Japanese encephalitis vaccine-specific envelope protein E138K mutation does not attenuate virulence of West Nile virus

Jaclyn A Kaiser; Huanle Luo; Steven G Widen; Thomas G Wood; Claire Y-H Huang; Tian Wang; Alan D T Barrett

doi:10.1038/s41541-019-0146-0

Japanese encephalitis vaccine-specific envelope protein E138K mutation does not attenuate virulence of West Nile virus

NPJ Vaccines. 2019 Dec 5:4:50. doi: 10.1038/s41541-019-0146-0. eCollection 2019.

Authors

Jaclyn A Kaiser¹, Huanle Luo¹, Steven G Widen², Thomas G Wood², Claire Y-H Huang³, Tian Wang^{1

4

5}, Alan D T Barrett^{1

4

5}

Affiliations

¹ 1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555 USA.
² 2Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555 USA.
³ 3Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, CO 80521 USA.
⁴ 4Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555 USA.
⁵ 5Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX 77555 USA.

Abstract

West Nile (WNV) and Japanese encephalitis viruses (JEV) are closely related, mosquito-borne neurotropic flaviviruses. Although there are no licensed human vaccines for WNV, JEV has multiple human vaccines, including the live, attenuated vaccine SA14-14-2. Investigations into determinants of attenuation of JE SA14-14-2 demonstrated that envelope (E) protein mutation E138K was crucial to the attenuation of mouse virulence. As WNV is closely related to JEV, we investigated whether or not the E-E138K mutation would be beneficial to be included in a candidate live attenuated WNV vaccine. Rather than conferring a mouse attenuated phenotype, the WNV E-E138K mutant reverted and retained a wild-type mouse virulence phenotype. Next-generation sequencing analysis demonstrated that, although the consensus sequence of the mutant had the E-E138K mutation, there was increased variation in the E protein, including a single-nucleotide variant (SNV) revertant to the wild-type glutamic acid residue. Modeling of the E protein and analysis of SNVs showed that reversion was likely due to the inability of critical E-protein residues to be compatible electrostatically. Therefore, this mutation may not be reliable for inclusion in candidate live attenuated vaccines in related flaviviruses, such as WNV, and care must be taken in translation of attenuating mutations from one virus to another virus, even if they are closely related.

Keywords: Live attenuated vaccines.