Engineering attenuated virus vaccines by controlling replication fidelity

Nature Medicine 14, 154 - 161 (2008)

Speaker: Yi Shung Chen (陳怡璇)                                            Time: 15:00~16:00, Apr 23, 2008

Commentator: Shun-hua Chen, Ph.D.(陳舜華老師)         Place: Room 601

Abstract

The attenuated viral vaccine is the most effective strategy for combating the viral diseases because it typically elicits a lifelong protection. However, it has a potential risk of reversing to pathogenic phenotype, and shedding into the environment¹. The high mutation frequencies of RNA viruses are thought to aid these viruses in rapid evolution and adaption in the host². It has been shown previously that increasing the fidelity of a viral RNA polymerase could restrict the genetic diversity of the viral population, leading to an attenuated phenotype in the animal³_. In this study, the authors tested the replication fidelity of RNA-dependent RNA polymerase (RDRP) in poliovirus type 1 Mahoney variant whose Gly64 has been substituted by a variety of amino acids. Five stable vaccine candidates with high replication fidelity screened with ribavirin, a base analog that induces lethal mutagenesis when being miscorporated by the viral RNA polymerase, were obtained. These candidates were further evaluated for their efficiency in a cPVR transgenic mouse expressing the human poliovirus receptor. Compared to the wild-type and the currently used Sabin type 1 vaccine strains, these candidates showed higher LD₅₀ value, delayed in symptoms onset, and could not enter and/or establish a productive infection in the central nervous system. The mouse-to-mouse passage was also performed to examine the stability of these candidates, and they were found to be stable even after 5 passages. Further, they were highly immunogenic inducing neutralizing antibodies that protected the vaccinated mice against 5LD₅₀ intraperitoneally inoculated wild-type poliovirus even six months later. In this mouse model, these vaccine candidates were equivalent or superior to the current Sabin type 1 vaccine strain and had a long-lived protection effect. From this and previous results, the authors suggested that restricting the viral quasispecies diversity may be a general approach for the rational design of a stable, attenuated and immunogenic vaccine, and it may be applied to a wide variety of RNA viruses.

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