We attempted to improve the immunogenicity of the adenovirus-based vaccine by protecting it from the harsh environment of the gastrointestinal tract and from neutralization by antiadenovirus antibodies by PEGylation. Interestingly, the T-cell mediated immune response was significantly reduced and antibody levels increased in naïve animals given a single oral dose of the PEGylated vaccine with respect to that seen in animals given the same dose of unmodified Ad5-ZGP. It has been shown that modification of virus capsids by PEGylation can significantly dampen the T-cell mediated immune response against the virus and stimulate the antibody response against a secreted antigen [26, 27, 30, 54] . Taken together, these data support the notion that the exposition of the virus capsid proteins facilitates the immune response against the encoded antigen. Optimization of PEGylation chemistries and/or densities on adenovirus-based vaccine that promote and strengthen protective immune responses following oral immunization is currently underway.