A vaccine candidate for eastern equine encephalitis virus based on IRES-mediated attenuation

Abstract

To develop an effective vaccine against eastern equine encephalitis (EEE), we engineered a recombinant EEE virus (EEEV) that was attenuated and capable of replicating only in vertebrate cells, an important safety feature for live vaccines against mosquito-borne viruses. The subgenomic promoter was inactivated with 13 synonymous mutations and expression of the EEEV structural proteins was placed under the control of an internal ribosomal entry site (IRES) derived from encephalomyocarditis virus (EMCV). We tested this vaccine candidate for virulence, viremia and efficacy in the murine model. A single subcutaneous immunization with 104 infectious units protected 100% of mice against intraperitoneal challenge with a highly virulent North American EEEV strain. None of the mice developed any signs of disease or viremia after immunization or following challenge. Our findings suggest that the IRES-based attenuation approach can be used to develop a safe and effective vaccine against EEE and other alphaviral diseases.

IRES-based Venezuelan equine encephalitis vaccine candidate elicits protective immunity in mice

“…7A and 7B). These results are consistent with blind passage of other IRES-containing alphavirus vaccines (Pandya et al, 2012; Plante et al, 2011; Volkova et al, 2008), reflecting the inability of IRES to drive translation of viral structural proteins in insect cells.…”

“…The IRES-based attenuation technology described here has also been successfully applied to other alphaviruses to create safe and efficacious vaccines (Pandya et al, 2012; Plante et al, 2011; Volkova et al, 2008). The technology is easily transferable between different alphaviruses because the mechanism of attenuation is a property of changes the alphavirus gene expression, and not of a particular virus strain.…”

Mapping eastern equine encephalitis virus risk for white-tailed deer in Michigan

“…A vaccine is commercially available to prevent EEE in horses (Pandyaet al, 2012). As the equivalent is unavailable for humans, reducing exposure to mosquitoes is the most reliable way to prevent human EEEV infections.…”

Can understanding the virulence mechanisms of RNA viruses lead us to a vaccine against eastern equine encephalitis virus and other alphaviruses?

“…Two EEEV live attenuated vaccines (LAV), a chimeric Sindbis (SINV) virus encoding the structural proteins of EEEV and a similar vaccine encoding an internal ribosome entry site (IRES) in the subgenomic promoter, have shown protective efficacy in animal models but as yet are unlicensed [6,7]. A LAV against VEEV is similarly available as an IND, but is not likely to be approved due to poor immunogenicity and adverse reactions in 20% of vaccines [8].…”

“…Interestingly, removal of the miR-142-3p binding sites from EEEV and the EEEV IRES LAV were unable to establish viral replication in mosquitoes thus eliminating this potential transmission from vaccinees to mosquitoes [6,23]. …”