Self-Adjuvanting T Cell Epitope Lipopeptides Induce Interferon-Gamma-Producing Memory T Cells and Protect Against Ocular Herpes

Abstract

Purpose:: An important phase in developing an ocular herpes simplex virus type 1 (HSV-1) sub-unit vaccine is the identification of an adjuvant-free antigen delivery system capable of sustaining long-term memory T cell immunity. We showed recently that five immunodominant CD4(+) Th1-type T-cell peptide epitopes (gD1-29, gD49-82, gD146-179, gD228-257 and gD332-358), from HSV-1 glycoprotein D (gD) delivered in mice with Montanide ISA-720 adjuvant conferred protective immunity against ocular infection. (BenMohamed, et al, Virol. 77: 9463, 2003). We studied T cell immunity induced by these peptide epitopes covalently linked to a palmitic acid moiety (self-adjuvanting lipopeptides) using the high-yield chemoselective ligation method and delivered subcutaneously in adjuvant-free saline.

Methods:: The longevity of memory T cells induced by this molecularly defined vaccine formulation and its protective efficacy were assessed in a mouse model of ocular HSV-1 infection, in terms of virus replication in the eye, ocular disease and survival. The effect of CD4+CD25+ naturally occurring T cells on lipopeptide immunogenicity was also investigated.

Results:: Three out of five gD lipopeptides, that drive dendritic cell maturation in vitro, induced virus-specific primary and long-term memory CD4(+) Th1 responses, associated with a reduction in severity of ocular herpes infection and disease. Although no single lipopeptide protected against lethal ocular infection, immunization with a cocktail of the three highly immunogenic Th1 lipopeptides provided protection against lethal infection and resulted in a lower peak virus titer in eyes. Depletion of CD4+CD25+ naturally occurring T cells affected the immunogenicity of some lipopeptides.

Conclusions:: The efficacy and safety of these highly purified self-adjuvanting lipopeptides, together with the strength and durability of induced protective T cells provide a molecularly defined formulation that could serve as a model for a possible human HSV vaccine.

Keywords: herpes simplex virus • immunomodulation/immunoregulation • antigen presentation/processing