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ABSTRACTA recombinant vaccine (rF1V) is being developed for protection against pneumonic plague. This study was performed to address essential data elements to establish a well-characterized Swiss Webster mouse model for licensing the rF1V vaccine using the FDA's Animal Rule. These elements include the documentation of challenge material characteristics, aerosol exposure parameters, details of the onset and severity of clinical signs, pathophysiological response to disease, and relevance to human disease. Prior to animal exposures, an evaluation of the aerosol system was performed to determine and understand the variability of the aerosol exposure system. Standardized procedures for the preparation ofYersinia pestischallenge material also were developed. The 50% lethal dose (LD50) was estimated to be 1,966 CFU using Probit analysis. Following the LD50determination, pathology was evaluated by exposing mice to a target LD99(42,890 CFU). Mice were euthanized at 12, 24, 36, 48, 60, and 72 h postexposure. At each time point, samples were collected for clinical pathology, detection of bacteria in blood and tissues, and pathology evaluations. A general increase in incidence and severity of microscopic findings was observed in the lung, lymph nodes, spleen, and liver from 36 to 72 h postchallenge. Similarly, the incidence and severity of pneumonia increased throughout the study; however, some mice died in the absence of pneumonia, suggesting that disease progression does not require the development of pneumonia. Disease pathology in the Swiss Webster mouse is similar to that observed in humans, demonstrating the utility of this pneumonic plague model that can be used by researchers investigating plague countermeasures.

Nonhuman primates (NHP) are considered to be the most appropriate model for predicting how humans will respond to many infectious diseases. Due to ethical and monetary concerns associated with the use of NHP, rodent models that are as predictive of responses likely to be seen in human vaccine recipients are warranted. Using implanted telemetry devices, body temperature and activity were monitored in inbred and outbred mouse strains following administration of the live-attenuated vaccine for Venezuelan equine encephalitis virus (VEEV), V3526. Following analysis of individual mouse data, only outbred mouse strains showed changes in diurnal temperature and activity profiles following vaccination. Similar changes were observed following VEEV challenge of vaccinated outbred mice. From these studies, we conclude, outbred mouse strains implanted with telemeters are a sensitive model for predicting responses in humans following vaccination. Keywordsvaccine; mouse; telemetry IntroductionThe use of live-attenuated vaccines for prevention of disease in humans and animals has a long, successful history. The ability of the live-attenuated virus vaccines to replicate to a limited extent in the recipient is thought to elicit an immune response reflective of the full repertoire of responses seen in an animal infected by the wild type virus. Live virus vaccines like TC-83, Drive, Frederick, MD 21702, 301-607-5082 (phone), 301-607-5098 (fax), smartin40@csc.com. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptVaccine. Author manuscript; available in PMC 2010 November 16. Published in final edited form as:Vaccine. With the ability to manipulate DNA sequences with high precision, it has been predicted that reversion to virulence of vaccine viruses could be prevented by using more complex arrays of attenuating mutations using site directed mutagenesis. A live-attenuated VEEV vaccine candidate, V3526, was developed by Davis et al. [2]. V3526 contains a deletion of the PE2 cleavage signal (furin cleavage site) combined with a second-site suppressor mutation in the E1 glycoprotein. These mutations attenuate the virus in its ability to cause overt clinical disease in animals while making reversion practically impossible; however, the virus maintains the ability to replicate and elicit a protective immune response in animals.Extensive nonclinical testing repeatedly demonstrated that the V3526 vaccine was superior in safety and efficacy when assayed in a variety of rodents [3][4][5][6][7], nonhuman primates (NHP) [8][9][10] and horses [11] compared to fu...