Vaccines against many pathogens for which conventional approaches have failed remain an unmet public health priority. Synthetic peptide-based vaccines offer an attractive alternative to whole protein and whole organism vaccines, particularly for complex pathogens that cause chronic infection. Previously, we have reported a promising lipid core peptide (LCP) vaccine delivery system that incorporates the antigen, carrier, and adjuvant in a single molecular entity. LCP vaccines have been used to deliver several peptide subunit-based vaccine candidates and induced high titre functional antibodies and protected against Group A streptococcus in mice. Herein, we have evaluated whether LCP constructs incorporating defined CD4+ and/or CD8+ T cell epitopes could induce epitope-specific T cell responses and protect against pathogen challenge in a rodent malaria model. We show that LCP vaccines failed to induce an expansion of antigen-specific CD8+ T cells following primary immunization or by boosting. We further demonstrated that the LCP vaccines induced a non-specific type 2 polarized cytokine response, rather than an epitope-specific canonical CD8+ T cell type 1 response. Cytotoxic responses of unknown specificity were also induced. These non-specific responses were able to protect against parasite challenge. These data demonstrate that vaccination with lipid core peptides fails to induce canonical epitope-specific T cell responses, at least in our rodent model, but can nonetheless confer non-specific protective immunity against Plasmodium parasite challenge.
The immunoneutralization of gonadotropin-releasing hormone (GnRH) can be used for the treatment of human hormone-dependent male and female cancers or as immunocontraceptives in animals. Vaccine candidates 1 [Th(K-LP)GnRH], 2 [GnRH(K-LP)Th], 3 [GnRH(K-Th)LP], and 4 [Th(K-GnRH)LP] (for which K=lysine, LP=lipopeptide Ser-Ser-C16 -C16 , and Th=T helper cell epitope influenza HA2), were synthesized by assembling a CD4(+) T helper cell epitope (Th), GnRH, and an adjuvanting lipid moiety (LP) in various spatial arrangements. All compounds were efficiently taken up by antigen-presenting cells with significant immunogenicity without an external adjuvant. Compounds 2, 3, and 4, in which GnRH is conjugated through its C terminus, produced higher GnRH-specific antibody responses than construct 1, in which the GnRH moiety is conjugated through its N terminus. All four constructs induced a significant antiproliferative effect (up to 55 %) on GnRH-receptor-positive LNCaP cells, but showed weaker activity in the GnRH-receptor-negative SKOV-3 cell line. Marked degenerative changes were observed in morphology and follicular development in the ovaries of immunized mice, with approximately 30 % higher degenerative antral and atretic follicles.
Luteinising hormone-releasing hormone (LHRH), also known as gonadotropin-releasing hormone (GnRH) and luliberin, is a key hormone associated with controlling functions of reproductive organs in both males and females. Anti-LHRH vaccines can produce immunity against LHRH resulting in castration effects, which can be applied for contraception in animals or the treatment of hormone-dependent diseases. A selfadjuvanting delivery system for peptide-based vaccines is a safe and effective approach to address the problem of toxic adjuvants used in animals and humans. Lipid core peptide (LCP) provides self-adjuvanting properties and is recognised to interact with specific Tolllike receptors on antigen presenting cells. Lipidic adjuvant, in conjugation with polylysine or a carbohydrate core in a multiple antigen peptide (MAP) system, has shown significant contribution to enhance the immunogenicity of small antigens like peptides and these approaches of modification have been adapted to reder immunogenicity studies.One of the approaches is use carbohydrates to induce immunity is an effective and new strategy if the obstacles associated with poor quality of antibody response are overcome.Modified monosaccharaides such as glucose or galactose scaffold offer MAP system-like properties that provide attachment sites for conjugation of multiple identical epitopes.Moreover, different carbohydrate groups provide different orientations for the side chains.This structural conformation-related effect may augment immunity in vaccination. A carbohydrate-based anti-LHRH vaccine candidate was synthesised with a galactose scaffold. D-galactose was modified as a scaffold to provide conjugation sites for the attachment of four LHRH epitopes. However, due to low efficiency of the method, the synthesis resulted in a low yield of galactose scaffold, therefore sufficient final vaccine candidate was not achieved to be used in immunological studies.Another approache of modification uses three components to form four branched vaccine Overall, this project unravelled the ability of different applied synthetic strategies and delivery systems to stimulate anti-LHRH immune response, and contributes to the development of future immunocontraceptives or vaccines against hormone-dependent cancers.iv
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