There is a current biodefense interest in protection against Anthrax. Here we developed a new generation of stable and effective anthrax vaccine. We studied the immune response elicited by rPA delivered intranasally with a novel mucosal adjuvant, a mast cell activator Compound 48/80. The vaccine formulation was prepared in a powder form by spray-freeze-drying (SFD) under optimized conditions to produce particles with a target size of D50=25μm, suitable for delivery to the rabbit nasal cavity. Physicochemical properties of the powder vaccines were characterized to assess their delivery and storage potential. Structural stability of rPA was confirmed by CD and ATR-FTIR, while functional stability of rPA and C48/80 was monitored by cell-based assays. Animal study was performed using a unitdose powder device for direct nasal application. Results showed that C48/80 provided effective mucosal adjuvant activity in rabbits. Freshly prepared SFD powder vaccine formulations or powders stored for over two years at room temperature elicited significantly elevated serum PA-specific and lethal toxin neutralization antibody titers that were comparable to that induced by IM immunization with rPA. Nasal delivery of this vaccine formulation may be a viable alternative to the currently licensed vaccine, or an attractive vaccine platform for other mucosally transmitted diseases.
IL-1α and IL-1β were evaluated for their ability to provide adjuvant activity for the induction of serum antibody responses when nasally-administered with protein antigens in mice and rabbits. In mice, intranasal (i.n.) immunization with pneumococcal surface protein A (PspA) or tetanus toxoid (TT) combined with IL-1β induced protective immunity that was equivalent to that induced by parenteral immunization. Nasal immunization of awake (i.e., not anesthetized) rabbits with IL-1-adjuvanted vaccines induced highly variable serum antibody responses and was not as effective as parenteral immunization for the induction of antigen-specific serum IgG. However, i.n. immunization of deeply anesthetized rabbits with rPA + IL-1α consistently induced rPA-specific serum IgG ELISA titers that were not significantly different than those induced by intramuscular (IM) immunization with rPA + alum although lethal toxin neutralizing titers induced by nasal immunization were lower than those induced by IM immunization. Gamma scintigraphy demonstrated that the enhanced immunogenicity of nasal immunization in anesthetized rabbits correlated with an increased nasal retention of i.n. delivered non-permeable radio-labeled colloidal particles. Our results demonstrate that, in mice, IL-1 is an effective adjuvant for nasally-administered vaccines for the induction of protective systemic immunity and that in non-rodent species, effective induction of systemic immunity with nasally-administered vaccines may require formulations that ensure adequate retention of the vaccine within the nasal cavity.
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