A genetically stable Zika virus vaccine candidate protects mice against virus infection and vertical transmission
Open Access
- 17 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in npj Vaccines
- Vol. 6 (1), 1-11
- https://doi.org/10.1038/s41541-021-00288-6
Abstract
Although live attenuated vaccines (LAVs) have been effective in the control of flavivirus infections, to date they have been excluded from Zika virus (ZIKV) vaccine trials due to safety concerns. We have previously reported two ZIKV mutants, each of which has a single substitution in either envelope (E) glycosylation or nonstructural (NS) 4B P36 and displays a modest reduction in mouse neurovirulence and neuroinvasiveness, respectively. Here, we generated a ZIKV mutant, ZE4B-36, which combines mutations in both E glycosylation and NS4B P36. The ZE4B-36 mutant is stable and attenuated in viral replication. Next-generation sequence analysis showed that the attenuating mutations in the E and NS4B proteins are retained during serial cell culture passages. The mutant exhibits a significant reduction in neuroinvasiveness and neurovirulence and low infectivity in mosquitoes. It induces robust ZIKV-specific memory B cell, antibody, and T cell-mediated immune responses in type I interferon receptor (IFNR) deficient mice. ZIKV-specific T cell immunity remains strong months post-vaccination in wild-type C57BL/6 (B6) mice. Vaccination with ZE4B-36 protects mice from ZIKV-induced diseases and vertical transmission. Our results suggest that combination mutations in E glycosylation and NS4B P36 contribute to a candidate LAV with significantly increased safety but retain strong immunogenicity for prevention and control of ZIKV infection.Keywords
This publication has 61 references indexed in Scilit:
- LoFreq: a sequence-quality aware, ultra-sensitive variant caller for uncovering cell-population heterogeneity from high-throughput sequencing datasetsNucleic Acids Research, 2012
- Vγ4+T cells regulate host immune response to West Nile virus infectionFEMS Immunology & Medical Microbiology, 2011
- Immune responses to an attenuated West Nile virus NS4B-P38G mutant strainVaccine, 2011
- Pivotal Role of Antibody and Subsidiary Contribution of CD8+T Cells to Recovery from Infection in a Murine Model of Japanese EncephalitisJournal of Virology, 2011
- Stability of RNA virus attenuation approachesVaccine, 2011
- A Protective Role for Dengue Virus-Specific CD8+ T CellsThe Journal of Immunology, 2009
- Effectiveness of Maternal Influenza Immunization in Mothers and InfantsThe New England Journal of Medicine, 2008
- Genetic and Serologic Properties of Zika Virus Associated with an Epidemic, Yap State, Micronesia, 2007Emerging Infectious Diseases, 2008
- Differential Effects of Mutations in NS4B on West Nile Virus Replication and Inhibition of Interferon SignalingJournal of Virology, 2007
- CD4+T-Cell Responses Are Required for Clearance of West Nile Virus from the Central Nervous SystemJournal of Virology, 2006