Genetic stability of live-attenuated Zika vaccine candidates

Antonio E. Muruato, Chao Shan, Camila R. Fontes-Garfias, Yang Liu, Zengguo Cao, Qiang Gao, Scott Weaver, Pei-Yong Shi

Research output: Contribution to journalArticle

Abstract

Zika virus (ZIKV) has drawn global attention as the etiologic agent of Zika Congenital Syndrome in babies born to infected pregnant women. To prevent future ZIKV outbreaks and protect persons at risk for severe disease, we developed two live-attenuated vaccine (LAV) candidates containing 10- or 20-nucleotide deletions in the 3′UTR of the viral genome (Δ10 and Δ20). After a single-dose immunization, both Δ10 and Δ20 LAVs protected mice and non-human primates against ZIKV infection. Here, we characterized the stability, safety, and efficacy of the LAVs after continuously culturing them on manufacture Vero cells for ten rounds. Whole genome sequencing showed that passage 10 (P10) LAVs retained the engineered Δ10 and Δ20 deletions; one to four additional mutations emerged at different regions of the genome. In A129 mice, the P10 LAVs exhibited viremia higher than the un-passaged LAVs, but lower than wild-type ZIKV; unlike wild-type ZIKV-infected mice, none of the P10 LAV-infected mice developed disease or death, demonstrating that the P10 LAVs remained attenuated. Mice immunized with a single dose of the P10 LAVs developed robust neutralizing antibody titers (1/1,000 to 1/10,000) and were protected against epidemic ZIKV challenge. The P10 LAVs did not exhibit increased neurovirulence. Intracranial inoculation of one-day-old CD1 pups with 103 focus-forming units of the P10 Δ10 and Δ20 LAVs resulted in 100% and ≥80% survival, respectively. Furthermore, the P10 LAVs remained incompetent in infecting Aedes aegypti mosquitoes after intrathoracic microinjection. Our results support the phenotypic stability and further development of these promising LAVs for ZIKV.

Original languageEnglish (US)
Article number104596
JournalAntiviral research
Volume171
DOIs
StatePublished - Nov 1 2019

Fingerprint

Attenuated Vaccines
Genome
Vero Cells
Aedes
Viral Genome
Viremia
Microinjections
Neutralizing Antibodies
Culicidae
Primates
Disease Outbreaks
Zika Virus
Pregnant Women
Immunization
Nucleotides
Safety
Mutation
Survival

Keywords

  • Flavivirus
  • Live-attenuated vaccine
  • Vaccine development
  • Virulence
  • Zika virus

ASJC Scopus subject areas

  • Pharmacology
  • Virology

Cite this

Muruato, A. E., Shan, C., Fontes-Garfias, C. R., Liu, Y., Cao, Z., Gao, Q., ... Shi, P-Y. (2019). Genetic stability of live-attenuated Zika vaccine candidates. Antiviral research, 171, [104596]. https://doi.org/10.1016/j.antiviral.2019.104596

Genetic stability of live-attenuated Zika vaccine candidates. / Muruato, Antonio E.; Shan, Chao; Fontes-Garfias, Camila R.; Liu, Yang; Cao, Zengguo; Gao, Qiang; Weaver, Scott; Shi, Pei-Yong.

In: Antiviral research, Vol. 171, 104596, 01.11.2019.

Research output: Contribution to journalArticle

Muruato AE, Shan C, Fontes-Garfias CR, Liu Y, Cao Z, Gao Q et al. Genetic stability of live-attenuated Zika vaccine candidates. Antiviral research. 2019 Nov 1;171. 104596. https://doi.org/10.1016/j.antiviral.2019.104596
Muruato, Antonio E. ; Shan, Chao ; Fontes-Garfias, Camila R. ; Liu, Yang ; Cao, Zengguo ; Gao, Qiang ; Weaver, Scott ; Shi, Pei-Yong. / Genetic stability of live-attenuated Zika vaccine candidates. In: Antiviral research. 2019 ; Vol. 171.
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