The modified mRNA vaccine protects immunocompromised AG129 mice from lethal challenge and multi-tissue infection by Zika virus.

The multiple epidemics of Zika virus (ZIKV) posed a substantial threat to public health. Clinical evidence suggests that ZIKV could break through the blood-brain, blood-placenta, and blood-testis barriers, leading to severe outcomes such as congenital malformations in newborns and Guillain-Barré syndrome in adults. Currently, there are no specific treatments for ZIKV infection. To address the antibody-dependent enhancement (ADE) of dengue virus (DENV) infection induced by ZIKV vaccination, we designed two modified prM-E RNAs (ZA and ZB) with specific mutations either shielding or disrupting the conserved fusion-loop epitope in the E protein. Then, we chose the mRNA-LNP vaccine platform to evaluate the safety and efficacy. After prime-boost immunization, ZA vaccine could induce high levels of T cells secreting IFN-γ and exhibit limited neutralizing ability against Asian-lineage and African-lineage ZIKV. After ZIKV challenge, ZA vaccine could provide complete protection in immunocompromised AG129 mice at low levels of neutralizing antibodies, preventing viral dissemination to the brain, uterus, and testes. Importantly, the ZA vaccine also reduced the ADE effect of DENV infection. Although ZB vaccine exhibited good immunogenicity, it could not achieve complete viral clearance in AG29 mice. Our findings suggested that the ZA vaccine could prevent both lethal ZIKV infection and DENV ADE induced by infection or vaccination.