Dual-Antigen CCHFV Vaccine Induces Neutralizing Immunity and Protection Against Lethal Challenge

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Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is a WHO-priority pathogen with high mortality and wide global distribution. A major challenge in CCHFV vaccine development is identifying antigens that induce functional cellular and humoral immunity. We previously showed that the CCHF nucleoprotein (NP) elicits protective responses in mice and non-human primates but does not induce neutralizing antibodies. We therefore systematically screened six chimeric DNA vaccines expressing different CCHF glycoproteins combined with NP. A construct comprising the ectodomain of the glycoprotein Gc and NP elicited robust antibody and T-cell responses to both antigens. The Gc-NP gene was subsequently developed as a lipid nanoparticle-formulated mRNA vaccine using a scalable manufacturing pipeline. Gc-NP mRNA-LNP induced robust antigen-specific humoral and cellular responses comparable to those elicited by the corresponding DNA vaccine, despite the substantially lower dose. Both vaccine approaches generated Gc-directed neutralizing antibody responses against CCHFV pseudovirus and protected mice against homologous Hoti and heterologous IbAr10200 strain challenge. These findings demonstrate that systematic antigen screening combined with genetic vaccine platforms can identify a potent multi-antigen CCHF vaccine candidate. HIGHLIGHTS: A systematic screening of DNA-based genes identified a highly immunogenic combination of the Gc protein ectodomain and NP. This novel vaccine candidate induced Gc-specific neutralizing antibodies and T-cell responses against both NP and Gc. An mRNA-LNP vaccine expressing the Gc-NP gene further improved immunogenicity and conferred protection against lethal challenge with both CCHFV Hoti and IbAr10200 strains in mice. GRAPHICAL

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