Phase I Dose-Escalation Study of a Monovalent Heat Shock Protein 70-Herpes Simplex Virus Type 2 (HSV-2) Peptide-Based Vaccine Designed To Prime or Boost CD8 T-Cell Responses in HSV-Naïve and HSV-2-Infected Subjects

Abstract

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...

Hsp110-Mediated Enhancement of CD4 + T Cell Responses to the Envelope Glycoprotein of Members of the Family Flaviviridae In Vitro Does Not Occur In Vivo

“…Our findings echo those of a phase I trial using a recombinant human Hsp70 preparation complexed to a herpes simplex virus (HSV) peptide (AG-702), which gave poor results, as no peptide-specific responses were detected in patients or healthy controls (13). A new formulation, which uses a combination of HSV peptides and adjuvants, is currently in phase I trials, and the results are anticipated soon.…”

Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine

“…Continuous cell lines were Mycoplasma negative (Lonza). moDCs were cultured from adherent or CD14 positively selected (Miltenyi) PBMCs using media, conditions, and recombinant human GM-CSF and IL-4 as described previously (53). Media (72, 79) used 10% Fetalclone III (Fisher) instead of FCS.…”

“…For direct testing of PBMCs ex vivo, duplicate IFN-γ ELISPOT was done as described previously, except that unmanipulated PBMCs were used (53). Thawed PBMCs were tested at 7.5 × 10 5 /well.…”

Proteomics for development of vaccine

“…Bionorpharma has made a vaccine composed of four synthetic peptides based on the major core protein p24 of HIV type I [119]. Anti-herpes simplex virus (HSV) vaccine, AG-707, consists of recombinant human heat shock protein Hsp70 combined with 32 synthetic peptides from the HSV-2 proteome and was designed as therapeutic vaccine for treatment of genital herpes (http://www.antigenics.com/, [120]). All candidate vaccines mentioned above have completed Phase I clinical testing.…”

“…Apart from vaccinia virus, many other viruses need improvement in existing vaccines. Although the use of peptide epitopes as an antiviral vaccine has so far not yielded a licensed product, several new strategies provided promising data [114,[119][120][121].…”