Monath T P
Research & Medical Affairs, OraVax Inc., Cambridge MA, USA.
Dev Biol Stand. 1996;87:219-25.
Yellow fever, an acute mosquito-borne viral haemorrhagic fever, is preventable by use of the live, attenuated 17D vaccine. The vaccine is used principally in tropical climates and is subject to potentially adverse conditions. Lyophilized vaccine without stabilizers deteriorates rapidly when exposed to temperatures above -20 degrees C. In 1987, the WHO recommended that each lot of vaccine meet the following stability test: maintenance of potency (> 1,000 mouse i.c.LD50/human dose) with mean loss of titre < 1.0 log10 after being held at 37 degrees C for 14 days. In 1987, only 5 out of 12 yellow fever vaccines produced worldwide met the stability standards. To improve stability of the vaccine, a number of additives have been systematically investigated. A successful formulation, now used by a number of manufacturers, employs sugars, amino acids, and divalent cations [lactose (4%), sorbitol (2%), histidine (0.01 M), alanine (0.01 M), in phosphate buffered saline with Ca2+ and Mg2+]. As opposed to vaccine produced without stabilizers, which loses 1.5-2.5 log10/dose, stabilized vaccines lose only 0.3-0.5 log10 after being held at 37 degrees C for 14 days. The vaccine is stable after storage for > or = two years at 4 degrees C and 22 degrees C, and has a stability profile as good or better than many other live and inactivated vaccines currently used in the EPI, including measles, pertussis, oral and inactivated poliomyelitis vaccines. WHO is taking steps to enssure that all 11 current YF vaccine manufacturers produce vaccines that meet accepted stability standards. The principal rationale for increasing 17D vaccine stability beyond that achieved with the present stabilizers would be the improvement in stability of other EPI vaccines, to the point where yellow fever vaccine was the most sensitive vaccine among those deployed. The acceptable characteristics of current stabilized 17D vaccines and the high cost of changing and validating new vaccine formulations precludes a major investment at this time. Despite its stability when freeze dried, yellow fever 17D vaccine is quite unstable after reconstitution and must be discarded after one hour. Improvement in vaccine stability after reconstitution would thus reduce cost, stretch supplies of vaccine, and ensure against vaccine failures due to use of degraded vaccine. This is an area for future research.
黄热病是一种由蚊子传播的急性病毒性出血热，使用减毒活17D疫苗可预防。该疫苗主要用于热带气候地区，且容易受到潜在不利条件的影响。不含稳定剂的冻干疫苗在暴露于高于-20摄氏度的温度时会迅速变质。1987年，世界卫生组织建议每批疫苗应符合以下稳定性测试：在37摄氏度下保存14天后，效力维持（>1000小鼠脑内半数致死量/人用剂量），且滴度平均损失<1.0 log10。1987年，全球生产的12种黄热病疫苗中只有5种符合稳定性标准。为提高疫苗的稳定性，已对多种添加剂进行了系统研究。一种成功的配方目前被多家制造商采用，该配方使用了糖、氨基酸和二价阳离子[乳糖（4%）、山梨醇（2%）、组氨酸（0.01M）、丙氨酸（0.01M），在含有Ca2+和Mg2+的磷酸盐缓冲盐水中]。与未添加稳定剂的疫苗相比，未添加稳定剂的疫苗每剂量损失1.5 - 2.5 log10，而添加稳定剂的疫苗在37摄氏度下保存14天后仅损失0.3 - 0.5 log10。该疫苗在4摄氏度和22摄氏度下储存≥两年后仍稳定，其稳定性与扩大免疫规划（EPI）目前使用的许多其他活疫苗和灭活疫苗相当或更好，包括麻疹、百日咳、口服和灭活脊髓灰质炎疫苗。世界卫生组织正在采取措施确保目前的11家黄热病疫苗生产商生产符合公认稳定性标准的疫苗。提高17D疫苗稳定性至超过目前稳定剂所达到的水平的主要理由是改善其他EPI疫苗的稳定性，使黄热病疫苗成为所使用疫苗中最敏感的疫苗。目前添加稳定剂的17D疫苗的可接受特性以及更换和验证新疫苗配方的高成本使得此时无法进行重大投资。尽管黄热病17D疫苗冻干后很稳定，但复溶后非常不稳定，必须在一小时后丢弃。因此，提高复溶后疫苗的稳定性将降低成本、延长疫苗供应，并确保不会因使用降解疫苗而导致疫苗失效。这是未来研究的一个领域。
