Japanese encephalitis virus live attenuated vaccine strains display altered immunogenicity, virulence and genetic diversity

Emily H Davis; Andrew S Beck; Li Li; Mellodee M White; Marianne Banks Greenberg; Jill K Thompson; Steven G Widen; Alan D T Barrett; Nigel Bourne

doi:10.1038/s41541-021-00371-y

Japanese encephalitis virus live attenuated vaccine strains display altered immunogenicity, virulence and genetic diversity

NPJ Vaccines. 2021 Sep 2;6(1):112. doi: 10.1038/s41541-021-00371-y.

Authors

Emily H Davis^#¹, Andrew S Beck^#^{1

2}, Li Li¹, Mellodee M White³, Marianne Banks Greenberg³, Jill K Thompson⁴, Steven G Widen⁴, Alan D T Barrett^{5

6}, Nigel Bourne^{7

8}

Affiliations

¹ Department of Pathology, The University of Texas Medical Branch, Galveston, TX, USA.
² Viral Vaccine Preventable Diseases Branch, Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
³ Department of Pediatrics, The University of Texas Medical Branch, Galveston, TX, USA.
⁴ Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA.
⁵ Department of Pathology, The University of Texas Medical Branch, Galveston, TX, USA. abarrett@utmb.edu.
⁶ Sealy Institute for Vaccine Sciences, The University of Texas Medical Branch, Galveston, TX, USA. abarrett@utmb.edu.
⁷ Department of Pediatrics, The University of Texas Medical Branch, Galveston, TX, USA. nibourne@utmb.edu.
⁸ Sealy Institute for Vaccine Sciences, The University of Texas Medical Branch, Galveston, TX, USA. nibourne@utmb.edu.

^# Contributed equally.

Abstract

Japanese encephalitis virus (JEV) is the etiological agent of Japanese encephalitis (JE). The most commonly used vaccine used to prevent JE is the live-attenuated strain SA14-14-2, which was generated by serial passage of the wild-type (WT) JEV strain SA14. Two other vaccine candidates, SA14-5-3 and SA14-2-8 were derived from SA14. Both were shown to be attenuated but lacked sufficient immunogenicity to be considered effective vaccines. To better contrast the SA14-14-2 vaccine with its less-immunogenic counterparts, genetic diversity, ribavirin sensitivity, mouse virulence and mouse immunogenicity of the three vaccines were investigated. Next generation sequencing demonstrated that SA14-14-2 was significantly more diverse than both SA14-5-3 and SA14-2-8, and was slightly less diverse than WT SA14. Notably, WT SA14 had unpredictable levels of diversity across its genome whereas SA14-14-2 is highly diverse, but genetic diversity is not random, rather the virus only tolerates variability at certain residues. Using Ribavirin sensitivity in vitro, it was found that SA14-14-2 has a lower fidelity replication complex compared to SA14-5-3 and SA14-2-8. Mouse virulence studies showed that SA14-2-8 was the most virulent of the three vaccine strains while SA14-14-2 had the most favorable combination of safety (virulence) and immunogenicity for all vaccines tested. SA14-14-2 contains genetic diversity and sensitivity to the antiviral Ribavirin similar to WT parent SA14, and this genetic diversity likely explains the (1) differences in genomic sequences reported for SA14-14-2 and (2) the encoding of major attenuation determinants by the viral E protein.

Abstract

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