Groups of 8 mice (4 male and 4 female) were vaccinated subcutaneously (SC) with viral replicon particles (VRP) (back-titer dose: 2 × 104 TCID50) at various intervals relative to SC challenge (−14, −7, −3, −1, or +1 days post infection [dpi]) with CCHFV Turkey-200406546 (target dose: 100 TCID50; backtiter dose: 24 TCID50). One mouse was removed prior to challenge from the +1 dpi group due to severe malocclusion resulting in a failure to maintain weight. Two unvaccinated control groups were challenged in parallel, one with the same dose of inoculum (24 TCID50) as the vaccinated groups, and the other with a 10-fold dilution of the inoculum (target dose: 10 TCID50; back-titer dose: 2.4 TCID50). (A) Weight change from baseline at −1 dpi (−25% weight loss criteria for euthanasia indicated in grey); time of vaccination and challenge, indicated by green and red vertical dotted lines, respectively; individual clinical scores (0–10); mean clinical scores; and survival. Grey shading in individual or mean clinical score graphs indicate animals no longer in study (i.e., met euthanasia criteria). (B) Mean water intake (mL) per mouse in the experimental group.