RESUMO
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.
Assuntos
Células Cultivadas/efeitos dos fármacos , Imunidade Ativa/efeitos dos fármacos , Imunidade Ativa/genética , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/prevenção & controle , Zika virus/genética , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Chlorocebus aethiops , Cricetinae , Modelos Animais de Doenças , Células Germinativas Embrionárias/efeitos dos fármacos , Feminino , Variação Genética , Genótipo , Humanos , Rim/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Vacinação , Células Vero/efeitos dos fármacos , Proteínas não Estruturais Virais/genética , Vacinas Virais/genética , Vacinas Virais/imunologiaRESUMO
The Zika virus (ZIKV) and poxvirus infection are considered as public health emergencies, necessitating the development of effective vaccines. Here, we report novel recombinant DNA-based and non-replicating vaccinia virus (NTV)-based vaccine candidates that express the precursor membrane-envelope (prME) or envelope (E) glycoproteins of ZIKV. After immunization of BABL/c mice with the vaccines using a homologous protocol (DNA/DNA, NTV/NTV) or heterogeneous (DNA/NTV) protocol, a similar level of anti-E IgG and neutralizing antibodies (microneutralization test) were detected in the mice. However, a significantly higher level of E-specific T cell responses was elicited in mice when a heterogeneous prime-boost protocol was used (DNA/NTV) with either the DNA-based or NTV-based vaccines. Furthermore, neutralizing antibodies and a T cell immune response against the vaccinia virus (VV) were detected in mice that were subjected to the prime-boost protocol (DNA/NTV), whereas those subjected to a homologous NTV/NTV protocol had higher levels of anti-VV IgG and neutralizing antibodies. Lastly, a novel H-2d-restricted CD8 T-cell epitope, VRSYCYEASISDMAS, was identified in the ZIKV E protein. These data demonstrate proof of concept of a bivalent vaccine candidate against ZIKV and orthopoxvirus, and support the use of DNA-prME prime and NTV-E boost protocols to protect against ZIKV and orthopoxvirus infections.
