Using a virion assembly-defective dengue virus as a vaccine approach

Chao Shan, Xuping Xie, Jing Zou, Roland Züst, Bo Zhang, Rebecca Ambrose, Jason Mackenzie, Katja Fink, Pei Yong Shi

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Dengue virus (DENV) is the most prevalent mosquito-transmitted viral pathogen in humans. The recently licensed dengue vaccine has major weaknesses. Therefore, there is an urgent need to develop improved dengue vaccines. Here, we report a virion assembly-defective DENV as a vaccine platform. DENV containing an amino acid deletion (K188) in nonstructural protein 2A (NS2A) is fully competent in viral RNA replication but is completely defective in virion assembly. When transcomplemented with wild-type NS2A protein, the virion assembly defect could be rescued, generating pseudoinfectious virus (PIV NS2A ) that could initiate single-round infection. The trans-complementation efficiency could be significantly improved through selection for adaptive mutations, leading to high-yield PIV NS2A production, with titers of >10 7 infectious-focus units (IFU)/ml. Mice immunized with a single dose of PIV NS2A elicited strong T cell immune responses and neutralization antibodies and were protected from wild-type-virus challenge. Collectively, the results proved the concept of using assembly-defective virus as a vaccine approach. The study also solved the technical bottleneck in producing high yields of PIV NS2A vaccine. The technology could be applicable to vaccine development for other viral pathogens. IMPORTANCE Many flaviviruses are significant human pathogens that pose global threats to public health. Although licensed vaccines are available for yellow fever, Japanese encephalitis, tick-borne encephalitis, and dengue viruses, new approaches are needed to develop improved vaccines. Using dengue virus as a model, we developed a vaccine platform using a virion assembly-defective virus. We show that such an assembly-defective virus could be rescued to higher titers and infect cells for a single round. Mice immunized with the assembly-defective virus were protected from wild-type-virus infection. This vaccine approach could be applicable to other viral pathogens.

Original languageEnglish (US)
Article numbere01002
JournalJournal of virology
Volume92
Issue number21
DOIs
StatePublished - Nov 1 2018

Keywords

  • Dengue virus
  • Flavivirus vaccine
  • NS2A
  • Trans-complementation
  • Viral assembly

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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  • Cite this

    Shan, C., Xie, X., Zou, J., Züst, R., Zhang, B., Ambrose, R., Mackenzie, J., Fink, K., & Shi, P. Y. (2018). Using a virion assembly-defective dengue virus as a vaccine approach. Journal of virology, 92(21), [e01002]. https://doi.org/10.1128/JVI.01002-18