Abstract
SummaryThe global Zika virus (ZIKV) outbreak and its link to foetal and newborn microcephaly and severe neurological complications in adults call for the urgent development of ZIKV vaccines. In response, we developed a subunit vaccine based on the ZIKV envelope (E) protein and investigated its immunogenicity in mice. Transient expression of ZIKV E (zE) resulted in its rapid accumulation in leaves of Nicotiana benthamiana plants. Biochemical analysis revealed that plant‐produced ZIKV E (PzE) exhibited specific binding to a panel of monoclonal antibodies that recognize various zE conformational epitopes. Furthermore, PzE can be purified to >90% homogeneity with a one‐step Ni2+ affinity chromatography process. PzE are found to be highly immunogenic, as two doses of PzE elicited both potent zE‐specific antibody and cellular immune responses in mice. The delivery of PzE with alum induced a mixed Th1/Th2 immune response, as the antigen‐specific IgG isotypes were a mixture of high levels of IgG1/IgG2c and splenocyte cultures from immunized mice secreted significant levels of IFN‐gamma, IL‐4 and IL‐6. Most importantly, the titres of zE‐specific and neutralizing antibodies exceeded the threshold that correlates with protective immunity against multiple strains of ZIKV. Thus, our results demonstrated the feasibility of plant‐produced ZIKV protein antigen as effective, safe and affordable vaccines against ZIKV.
Highlights
Zika virus (ZIKV) used to be an obscure pathogen that only caused self-limiting febrile illnesses in humans
Similar to the closely related dengue virus (DENV), West Nile virus (WNV), tickborne encephalitis virus (TBEV) and yellow fever virus (YFV), the Envelope (E) glycoprotein of ZIKV has a three-ectodomain (EDI, EDII and EDIII) structure and is responsible for viral assembly, cellular receptor attachment and the subsequent membrane fusion involved in viral entry into host cells (Dai et al, 2016; Lazear and Diamond, 2016)
Expression of Zika virus envelop protein in Nicotiana benthamiana plants The coding sequence of ZIKV E (zE) (Figure S1) was fused to that of hexahistidine tags (His6) (Figure S2) and cloned into a MagnICONbased plant expression vector (Giritch et al, 2006). zE was transiently expressed in N. benthamiana plants by infiltrating the zE-His6 construct-containing Agrobacterium tumefaciens strain into leaves
Summary
Zika virus (ZIKV) used to be an obscure pathogen that only caused self-limiting febrile illnesses in humans. Recent ZIKV outbreaks, have linked ZIKV infection to severe and frequent neurological diseases such as microcephaly in infants and Guillain–Barre0 syndrome in adults (Attar, 2016; Cao-Lormeau et al, 2016). Despite this global health threat, no licensed vaccine or therapeutic treatment is currently available for human use. For approved human YFV and TBEV vaccines, neutralizing antibodies are found to correlate with protection (Belmusto-Worn et al, 2005; Heinz et al, 2007). Neutralizing antibodies are essential in providing protection against lethal challenges of WNV, DENV, and recently
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