This was a phase I study to assess the safety, tolerability, and immunogenicity of escalating doses of AG-702, a noncovalent complex of an HLA A*0201-restricted epitope in the glycoprotein B protein of herpes simplex virus type 2 (gB2) and truncated human constitutive heat shock protein 70. Similar vaccines have been immunogenic in animals. Three injections of 10 to 250 g were administered intradermally to HLA A*0201-bearing subjects who were either herpes simplex virus type 2 (HSV-2)-infected or HSV uninfected. Sixty-two participants received the vaccine, 60 completed the protocol, and T-cell data were accrued for 56 subjects. The vaccine was safe and well tolerated. New or boosted responses to the HSV-2 CD8 epitope were not detected. Baseline responses to an epitope in virion proteins 13/14 were higher than responses to the gB2 epitope. A heat shock protein vaccine with an HSV-2 peptide appears to be safe at the doses studied in healthy adults with or without HSV infection. Modifications of the dose, adjuvant, route, schedule, or HSV antigen may be required to improve responses.Herpes simplex virus type 2 (HSV-2) is a major cause of genital ulcer disease, causing severe infections in neonates and immunocompromised persons, and it is a cofactor in human immunodeficiency virus type 1 (HIV-1) transmission (5). Existing HSV control strategies, including oral nucleoside therapy (6) and regular use of condoms (50), have logistic, biological, or behavioral limitations. It has been proven that limiting HSV-2 shedding can limit HSV-2 transmission (6). Intensive research has focused on therapeutic and prophylactic vaccines to limit HSV-2 shedding and disease. Immunotherapy with HSV-2 glycoproteins has demonstrated short-term efficacy but substantial reactogenicity with some adjuvants (8,43,44). This vaccine format is known to elicit or boost antibody and CD4-cell responses but is unlikely to boost CD8 responses (23,42).Several lines of evidence support critical roles for CD8 T cells in the control of HSV infections. Local infiltration of HSV-specific cytotoxic T lymphocytes (CTL) correlates with the clearance of infectious HSV-2 in human recurrent genital herpes (26). HSV-2-specific CD8 T cells persistently infiltrate healed genital herpes lesions and localize near sensory nerve endings (53). HSV-specific CD8 T cells with cytotoxic and gamma interferon (IFN-␥) functional activity also localize to latently infected human trigeminal ganglia (48). The precursor frequency of HSV-2-specific CD8 CTL is correlated with HSV-2 severity in HIV-1/HSV-2-coinfected men (37), and cross-sectional studies show human leukocyte antigen (HLA) class I associations with HSV-2 severity (29). In mice, HSV-2-specific CD8 T cells infiltrate acutely and latently infected ganglia and mediate control over viral reactivation in an IFN-␥-dependent manner (20). Vaccines containing a CD8 epitope as the sole HSV component can protect mice from HSV challenge (4). Candidate replication-competent and -incompetent HSV strains have entered clinical trials a...