Multi-antigen DNA vaccine targeting non-structural proteins confers robust T Cell-mediated protection against Zika virus
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Date
2026
Authors
Santos, R.
Mekonnen, Z.A.
Yeow, A.E.L.
Whelan, D.M.
Al-Delfi, Z.
Eyre, N.S.
Beard, M.R.
Barouch, D.H.
O'Connor, D.H.
Masavuli, M.G.
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npj Vaccines, 2026; 11(1):35-1-35-14
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Ryan Santos, Zelalem A. Mekonnen, Arthur Eng Lip Yeow, Dawn M.Whelan, Zahraa Al-Delfi, Nicholas S. Eyre, Michael R. Beard, Dan H. Barouch, David H. O, Connor, Makutiro G. Masavuli, Branka Grubor-Bauk
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Abstract
Zika virus (ZIKV) vaccine development has been hindered by the risk of antibody-dependent enhancement (ADE), particularly in dengue-endemic regions, where sub-neutralizing antibodies can exacerbate disease severity. T cell-based vaccines targeting non-structural (NS) antigens represent a safer alternative that bypasses this risk. Using immunocompetent BALB/c mice, we performed highresolution in vivo mapping of ZIKV specific CD8⁺ and CD4⁺ T cell responses following ZIKVPRVABC59 infection, identifying high avidity, polyfunctional memory T cells targeting conserved NS1, NS3 and NS4 proteins. Guided by these data, we developed DNA vaccines encoding full-length NS3 and NS4 and evaluated their efficacy against ZIKV infection alone or combined with a validated construct encoding secreted NS1 (p-tpaNS1). NS3 and NS4 vaccination elicited robust cytotoxic and IFN-γ producing T cell responses, while co-administration with p-tpaNS1 significantly reduced peak serum viremia achieving earlier and stronger viral control. Although NS1 alone conferred strong protection, the multi-antigen formulation demonstrated additive benefits. This T cell-based vaccine approach, targeting conserved NS proteins, offers a scalable, thermostable platform with potential for safe deployment in childbearing women and resource-limited regions. Given NS protein conservation and cross-reactivity across flaviviruses, it also provides a promising foundation for next-generation panflavivirus vaccine development, although this remains to be directly tested.
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© The Author(s) 2026. This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.