Rational Zika vaccine design via the modulation of antigen membrane anchors in chimpanzee adenoviral vectors

Abstract

Zika virus (ZIKV) emerged on a global scale and no licensed vaccine ensures long-lasting anti-ZIKV immunity. Here we report the design and comparative evaluation of four replication-deficient chimpanzee adenoviral (ChAdOx1) ZIKV vaccine candidates comprising the addition or deletion of precursor membrane (prM) and envelope, with or without its transmembrane domain (TM). A single, non-adjuvanted vaccination of ChAdOx1 ZIKV vaccines elicits suitable levels of protective responses in mice challenged with ZIKV. ChAdOx1 prME ∆TM encoding prM and envelope without TM provides 100% protection, as well as long-lasting anti-envelope immune responses and no evidence of in vitro antibody-dependent enhancement to dengue virus. Deletion of prM and addition of TM reduces protective efficacy and yields lower anti-envelope responses. Our finding that immunity against ZIKV can be enhanced by modulating antigen membrane anchoring highlights important parameters in the design of viral vectored ZIKV vaccines to support further clinical assessments.

Assessment of Immunogenicity and Efficacy of a Zika Vaccine Using Modified Vaccinia Ankara Virus as Carriers

“…Here, we developed four MVA-ZIKV vaccines expressing the envelope gene, with or without its transmembrane domain, both in the presence and absence of the prM antigens. In our hands, the use of MVA was not as efficient as the ChAdOx1 counter-parts [17]. MVA-ZIKV vaccine candidates induced modest levels of anti-ZIKV E antibodies after a single vaccination approach and they failed to confer sterile protection.…”

“…We have previously demonstrated that a non-replicative adenoviral-vectored vaccine expressing ZIKV antigens induces high levels of immunity and protective efficacy in a ZIKV mice challenge model against a ZIKV-BR strain, all upon an adjuvanted, single adenoviral-based vaccine [17]. Here, we explored the suitability of different viral-vectored platforms other than adenoviral-vectored vaccines; the modified vaccinia Ankara (MVA) virus was engineered to express the same antigens that were previously expressed in adenoviral-vectored vaccines.…”

“…To assess the efficacy of the our MVA-ZIKV vaccine candidates, BALB/c mice at four-weeks post-immunisation (n = 5) were intravenously challenged with ZIKV (strain Brazil ZKV2015; ZIKV-BR), as previously described [17]. Vaccine efficacy was measured as partial or complete reduction of viremia, by retro-transcriptase (RT)-quantitative polymerase chain reaction (qPCR); at 0, 1, 2, 3, 4, and 7-days post ZIKV challenge ( Figure 3).…”

“…The modified vaccinia virus Ankara (MVA) has been extensively studied as a vectored-vaccine against various infectious diseases, reaching clinical trials, where it has been regarded as a safe, cost effective, and efficacious vaccine vector [12][13][14][15][16]. We have previously reported the development of four ChAdOx1 ZIKV vaccine candidates and their protective efficacy in a homologous ZIKV challenge model [17]. All four ChAdOx1 ZIKV vaccine candidates (prME, prME ∆TM, Env, and Env ∆TM) were shown to stimulate the production of anti-E ZIKV antibodies and demonstrated protective efficacy in a homologous ZIKV-lineage challenge model.…”

Vaccine platforms for the prevention of Lassa fever

“…Application of the ChAdOx1 platform to a diverse range of emerging pathogens is supported by multiple studies demonstrating that a single dose of ChAdOx1-vectored vaccine fully protected inbred BALB/c mice, sheep, goats, and cattle from lethal Rift Valley fever, protected 100% of transgenic human dipeptidyl peptidase-4 mice from lethal Middle East respiratory syndrome, and offered inbred BALB/c mice sterilising protection from Zika virus infection [107][108][109][110]. Each of these vaccine candidates has potently induced antigen-specific T-cell responses and high titre neutralising antibodies [107][108][109][110][111].…”