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Toward Viral Vaccine Development: A Modified Venezuelan Equine Encephalitis Replicon as Strategy for Optimizing Immunogenicity

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Technical Report

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Uniformed Services University Of The Health Sciences Bethesda United States

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Alphaviral vectors have been used as vaccines for immunization against several viral infections. However, these vectors typically induce rapid cytopathic effects in mammalian cells. The cytopathicity of these vectors allow for only transient expression of transgenes. In viral models where long-term expression may be needed to induce adequately differentiated immune responses, the current wild-type alphaviral vectors may not be sufficiently immunogenic. This thesis describes development of attenuated, prolonged-expression, Venezuelan equine encephalitis virus VEE vectors by modifying the non-structural protein-2 gene NsP2 through the introduction of single or double point mutations. We studied the potential of wild-type and modified VEE replicon particles VRPs for optimizing and enhancing the immunogenicity of HIV-1 envelope glycoprotein and to the fusion F and attachment G glycoproteins of two zoonotic pathogens, Hendra and Nipah viruses, in a murine and rabbit model. We demonstrate in this study that modified VRPs are efficient in optimizing neutralizing antibody responses. Three-fold lower doses and only two vaccinations of modified VRPs were sufficient to induce maximal HIV-1 neutralizing antibody responses in mice compared to three vaccinations of wild-type VRPs. We also report here for the first time that, high-level cross-reactive neutralizing antibodies against henipaviruses were achieved using VRPs. Overall, these data suggest that the use of modified alphavirus-based vaccine platforms should be given consideration for the development of viable antiviral vaccines.

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