http://www.fda.gov/cber/research/0200706.htm

Project Title

Vaccine Safety: Pathogenesis of Virus Vaccine Neurotoxicity

Principal Investigator

K. M. Carbone

Laboratory

Laboratory of Pediatric and Respiratory Viral Diseases; Division of Viral Products; Office of Vaccines Research and Review

Project Summary

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.

Publications

• J Virol 1998 Oct;72(10):8037-42
  Comparison of the neurovirulence of a vaccine and a wild-type mumps virus strain in the developing rat brain.
  Rubin SA, Pletnikov M, Carbone KM
  Pub Med

   

• J Vet Diagn Invest 1998 Oct;10(4):338-43
  Clinical, serologic, and histopathologic characterization of experimental Borna disease in ponies.
  Katz JB, Alstad D, Jenny AL, Carbone KM, Rubin SA, Waltrip RW 2nd
  Pub Med

   

• Behav Brain Res 1999 Apr;100(1-2):43-50
  Developmental brain injury associated with abnormal play behavior in neonatally Borna disease virus-infected Lewis rats: a model of autism.
  Pletnikov MV, Rubin SA, Vasudevan K, Moran TH, Carbone KM
  Pub Med

   

• Brain Res Bull 1999 Jan 1;48(1):23-30
  Borna disease virus-induced hippocampal dentate gyrus damage is associated with spatial learning and memory deficits.
  Rubin SA, Sylves P, Vogel M, Pletnikov M, Moran TH, Schwartz GJ, Carbone KM
  Pub Med

   

• J Infect Dis 1999 Aug;180(2):521-525
  The Mumps Virus Neurovirulence Safety Test in Rhesus Monkeys:A Comparison of Mumps Virus Strains.
  Rubin SA, Snoy PJ, Wright KE, Brown EG, Reeve P, Beeler JA, Carbone KM
  Pub Med

   

• Physiol Behav 1999 Jul;66(5):823-31
  Persistent neonatal Borna disease virus (BDV) infection of the brain causes chronic emotional abnormalities in adult rats.
  Pletnikov MV, Rubin SA, Schwartz GJ, Moran TH, Sobotka TJ, Carbone KM
  Pub Med

   

• J Virol 2000 Jun 1;74(11):5382-5384
  Evaluation of a Neonatal Rat Model for Prediction of Mumps Virus Neurovirulence in Humans.
  Rubin SA, Pletnikov M, Taffs R, Snoy PJ, Kobasa D, Brown EG, Wright KE, Carbone KM
  Pub Med

   

• Dev Brain Res 2000 Feb 7;119(2):179-85
  Effects of neonatal rat Borna disease virus (BDV) infection on the postnatal development of the brain monoaminergic systems.
  Pletnikov MV, Rubin SA, Schwartz GJ, Carbone KM, Moran TH
  Pub Med

   

• Ann N Y Acad Sci 2001 Jun;939:318-9
  Rat model of autism spectrum disorders. Genetic background effects on Borna disease virus-induced developmental brain damage.
  Pletnikov MV, Jones ML, Rubin SA, Moran TH, Carbone KM
  Pub Med

   

• Clin Microbiol Rev 2001 Jul;14(3):513-27
  Borna disease virus and human disease.
  Carbone KM
  Pub Med

   

• Mol Psychiatr 2000 Nov;5(6):577
  Borna again, starting from the beginning.
  Carbone KM, Pletnikov M
  Pub Med

   

• Ann Clin Biochem 2001 Jul;38(Pt 4):348-55
  Synthetic peptide-based electrochemiluminescence immunoassay for anti-Borna disease virus p40 and p24 antibodies in rat and horse serum.
  Yamaguchi K, Sawada T, Yamane S, Haga S, Ikeda K, Igata-Yi R, Yoshiki K, Matsuoka M, Okabe H, Horii Y, Nawa Y, Waltrip RW 2nd, Carbone KM
  Pub Med

   

• Brain Res Dev Brain Res 2001 Jan 31;126(1):1-12
  Neonatal Borna disease virus infection (BDV)-induced damage to the cerebellum is associated with sensorimotor deficits in developing Lewis rats.
  Pletnikov MV, Rubin SA, Carbone KM, Moran TH, Schwartz GJ
  Pub Med

   

• Curr Opin Microbiol 2001 Aug;4(4):467-75
  Borna disease: virus-induced neurobehavioral disease pathogenesis.
  Carbone KM, Rubin SA, Nishino Y, Pletnikov MV
  Pub Med

Last Updated: 4/1/2002