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.

A Chimeric Multi-Human Epidermal Growth Factor Receptor-2 B Cell Epitope Peptide Vaccine Mediates Superior Antitumor Responses

“…We have demonstrated in the past that this chimeric peptide vaccine strategy can elicit robust Ab responses in multiple strains of mice and outbred animals (24,57,84,85). In the present study we evaluated four novel HER-2 B cell epitopes to assess the possibility of developing a multiepitope peptide vaccine that could elicit a superior antitumor response.…”

A paradigm shift: Cancer therapy with peptide-based B-cell epitopes and peptide immunotherapeutics targeting multiple solid tumor types: Emerging concepts and validation of combination immunotherapy

“…28 We addressed the third hurdle by engineering chimeric peptide constructs by incorporating a 'promiscuous' T-cell epitope, which can bind multiple haplotypes with the appropriate B-cell epitope. 29 We surveyed several "promiscuous" T cell-epitope and found that the measle virus fusion (MVF) protein (epitope sequence 298-302) to be the most efficacious. Another T-helper epitope peptide P30 from tetanus toxoid was used as the immunostimulant in MUC1 glycopeptide antitumor vaccines and apparently it also acts as a builtin adjuvant P30-conjugated glycopeptide vaccines.…”

“…[36][37][38][39][40][41] We begin by predicting B-cell epitopes followed by molecular modeling to recapitulate the native structure of the tumor antigen. 23,29,42 This is followed by the design of the chimeric vaccine by incorporating a "promiscuous" T cell epitope for the production of antipeptide-antibodies in animals. [25][26][27]43 Stable peptide mimics are designed, synthesized and tested in a series of in vitro assays in different human cancer cell lines to corroborate efficacy with antipeptide antibodies.…”

Injectable polymer microspheres enhance immunogenicity of a contraceptive peptide vaccine

“…A synthetic peptide antigen, C-TT2-CTP35, consisting of a B-cell epitope from CTP (residues 111-145) [7] and a T-cell epitope from tetanus toxoid (TT) (residues 830-844, designated as TT2) [8,9] has been shown to elicit antibody responses comparable to those induced by the same CTP fragment conjugated to diphtheria toxoid [10]. As a "promiscuous" or universal T-cell epitope, TT2 provides advantage of not being MHC-restricted and thus broadly reactive in multiple haplotypes, as compared with TT or diphtheria toxoid, which often have been used as carriers for hCG vaccines to provide the T-cell helper effect [8,9]. However, strong adjuvant oily vehicles such as a combination of squalene, surface active agents, and/or bacteria surface component analogues were necessary to induce strong immune responses to C-TT2-CTP35 -a recurring problem for poorly immunogenic peptide vaccines [3,10].…”