Theakston R D G, Warrell D A, Griffiths E
Alistair Reid Venom Research Unit, WHO Collaborating Centre for the Control of Antivenoms, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
Toxicon. 2003 Apr;41(5):541-57. doi: 10.1016/s0041-0101(02)00393-8.
A workshop to discuss progress in the standardization and control of antivenoms, organized by the Quality Assurance and Safety of Biologicals Unit of WHO, was held at the National Institute for Biological Standards and Control, Potters Bar, England, 7-9 February 2001. This was the first meeting convened by the WHO on this subject since 1979 and it brought together experts from academic institutions, antivenom manufacturers and national regulatory authorities from 21 countries. The meeting reviewed antivenom production and quality control measures and special consideration was given to the current crisis in antivenom production and supply in sub-Saharan Africa. The importance of snake bite and scorpion stings as public health issues was re-emphasised. The majority of commercial antivenoms are raised against snake or scorpion venoms.The review of antivenom production methods indicated that the vast majority of commercial antivenoms were still produced by traditional technology in horses, although some antisera were raised in sheep and rabbits. Methods used for plasma fractionation included salt and heat coagulation, caprylic acid stabilization or ion exchange chromatography, as well as immunoglobulin digestion with pepsin to produce F(ab')(2) or with papain to produce Fab fragments. The meeting agreed that there was much room for improving the production, quality control and safety profile of these products and that lessons could be learnt from the experience gained with the preparation of human immunoglobulins. Many basic assumptions, such as the need to remove Fc fragments by enzyme digestion and to freeze-dry antivenom preparations, required critical re-examination and more attention should be given to clinical trials as a means of assessing efficacy and safety and of defining the average initial dose. The Workshop also discussed concerns about the risks of transmitting infectious agents to humans via animal blood products, especially those posed by viruses or prions and it was agreed that this aspect needed attention. However, there was no documented or even suspected example of this ever having occurred in the case of antivenom treatment. Current WHO Requirements for the production and control of antivenoms and for immune sera of animal origin date from the late 1960s. The Workshop recommended that these be updated to take account of the progress that had taken place in the production and quality control of biologicals in recent years. In addition, the Workshop discussed the need for better standardization of both the venoms and antivenoms, but concluded that international standards and reference materials were not appropriate in the antivenom field due to the considerable variation in venom characteristics from the same species from region to region. Instead, it was recommended that national or regional standards be prepared and used.
2001年2月7日至9日，由世界卫生组织生物制品质量保证与安全部门组织的一次关于抗蛇毒血清标准化和控制进展的研讨会在英国波特斯巴的国家生物标准与控制研究所召开。这是自1979年以来世界卫生组织首次就该主题召开的会议，来自21个国家的学术机构、抗蛇毒血清制造商和国家监管当局的专家齐聚一堂。会议回顾了抗蛇毒血清的生产和质量控制措施，并特别关注了撒哈拉以南非洲地区目前抗蛇毒血清生产和供应的危机。再次强调了蛇咬伤和蝎子蜇伤作为公共卫生问题的重要性。大多数商业抗蛇毒血清是针对蛇毒或蝎子毒液制备的。对抗蛇毒血清生产方法的审查表明，绝大多数商业抗蛇毒血清仍采用传统的马生产技术，不过也有一些抗血清是在绵羊和兔子体内制备的。用于血浆分离的方法包括盐析和热凝固、辛酸稳定化或离子交换色谱法，以及用胃蛋白酶消化免疫球蛋白以产生F(ab')(2)片段或用木瓜蛋白酶消化以产生Fab片段。会议一致认为，这些产品在生产、质量控制和安全性方面有很大的改进空间，可以从人免疫球蛋白制备的经验中吸取教训。许多基本假设，如通过酶消化去除Fc片段以及对抗蛇毒血清制剂进行冷冻干燥的必要性，都需要进行严格的重新审视，并且应更加重视临床试验，将其作为评估疗效和安全性以及确定平均初始剂量的手段。研讨会还讨论了通过动物血液制品将传染因子传播给人类的风险问题，特别是病毒或朊病毒带来的风险，与会者一致认为这方面需要关注。然而，在抗蛇毒血清治疗的情况下，没有记录在案甚至疑似发生这种情况的例子。世界卫生组织目前关于抗蛇毒血清和动物源性免疫血清生产与控制的要求可追溯到20世纪60年代末。研讨会建议对这些要求进行更新，以考虑到近年来生物制品生产和质量控制方面取得的进展。此外，研讨会讨论了对毒液和抗蛇毒血清进行更好标准化的必要性，但得出结论认为，由于同一物种毒液特性在不同地区存在很大差异，国际标准和参考物质不适用于抗蛇毒血清领域。相反，建议制备和使用国家或区域标准。
