Zika virus, a member of the Flaviviridae family, is primarily transmitted by infected Aedes species mosquitoes. In 2016, Zika infection emerged as a global health emergency for its explosive spread and the remarkable neurological defects in the developing fetus. Development of a safe and effective Zika vaccine remains a high priority owing to the risk of re-emergence and limited understanding of Zika virus epidemiology. We engineered a non-integrating lentiviralvector(NILV)-based Zika vaccine encoding the consensus pre-membrane and envelope glycoprotein of circulating Zika virus strains. We further evaluated the immunogenicity and protective efficacy of this vaccine in both immunocompromised and immunocompetent mouse models. A single immunization in both mouse models elicited a robust neutralizing antibody titer and afforded full protection against Zika challenge as early as 7 days post-immunization. This NILV-based vaccine also induced a long-lasting immunity when immunized mice were challenged 6 months after immunization. Altogether, our NILV Zika vaccine provides a rapid yet durable protection through a single dose of immunization without extra adjuvant formulation. Our data suggest a promising Zika vaccine candidate for an emergency situation, and demonstrate the capacity of lentiviral vector as an efficient vaccine delivery platform.Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.