Rationalizing the development of live attenuated virus vaccines - PubMed (original) (raw)

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Rationalizing the development of live attenuated virus vaccines

Adam S Lauring et al. Nat Biotechnol. 2010 Jun.

Abstract

The design of vaccines against viral disease has evolved considerably over the past 50 years. Live attenuated viruses (LAVs)-those created by passaging a virus in cultured cells-have proven to be an effective means for preventing many viral diseases, including smallpox, polio, measles, mumps and yellow fever. Even so, empirical attenuation is unreliable in some cases and LAVs pose several safety issues. Although inactivated viruses and subunit vaccines alleviate many of these concerns, they have in general been less efficacious than their LAV counterparts. Advances in molecular virology--creating deleterious gene mutations, altering replication fidelity, deoptimizing codons and exerting control by microRNAs or zinc finger nucleases--are providing new ways of controlling viral replication and virulence and renewing interest in LAV vaccines. Whereas these rationally attenuated viruses may lead to a new generation of safer, more widely applicable LAV vaccines, each approach requires further testing before progression to human testing.

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Figures

Figure 1

Figure 1. miRNA-virus vaccine strategy

Genes coding for one or more microRNA are transcribed as long precursor pri-miRNA, which are processed by the nuclear ribonuclease Drosha to ~ 60 nucleotide hairpin intermediates. These small RNA are transported to the cytoplasm where they are trimmed by Dicer to roughly ~ 22 nucleotides. Mature miRNA are loaded into the RNA-induced silencing complex (RISC), where they mediate either degradation or translational repression of target messages. Viral replication can be regulated in a tissue specific manner by incorporating miRNA target sites into the viral genome. Viral RNA are cleaved in cells expressing the corresponding miRNA (e.g. brain, top cell), and viral production is restricted to cells in which the miRNA is not expressed (e.g. intestine, bottom cell). The engineered virus can therefore trigger a natural immune response in target tissues without the associated risk of dissemination and disease.

Figure 2

Figure 2. ZFN-virus vaccine strategy

Zinc finger nucleases use an array of three zinc finger (ZF) domains to recognize specific 9bp sequences in the virus genome. The ZF array is fused to DNA nuclease domain (lightning bolt) to create the zinc finger nuclease (ZFN). This nuclease is only active upon dimerization. A pair of ZFNs can be designed to bind 9bp sequences, spaced 5–6bp apart, to bring the nuclease domains close enough to dimerize, thus cleaving the double-stranded DNA sequence. ZFNs can be designed that target multiple, essential viral sequences, such as the origin of replication, the viral DNA packaging signal, sequences essential for establishment and maintenance of latency, and genes essential for viral replication. These ZFNs can be encoded in the viral genome itself using recombinant techniques. The expression of the ZFNs can be temporally controlled using viral promoters to allow a balance between expression of immunogenic viral proteins and cleavage of circular episomal DNA to linear DNA. This linear DNA is incapable of replication and establishment of latency. Thus, a ZFN-virus vaccine can elicit an immune response equal to that of the parental virus, but can limit its own replication and latency, without the need for a competent immune system.

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