Abstract
The live-attenuated TC-83 strain is the only licensed veterinary vaccine available to protect equids against Venezuelan equine encephalitis virus (VEEV) and to protect humans indirectly by preventing equine amplification. However, TC-83 is reactogenic due to its reliance on only two attenuating point mutations and has infected mosquitoes following equine vaccination. To increase its stability and safety, a recombinant TC-83 was previously engineered by placing the expression of the viral structural proteins under the control of the Internal Ribosome Entry Site (IRES) of encephalomyocarditis virus (EMCV), which drives translation inefficiently in insect cells. However, this vaccine candidate was poorly immunogenic. Here we describe a second generation of the recombinant TC-83 in which the subgenomic promoter is maintained and only the capsid protein gene is translated from the IRES. This VEEV/IRES/C vaccine candidate did not infect mosquitoes, was stable in its attenuation phenotype after serial murine passages, and was more attenuated in newborn mice but still as protective as TC-83 against VEEV challenge. Thus, by using the IRES to modulate TC-83 capsid protein expression, we generated a vaccine candidate that combines efficient immunogenicity and efficacy with lower virulence and a reduced potential for spread in nature.
Highlights
Arboviruses (Arthropod-Borne viruses) comprise a group of viruses transmitted among vertebrates by hematophagous arthropods
By using an attenuation approach that allows the modulation of the virus capsid protein expression, we generated a new version of TC-83 that is more attenuated but still induces a protective immune response in mice
To improve the immunogenicity of Venezuelan equine encephalitis virus (VEEV)/mutSG/Internal Ribosome Entry Site (IRES)/1, we developed a new IRES-based variant of TC-83 in which only the capsid protein is placed under IRES translational control, leaving an intact subgenomic promoter driving the expression of the major antigens, the glycoproteins E1 and E2
Summary
Arboviruses (Arthropod-Borne viruses) comprise a group of viruses transmitted among vertebrates by hematophagous arthropods. They include members of a wide range of viral families, such as Rhabdoviridae, Bunyaviridae, Flaviviridae and Togaviridae, with a worldwide distribution. Mostly restricted to sylvatic, enzootic cycles between reservoir vertebrate hosts (mainly rodents and birds) and arthropod vectors, environmental alterations and continuous changes in human and animal demographics have created factors favorable to arboviral emergence from limited cycles, threatening domestic animals and humans [1]. Arboviral epizootics in animals and/or epidemics in human populations are regularly reported. They have significant socioeconomic impacts, and contribute to the maintenance of continuous public-health threats around the world
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