Telemetric analysis to detect febrile responses in mice following vaccination with a live-attenuated virus vaccine

Abstract

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...

Safety and protective efficacy of INA-inactivated Venezuelan equine encephalitis virus: Implication in vaccine development

“…Live attenuated V3526 has shown excellent protective efficacy in animal models [17,18] and robust immune response in phase I clinical trial [25]. However, its development as a live attenuated vaccine was halted due to a flu-like syndrome and fever in the recipients [24,25]. Therefore, it will be desirable to inactivate V3526 in a way that conserves its immunogenicity to generate a safer vaccine candidate without any residual virulence.…”

“…V3526 has excellent immunogenic activity, but also causes febrile illness and low level neurotropism in non human primates [17,18,[21][22][23]. In phase I clinical trial, V3526 induced a robust immune response; however, a high frequency of fever and a flu-like syndrome were reported which led to the cessation of the development of V3526 as a live attenuated vaccine [24,25].The residual virulence associated with the vaccine candidates has again focused the attention on the inactivated vaccine preparation. We have previously demonstrated that 1,5 iodonaphthyl azide (INA) completely inactivated the virulent strain of VEEV, V3000 in vitro [26].…”

A multisystem approach for development and evaluation of inactivated vaccines for Venezuelan equine encephalitis virus (VEEV)

“…However, evaluation of the V3526 vaccine in Phase 1 clinical studies (Holley et al, 2008) resulted in adverse events in a number of vaccine recipients that stopped further development of the vaccine as a live attenuated vaccine product. Because live attenuated vaccines for VEEV have shown high frequency of adverse reactions (Kinney 1972; Edelman et al, 1979; Martin et al, 2009), DVC sought to produce a non-infectious V3526 vaccine, the intent of which was to significantly reduce the adverse reaction profile of V3526, while retaining its potential as a protective immunogen against subtype I VEEV. Of particular interest was to proceed with the development of an inactivated V3526 that ultimately could be used as a primary vaccine to protect personnel at risk to accidental or intentional VEEV exposure.…”

Combined Alphavirus Replicon Particle Vaccine Induces Durable and Cross-Protective Immune Responses against Equine Encephalitis Viruses

“…DNA vaccines, administered by several means, have also shown efficacy in rodents and nonhuman primates (12)(13)(14). Live attenuated vaccines developed using modern molecular techniques provided good immunogenicity, safety, and protection in rodents and nonhuman primates although in phase I clinical trials mild fever responses were seen at very low dosages (15)(16)(17). Other approaches using live attenuated vaccines are being evaluated and have shown promise in mice and nonhuman primates (18)(19)(20).…”