新发传染病相关的药品技术战略储备思考

目的： 对新发传染病相关的药品技术战略储备进行探讨,旨在为战胜此次新冠肺炎疫情,更为下一次可能的疫情做好准备。方法： 梳理了世界卫生组织、欧盟、美国对与公共健康威胁相关的药品技术储备情况,主要阐述了新发传染病相关的疫苗技术储备信息,给出WHO建议的新型冠状病毒肺炎（COVID-19）药品研发信息,EMA在公共健康威胁（例如大流行性流感）相关药品方面的技术储备情况,并总结了EMA对大流行防备疫苗的技术要求。结果与结论： 建议在我国建立由国家主导并投资的与公共健康威胁相关的预防用疫苗或治疗用药物的技术和产品战略储备,例如为新发传染病的疫苗开发制定清晰的计划、法规和程序。药品技术和产品的战略储备可包括：1）政府部门制定与公共健康威胁相关疾病的清单,例如可能引起重大流行病的突发疾病用药优先研发清单;2）审评审批方面可考虑制定大流行性疾病疫苗（包括大流行防备疫苗）、大流行性疾病治疗药物研发的技术要求,涉及质量、非临床、临床、申报程序等内容;3）通过国家科技立项等方式投资预防用疫苗及治疗用药物的研制;4）引导生产企业进行相关的药品战略储备。     

基于专利信息的抗原免疫检测技术发展研究

目的 分析抗原免疫检测技术领域专利的技术信息和法律信息,为相关企业提供研发方向和专利布局的建议。方法 运用专利分析手段,结合数据可视化呈现,对雅培、万孚生物、华大基因等相关企业在免疫检测领域的研发趋势和研究热点进行系统分析。结果 雅培在免疫检测领域的专利布局较为全面,在国际竞争中占据优势地位,虽然中国企业的免疫检测技术各有专长,但是产业布局和专利布局的全面性较弱。结论 中国企业应加强跨学科研究,争取在多样本多病原体高通量检测、磁微粒化学发光检测、微流控芯片检测等前沿技术方向取得突破,以及考虑自身特点选择合适的专利保护策略。     

疫苗平台技术的国际发展及对我国新发传染病战略储备的启示

新型冠状病毒肺炎(COVID-19)疫情凸显出储备快速研发疫苗技术的必要性，以核酸疫苗和病毒载体疫苗为代表的疫苗平台技术只需要病毒基因序列即可启动研发，并在短期内快速扩产，适用于传播速度快、波及范围广且人群普遍缺乏免疫力的新发传染病。但由于该研究领域尚处于快速发展阶段，鲜有国内文献对相关概念、定义和分类进行描述。本研究系统梳理了相关文献和资料文件，总结疫苗平台技术的定义、发展现状及应用前景，阐述开发疫苗平台技术对于新发传染病应急研发的重要作用，为我国建立相关疫苗平台技术战略储备、提高新发传染病预防和应对能力提供科学依据和对策建议。     

手足口病疫苗研究进展

摘 要手足口病是由多种肠道病毒引起的,为5岁以下儿童常见的传染病,已经成为亚太地区重要的公共卫生问题。由于缺乏有效的抗病毒药物,因此疫苗接种是预防该病暴发的重要措施。目前中国自主研发的EV71疫苗已上市,其他类型的疫苗也显示出良好的发展前景,本文就手足口病疫苗的研究进展进行论述。     

美国FDA“动物（效应）法规”在生物防御药物开发中的应用及启示

目的： 在应对重大公共卫生事件中，为我国相关生物防御药物的上市审批和应用储备提供参考依据和解决思路。方法： 结合审批实例，对美国FDA"动物（效应）法规"的主要内容、应用范围和实施状况进行综述，针对美国和我国现阶段应对重大公共卫生事件的药品审批机制进行讨论。结果与结论： 在针对可能发生的生物恐怖袭击事件及重大疫情开展的药物研发中，评价尺度可以与普通药物有所区别，应视情做好相应生物防御药物的战略储备，为应对突发重大公共卫生事件提供系统性支持。     

血源筛查核酸检测体系的发展、应用及监管

目的：对我国血源筛查核酸检测体系的研发、应用和监管提供建议。方法：概述血源筛查核酸检测的技术方法，梳理核酸血筛体系的研究进展、应用及监管现状，并结合我国国情提出针对性建议。结果与结论：应用核酸检测试剂检测病原体核酸，可显著缩短病原体检测"窗口期"。近年来，国产核酸检测试剂的灵敏度及检测仪器的自动化水平都有了显著提升，但是国产核酸检测体系质量和性能还有很大进步空间。建议加大对符合我国国情的核酸检测试剂的研究投入；加强核酸检测体系使用的管理；统筹规范检测模式、检验标准和检验参考品。     

多院区模式下口服药品单剂量摆药机突发故障应急处理及思考

摘 要 目的：通过口服药品单剂量摆药机（ADDS）突发故障的跨院区应急实践,制定相应的应急预案以保障患者临床药物治疗。方法: 分析ADDS突发故障应急处理的特性和梳理跨院区应急处理过程中的难点,采取有效的应对措施。结果: 依据跨院区应急处理实践,制定了相应应急处置预案,成立了应急处置小组,制定了应急处置流程。结论: ADDS突发故障跨院区应急处理方案切实、高效、可行。     

小核酸药物配体缀合递送技术专利分析

目的 为中国小核酸药物研发企业的研发战略规划和专利战略制定提供参考。方法 通过智慧芽专利数据库检索小核酸药物配体缀合技术相关专利,通过人工标引的方式筛选获得该领域的核心专利及外围专利。首先对相关专利整体进行申请趋势分析,其次对小核酸药物配体缀合3类技术的核心专利进行详细分析。结果与结论 从整体来看,小核酸药物配体缀合递送技术绝大多数核心专利均掌握在Ionis、Alnylam、Arrowhead、Arbutus等国际顶尖核酸药物研发企业手中,而中国企业的研究能力和专利布局强度较弱。小核酸药物配体缀合递送技术主要包括半乳糖衍生物缀合递送技术、脂质衍生物缀合递送技术、细胞穿透肽缀合递送技术。其中最具发展潜力的是半乳糖衍生物缀合递送技术。脂质衍生物缀合递送技术近年来相对于半乳糖衍生物缀合递送技术所受到的关注度相对较低,多数专利布局时间过早,大都处于失效状态。细胞穿透肽缀合递送技术近年来越来越受到重视。     

光响应生物材料研究进展及应用

目的：对光响应生物材料在药物控制系统及组织工程支架方面的研究及应用进行综述,为推进基础研究成果走向临床转化提供参考。方法：通过文献研究,归纳光响应生物材料的分类及光化学反应机理,讨论其在药物控制系统及组织工程支架领域中的应用,探讨其在临床转化中面临的挑战,并对未来发展方向进行展望。结果与结论：由于光源具有很多优点,使得光响应生物材料在药物控释系统、生物传感器、荧光探针及组织工程支架等生物医药领域得到广泛的关注。尽管近年来光响应生物材料基础理论研究已经取得巨大进展,但是在临床转化中仍存在激发光源和生物相容性等问题。未来新材料研发上如果能有创新,例如制备出对近红外光响应的生物材料或者兼具对多种刺激如光、pH、酶等有响应的生物材料,将会给光响应生物材料在医疗领域应用带来更大希望。     

聚乙二醇修饰壳聚糖在生物医学领域的研究进展

摘 要 目的： 为聚乙二醇修饰壳聚糖的深入研究提供参考。方法: 通过查阅、检索2004～2014年国内外相关文献及资料,并进行总结归纳。结果:聚乙二醇修饰壳聚糖的方法多样,可应用于制备纳米药物载体、制备基因治疗的载体、温敏性水凝胶、高分子前药以及组织工程修复材料。结论: 聚乙二醇修饰的壳聚糖在生物医药领域研究广泛,但相关研究仅限于体外,体内研究需进一步系统和深入。     

Nucleic acid vaccination strategies against infectious diseases

Introduction: Gene vaccines are an interesting and emerging alternative for the prevention of infectious diseases, as well as in the treatment of other pathologies including cancer, allergies, autoimmune diseases, or even drug dependencies. When applied to the target organism, these vaccines induce the expression of encoded antigens and elicit the corresponding immune response, with the potential ability of being able to induce antibody-, helper T cell-, and cytotoxic T cell-mediated immune responses.

Areas covered: Special attention is paid to the variety of adjuvants that may be co-administered to enhance and/or to modulate immune responses, and to the methods of delivery. Finally, this article reviews the efficacy data of gene vaccines against infectious diseases released from current clinical trials.

Expert opinion: Taken together, this approach will have a major impact on future strategies for the prevention of infectious diseases. Better-designed nucleic acid constructs, novel delivery technologies, as well as the clarification of the mechanisms for antigen presentation will improve the potential applications of this vaccination strategy against microbial pathogens.     

Targeting the TLR9–MyD88 pathway in the regulation of adaptive immune responses

Importance of the field: Toll-like receptors (TLRs) are innate immune receptors critical in the innate immune defense against invading pathogens. Recent advances also reveal a crucial role for TLRs in shaping adaptive immune responses, conferring a potential therapeutic value to their modulation in the treatment of diseases.

Areas covered in this review: The aim of this review is to discuss TLR9, the TLR9–MyD88 signaling pathway and its role in regulation of adaptive immune responses, as well as potential therapeutic implications by targeting this pathway.

What the reader will gain: This review shows that the TLR9–MyD88 signaling pathway plays a critical role in promoting adaptive immune responses and that modulation of this pathway may have enormous therapeutic potential in enhancing vaccine potency, controlling autoimmunity, as well as improving the outcome of viral-vector-mediated gene therapy.

Take home message: Although TLR9 agonists have been used as adjuvants for enhancing vaccine potency, further exploitation of the TLR9–MyD88 pathway and its dynamic interaction with the immune system in vivo is needed to provide more effective therapeutic inventions in the design of vaccines for infectious diseases, allergies and cancer, in the control of autoimmunity, as well as in the improvement of viral-vector-mediated gene therapy.     

How can monoclonal antibodies be harnessed against neglected tropical diseases and other infectious diseases?

ABSTRACT

Introduction: Monoclonal antibody-based therapies now represent the single-largest class of molecules undergoing clinical investigation. Although a handful of different monoclonal antibodies have been clinically approved for bacterial and viral indications, including rabies, therapies based on monoclonal antibodies are yet to fully enter the fields of neglected tropical diseases and other infectious diseases.

Areas covered: This review presents the current state-of-the-art in the development and use of monoclonal antibodies against neglected tropical diseases and other infectious diseases, including viral, bacterial, and parasitic infections, as well as envenomings by animal bites and stings. Additionally, a short section on mushroom poisonings is included. Key challenges for developing antibody-based therapeutics are discussed for each of these fields.

Expert opinion: Neglected tropical diseases and other infectious diseases represent a golden opportunity for academics and technology developers for advancing our scientific capabilities within the understanding and design of antibody cross-reactivity, use of oligoclonal antibody mixtures for multi-target neutralization, novel immunization methodologies, targeting of evasive pathogens, and development of fundamentally novel therapeutic mechanisms of action. Furthermore, a huge humanitarian and societal impact is to gain by exploiting antibody technologies for the development of biotherapies against diseases, for which current treatment options are suboptimal or non-existent.     

Emerging and reemerging pathogens

From 1973 to 1995, 29 new and reemerging pathogenic microbes were recognized. However, in discussions about emerging infectious diseases, the focus is often on the clinical effects of the host-parasite relationship, rather than the examination of the biology of the pathogen. Many of what we refer to as emerging diseases are characterized better as 'diseases of human progress'. Thus, the aerosolization of water has played an important role in the emergence of Legionella pneumophila infections. New diseases are superimposed on endemic diseases such as diarrhoeal diseases, malaria and tuberculosis. In addition, many pathogens are becoming increasingly resistant to standard antimicrobial drugs, making treatment difficult and in some cases impossible. We summarize our experience on emerging parasitic diseases (primary amoebic meningoencephalitis, respiratory cryptosporidiosis, and diplogonoporiasis), and selected problems of bacterial resistance (MDR tuberculosis caused by Mycobacterium bovis and macrolide-resistance mechanisms of Streptococcus pneumoniae and S. pyogenes).     

预防传染病mRNA疫苗原材料、原液质控要点分析

目的：梳理归纳预防传染病mRNA疫苗原材料和原液质控要点,为我国此类产品质量控制提供参考。方法：通过梳理世界卫生组织及相关标准和审评机构关于预防传染病mRNA疫苗原材料、原液质控指导文件,以及相关监管指南和文献,总结归纳预防传染病mRNA疫苗原材料和原液关键质量控制属性及相关要求。结果与结论：作为新型生物制品,mRNA疫苗核酸结构和脂质体包裹制剂的特性决定了该类疫苗质控特点,序列和完整性、含量及纯度、加帽率和包封率是mRNA疫苗特有的、决定有效性和安全性的关键质量参数。从原材料和原液制备阶段就建立多个与mRNA特性相关的质控要点及其检测方法,将有助于保障预防传染病mRNA疫苗安全有效、质量可控。     

Toll-like receptors as potential therapeutic targets in cardiac dysfunction

Introduction: The innate immune system can detect the highly conserved, relatively invariant structural motifs of pathogens. The most important innate immune receptors, Toll-like receptors (TLRs), represent a first line of defense against infectious pathogens, and play a pivotal role in initiating and shaping innate and adaptive immune responses. TLRs are not only expressed in immune cells, but also in cardiovascular cells. In addition to their role in response to microbial infections, evidence suggests that TLRs can also recognize endogenous ligands and may play a role in mediating cardiomyocyte cell death and survival after non-infectious injury.

Areas covered: TLRs could be a link between cardiovascular diseases and the immune system. Experimentally, there is good evidence that TLR activation contributes to development and progression of both acute cardiac injury and chronic heart failure. The role of TLRs in myocardial ischemia–reperfusion, remodeling, septic cardiomyoparthy, autoimmune- and viral myocarditis, anthracycline-induced cardiomyopathy and cardiac hypertrophy, in basic as well as clinical science are discussed.

Expert opinion: Evidence, mainly from animal experiments, indicates that TLRs contribute to all of the myocardial disease states reviewed in this paper. However, the relevance of TLRs as therapeutic targets remains to be defined as clinical data is sparse.     

Puces à protéines : nouvelle approche du diagnostic des maladies infectieuses

Protein arrays enable interactions with various types of molecules to be detected. They have therefore become a powerful tool to study human pathologies, to evaluate the immune response to viral and bacterial antigens, to develop diagnostic tests and to assess candidates for vaccines. The advantages of this emerging technology are based on its capacity to compare and characterise a huge number of target proteins simultaneously, thus replacing numerous individual binding reactions by a single test, and to monitor many parameters in parallel in complex biological solutions. Screening the proteome of pathogenic microorganisms is another high-throughput means to identify new diagnostic and prognostic markers and new antimicrobial targets. The review describes different stages of the technology, the characteristics of antigen and antibody arrays and their contribution to the study of infectious diseases as well as to the development of new applications in microbiology.     

我国体外诊断试剂产品注册管理现状分析

目的：对体外诊断试剂产品中注册管理相关法规和技术文件进行梳理、总结和分析,有利于从业人员和监管人员全面掌握注册制度的关键环节和配套要求,提升体外诊断试剂产品监管的科学性、准确性,提高企业开展相关产品注册的效率和质量。方法：从监督管理变化视角对注册管理办法的产品分类规则、执行标准、临床评价、审查指导原则、特殊审批程序等监管内容进行解读,分析体外诊断试剂行业的前景与面临的问题,阐释修订后的法规在保证体外诊断试剂安全有效、质量可控方面起到的明显成效。结果与结论：通过对体外诊断试剂产品注册管理法规进行修订,实现了对分类规则的调整,解决了部分产品分类与其风险不匹配等问题,完善了产品执行标准,使标准发挥出技术支撑作用,贯彻落实企业主体责任,加大临床试验管理力度,发布审查指导原则,补充特殊审批条件,在保证体外诊断试剂的安全、有效、质量可控方面发挥了显著作用,对我国体外诊断试剂整体行业的发展产生了深远影响。     

Bacterial resistance to antibiotics: active efflux and reduced uptake

Antibiotic resistance of bacterial pathogens is a fast emerging global crisis and an understanding of the underlying resistance mechanisms is paramount for design and development of new therapeutic strategies. Permeability barriers for and active efflux of drug molecules are two resistance mechanisms that have been implicated in various infectious outbreaks of antibiotic-resistant pathogens, suggesting that these mechanisms may be good targets for new drugs. The synergism of reduced uptake and efflux is most evident in the multiplicative action of the outer membrane permeability barrier and active efflux, which results in high-level intrinsic and/or acquired resistance in many clinically important Gram-negative bacteria. This review summarizes the current knowledge of these two important resistance mechanisms and potential strategies to overcome them. Recent advances in understanding the physical structures, function and regulation of efflux systems will facilitate exploitation of pumps as new drug targets.