A safe replication-defective Zika virus vaccine protects mice from viral infection and vertical transmission

With the explosive emergence of Zika virus (ZIKV) and the consequent devastating fetal malformations in infected expectant women, a safe and effective vaccine is urgently needed. Here, using our established NS1 trans-complementation system, we generated high titer of replication-defective ZIKV with NS1 deletion (ZIKV-ΔNS1) in the BHK-21 cell line stably expressing NS1 (BHK_NS1). NS1 deletion of ZIKV-ΔNS1 was stably maintained as no replicative virus was found in naïve BHK-21 cells after continuous passaging of ZIKV-ΔNS1 in BHK_NS1 cells. The safety of ZIKV-ΔNS1 was demonstrated when a high dose of ZIKV-ΔNS1 (10⁷ IU) was used to infect the highly susceptible type I and type II interferon (IFN) receptor-deficient mice. ZIKV-ΔNS1 could induce antibody responses in both immunocompetent (BALB/c) and immunodeficient mice and a single dose of ZIKV-ΔNS1 vaccine protected the immunodeficient mice from a highly lethal dosage of challenge with WT ZIKV. ZIKV-ΔNS1 immunization also attenuated vertical transmission during pregnancy of type I IFN receptor-deficient IFNAR^-/- mice and protected fetuses from ZIKV infection. Our data reported here not only provide a promising ZIKV vaccine candidate with a satisfied balance between safety and efficacy, but also demonstrate the potential of the NS1 trans-complementation system as a platform for flavivirus vaccine development, especially for highly pathogenic flaviviruses.