Zika virus (ZIKV) envelope (E)
protein is the major target of
neutralizing antibodies in infected hosts and thus represents a candidate of interest for
vaccine design. However, a major concern in the development of
vaccines against ZIKV and the related dengue virus is the induction of cross-reactive poorly
neutralizing antibodies that can cause antibody-dependent enhancement (ADE) of
infection. This risk necessitates particular care in
vaccine design. Specifically, the engineered immunogens should have their cross-reactive
epitopes masked, and they should be optimized for eliciting virus-specific strongly
neutralizing antibodies upon vaccination. Here, we developed ZIKV subunit- and virus-like particle (VLP)-based
vaccines displaying E in its wild-type form or E locked in a covalently linked dimeric (cvD) conformation to enhance the exposure of E dimers to the immune system. Compared with their wild-type derivatives, cvD immunogens elicited
antibodies with a higher capacity to neutralize
virus infection in cultured cells. More importantly, these immunogens protected animals from lethal challenge with both the African and Asian lineages of ZIKV, impairing virus dissemination to brain and sexual organs. Moreover, the locked conformation of E reduced the exposure of
epitopes recognized by cross-reactive
antibodies and therefore showed a lower potential to induce ADE in vitro Our data demonstrated a higher efficacy of the VLPs in comparison with that of the soluble dimer and support VLP-cvD as a promising ZIKV
vaccine.IMPORTANCE
Infection with Zika virus (ZIKV) leads to the production by the host of
antibodies that target the viral surface envelope (E)
protein. A subset of these
antibodies can inhibit
virus infection, thus making E a suitable candidate for the development of
vaccine against the virus. However, the anti-ZIKV E
antibodies can cross-react with the E
protein of the related dengue virus on account of the high level of similarity exhibited by the two
viral proteins. Such a scenario may lead to
severe dengue disease. Therefore, the design of a ZIKV
vaccine requires particular care. Here, we tested two candidate
vaccines containing a recombinant form of the ZIKV E
protein that is forced in a covalently stable dimeric conformation (cvD). They were generated with an explicit aim to reduce the exposure of the cross-reactive
epitopes. One
vaccine is composed of a soluble form of the E
protein (sE-cvD), the other is a more complex virus-like particle (VLP-cvD). We used the two candidate
vaccines to immunize mice and later infected them with ZIKV. The animals produced a high level of inhibitory
antibodies and were protected from the
infection. The VLP-cvD was the most effective, and we believe it represents a promising ZIKV
vaccine candidate.