WHO对HPV疫苗质量、安全性及有效性指导原则.docx

GUIDELINES TO ASSURE THE QUALITY, SAFETY AND EFFICACY OF RECOMBINANT HUMAN PAPILLOMAVIRUS VIRUS?LIKE PARTICLE VACCINES HPV二、Special consideration section: 在生产、非临床及临床中过程中的考虑因素：生产方面：VLP是复杂的生物产物，必须在不同水平下对其进行检测分析。因而在其生产过程及质量控制上必须考虑以下几个因素：新的表达体系如杆状病毒（GSK），新的特殊要求。但我们用的毕赤酵母，相对比较常见。新佐剂（略）天然的L1蛋白是没有被糖基化修饰，目前的两种表达体系，在糖基化修饰上不存大问题,但要对糖基化及其位点进行分析。L1衣壳蛋白亚单位的解聚与再聚，可能有利于纯化，并得到更稳定的VLP。目前，我们的路线可能是不经解聚，直接纯化获得VLP。个人感觉，到后期可以兵分两路，一路直接获得VLP，而另一路则将VLP解聚后，再进行纯化与重组。纯化后的L1 VLP要进行生化及免疫上的鉴定，并测定L1的浓度、纯度及组聚情况。如加入了防腐剂，应对其免疫性进行验证，并确认不会有负作用非临床方面：关键就是要证明其免疫原性，并能否产生免疫中和抗体。临床方面：（略）三、生产指导（Part A. Guidelines on manufacturing）3.1定义 definitions3.1.1国际名称和专有名称国际名称：重组人乳头瘤类病毒颗粒疫苗（基因型16 L1蛋白）3.1.2定义描述重组HPV VLP疫苗为无菌的液态疫苗，里面含纯化后由一种或多种HPV基因型重组的主要的衣壳蛋白，并与相应佐剂混合。3.1.3国际标准品在此指导原则编写时，市场上暂无国际标准品提供。但有相应试剂在实验室水平上，在进行注射后进行生物效价方面的评价如抗体滴度和病毒DNA检测。3.2术语Terminology The definitions given below apply to this document only. HPV L1 protein: The major structural protein of human papillomavirus, of which 360 molecules are found in the native virion associated in 72 pentameric capsomers. L1 virus?like particle: A non?infectious, non?enveloped, icosahedral capsid particle which does not contain viral DNA and which is composed of regular arrays of L1 pentameric capsomers. Parental yeast cell: Yeast host cell to be manipulated for the expression of protein(s) to give rise to a recombinant yeast production strain. Inoculum intermediate: A quantity of recombinant baculovirus of uniform composition, derived from the working seed lot. The inoculum intermediate has a defined shelf?life. It is intended to be used to initiate the production of recombinant L1 proteins. Cell bank: A collection of ampoules containing aliquots of a suspension of cells from a single pool of cells of uniform composition, stored frozen under defined conditions (typically ?60 °C for yeast, and in liquid nitrogen for insect or mammalian cell lines). Master cell bank (MCB): A collection of containers containing aliquots of a suspension of cells from a single pool of c