In order to define the potential and applicability of replication-competent foamy virus-based vaccine vectors, recombinant feline foamy virus (FFV) vectors encoding defined segments of the feline calicivirus (FCV) capsid protein E domain were constructed. In cell cultures, these FFV-FCV vectors efficiently transduced and expressed a hybrid fusion protein consisting of the essential FFV Bet protein and the attached FCV E domains. The stability of the vectors in vitro was inversely correlated to the size of the heterologous insert. The deletion of a part of the FFV U3 sequence in these FFV-FCV vectors did not interfere with replication and titer in cell cultures but increased the genetic stability of the hybrid vectors. Selected chimeric vectors were injected into immunocompetent cats and persisted in the transduced host concomitant with a strong and specific humoral immune response against vector components. In a substantial number of cats, antibodies directed against the FCV E domain were induced by the FFV-FCV vectors, but no FCV-neutralizing activities were detectable in vitro. When the vaccinated cats were challenged with a high-titer FCV dose, sterile immunity was not induced by any of the hybrid FFV-FCV vectors. However, the FFV-FCV vector with a truncated U3 region of the long terminal repeat promoter significantly reduced the duration of FCV shedding after challenge and suppressed the appearance of FCV-specific ulcers. Possible mechanisms contributing to the partial protection will be discussed.The great success of applied virology during the last century has been mainly due to the development and application of efficient and safe antiviral vaccines. These prevent virus-mediated disease or spread of the infectious agent and have even resulted in the eradication of poxvirus (reviewed in reference 7). These achievements are on one hand based on the injection of defined virus-derived proteins, as in the case of the hepatitis B virus vaccine or inactivated viruses, which are both capable of inducing a stable and broadly reactive humoral immunity. Alternatively, attenuated, apathogenic virus variants and/or related viruses inducing a stable cross-protection are used. Modified live virus vaccines have the great advantage of mimicking the natural route and mode of virus replication, inducing not only a humoral, mainly immunoglobulin G (IgG)-mediated immunity, but also stimulating the cell-mediated and/or mucosal arm of the adaptive immune response (7). Although these strategies have been efficient in controlling various viruses pathogenic to humans and livestock animals, vaccines against some virus infections are presently either not available or display only a limited degree of protection (23).Over the last several years, novel vaccination strategies have been developed based on recombinant, chimeric viruses used to deliver and efficiently express heterologous vaccine antigens in the recipient (28). These novel strategies include not only prophylactic preexposure vaccination but also therapeutic postexposure im...