Oral vaccination with modified vaccinia virus Ankara attached covalently to TMPEG-modified cationic liposomes overcomes pre-existing poxvirus immunity from recombinant vaccinia immunization

摘要

Development of a safe and effective vaccine for induction of mucosal immunity to the human immunodeficiency virus (HIV) envelope glycoprotein (Env, gp160) represents the best hope for containing the spread of an HIV epidemic worldwide. The highly attenuated modified vaccinia virus Ankara (MVA) is a laboratory virus well suited as a safe vaccine vector. However, the presence of pre-existing immunity to Vaccinia virus in the adult population represents a hindrance that limits the application of the MVA vector for inducing immunity to HIV antigens. Here, cationic liposomes were covalently attached to the surface of recombinant MVA expressing the HIV-1 strain IIIB Env glycoprotein and β-galactosidase (MVAIIIB/β-gal) using tresylmonomethoxypolyethylene glycol (TMPEG) grafted into a lipid membrane without compromising viral infectivity in vitro and in vivo. The orally administered MVAIIIB/β-gal–TMPEG/liposome complexes were capable of delivering the transgenes to mucosal tissues in mice with pre-existing poxvirus immunity based on β-galactosidase gene expression in intestinal tissues measured 18 h after infection. Importantly, the MVAIIIB/β-gal–TMPEG/liposome complexes enhanced Env-specific cellular and humoral immune responses in the mucosal and systemic tissues after repeated oral immunization of BALB/c mice. This approach may prove useful for induction of protective immunity against infectious diseases and cancer in populations with pre-existing immunity to vaccinia from smallpox vaccination.