Pre-clinical evaluation of a Zika virus vaccine

摘要

Abstract Since first detected in the Americas in May 2015 after rapidly spreading from Brazil, the mosquito-borne Zika virus (ZIKV) has attracted global attention. The ZIKV outbreak in Brazil has also been associated with a significant rise in the number of babies born with microcephaly and neurological disorders such as Guillain- Barré syndrome and has been declared a “global emergency” by the World Health Organization. Zika virus is related to dengue, yellow fever, Japanese encephalitis, and West Nile viruses, all of which are arthropod-borne flaviviruses. Building on successful flavivirus vaccine approaches reported in the literature as an initial attempt to develop a Zika virus vaccine, we have generated a panel of recombinant Zika virus subunit vaccines based on the extracellular portion of the ZIKV envelope gene or the EDIII domain of the ZIKV envelope gene. The EDIII loop of the flavivirus envelope gene is the receptor-binding domain and has been shown to be the most promising target for an antiviral neutralizing immunity. Both these antigens (E and EDIII) were generated as monomers (ZIKV-rE and ZIKV-rEDIII), as dimers in fusion with the fc portion of the human IgG1 (ZIKV-rEhIg and ZIKV-rEDIIIhIg), and as trimers in fusion with the T4 fibritin foldon trimerization domain (ZIKV-rEfl and ZIKV-rEDIIIfl). In the preliminary studies presented here, we tested the immunogenicity of trimeric ZIKV-rEfl and ZIKV-rEDIIIfl delivered transcutaneously using dissoluble microneedle array (MNA) delivery system into C57BL6 mice. The choice of the MNA-based antigen delivery system is justified because its efficacy and it is simple and easily adaptable to use in low hygiene and pure socio-economic environment. We compared their immunogenicity with the immunogenicity of the same antigens delivered with adenovirus 5-based vaccine vector. We now are proposing extending the testing to all six ZIKV recombinant subunit vaccines generated. The immunogenicity of these six subunit vaccines, named ZIKV-rE, ZIKV-rEDIII, ZIKV-rEhIg, ZIKV-rEDIIIhIg, ZIKV-rEfl, and ZIKV-rEDIIIfl, delivered via MNA, will be compared in C57B6 mice. Once the best performing ZIKV subunit vaccine is selected, the beneficial effect of adjuvant will be evaluated. Ultimately, we will test the efficacy of the selected subunit vaccine in a ZIKV surrogate animal challenge model. We hypothesize that administration of ZIKV subunit vaccines in a prime/boost regimen will elicit ZIKV-specific immunity that will lead to the effective immunization of pregnant mice with passage of passive immunity to newborns, which will be protected by ZIKV challenge.