(A) Representative single-specific mAbs, and all triple-specific mAbs, were tested for binding to chikungunya VLP. Symbol colors represent mAb specificity to the WEEV VLP (red), EEEV VLP (blue), VEEV VLP (green), or all three VLPs (black). Select triple-specific antibodies are shown as unique symbols due to their binding and neutralization profiles. Data are representative of at least two independent experiments. (B) Dock model of SKT05 and CHIKV VLP. (C) Binding to live cells infected with CHIKV, MAYV, ONNV, or RRV by SKT05 (red), CHK-265 (blue), RRV immune ascites fluid (purple), or a control mAb (gray) was determined by flow cytometry. Data are representative of three independent experiments performed in duplicate. (D-E) Arthritogenic alphavirus challenge outcome in mice (n=8/group) that received SKT05 (black) or the NHP α-SIV mAb ITS103.01 as a control (gray) one day prior to inoculation. Data are representative of two independent experiments. Viral load was determined in indicated tissues 3 days following inoculation with (D) CHIKV or (E) RRV. Footpad swelling (width x height) in the ipsilateral foot was measured prior to and 3 days following CHIKV inoculation. Statistical significance related to viral RNA was determined by a Mann-Whitney test and by unpaired t-test for footpad swelling (*p < 0.05, **p < 0.01, ***p < 0.001). The dotted line indicates the limit of detection for viral RNA analysis and the baseline foot measurement for foot swelling. See also Figures S6–S7.