Background: Human brain continues to develop during the first year of postnatal life. Since the developing brain is uniquely sensitive to damage following virus infection, administration of neurovirulent vaccines to infants can place the child's nervous system at increased risk for vaccine related injury. Mumps viruses, including certain vaccine strains (Urabe Am9, Leningrad 3, Sofia-6), are highly neurotropic and often neurovirulent. Since new mumps virus containing vaccines continue to be proposed, there is a need to develop a test to assess the vaccine's human neurovirulence potential. Such an effective test currently does not exist. Vaccine neurovirulence concerns have been raised regarding other viruses as well, including influenza virus, human parainfluenza virus III, poliovirus, dengue virus, Japanese encephalitis virus and human immunodeficiency virus. Thus, neurovirulence safety tests (NVST) are needed to identify a multitude of potentially neurovirulent vaccines that may cause CNS disease following vaccination. Progress: WON 3RD PLACE FOR OUTSTANDING RESEARCH PROJECT AT THE 2000 FDA SCIENCE FORUM NSVT Development: 1)Primate: Developed and tested a simplified, biologically relevant, standardized primate NVST. Monkeys were inoculated intrathalamically with various doses of wild type and vaccine strains representing a wide range of human neurovirulence. All virus inoculated monkeys developed inflammation within the ventricular system of the brain. The severity of the inflammation and damage induced by the attenuated strains were not statistically different from that induced by the wild type strains, regardless of dose administered. These studies support the conclusion that neurovirulence safety testing of mumps vaccines in primates may not be helpful in discriminating the neurovirulence potential in the human CNS. 2. Small animal: A newborn rat NVST was developed and tested with the same mumps virus strains used in the primate study. Unlike monkeys, inflammation was not observed in the rat brains, however, neuropathological abnormalities were present. The most prominent abnormality was hydrocephalus. All strains induced some degree of hydrocephalus in rat brain and the severity of hydrocephalus tracked with the known human clinical histories of the virus strains. Using hydrocephalus as a marker of neurovirulence, wild- type strains could be distinguished from vaccine strains and the relative neurovirulence among wild type strains and among vaccine strains could be distinguished as well. These experiments in other laboratories outside of CBER are underway to initiate early stages of validation of this model system.
