37 research outputs found
Design of Peptide-Based Nanovaccines Targeting Leading Antigens From Gynecological Cancers to Induce HLA-A2.1 Restricted CD8+ T Cell Responses
Gynecological cancers are a leading cause of mortality in women. CD8(+) T cell immunity largely correlates with enhanced survival, whereas inflammation is associated with poor prognosis. Previous studies have shown polystyrene nanoparticles (PSNPs) are biocompatible, do not induce inflammation and when used as vaccine carriers for model peptides induce CD8(+) T cell responses. Herein we test the immunogenicity of 24 different peptides, from three leading vaccine target proteins in gynecological cancers: the E7 protein of human papilloma virus (HPV); Wilms Tumor antigen 1 (WT1) and survivin (SV), in PSNP conjugate vaccines. Of relevance to vaccine development was the finding that a minimal CD8(+) T cell peptide epitope from HPV was not able to induce HLA-A2.1 specific CD8(+) T cell responses in transgenic humanized mice using conventional adjuvants such as CpG, but was nevertheless able to generate strong immunity when delivered as part of a specific longer peptide conjugated to PSNPs vaccines. Conversely, in most cases, when the minimal CD8(+) T cell epitopes were able to induce immune responses (with WT1 or SV super agonists) in CpG, they also induced responses when conjugated to PSNPs. In this case, extending the sequence around the CD8(+) T cell epitope, using the natural protein context, or engineering linker sequences proposed to enhance antigen processing, had minimal effects in enhancing or changing the cross-reactivity pattern induced by the super agonists. Nanoparticle approaches, such as PSNPs, therefore may offer an alternative vaccination strategy when conventional adjuvants are unable to elicit the desired CD8(+) T cell specificity. The findings herein also offer sequence specific insights into peptide vaccine design for nanoparticle-based vaccine carriers
A nanoparticle based Sp17 peptide vaccine exposes new immuno-dominant and species cross-reactive B cell epitopes
Sperm protein antigen 17 (Sp17), expressed in primary as well as in metastatic lesions in >83% of patients with ovarian cancer, is a promising ovarian cancer vaccine candidate. Herein we describe the formulation of nanoparticle based vaccines based on human Sp17 (hSp17) sequence derived peptides, and map the immuno-dominant T cell and antibody epitopes induced using such formulations. The primary T and B cell immuno-dominant region within Sp17 was found to be the same when using biocompatible nanoparticle carriers or the conventional "mix-in" pro-inflammatory adjuvant CpG, both mapping to amino acids (aa) 111-142. However, delivery of hSp17111-142as a nanoparticle conjugate promoted a number of new properties, changing the dominant antibody isotype induced from IgG2a to IgG1 and the fine specificity of the B cell epitopes within hSp17111-142, from an immuno-dominant region 134-142 aa for CpG, to region 121-138 aa for nanoparticles. Associated with this change in specificity was a substantial increase in antibody cross-reactivity between mouse and human Sp17. These results indicate conjugation of antigen to nanoparticles can have major effects on fine antigen specificity, which surprisingly could be beneficially used to increase the cross-reactivity of antibody responses
A nanoparticle based Sp17 peptide vaccine exposes new immuno-dominant and species cross-reactive B cell epitopes
Sperm protein antigen 17 (Sp17), expressed in primary as well as in metastatic lesions in >83% of patients with ovarian cancer, is a promising ovarian cancer vaccine candidate. Herein we describe the formulation of nanoparticle based vaccines based on human Sp17 (hSp17) sequence derived peptides, and map the immuno-dominant T cell and antibody epitopes induced using such formulations. The primary T and B cell immuno-dominant region within Sp17 was found to be the same when using biocompatible nanoparticle carriers or the conventional "mix-in" pro-inflammatory adjuvant CpG, both mapping to amino acids (aa) 111-142. However, delivery of hSp17111-142as a nanoparticle conjugate promoted a number of new properties, changing the dominant antibody isotype induced from IgG2a to IgG1 and the fine specificity of the B cell epitopes within hSp17111-142, from an immuno-dominant region 134-142 aa for CpG, to region 121-138 aa for nanoparticles. Associated with this change in specificity was a substantial increase in antibody cross-reactivity between mouse and human Sp17. These results indicate conjugation of antigen to nanoparticles can have major effects on fine antigen specificity, which surprisingly could be beneficially used to increase the cross-reactivity of antibody responses
CΡΠ°Π½Π΄Π°ΡΡΡΠ·ΠΎΠ²Π°Π½Π½ΠΈΠΉ Π΅ΠΊΡΡΡΠ°ΠΊΡ Ρ ΠΌΠ΅Π»Ρ Π² ΠΏΠΎΠ»Π΅Π³ΡΠ΅Π½Π½Ρ ΡΠΈΠΌΠΏΡΠΎΠΌΡΠ² ΠΌΠ΅Π½ΠΎΠΏΠ°ΡΠ·ΠΈ
ΠΠ½ΡΠ΅ΡΠ΅Ρ ΠΊ ΠΏΡΠΈΠΌΠ΅Π½Π΅Π½ΠΈΡ ΡΠΈΡΠΎΡΡΡΡΠΎΠ³Π΅Π½ΠΎΠ² ΠΏΡΠΈ Π²Π΅Π΄Π΅Π½ΠΈΠΈ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ² Ρ ΠΊΠ»ΠΈΠΌΠ°ΠΊΡΠ΅ΡΠΈΡΠ΅ΡΠΊΠΈΠΌΠΈ ΠΆΠ°Π»ΠΎΠ±Π°ΠΌΠΈ Ρ ΠΊΠ°ΠΆΠ΄ΡΠΌ Π³ΠΎΠ΄ΠΎΠΌ Π²ΠΎΠ·ΡΠ°ΡΡΠ°Π΅Ρ. Π€ΠΈΡΠΎΡΡΡΡΠΎΠ³Π΅Π½Ρ β ΡΡΠΎ ΠΏΡΠ΅ΠΈΠΌΡΡΠ΅ΡΡΠ²Π΅Π½Π½ΠΎ Π½Π΅ΡΡΠ΅ΡΠΎΠΈΠ΄Π½ΡΠ΅ ΠΏΠΎΠ»ΠΈΡΠ΅Π½ΠΎΠ»ΡΠ½ΡΠ΅ ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΡ ΡΠ°ΡΡΠΈΡΠ΅Π»ΡΠ½ΠΎΠ³ΠΎ ΠΏΡΠΎΠΈΡΡ
ΠΎΠΆΠ΄Π΅Π½ΠΈΡ, ΡΡΠ½ΠΊΡΠΈΠΎΠ½Π°Π»ΡΠ½ΠΎ ΠΈΠΌΠΈΡΠΈΡΡΡΡΠΈΠ΅ Π΄Π΅ΡΡΠ΅Π»ΡΠ½ΠΎΡΡΡ ΡΠ΅Π»ΠΎΠ²Π΅ΡΠ΅ΡΠΊΠΎΠ³ΠΎ ΡΡΡΡΠΎΠ³Π΅Π½Π° ΠΈ 17Ξ²-ΡΡΡΡΠ°Π΄ΠΈΠΎΠ»Π°. Π Π½Π°ΠΈΠ±ΠΎΠ»Π΅Π΅ Π½Π°ΡΡΡΠ΅Π½Π½ΡΠΌ ΠΈΡΡΠΎΡΠ½ΠΈΠΊΠ°ΠΌ ΡΠΈΡΠΎΡΡΡΡΠΎΠ³Π΅Π½ΠΎΠ² ΠΎΡΠ½ΠΎΡΡΡ ΡΠΎΡ ΠΈ ΠΊΡΠ°ΡΠ½ΡΠΉ ΠΊΠ»Π΅Π²Π΅Ρ (ΠΈΠ·ΠΎΡΠ»Π°Π²ΠΎΠ½Ρ), ΡΠ΅ΠΌΠ΅Π½Π° Π»ΡΠ½Π° (Π»ΠΈΠ³Π½Π°Π½Ρ) ΠΈ Ρ
ΠΌΠ΅Π»Ρ (ΠΏΡΠ΅Π½ΠΈΠ»ΡΠ»Π°Π²ΠΎΠ½ΠΎΠΈΠ΄Ρ) (Cos et al., 2003)
Mapping T and B cell epitopes in sperm protein 17 to support the development of an ovarian cancer vaccine
Ovarian cancer (OC) is the seventh most common cancer in women worldwide, and the leading cause of death from gynaecological malignancy. Immunotherapeutic strategies including cancer vaccines are considered less toxic and more specific than current treatments. Sperm surface protein (Sp17) is a protein aberrantly expressed in primary as well as in metastatic lesions in >83% of ovarian cancer patients. Vaccines based on the Sp17 protein are immunogenic and protective in animal models. To map the immunogenic regions and support the development of human Sp17 peptide based vaccines, we used 6 overlapping peptides of the human Sp17 sequence adjuvanted with CpG to immunise humanised HLA-A2.1 transgenic C57BL/6 mice, and assessed immunogenicity by ELISPOT and ELISA. No CD8 T cells were found to be induced to a comprehensive panel of 10 HLA-A2.1 or H-2K(b) binding predicted epitopes. However, one of the 6 peptides, hSp17111-142, induced high levels of antibodies and IFN-Ξ³ producing T cells (but not IL-17 or IL-4) both in C57BL/6 and in C57BL/6-HLA-A2.1 transgenic mice. C57BL/6 mice immunised with CpG adjuvanted hSp17111-142 significantly prolonged the life-span of the mice bearing the ovarian carcinoma ID8 cell line. We further mapped the immuno-dominant B and T cell epitope regions within hSp17111-142 using ELISPOT and competition ELISA. Herein, we report the identification of a single immuno-dominant B cell (134-142 aa) epitope and 2 T helper 1 (Th1) cell epitopes (111-124 aa and 124-138 aa). These result together support further exploration of hSp17111-142 peptide formulations as vaccines against ovarian cancer