The L.E.A.P.S.™ heteroconjugate vaccine antigen (JgD), composed of a T cell epitope from glycoprotein D (gD_8–23) of herpes simplex virus (HSV) linked with a peptide sequence from beta-2-microglobulin (aa38–50), elicited protection against lethal intraperitoneal (IP) challenge and prevented disease signs in most, and limited disease progression, for the rest of BALB/c mice challenged in the epidermal abrasion-zosteriform spread mouse infection model. JgD elicited a Th1 response in vaccinated mice as indicated by delayed type hypersensitivity (DTH) responses to HSV antigen, and gD and virion specific antibodies with an IgG2a/IgG1 >1. Vaccination with the JgD peptide delayed the onset of disease signs, reduced severity of the disease and reduced mortality rates in mice with different MHC backgrounds as compared to their respective control mice. CD8 cells were demonstrated as important for initiation of the immune response to JgD and CD4 cells and interferon gamma (IFN-γ) for delivering immune protection in BALB/c mice, as indicated in monoclonal antibody ablation studies. JgD, and other J-L.E.A.P.S.™ vaccine antigens, appear to prime T cells to initiate a Th1 response, which is subsequently boosted upon viral challenge to result in protection.