Since the developing nervous system is uniquely sensitive to damage following virus infection, postnatal CNS development during the first several years of life provides for continued susceptibility of the infant CNS to damage by viral infection after birth. Administering insufficiently attenuated vaccines to infants may place the child's CNS at increased risk for injury. Thus, it is imperative to develop methods of pre-clinical neurovirulence testing with which to predict which vaccines might have significant neurovirulence potential for human CNS. Thus, it is important to develop valid molecular biological, in vitro and in vivo models to evaluate the pathogenesis of the neurotoxic effects of vaccine viruses. Development of these models will lead to improved safety of childhood vaccines, cost saving and improved predictability of neurovirulence testing, and information obtained in these studies will be useful in testing potentially neurovirulent vaccines (e.g., measles, mumps, HIV, parainfluenza, Japanese encephalitis). Progress: 2001 CBER Outstanding Regulatory Research Project 1. Molecular Markers of Neurotoxicity: We have identified vaccine virus-related perturbations in CNS gene expression by standard semiquantitative RT-PCR and by differential display techniques, including endogenous immune mediators of the CNS. We have recovered un-characterized gene products from new genes that are altered by virus infection of the brain. We have initiated RPA to compare changes in endogenous immune mediators in the CNS in animals infected with low and high neurovirulence strains of mumps virus.2. Animal Models of CNS Diseases Following Childhood Virus Infection: Autism. Viruses are known etiologic agents of autism (e.g., rubella). Therefore, concerns are raised regarding a possible relationship between childhood vaccines and autism. Because no valid animal models existed to study the pathogenesis of the neuroanatomical and behavioral signs of autism, we developed a rat model of autism using neonatal infection with neurotropic viruses. We have characterized autistic-like changes in neuroanatomy, neurochemistry, neurological disease and behavior in these rats. In addition, we have identified regional and developmental changes in neurotransmitters, including serotonin and norepinephrine. A developmental study of damage to developing brain (e.g., cerebellum)in virus infected rats was performed demonstrating anatomical, behavioral and neurological consequences.
