[Alternative for the neurovirulence test (NVT) in primates for safety-testing of poliomyelitis attenuated life virus vaccine (Sabin): NVT in transgenic mice] [Article in German]

Abstract

The neurovirulence test established by Albert B. Sabin is required according to different pharmaceutical monographies (WHO Technical Report Series, US-Pharmacopoeia, European Pharmacopoeia, etc) and is used for evaluation of sufficient and consistent attenuation of life monovalent poliomyelitis virus bulk lots (Sabin) which are used for the manufacture of oral poliomyelitis vaccines (OPV). Since this animal experiment is based on the use of relatively high numbers of primates (at least 22 animals per test vaccine for the virus serotypes 1 and 2 and at least 36 animals for serotype 3) it is searched for alternatives since several years. Besides a molecular approach (MAPREC) a test based on the use of transgenic mice seems to be a promising alternative for the primate model.
The isolation and introduction of the human poliomyelitis virus receptor gene into the mouse genome made small laboratory animals susceptible for poliomyelitis for the first time. After infection with attenuated virus, the transgenic animals develop the same clinical symptomatic and the respective lesions in the central nerve system (CNS) as observed in monkeys. In a WHO collaborative study it could be demonstrated that the transgenic mouse neurovirulence test for OPV serotype 3 is at least as sensitive as the monkey neurovirulence test. Furthermore, it was shown that there is a strong correlation between the strength of the clinical defects and the spread of the specific histopathological lesions in the CNS. Therefore, the observation and description of the clinical symptoms seems to be sufficient for the evaluation of the experiment. Thus the time-consuming histopathological investigation can be avoided, since it does not provide additional information to the results of the clinical investigations. In a first evaluation, similar results were shown for serotype 2, however there are not yet sufficient data on serotype 1.
In 1997 an extended validation study under the participation of 5 laboratories from 3 continents has been initiated by the WHO with the objective to test a sufficient number of OPV serotype 3 charges from different manufacturers and to gain further informations on the consistency and validity of the mouse neurovirulence test. Results obtained from recent experiments suggest that the neurovirulence test of serotype 3 in transgenic mice may be included into the monographies as an alternative method for the monkey NVT.