ABSTRACT
Toxoplasma gondii (T. gondii) infection causes severe zoonotic toxoplasmosis, which threatens the safety of almost one-third of the human population globally. However, there is no effective protective vaccine against human toxoplasmosis. This necessitates anti-T. gondii vaccine development, which is a main priority of public health. In this study, we optimized the adjuvant system 04 (AS04), a vaccine adjuvant constituted by 3-O-desacyl-4'-monophosphoryl lipid A (a TLR4 agonist) and aluminum salts, by packing it within natural extracts of ß-glucan particles (GPs) from Saccharomyces cerevisiae to form a GP-AS04 hybrid adjuvant system. Through a simple mixing procedure, we loaded GP-AS04 particles with the total extract (TE) of T. gondii lysate, forming a novel anti-T. gondii vaccine GP-AS04-TE. Results indicated that the hybrid adjuvant can efficiently and stably load antigens, mediate antigen delivery, facilitate the dendritic uptake of antigens, boost dendritic cell maturation and stimulation, and increase the secretion of pro-inflammatory cytokines. In the mouse inoculation model, GP-AS04-TE significantly stimulated the function of dendritic cells, induced a very strong TE-specific humoral and cellular immune response, and finally showed a strong and effective protection against toxoplasma chronic and acute infections. This work proves the potential of GP-AS04 for exploitation as a vaccine against a range of pathogens.
Subject(s)
Adjuvants, Vaccine/therapeutic use , Aluminum Hydroxide/therapeutic use , Lipid A/analogs & derivatives , Nanocomposites/therapeutic use , Protozoan Vaccines/therapeutic use , Toxoplasma/immunology , Toxoplasmosis/prevention & control , Adjuvants, Vaccine/chemistry , Adjuvants, Vaccine/toxicity , Aluminum Hydroxide/chemistry , Aluminum Hydroxide/immunology , Aluminum Hydroxide/toxicity , Animals , Dendritic Cells/drug effects , Fungal Polysaccharides/chemistry , Fungal Polysaccharides/therapeutic use , Fungal Polysaccharides/toxicity , Immunity, Cellular/drug effects , Immunity, Humoral/drug effects , Lipid A/chemistry , Lipid A/immunology , Lipid A/therapeutic use , Lipid A/toxicity , Male , Mice, Inbred C57BL , Nanocomposites/chemistry , Nanocomposites/toxicity , Phagocytes/drug effects , Protozoan Vaccines/chemistry , Protozoan Vaccines/immunology , Protozoan Vaccines/toxicity , Saccharomyces cerevisiae/chemistry , Tissue Extracts/chemistry , Tissue Extracts/immunology , Tissue Extracts/therapeutic use , Tissue Extracts/toxicity , Toxoplasma/chemistry , Toxoplasmosis/immunology , beta-Glucans/chemistry , beta-Glucans/therapeutic use , beta-Glucans/toxicityABSTRACT
Adjuvants potentiate the immune response against co-inoculated antigens in the vaccine formulation. Based on the mechanism of action, the adjuvants are classified as immunostimulatory adjuvants and vaccine delivery systems. (S)-4,5-Dihydroxy-2,3-pentanedione (DPD) is the precursor of bacterial quorum sensing molecule, autoinducer (AI)-2. We tested the immunogenicity and adjuvant potential of microparticulate formulation of (S)-DPD via in vitro evaluation. By formulating the microparticles of (S)-DPD, we consolidated the advantages of both the classes of adjuvants. The microparticulate (S)-DPD was tested for its immunogenicity and cytotoxicity. We further tested its adjuvant effect by combining it with particulate vaccines for measles and gonorrhea and compared the adjuvant effect observed with the microparticulate formulations of the FDA-approved adjuvants alum, MPL A®, and MF59®. Microparticulate (S)-DPD was found to be non-cytotoxic towards the antigen-presenting cells and had an adjuvant effect with microparticulate gonorrhea vaccine. Further studies with additional bacterial vaccines and the in vivo evaluation will confirm the potential of microparticulate (S)-DPD as a probable vaccine adjuvant candidate.
