A DNA vaccine encoding prM and E protein has been shown to induce protection against Zika virus (ZIKV) infection in mice and monkeys. However， its effectiveness in humans remains undefined. Moreover， identification of which immune cell types are specifically infected in humans is unclear. We show that human myeloid cells and B cells are primary targets of ZIKV in humanized mice. We also show that a DNA vaccine encoding full length prM and E protein protects humanized mice from ZIKV infection. Following administration of the DNA vaccine， humanized DRAG mice developed antibodies targeting ZIKV as measured by ELISA and neutralization assays. Moreover， following ZIKV challenge， vaccinated animals presented virtually no detectable virus in human cells and in serum， whereas unvaccinated animals displayed robust infection， as measured by qRT-PCR. Our results utilizing humanized mice show potential efficacy for a targeted DNA vaccine against ZIKV in humans.