A randomized dose-escalation phase I clinical trial of a nucleoprotein-based genetic vaccine against Crimean-Congo Hemorrhagic Fever

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Abstract
Crimean–Congo haemorrhagic fever virus (CCHFV) is an emerging tick-borne virus transmitted primarily by Hyalomma ticks, whose geographic distribution is expanding. CCHFV infection is associated with high case-fatality rates, and there are currently no widely approved vaccines available globally. We were the first to demonstrate that a genetic DNA vaccine (CCHF-N-pVAX1) targeting the nucleoprotein (N) of CCHFV can confer robust protection against lethal disease in mice and attenuate clinical symptoms in non-human primates (NHPs), providing proof-of-concept for a previously underexplored vaccine strategy through activation of NP-specific T cells and antibodies. The CCHF-N-pVAX1 vaccine was tested in a phase I clinical trial in 15 healthy volunteers (HVs) with three dose groups (0.45 mg, 0.90 mg, and 1.80 mg). Five HVs per group received vaccinations at day 0, 28, and 84 given intramuscularly using in vivo electroporation (EP; IGEA Medical), followed by 3 months of follow-up. The protocol-defined completed study reports the primary safety evaluation and secondary immunogenicity assessments through day 169. No power calculations were performed. All patients experienced temporary pain in close proximity to the vaccination/EP procedure. The vaccine was safe, and no serious adverse event (SAE) occurred. 139 other Adverse Events (AEs) occurred; 69 reactogenicity and 70 other. The AEs were mostly of mild grade (n = 123); 10 AEs were of moderate intensity, and 6 AEs were of severe intensity (diarrhea (n = 1), headache (n = 1), and fatigue (n = 4)). Most AEs (114/139) were likely or possibly related to the vaccine/EP. CCHFV N-specific antibodies and T cells appeared after the 2nd dose, and mean levels peaked after the 3rd dose at 1207 ± 2747 (endpoint titres) and 621 ± 561 (IFN-g spotforming cells), respectively. The T cell responses remained high during the 3-month follow-up. The data was consistent with our previous studies in NHPs. In conclusion, we show for the first time that a genetic nucleoprotein-based vaccine against CCHF is safe and immunogenic in humans, inducing strong T- and B-cell responses in most vaccine recipients, and suggesting a potential to confer protection against severe disease in humans. EU clinical trial number 2023-508556-18-00/IN, ClinicalTrials.gov identifier NCT06684431.

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