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A live-attenuated Zika virus vaccine candidate induces sterilizing immunity in mouse models

Nature Medicine volume 23, pages 763–767 (2017)Cite this article

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Abstract

Zika virus (ZIKV) infection of pregnant women can cause a wide range of congenital abnormalities, including microcephaly, in the infant, a condition now collectively known as congenital ZIKV syndrome1. A vaccine to prevent or significantly attenuate viremia in pregnant women who are residents of or travelers to epidemic or endemic regions is needed to avert congenital ZIKV syndrome, and might also help to suppress epidemic transmission. Here we report on a live-attenuated vaccine candidate that contains a 10-nucleotide deletion in the 3′ untranslated region of the ZIKV genome (10-del ZIKV). The 10-del ZIKV is highly attenuated, immunogenic, and protective in type 1 interferon receptor–deficient A129 mice. Crucially, a single dose of 10-del ZIKV induced sterilizing immunity with a saturated neutralizing antibody titer, which no longer increased after challenge with an epidemic ZIKV, and completely prevented viremia. The immunized mice also developed a robust T cell response. Intracranial inoculation of 1-d-old immunocompetent CD-1 mice with 1 × 104 infectious focus units (IFU) of 10-del ZIKV caused no mortality, whereas infections with 10 IFU of wild-type ZIKV were lethal. Mechanistically, the attenuated virulence of 10-del ZIKV may be due to decreased viral RNA synthesis and increased sensitivity to type-1-interferon inhibition. The attenuated 10-del ZIKV was incapable of infecting mosquitoes after oral feeding of spiked-blood meals, representing an additional safety feature. Collectively, the safety and efficacy results suggest that further development of this promising, live-attenuated ZIKV vaccine candidate is warranted.

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Figure 1: Characterization of the 3′UTR-deletion mutant viruses in cell culture.
Figure 2: Characterization of 3′UTR mutants in the A129 mouse model.
Figure 3: T cell responses after primary infection with WT ZIKV or the 10-del mutant.
Figure 4: Safety evaluation of 10-del virus.

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Gene Expression Omnibus

  • KU501215

  • KU955593.1

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Acknowledgements

We thank colleagues at the University of Texas Medical Branch for their helpful discussions during the course of this study. We are grateful to M.A. Garcia-Blanco and S.S. Brarick for providing lab space and equipment during the early stage of this work. P.-Y.S. was supported by a University of Texas Medical Branch (UTMB) start-up award, UTMB Innovation and Commercialization award, University of Texas STARs Award, CDC grant for the Western Gulf Center of Excellence for Vector-Borne Diseases, Pan American Health Organization grant SCON2016-01353, and UTMB CTSA UL1TR-001439. This research was also partially supported by a US National Institutes of Health grant AI120942 to S.C.W.

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Authors and Affiliations

  1. Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA

    Chao Shan, Bruno T D Nunes, Xuping Xie, Daniele B A Medeiros, Maki Wakamiya & Pei-Yong Shi

  2. Institute for Human Infections & Immunity, University of Texas Medical Branch, Galveston, Texas, USA

    Antonio E Muruato, Robert B Tesh, Alan D Barrett, Scott C Weaver & Shannan L Rossi

  3. Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas, USA

    Antonio E Muruato & Scott C Weaver

  4. Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Pará State, Brazil

    Bruno T D Nunes, Daniele B A Medeiros & Pedro F C Vasconcelos

  5. Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas, USA

    Huanle Luo, Tian Wang & Scott C Weaver

  6. Department of Pathology and Center for Biodefense & Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA

    Robert B Tesh, Alan D Barrett, Tian Wang & Shannan L Rossi

  7. Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, USA

    Alan D Barrett, Tian Wang, Scott C Weaver & Pei-Yong Shi

  8. Sealy Center for Structural Biology & Molecular Biophysics, University of Texas Medical Branch, Galveston, Texas, USA

    Scott C Weaver & Pei-Yong Shi

  9. Department of Pathology, Pará State University, Belém, Brazil

    Pedro F C Vasconcelos

  10. Department of Phamarcology & Toxicology, University of Texas Medical Branch, Galveston, Texas, USA

    Pei-Yong Shi

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Contributions

C.S., A.E.M., B.T.D.N., H.L., X.X., and D.B.A.M. performed experiments and data analysis. M.W., R.B.T., A.D.B., S.C.W., P.F.C.V., T.W., S.L.R., and P.-Y.S. designed the experiments and interpreted the results. C.S., A.E.M., T.W., S.C.W., P.F.C.V., S.L.R., and P.-Y.S. wrote the manuscript.

Corresponding authors

Correspondence to Shannan L Rossi or Pei-Yong Shi.

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The authors have filed a patent related to the technology presented in this paper.

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Shan, C., Muruato, A., Nunes, B. et al. A live-attenuated Zika virus vaccine candidate induces sterilizing immunity in mouse models. Nat Med 23, 763–767 (2017). https://doi.org/10.1038/nm.4322

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