Experiments in mice have suggested that engagement of receptors of innate immunity has an adjuvant effect on adaptive immune responses. Such studies need to be extended to humans. We have here constructed recombinant scFv-based vaccine candidate proteins (vaccibodies) that target human TLR2 and CD14 for delivery of large antigens. Vaccibodies are homodimers, each chain consisting of scFv specific for surface molecules on antigen-presenting cells (APC), a homodimerization motif, and an antigenic unit. The TLR2- and CD14-specific vaccibodies bound their respective target receptors expressed on transfected CHO cells and PBMC. Large proteins such as paired mouse Ckappa-domains (229 aa) and fragment C of tetanus toxin (TetC, 451 aa) could be expressed as antigenic units with intact serological determinants detected by mAb or polyclonal antisera. In the presence of monocytes, TLR2- and CD14-specific vaccibodies having either Ckappa or TetC as antigenic unit were 100-10,000 more efficient at stimulating T cell clones in vitro compared to non-targeted vaccibodies expressing the same antigens. The results show that TLR2 and CD14 are efficient targets for delivery of antigen to APC for stimulation of HLA class II-restricted CD4(+) T cells. Thus, receptors of innate immunity should be further explored as targets for vaccines.