Heterologous Prime-Boost Immunizations with a Virosomal and an Alphavirus Replicon Vaccine

Abstract

Heterologous prime-boost immunization strategies in general establish higher frequencies of antigen-specific T lymphocytes than homologous prime-boost protocols or single immunizations. We developed virosomes and recombinant Semliki Forest virus (rSFV) as antigen delivery systems, each capable of inducing strong CTL responses in homologous prime-boost protocols. Here, we demonstrate that a heterologous prime-boost with recombinant Semliki Forest virus (rSFV) encoding a fusion protein of E6 and E7 of human papillomavirus (HPV) type 16 and virosomes containing the HPV16 E7 protein resulted in higher numbers of antigen-specific CTL in mice than homologous protocols. Evasion of vector-specific immunity appeared to play a role in establishing these high frequencies, as coinduction of vector-specific responses during the prime immunization reduced the frequency of antigen-specific CTL after a heterologous booster. However, the high numbers of CTL initially primed by the heterologous protocols did not correlate with enhanced responsiveness to in vitro antigenic stimulation, nor in improved cytolytic activity or antitumor responses in vivo compared to a homologous protocol with rSFV. This lack of correlation could not be explained by changes in numbers of regulatory T cells. However, we observed differences in the frequencies of T cell subsets within the E7-specific CD8(+) T cell population, e.g. higher frequencies of central memory T cells upon homologous immunizations compared to heterologous immunizations. The induction of central memory T cells is crucial for a cancer vaccine as these cells are known to rapidly expand upon recall stimulation. This study demonstrates that the strongly increased number of antigen-specific CTL as induced by heterologous prime-boost immunizations, often used as a proof for the enhanced efficacy of such regimes, does not necessarily equal superior functional antitumor responses.

Liposomes as vaccine delivery systems: a review of the recent advances

“…It is excellently tolerable and highly immunogenic, conferring protection of at least 9-11 years in vaccinated individuals [Ambrosch et al 1997;Gluck and Walti, 2000;Bovier et al 2010]. [Walczak et al 2011]. Today, a second generation of influenza virosomes has evolved for various preclinical and clinical stage vaccine candidates.…”

Potent therapeutic efficacy of an alphavirus replicon DNA vaccine expressing human papilloma virus E6 and E7 antigens

“…40,41 It has also been previously observed that homologous SFV replicon immunization results in better tumor control over homologous adenovirus immunization or heterologous immunization due to a favored central memory T cell response. 39,42 It would also be of value to determine whether this decrease is due to T cell exhaustion and hence, assessment of exhaustion markers, such as programmed death protein 1 (PD-1) is warranted.…”

Virosome, a hybrid vehicle for efficient and safe drug delivery and its emerging application in cancer treatment

“…Virosome-fomulated cervical cancer vaccines have been actively studied recently (74,75). In a murine model system, a vigorous class I MHC-restricted cytotoxic T-lymphocyte (CTL) response against HPV-transformed tumor cells was established by using fusion-active infl uenza virosomes which contained recombinant human papillomavirus type 16 (HPV16) E7 protein antigen.…”