In vivo induction of a high-avidity, high-frequency cytotoxic T-lymphocyteresponse is associated with antiviral protective immunity

Many approaches are currently being developed to deliver exogenous antigen into the major histocompatibility complex class I-restricted antigen pathwa y, leading to in vivo priming of CD8(+) cytotoxic T cells. One attractive p ossibility consists of targeting the antigen to phagocytic or macropinocyti c antigen-presenting cells. In this study, we demonstrate that strong CD8() class I-restricted cytotoxic responses are induced upon intraperitoneal i mmunization of mice with different peptides, characterized as CD8(+) T-cell epitopes, bound to 1-mu m synthetic latex microspheres and injected in the absence of adjuvant. The cytotoxic response induced against a lymphocytic choriomeningitis virus (LCMV) peptide linked to these microspheres was comp ared to the cytotoxic T-lymphocyte (CTL) response obtained upon immunizatio n with the nonreplicative porcine parvovirus-like particles (PPV:VLP) carry ing the same peptide (PPV:VLP-LCMV) previously described (C. Sedlik, M, F, Saron, J, Sarraseca, I. Casal, and C, Leclerc, Proc. Natl. Acad, Sci, USA 9 4:7503-7508, 1997), We show that the induction of specific CTL activity by peptides bound to microspheres requires CD4(+) T-cell help in contrast to t he CTL response obtained with the peptide delivered by viral pseudoparticle s. Furthermore, PPV:VLP are 100-fold more efficient than microspheres in ge nerating a strong CTL response characterized by a high frequency of specifi c T cells of high avidity. Moreover, PPV:VLP-LCMV are able to protect mice against a lethal LCMV challenge whereas microspheres carrying the LCMV epit ope fail to confer such protection. This study demonstrates the crucial inv olvement of the frequency and avidity of CTLs in conferring antiviral prote ctive immunity and highlights the importance of considering these parameter s when developing new vaccine strategies.