Comparative neurovirulence of attenuated and non-attenuated strains of Venezuelan equine encephalitis virus in mice.

Abstract

Abstract. A candidate live-attenuated virus vaccine for protection against Venezuelan equine encephalitis (VEE) (designated V3526) was tested in mice to measure the magnitude, duration, and kinetics of virus replication in the blood and the central nervous system and its phenotypic stability after multiple passages in mice and cell culture. All results were compared to parallel experiments with parental virus and the existing VEE virus vaccine, TC-83. Maximum virus titers in the brains of V3526-inoculated mice were between 10-and 100-fold less than those observed in brains of mice inoculated intracranially (ic) with either the parental virus or TC-83. Neither V3526 nor TC-83 was lethal in BALB/c mice inoculated ic. However, mice inoculated with TC-83 developed acute symptoms lasting at least 14 days. In contrast, ic inoculation of TC-83 was uniformly lethal for C3H/HeN mice. V3526 was avirulent in both BALB/c and C3H/HeN mice after ic inoculation. The virulence characteristics of V3526 remained unchanged after five serial ic passages in mouse brains or after five cell culture passages. Finally, pathologic changes induced after ic inoculation of V3526 were consistently less severe and of shorter duration than those observed in TC-83-inoculated mice. Based on these results, V3526 is stable and appears to be significantly less neurovirulent in mice than TC-83.

Genetically engineered, live attenuated vaccines for Venezuelan equine encephalitis: testing in animal models

“…The phenotypic properties of the viruses generated from clones in this study and in past studies [17,19,21,[26][27][28][29][30] provide the formal evidence that the identified single mutations were responsible for the observed attenuation. From the list of mutations, vaccine candidates for VEEV were constructed to provide a higher level of attenuation and a mathematical improbability of reversion to wild-type phenotype after production and vaccination.…”

“…Based on our results in non-human primates and those from cohort studies in rodents [17,[28][29][30] and mosquitoes [32], V3526 was selected for development into a human-use vaccine. These other studies, like this study, showed V3526 to be more safe, immunogenic and efficacious than TC-83, and without any indication of reversion to virulent phenotype.…”

Antibody to the E3 Glycoprotein Protects Mice against Lethal Venezuelan Equine Encephalitis Virus Infection

“…The stability of the cleavage deletion mutation (24) and attenuated phenotype of the virus prompted the evaluation of V3526 as a vaccine for animals and humans (34,37,52,53). In the course of preclinical evaluation of V3526 as a live vaccine, a series of MAbs were generated to further characterize the immune response elicited by vaccination with V3526.…”

Genetically engineered, live, attenuated vaccines protect nonhuman primates against aerosol challenge with a virulent IE strain of Venezuelan equine encephalitis virus

“…Interestingly, the PE2 cleavage signal deletion is lethal to the virus and requires a second site mutation, a Ser for Phe at E1 codon 253 in V3526, for viability. V3526 has been shown to be safe [8] and to protect mice against subcutaneous or aerosol challenge with a virulent VEEV-IA/B [9]. Recently, Pratt et al [10] reported that out of several vaccine candidates examined, V3526 was best able to protect nonhuman primates against aerosol challenge with a virulent VEEV-IA/B.…”