In vitro-synthesized infectious RNA as an attenuated live vaccine in a flavivirus model

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Abstract
Live virus vaccines have in many cases proven to be an extremely effective tool for the prevention of viral diseases1,2. However, the production of conventional live vaccines in eukaryotic cell cultures has many disadvantages, including the potential for contamination with adventitious agents3 and genetic alterations during propagation, making it necessary to do extensive testing before distribution4,5. Based on results obtained with a flavivirus6 (tick-borne encephalitis virus) in an experimental animal system, we propose a novel live attenuated virus vaccination strategy consisting of the application of in vitro-synthesized infectious RNA instead of the live virus itself. When administered using the GeneGun, less than 1 ng of RNA was required to initiate replication of virus that was attenuated by a specifically engineered deletion7 and this induced a protective immunity in laboratory mice. Because this approach uses RNA, it does not have the potential drawbacks of DNA vaccines8,9,10 and thus combines the advantages of conventional live virus vaccines1,2 (for example, mimicking natural infection and inducing long-lasting immunity) with those of nucleic acid-based vaccines2,8,11,12 (for example, ease of production without a requirement for eukaryotic cell culture, stability and purity).