Chimeric human papillomavirus virus-like particles (HPV cVLPs), containing the HPV16 non-structural protein E7, are potent vaccines for inducing antigen-specific protective immunity against HPV-transformed tumors in animal models. Previous data demonstrated that the effectiveness of cytotoxic T lymphocyte (CTL) induction after repetitive vaccination with the same cVLP, and thus vaccine efficacy, is limited by the presence of neutralizing antibodies induced after the first application. Here, we determined if altering the route of vaccine delivery or incorporation of the target antigen into VLPs of a heterologous papillomavirus type could overcome inhibition of MHC class I antigen presentation by neutralizing antibodies, resulting in a boosting of CD8(+) T-cell responses against the incorporated antigen, HPV16 E7. Mucosal delivery of cVLPs resulted in detection of systemic E7-specific CD8(+) T cells, however, these routes were not able to bypass the inhibitory effect of circulating antibodies against homologous VLP types. In contrast, mice immunized and boosted with heterologous cVLPs containing HPV16 E7 showed a higher frequency of E7-specific T cells in vitro and displayed reduced tumor growth in a therapeutic setting compared to mice treated with homologous cVLPs. The data indicate that the use of different cVLP types for prime/boost regimens is a promising strategy to increase the efficacy and usefulness of cVLP-based vaccines for the treatment of cervical neoplasia.