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Abstract
We describe a novel vaccine platform that can generate protective immunity to chikungunya virus (CHIKV) in C57BL/6J mice after a single immunization by employing an infectious RNA (iRNA), which upon introduction into a host cell launches an infectious attenuated virus. We and others have previously reported that an engineered deletion of 183 nucleotides in the nsP3 gene attenuates chikungunya virus (CHIKV) and reduces in vivo viral replication and viremia after challenge in mice, macaques and man. Here, we demonstrated that in vitro transfection of iRNA carrying the nsP3 deletion generated infectious viruses, and after intramuscular injection, the iRNA induced robust antibody responses in mice. The iRNA was superior at eliciting binding and neutralizing antibody responses as compared to a DNA vaccine encoding the same RNA (iDNA) or a non-propagating RNA replicon (RREP) lacking the capsid encoding gene. Subsequent challenge with a high dose of CHIKV demonstrated that the antibody responses induced by this vaccine candidate protected animals from viremia. The iRNA approach constitutes a novel vaccine platform with the potential to impact the spread of CHIKV. Moreover, we believe that this approach is likely applicable also to other positive-strand viruses.
Highlights
Clinical grade DNA vaccines are produced by large scale bacterial fermentation
The difference between iDNA and infectious RNA (iRNA) is that transcription of iDNA requires entry into the cell nucleus, a process that is believed only to occur in dividing c ells[31]
With increased understanding of the pathobiology of viruses, the implementation of reverse genetics can be used to engineer attenuations for the efficient development of safe and potent attenuated v accines[6,39,40]
Summary
Clinical grade DNA vaccines are produced by large scale bacterial fermentation. We and others have previously described that non-propagating self-replicating alphavirus replicon RNA vaccines provide protection against a number of infectious diseases in small animal models[25,26,27,28,29,30]. The replicase replicates the incoming iRNA and subsequently transcribes mRNA encoding the viral capsid and glycoproteins from a subgenomic viral promoter. This results in the assembly of new virions which are released by budding from the plasma membrane. We believe that the iRNA platform described here represents a promising vaccine candidate against CHIKV worth further investigation for clinical development
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