Hybrid hepatitis B virus core antigen as a vaccine carrier moiety. II. Expression in avirulent Salmonella spp. for mucosal immunization

Abstract

Hepatitis B virus (HBV) core antigen (HBcAg) is a highly immunogenic subviral particle. We and others have defined insertion sites for heterologous epitopes and successfully used hybrid particles to generate B and T cell immunity (reviewed in: Schödel et al. 1994a, 1995). Here we shall review recent progress in constructing avirulent Salmonella spp. expressing hybrid HBcAg particles carrying different epitopes. Hybrid HBcAg particles carrying virus neutralizing epitopes of the hepatitis B virus pre-S region or repeat epitopes of plasmodial circumsporozoite antigens were previously described (Schödel et al. 1992, 1994b). Salmonella spp. can be attenuated by defined genetic means so that they become avirulent, yet preserve invasiveness after oral uptake. Hybrid HBcAg-pre-S particles were expressed in Salmonella typhimurium and S. typhi vaccine strains. A single oral immunization of mice with such live recombinant S. typhimurium strains elicited a high titered serum anti-pre-S1 IgG response. Similarly, circumsporozoite repeat epitopes of three different malaria parasites were expressed as HBcAg-CS hybrids in recombinant S. spp. and were found to be highly immunogenic after oral immunization. To analyze mucosal immune responses, BALB/c mice were immunized with recombinant phoPc S. typhimurium expressing HBcAg by various mucosal routes (Hopkins et al., 1995). All routes of immunization resulted in high titered serum and local antibodies against HBcAg and S. typhimurium LPS. However, nasal immunization was most efficient in generating pulmonary IgA and rectal immunization in eliciting rectal IgA, suggesting some compartmentalization of the mucosal immune response.