title: Peptide vaccines incorporating a 'promiscuous' T-cell epitope bypass certain haplotype restricted immune responses and provide broad spectrum immunogenicity.
abstract: An ideal peptide vaccine should contain both B- and T-cell epitopes. Recognition of antigen by B cells is highly dependent on the three-dimensional conformation of the antigen whereas T cells recognize antigen only after it has been processed to release a peptide fragment which is bound to the major histocompatibility complex (MHC) class II molecule. However, T cells provide 'help' to B cells displaying the same processed, MHC-restricted form of the antigen, demonstrating that the T-cell response to a protein antigen is under genetic control. Thus, strategies for co-inclusion of T cell 'helper' epitopes with the B-cell determinant elicit immune responses that are in most cases genetically restricted to only one or a few alleles of the MHC with limited activity across divergent MHC class II haplotypes. This genetically restricted T cell stimulatory activity of peptides is a serious obstacle and consequently such constructs would be of limited practical value as a vaccine targeted to a majority of an outbred population. In the study described here, we have engineered two peptides to encompass the sequences from the universally immunogenic tetanus toxoid (TT) epitope and the contraceptive vaccine candidate lactate dehydrogenase C4 (LDH-C4). We demonstrate the feasibility of using 'promiscuous' T-cell epitopes colinearly constructed with a defined B-cell epitope to induce high titer antipeptide IgG antibodies specific for native protein antigen LDH-C4 in several inbred strains of mice, outbred mice and rabbits. There appears to be a strong correlation between the capacity for the hybrid peptides to be stimulatory for the corresponding T cells in C57BL/6 (H-2b) and C3H/HeJ (H-2k) mice and their ability to be immunogenic. This correlation, however, appears to break down in H-2d strains of mice since no antibodies were detected in BALB/c and barely detectable levels of antibodies in B10.D2 although activated T cells were detectable. Conversely, high titers of antipeptide antibodies are elicited in some strains (B10.BR (H-2k); C57BL/10 (H-2b) without detectable IL-2 responses. Finally, we show that a determinant which was previously restricted to H-2k can be rendered immunogenic in H-2b with the 'promiscuous' TT epitope. Thus, certain haplotype-restricted immune responses can be bypassed, setting forth the ground work for the design of a universal vaccine by broadening the effective response in a larger number of individuals typical of the genetically diverse outbred human population.
authors.affiliation: College of Medicine, Department of Obstetrics and Gynecology, Ohio State University, Columbus 43210.
authors.forename: P T
authors.initials: PT
authors.lastname: Kaumaya
authors.forename: S
authors.initials: S
authors.lastname: Kobs-Conrad
authors.forename: Y H
authors.initials: YH
authors.lastname: Seo
authors.forename: H
authors.initials: H
authors.lastname: Lee
authors.forename: A M
authors.initials: AM
authors.lastname: VanBuskirk
authors.forename: N
authors.initials: N
authors.lastname: Feng
authors.forename: J F
authors.initials: JF
authors.lastname: Sheridan
authors.forename: V
authors.initials: V
authors.lastname: Stevens
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis*; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D005260:Female; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D008285:Major Histocompatibility Complex; D051379:Mice; D008815:Mice, Inbred Strains / Q000276:immunology; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology; D015202:Protein Engineering; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011817:Rabbits / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013745:Tetanus Toxoid / Q000276:immunology*; D014614:Vaccines, Synthetic
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D010455:Peptides; D013745:Tetanus Toxoid; D014614:Vaccines, Synthetic