A cDNA clone of the classical swine fever virus (CSFV) strain Alfort/187 [Ruggli N, Tratschin JD, Mittelholzer C, Hofmann MA. Nucleotide sequence of classical swine fever virus strain Alfort/187 and transcription of infectious RNA from stably cloned full-length cDNA. J Virol 1996;70(6):3478-87] was used to construct two E2 deletion mutants lacking either the complete E2 gene or, alternatively, a stretch of 204 nucleotides encoding 68 amino acids located in the C-terminal region of the E2 glycoprotein. The respective in vitro synthesized mutant RNAs replicated in SK-6 cells but no infectious virus was generated. Both replicons could be packaged into virus particles in SK-6 cells constitutively expressing E2 of CSFV. For the resulting CSF virus replicon particles (CSF-VRP) A187-E2del373 and A187-E2del68 titers of 10(6) and 10(7) TCID(50)/ml, respectively, were obtained. Oronasal vaccination with 10(7) TCID(50) of either of the two CSF-VRP protected pigs against a challenge with a lethal dose of CSFV strain Eystrup. In contrast, after intradermal vaccination VRP A187-E2del68 but not VRP A187-E2del373 lacking the complete E2 gene induced a protective immune response. We conclude that E2-complemented CSF-VRP have the potential to be used as live-attenuated non-transmissible oral vaccines for pigs. In addition, our data suggest that E2 of CSFV is dispensable for the induction of mucosal but not of parenteral immunity.