Prime-only vaccination protects against CCHFV challenge. Groups of WT mice receiving indicated vaccinations were treated with MAR1-5A3 to abolish type I IFN signaling and challenged with CCHFV strain UG3010. Mice were weighed daily (a), monitored for survival (b) and body temperature monitored continuously via telemetry system (c). N = 8 mice per group except for sham-vaccinated telemetry data where N = 6. Statistical comparison to sham-vaccinated mice performed using a two-way ANOVA with Dunnett's multiple comparisons test or log-rank test with Bonferroni's correction for multiple comparisons (b). At day 5 p.i., viral loads in indicated tissues were quantified by qRT-PCR (d) or TCID50 assay (e) and statistical comparison between sham vaccinated mice and repRNA-vaccinated mice calculated using one-way ANOVA with Dunnett's multiple comparisons test. Statistical comparisons between sham-vaccinated and every repNP-vaccinated groups were significant. N = 6 per group. ns P >0.05, * P < 0.05, ** P < 0.01, *** P <0.001, **** P < 0.0001. (a, c, d, e) Data shown as mean plus standard deviation.