要由病原体衍生，模拟病原体相关分子模式，激活先天免疫系统的细胞。更多有效的佐剂的发现促进了对于癌症和慢性感染性疾病的预防和治疗性疫苗的发展。此外，新佐剂的发展也使疫苗经粘膜应用成为可能。     

脂质体用作疫苗佐剂的研究进展

脂质体作为疫苗佐剂可同时增强机体的体液和细胞介导免疫应答，对疫苗的增效作用可达数十倍甚至更高。大量动物试验还证实，脂质体也能明显增强抗原性较弱的合成肽和重组抗原的免疫原性，其佐剂疚明显优于铝佐剂，而且毒副反应轻微。脂质体的安全性及高效佐剂作用在部分人体试验中也已得到证实。简便、实用的脂质体制备工艺的建立和完善将进一步加快脂质体佐剂的实用化进程。     

脂质体佐剂疫苗研究进展

脂质体作为蛋白质及多肽抗原的佐剂和载体已被广泛应用。通过综述脂质体在细菌、病毒、寄生虫和肿瘤疫苗中的研究应用 ,提示脂质体在疫苗的研制中具有广阔的应用前景     

ISS佐剂乙型肝炎疫苗的Ⅰ期临床研究

免疫刺激性DNA序列(ISS)能刺激树突状细胞、巨噬细胞和自然杀伤细胞等产生Th1型细胞因子，并刺激B细胞增殖和免疫球蛋白分泌，与DNA或蛋白疫苗共同使用时具有Th1佐剂作用。作者对以合成的22体硫代磷酸寡脱氧核苷酸免疫刺激序列     

疫苗佐剂的分类和作用方式

本世纪初疫苗中已使用佐剂来增强疫苗效力，但迄今人用甚至兽用疫苗的佐剂大多数仍为铝盐。近年来许多新疫苗正在开发中，并期望通过增加疫苗组分和减少剂数来简化免疫程序，这就需要更有效的新佐剂。本文讨论佐剂的发展和作用方式，并尝试根据作用方式进行佐剂分类，以期有助于佐剂的选择。     

佐剂在流行性感冒疫苗中的应用

1流行性感冒流感病毒及流感病毒疫苗概况根据流感病毒（In fluenza V irus）的核蛋白（N ucleopro-te in,NP）和膜蛋白（M em brane P rote in,M P）不同,分为：甲（A）、乙（B）、丙（C）,甲型流感可造成大流行,乙型是局部爆发,丙型主要侵犯婴幼儿。根据血凝素（H em agg lu tin in,HA）和神经氨酸酶（N euram inn idase,NA）的不同,HA分为16个亚型,NA分为9个亚型,但能感染人类的只有少数HA（H1-H3）和NA（N1、N2）亚型[1]。     

WHO关于人用疫苗新佐剂的第二次专题讨论会

世界卫生组织 (WHO)于 2 0 0 0年 6月在法国昂西 Mérieux基金会举行了第二次佐剂专题讨论会 ,讨论了当前人用疫苗佐剂使用的最新情况。与会科学家报告了正在进行或接近临床试验的佐剂配方。每一与会者讨论了他们在临床前模型或人用疫苗研究中开发的疫苗佐剂     

含铝佐剂疫苗的全球性影响

儿童期疫苗可预防疾病的免疫预防已对儿童健康产生了巨大影响，在扩大免疫规划中所使用的许多疫苗含有铝佐剂，这些佐剂在有效使用基础疫苗中起重要作用，本文讨论了广泛使用的铝佐剂及其对疫苗可预防疾病的作用。     

调脂药物注册临床试验的考虑

本文旨在介绍调脂药物注册临床试验的主要考虑.有效性主要在于对血脂参数的影响、血管的保护作用和对于死亡率及心血管事件的影响.安全性集中在肝脏、肌肉和长期的心血管事件的发生上.同时本文也对调脂药物在儿童中开展试验的要求进行了阐述.     

Cancer vaccines entering Phase III clinical trials

The last 10 years have seen a growth in the number of tumour antigens identified from immune responses raised in patients. The discovery that tumours can be recognised by the immune system stimulated a great deal of work characterising the molecular mechanisms underlying immune recognition. This in turn has led to an impressive array of immunological approaches to the generation of cancer vaccines; these range from molecularly defined T cell epitopes, antibody-based vaccines, cytokine therapies, immune modulators and DNA vaccines, to whole cell vaccines and, more recently, combinations of these methods. Many of these approaches have entered Phase I/II trials and have shown interesting clinical results. Moreover, they have extended our knowledge of the immune system and our understanding of the mechanisms required to design a successful cancer vaccine. This review outlines some of the approaches that have led to some of these vaccines entering Phase III clinical trials, discusses their modes of action and reports on their current status in trial.     

Cancer vaccines entering Phase III clinical trials

The last 10 years have seen a growth in the number of tumour antigens identified from immune responses raised in patients. The discovery that tumours can be recognised by the immune system stimulated a great deal of work characterising the molecular mechanisms underlying immune recognition. This in turn has led to an impressive array of immunological approaches to the generation of cancer vaccines; these range from molecularly defined T cell epitopes, antibody-based vaccines, cytokine therapies, immune modulators and DNA vaccines, to whole cell vaccines and, more recently, combinations of these methods. Many of these approaches have entered Phase I/II trials and have shown interesting clinical results. Moreover, they have extended our knowledge of the immune system and our understanding of the mechanisms required to design a successful cancer vaccine. This review outlines some of the approaches that have led to some of these vaccines entering Phase III clinical trials, discusses their modes of action and reports on their current status in trial.     

Glycoconjugates as vaccines for cancer immunotherapy: clinical trials and future directions

The immune system recognizes and potentially eliminates tumors that express antigenic molecules. The theory of "cancer immunosurveillance", describing lymphocytes as sentinels capable of recognizing nascent transformed cells and thus maintaining tissue homeostasis, has been proposed as far back as 50 years ago. The modern vision of immune responses against cancer is more complex because the immune system sculpts the immunogenic phenotype of developing tumors by not only facilitating their elimination, but also their progression in regards to the role of regulatory T cells and the subpopulation of natural killer T cells (NKT). Manipulation of adaptive immunity through therapeutic approaches is relevant to prevent metastasis and, in some cases, to treat primary tumors if the relevant antigens have been identified. Here we review the use of glycoconjugates containing tumor-associated carbohydrate antigens (TACA) in immunotherapy and their use as vaccines in clinical and pre-clinical trials. We also describe a new experimental vaccine model for the generation of CD8+ cytotoxic T cells (CTL) that involves designer TACA-containing glycopeptides with high affinity for class I molecules of the major histocompatibility complex (MHC).     

生物制品首次临床试验起始剂量拟定的一般考虑

全新药物从临床前向临床推进的过程中,首次临床试验起始剂量的拟定是一个关键风险控制节点。生物制品与小分子药物存在不同的药理作用特点和毒性风险,在首次临床试验起始剂量的拟定上具有与小分子药物不同的考虑侧重点。重点阐述支持首次临床试验起始剂量拟定所需要的临床前研究信息;根据国内外的指导原则,介绍了基于毒性终点、药理终点、以及PK/PD模型进行起始剂量拟定的方法;通过回顾性分析,发现尽管毒性反应剂量法依然是传统保守的方法,但是对于具有免疫激发作用的生物制品更倾向于采用最低预期生物效应剂量法。研究者应基于药物的特点,采用多种方法拟定首次临床试验起始剂量,选取最合适安全的剂量,并加强与监管机构沟通与交流。     

抗肿瘤药物申报联合用药早期临床试验的考虑

抗肿瘤新药是当前新药研发的热点。为获得更大的临床获益,积极探索不同形式的联合用药方案,是抗肿瘤药物研发的必然方向。本文将从技术审评角度,阐述当前开展抗肿瘤药物申报联合用药早期临床试验的申报要求与审评考虑。     

新药临床试验中的桥接试验

目的：介绍新药临床试验中桥接试验的概念和实施策略。方法：本文介绍了ICH E5中提出的桥接试验的概念和亚洲桥接试验的现况，结合实例介绍了桥接策略的具体实施。结果：随着ICH E5的发布以及桥接试验在一些国家和地区的成功实施，桥接试验已经成为新药注册申请的一个重要形式。结论：桥接试验对于外推国外的临床试验数据，判断药品种族差异，减少重复试验。缩短新药审批时间将有重要的意义。     

Adaptive clinical trials for new drug applications in Japan

Adaptive design is regarded as an efficient method for clinical trials in order to increase the success rate of a new drug in development, and recently has been actively discussed among regulatory agencies, industry and academia. Since adaptive design involves interim analyses and is more complex than traditional fixed design, some points such as possibility of introducing statistical and operational bias should be considered when planning and implementing such trials. In this article, we share our perspectives in the consideration of adaptive design clinical trials based on our experiences discussing adaptive design in clinical trial consultation meetings in Japan.     

Considerations for non-clinical safety studies of therapeutic peptide vaccines

Guidelines for non-clinical studies of prophylactic vaccines against infectious diseases have been published widely, but similar guidelines for therapeutic vaccines, and especially therapeutic peptide vaccines, have yet to be established. The approach to non-clinical safety studies required for therapeutic vaccines differs from that for prophylactic vaccines due to differences in the risk–benefit balance and the mechanisms of action. We propose the following guidelines for non-clinical safety studies for therapeutic peptide vaccines. (i) Since the main safety concern is related to the immune response that might occur at normal sites that express a target antigen, identification of these possible target sites using in silico human expression data is important. (ii) Due to the strong dependence on HLA, it is not feasible to replicate immune responses in animals. Thus, the required non-clinical safety studies are characterized as those detecting off-target toxicity rather than on-target toxicity.