Mouse neurotoxicity test for vaccinia-based smallpox vaccines

• Published in: Vaccine 2004-03, Vol.22 (11), p.1486-1493
• Main Authors: Li, Zhongqi, Rubin, Steven A, Taffs, Rolf E, Merchlinsky, Michael, Ye, Zhiping, Carbone, Kathryn M
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Antibodies, Viral - analysis; Antibodies, Viral - biosynthesis; Antigens, Viral - immunology; Applied microbiology; Biological & chemical weapons; Biological and medical sciences; Bioterrorism; Brain; Brain - pathology; Brain - virology; Brain Chemistry - physiology; Confidence intervals; Encephalitis; Fluorescent Antibody Technique, Indirect; Fundamental and applied biological sciences. Psychology; Glial Fibrillary Acidic Protein - metabolism; Immunohistochemistry; Infections; Mice; Microbiology; Miscellaneous; Mortality; Myelin Sheath - pathology; Nervous System Diseases - etiology; Nervous System Diseases - pathology; Nervous System Diseases - virology; Neurons - pathology; Neurotoxicity; Smallpox; Smallpox vaccine; Smallpox Vaccine - adverse effects; Smallpox Vaccine - immunology; Studies; Survival Analysis; Vaccines; Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects); Vaccinia - complications; Vaccinia - pathology; Vaccinia - virology; Vaccinia virus; Vaccinia virus - immunology; Variola virus; Viral Plaque Assay; Virology; Virus Replication
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2003.10.022

The only US FDA licensed smallpox vaccine, Dryvax, was associated with rare but serious neurological adverse events. After smallpox was eradicated in the United States, mass vaccination ceased in 1971. As counter-bioterrorism/biowarfare measures, new smallpox vaccines are now being investigated. However, there are no established pre-clinical neurotoxicity assays with which to evaluate these new vaccines prior to licensure. Here we report the development and initial characterization of a small animal neurotoxicity assay for vaccinia-based smallpox vaccines using Dryvax virus as a reference vaccine strain and the neuroadapted Western Reserve (WR) strain as a neurotoxic positive control. In neonatally inoculated mice, the WR strain produced significantly greater and more rapid onset of mortality than the Dryvax vaccine reference. Expression of virus antigen in neural cells and infectious virus replication in the brain was also significantly different between the two strains. In addition, the appearance of high titer virus antibody correlated with the clearance of virus from brain. With further validation, this assay incorporating a licensed vaccine reference standard and positive control strain may provide important pre-clinical neurotoxicity data on new vaccinia-based smallpox vaccine strains.