Characterisation of the immunological events induced by biodegradable polymer vaccines.

Abstract

This study was performed to unravel the adjuvant mechanisms of biodegradable microsphere vaccines based on poly (lactide-co-glycolide) (PLGA) polymer. Those microspheres have been extensively investigated as efficient vaccine adjuvant and delivery systems. However, their mode of action and their in vivo processing remain unclear. A better understanding of the adjuvant mechanisms would prove essential for the design of new generation vaccines required to be safer, given in less doses and stable at room temperature. This study focused on the sub-cutaneous administration of encapsulated protein models diphtheria and tetanus toxoids (DT and TT). The experimental work covered three aspects: (i) the uptake and transport of subcutaneously injected PLGA MS DT by macrophages and dendritic cells in vivoin mice; (ii) the influence of physico-chemical properties of the PLGA MS formulations on the toxoids immunogenicity in mice and guinea pigs; (iii) the immunogenicity of a multivalent encapsulated PLGS MS loaded with individual or multiple childhood vaccine antigens. This is probably the first study on the particle uptake and biodistribution of sub-cutaneously injected PLGA MS by antigen presenting cells in mice. Tracking of the fluorescent particles by microscopy confirmed previously postulated adjuvant mechanisms such as the depot effect at the injection site mimicking multiple injections; the efficient uptake of the particles by antigen presenting cells (APCs) and the active transport and relocalisation of the particles within lymphoid organs via APCs. These mechanisms were influenced mainly by the hydrophobic nature of the polymer and the size of the microspheres. When the formulation was optimized, a single dose of microencapsulated vaccine on its own (without addition of a potent adjuvant) protected better than two doses of the commercial alum-adsorbed vaccine. This study also demonstrates the feasibility of a multivalent paediatric encapsulated vaccine based on diphtheria, tetanus, pertussis and Hib antigens. The implementation of such a vaccine in the immunisation schedule would be a major achievement in the reduction of the number of injections given to the infants.