There is a great need for developing safe, yet effective adjuvants for vaccine applications. With the increasing need in generating protective and therapeutic vaccines against a wide range of established and emerging infectious pathogens (Class A, B and C), it is critical that platform technologies and effective adjuvants are developed that might be widely applicable to a variety of disease targets. Currently, aluminum salts (Alum) are the only FDA approved vaccine adjuvants in the US. However, its safety, efficacy and applicability in stimulating a balanced humoral and cellular immunity in a wide range of vaccines, especially genetic vaccines, is questionable. Although, several new adjuvants are in pre-clinical and clinical trials and some have been approved in European markets, the primary drawback has been adjuvant-associated toxicity. Successful vaccine development still requires new and improved adjuvants. It has been observed that polymer microparticles could act as effective adjuvants when delivered with protein/peptide antigens, although the precise mechanisms are mostly speculative. The adjuvancy is likely due to (a) passive targeting to dendritic cells (DCs) (b) a sustained release (depot) effect leading to prolonged antigen exposure and (c) recent observations of significantly improved antigen presentation by DCs by as yet unidentified mechanism. We have developed a novel, surface-functionalized, microparticle design for the combinatorial delivery of genetic vaccines and associated immuno-stimulatory molecules. The fundamental hypotheses are (i) rational combination of biodegradable polymers with transfection-enhancing polyamines would increase pDNA transfection to antigen presenting cells and (ii) a sustained gradient of DC chemo-attractants from the administered formulation would significantly enhance delivery efficacy leading to increased immune response against genetic antigens. We propose here, a strategy for combinatorial delivery of chemokines and surface-adsorbed pDNA antigens/adjuvants within a single injectable formulation. These concepts, in synergy, should significantly enhance the adjuvancy of synthetic polymer particles in delivering pDNA vaccines for a wide range of established and emerging infectious diseases. ? ? ?
| Singh, Ankur; Suri, Shalu; Roy, Krishnendu (2009) In-situ crosslinking hydrogels for combinatorial delivery of chemokines and siRNA-DNA carrying microparticles to dendritic cells. Biomaterials 30:5187-200 |
