Protective immunity against ocular herpes infection and disease induced by highly immunogenic self-adjuvanting glycoprotein D lipopeptide vaccines.
OBJECTIVE
An important phase in the development of an ocular herpes simplex virus type 1 (HSV-1) subunit vaccine is the identification of an efficient, safe, and adjuvant-free antigen delivery system capable of inducing and sustaining long-term memory T-cell protective immunity. This study was conducted to test the hypothesis that immunization with self-adjuvanting lipopeptide bearing HSV-1 glycoprotein D (gD) T-cell epitopes would elicit long-term HSV-specific T cells and decrease infection, disease, or both in a ocular herpes mouse model.


METHODS
Five immunodominant CD4(+) T-cell peptide epitopes (gD(1-29), gD(49-82), gD(146-179), gD(228-257), and gD(332-358)), recently identified from HSV-1 gD, were covalently linked to a palmitic acid moiety (lipopeptides) and delivered subcutaneously in adjuvant-free saline. The primary and memory T cells induced by these molecularly defined lipopeptides and their protective efficacy were assessed, in terms of virus replication in the eye, ocular disease, and survival.


RESULTS
Three gD lipopeptides, that drive dendritic cell maturation in vitro, induced long-term, virus-specific, IFN-gamma-producing CD4(+) Th(1) responses, associated with a reduction in ocular herpes infection and disease. Immunization with a cocktail of these three highly immunogenic Th(1) lipopeptides increased survival, lowered the peak of ocular virus titer, and cleared the ocular disease.


CONCLUSIONS
Vaccination with a mixture self-adjuvanting lipopeptides containing novel HSV-1 immunodominant gD T-cell epitopes protected mice from ocular herpes infection and disease. The strength of protective immunity induced by these lipopeptides together with their safety provide a molecularly defined vaccine formulation that could combat ocular herpes infection and disease in humans.
Bettahi
Ilham
I
Laboratory of Cellular and Molecular Immunology, The Eye Institute, School of Medicine, University of California Irvine, Irvine, California 92868, USA.
Nesburn
Anthony B
AB
Yoon
Susan
S
Zhang
Xiuli
X
Mohebbi
Amir
A
Sue
Valerie
V
Vanderberg
Aaron
A
Wechsler
Steven L
SL
BenMohamed
Lbachir
L
D000276:Adjuvants, Immunologic; D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D022301:Herpes Simplex Virus Vaccines / Q000008:administration & dosage*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D007109:Immunity; D007114:Immunization; D016056:Immunodominant Epitopes / Q000276:immunology; D016849:Keratitis, Herpetic / Q000276:immunology / Q000517:prevention & control*; D008074:Lipoproteins / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology*; D014611:Vaccination; D014759:Viral Envelope Proteins / Q000276:immunology*; D014779:Virus Replication
D000276:Adjuvants, Immunologic; D018984:Epitopes, T-Lymphocyte; D022301:Herpes Simplex Virus Vaccines; D016056:Immunodominant Epitopes; D008074:Lipoproteins; D010446:Peptide Fragments; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1