Evaluation of a rat model for mumps virus neurovirulence testing

Powell, Caroline Louise (2005). Evaluation of a rat model for mumps virus neurovirulence testing. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.000101df

Abstract

Safety is an important aspect in the licensing of any vaccine. Prior to placement on the market, any risks and side-effects attributable to the vaccine must be as well documented as possible. One of the main priorities in the safety of a vaccine containing live microorganisms is the level of neurovirulent activity of the vaccine components. Every batch of the oral polio vaccine is tested for neurovirulent activity by inoculation into the central nervous system of macaques. Seed stocks for the live mumps virus vaccines are tested likewise. However, relying on the macaque model is an inadequate marker of neurovirulence of mumps vaccines as the animal system does not fully mimic the human pathological processes, thereby making results difficult to interpret. Further inadequacies of this model include the small experimental group used, the cost of purchasing and maintaining macaques, as well as the ethics involved in using non-human primates. As a result, many alternative animal models have been investigated, from using different monkey species to using smaller animals. Of the animal models investigated, the marmoset monkey model shows prospects; however, the use of large animals is not desirable. Of the smaller animal models, the rat model, currently being developed by the Food and Drug Administration in USA and NIBSC, holds many advantages. Rats are cheaper, easier to handle and can be used in larger experimental groups, and the CNS of neonatal rats shows recordable and reproducible susceptibility to the mumps virus. The aim of this project was to evaluate the rat model using various vaccine, vaccine-derived and wild-type viruses. These were used in order to establish if the model can distinguish between virulent wild-type and attenuated vaccine strains and mixed and pure preparations of vaccines of a related strain shown to have caused meningitis in children. The results conclude that the neonatal rat model is on a par with the macaque model in distinguishing between wild-type and vaccine strains; however, neither model can distinguish between a vaccine and its derived variants causing adverse events in the recipients. However, a smaller animal model is more desirable and the method of diagnosing neurovirulent activity in rats, by measuring the enlargement of the lateral ventricle, is much simpler than histological analysis of lesions in the macaque brain. The results of the FDA/NIBSC collaboration showed varying degrees of difference, highlighting a need to standardize the test for future applications.