Abstract
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.
Highlights
For decades Zika virus (ZIKV) was largely ignored as a human pathogen but the recent epidemic in South America has brought to light neurological complications (i.e.Guillain-Barré syndrome)(1) and congenital Zika syndrome(2) making ZIKV a public health threat in affected countries
One vaccine is composed of a soluble form of the E protein, the other is a more complex virus-like particle (VLP-covalently linked dimeric (cvD))
Expression and purification of E covalent dimer-based vaccines: We focused on designing antigens that would elicit antibodies to the complex quaternary epitopes that span two or more ZIKV E molecules
Summary
For decades Zika virus (ZIKV) was largely ignored as a human pathogen but the recent epidemic in South America has brought to light neurological complications (i.e.Guillain-Barré syndrome)(1) and congenital Zika syndrome (i.e. microcephaly and other malformations)(2) making ZIKV a public health threat in affected countries. During the initial stages of flavivirus genesis, the E protein is associated with the precursor-membrane protein (prM) and assumes a trimeric conformation; only during the passage in the trans-Golgi network, where the viral particle encounters an acidic environment, the trimers dissociate to reassemble as dimers [16]. This new conformation is necessary to allow furin-mediated cleavage of prM into pr and M generating a mature E dimer [17]. Antibodies to prM contribute to ADE [22]
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