Zika virus (ZIKV) is a flavivirus that is responsible for the current epidemic in Brazil and the Americas1, 2. ZIKV has been causally associated with fetal microcephaly, intrauterine growth restriction, and other birth defects in both humans3, 4, 5, 6, 7, 8 and mice9, 10, 11. The rapid development of a safe and effective ZIKV vaccine is a global health priority1, 2, but very little is currently known about ZIKV immunology and mechanisms of immune protection. Here we show that a single immunization with a plasmid DNA vaccine or a purified inactivated virus vaccine provides complete protection in susceptible mice against challenge with a strain of ZIKV involved in the outbreak in northeast Brazil. This ZIKV strain has recently been shown to cross the placenta and to induce fetal microcephaly and other congenital malformations in mice11. We produced DNA vaccines expressing ZIKV pre-membrane and envelope (prM-Env), as well as a series of deletion mutants. The prM-Env DNA vaccine, but not the deletion mutants, afforded complete protection against ZIKV, as measured by absence of detectable viraemia following challenge, and protective efficacy correlated with Env-specific antibody titers. Adoptive transfer of purified IgG from vaccinated mice conferred passive protection, and depletion of CD4 and CD8 T lymphocytes in vaccinated mice did not abrogate this protection. These data demonstrate that protection against ZIKV challenge can be achieved by single-shot subunit and inactivated virus vaccines in mice and that Env-specific antibody titers represent key immunologic correlates of protection. Our findings suggest that the development of a ZIKV vaccine for humans is likely to be achievable.
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Extended data figures and tables
Extended Data Figures
- Extended Data Figure 1: ZIKV maximum likelihood phylogenetic tree. (839 KB)
The ZIKV-BR and ZIKV-PR challenge isolates are depicted with red arrows.
- Extended Data Figure 2: ZIKV amino acid sequence comparisons. (189 KB)
Number of and percentage of amino acid differences in the polyprotein are shown for the following ZIKV isolates: Brazil/ZKV2015 (Brazil strain; ZIKV-BR challenge stock), PRVABC59 (Puerto Rico strain; ZIKV-PR challenge stock), BeH815744 (Brazil strain; immunogen design), H/PF/2013 (French Polynesian strain), and MR766 (African strain).
- Extended Data Figure 3: prM-specific antibody responses in DNA-vaccinated mice. (168 KB)
In the experiment described in Fig. 2, humoral immune responses were assessed at week 3 following vaccination by prM-specific ELISA. Red bars reflect medians.
- Extended Data Figure 4: Immunogenicity and protective efficacy of prM-Env DNA vaccine in SJL mice. (237 KB)
SJL mice (n = 5 per group) received a single immunization by the i.m. route with 50 μg prM-Env DNA vaccine or a sham vaccine and were challenged at week 4 by the i.v. route with 105 viral particles (102 PFU) ZIKV-BR. Humoral immune responses were assessed at week 3 after vaccination by Env-specific ELISA (top). Red bars reflect medians. Serum viral loads are shown following ZIKV-BR challenge (bottom).
- Extended Data Figure 5: Protective efficacy of prM-Env DNA vaccine in C57BL/6 mice. (231 KB)
C57BL/6 mice (n = 5 per group) received a single immunization by the i.m. route with 50 μg prM-Env DNA vaccine or a sham vaccine and were challenged at week 4 by the i.v. route with 105 viral particles (102 PFU) ZIKV-BR or ZIKV-PR. Serum viral loads are shown following challenge.
- Extended Data Figure 6: Protective efficacy of various DNA vaccines in C57BL/6 mice. (210 KB)
C57BL/6 mice (n = 5 per group) received a single immunization by the i.m. route with 50 μg of various DNA vaccines and were challenged at week 4 by the i.v. route with 105 viral particles (102 PFU) ZIKV-BR. Serum viral loads are shown following challenge.
- Extended Data Figure 7: Adoptive transfer of low titers of Env-specific IgG. (166 KB)
Serum viral loads in mice that received adoptive transfer of low titers of Env-specific IgG (as defined in Fig. 3a) and were then challenged with ZIKV-BR.
- Extended Data Figure 8: CD4+ and CD8+ T-lymphocyte depletion. (175 KB)
CD4+ and/or CD8+ T-lymphocyte depletion following monoclonal antibody treatment of Balb/c mice vaccinated with prM-Env DNA.