NS1-based DNA vaccination confers mouse protective immunity against ZIKV challenge

The recent pandemic of Zika virus (ZIKV) infections highlight the urgent need for the development of a safe and efficacious ZIKV vaccine. We previously demonstrated that robust humoral and cellular immunity was elicited in BALB/c mice by ZIKV DNA vaccine encoding the precursor membrane (prM) and envelope (E) proteins while the protective efficacies were not evaluated against ZIKV challenge. To further explore the protective immunity elicited by various targets of ZIKV, we constructed a novel DNA-based vaccine expressing nonstructural protein 1 (NS1), named as VRC-NS1, and evaluated and compared immune responses and protective efficacies of three ZIKV DNA vaccine candidates (VRC-prME, VRC-NS1, and VRC-prME+VRC-NS1) using an A129 (Ifnar^-/-) murine challenge model. The results showed that each of DNA vaccine candidates induced robust antigen-specific humoral immunity and conferred protection against ZIKV-SMGC-1 with two doses (20 μg per dose) of homologous intramuscularly (i.m.) immunizations via in vivo electroporation. All DNA vaccine candidates induced significant protection against infection-associated weight loss in addition to preventing viral replication in blood, brain and spleen tissue following in vivo viral challenge. Notably, NS1-based DNA vaccination alone was capable of conferring mouse protective immunity to reduce viremia and viral burden in tissues against ZIKV challenge, even though it did not induce neutralizing antibodies. These data demonstrated that VRC-NS1 and VRC-prME are highly promising vaccine candidates for ZIKV control. Furthermore, our results highlight an alternative strategy (DNA vaccine based on non-neutralizing antigen NS1) for designing novel flaviviral vaccines (including for ZIKV) and provide a foundation for the development of a safe and effective NS1-based vaccine against ZIKV infection.