title: Engineering attenuated virus vaccines by controlling replication fidelity.
abstract: Long-lasting protection against viral infection is best achieved by vaccination with attenuated viruses. Obtaining stably attenuated vaccine strains has traditionally been an empirical process, which greatly restricts the number of effective vaccines for viral diseases. Here we describe a rational approach for engineering stably attenuated viruses that can serve as safe and effective vaccines. Our approach exploits the observation that restricting viral population diversity by increasing replication fidelity greatly reduces viral tissue tropism and pathogenicity. We show that poliovirus variants with reduced genetic diversity elicit a protective immune response in an animal model of infection. Indeed, these novel vaccine candidates are comparable in efficacy to the currently available Sabin type 1 vaccine strain, but have the added advantage of being more stable, as their increased replication fidelity prevents reversion to the pathogenic wild-type phenotype. We propose that restricting viral quasispecies diversity provides a general approach for the rational design of stable, attenuated vaccines for a wide variety of viruses.
authors.affiliation: Department of Microbiology and Immunology, University of California-San Francisco, 600 16th Street, San Francisco, California 94143-2280, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Vignuzzi
authors.forename: Emily
authors.initials: E
authors.lastname: Wendt
authors.forename: Raul
authors.initials: R
authors.lastname: Andino
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001483:Base Sequence; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D005818:Genetic Engineering; D014644:Genetic Variation; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D007109:Immunity; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009928:Organ Specificity; D017955:Poliovirus / Q000201:enzymology / Q000276:immunology* / Q000472:pathogenicity / Q000502:physiology*; D012367:RNA, Viral / Q000235:genetics; D018523:Tropism; D014613:Vaccines, Attenuated / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology*; D014774:Virulence; D014779:Virus Replication; D017201:Virus Shedding
chemical_list: D012367:RNA, Viral; D014613:Vaccines, Attenuated; D014765:Viral Vaccines; D012321:DNA-Directed RNA Polymerases