An attenuated Zika virus NS4B protein mutant is a potent inducer of antiviral immune responses

Guangyu Li, Awadalkareem Adam, Huanle Luo, Chao Shan, Zengguo Cao, Camila R. Fontes-Garfias, Vanessa V. Sarathy, Cody Teleki, Evandro R. Winkelmann, Yuejin Liang, Jiaren Sun, Nigel Bourne, Alan D.T. Barrett, Pei Yong Shi, Tian Wang

Research output: Contribution to journalArticle

Abstract

Live attenuated vaccines (LAVs) are one of the most important strategies to control flavivirus diseases. The flavivirus nonstructural (NS) 4B proteins are a critical component of both the virus replication complex and evasion of host innate immunity. Here we have used site-directed mutagenesis of residues in the highly conserved N-terminal and central hydrophobic regions of Zika virus (ZIKV) NS4B protein to identify candidate attenuating mutations. Three single-site mutants were generated, of which the NS4B-C100S mutant was more attenuated than the other two mutants (NS4B-C100A and NS4B-P36A) in two immunocompromised mouse models of fatal ZIKV disease. The ZIKV NS4B-C100S mutant triggered stronger type 1 interferons and interleukin-6 production, and higher ZIKV-specific CD4+ and CD8+ T-cell responses, but induced similar titers of neutralization antibodies compared with the parent wild-type ZIKV strain and a previously reported candidate ZIKV LAV with a 10-nucleotide deletion in 3′-UTR (ZIKV-3′UTR-Δ10). Vaccination with ZIKV NS4B-C100S protected mice from subsequent WT ZIKV challenge. Furthermore, either passive immunization with ZIKV NS4B-C100S immune sera or active immunization with ZIKV NS4B-C100S followed by the depletion of T cells affords full protection from lethal WT ZIKV challenge. In summary, our results suggest that the ZIKV NS4B-C100S mutant may serve as a candidate ZIKV LAV due to its attenuated phenotype and high immunogenicity.

Original languageEnglish (US)
Article number48
Journalnpj Vaccines
Volume4
Issue number1
DOIs
StatePublished - Dec 1 2019

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ASJC Scopus subject areas

  • Immunology
  • Pharmacology
  • Infectious Diseases
  • Pharmacology (medical)

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