| Two of the worst global infectious diseases, smallpox and polio, have been virtually eliminated by widespread immunization programs. By contrast, vaccines for many other infectious diseases, such as human immunodeficiency virus and malaria, are poorly developed or simply unavailable. There is a critical need for flexible vaccine delivery systems that address the shortcomings of current vaccines and can be modulated to confront pathogens that are continually emerging and changing. Presented here is a class of nanomaterials endowed with material properties that allow for rapid optimization of vaccine design. The aim was to mimic infectious agents by incorporating antigen and pathogen-associated molecular patterns into a single biodegradable carrier that can easily cross biological barriers.;The carrier was chosen by directly comparing the two most ubiquitous drug and vaccine delivery vehicles, liposomes and poly (lactic-co-glycolic acid) (PLGA) nanoparticles, for immunization efficacy using a model antigen, ovalbumin. Vaccination with PLGA nanoparticles generated a population of effector-like lymphocytes that was two-fold larger and more adept at clearing a bacterial infection, compared to vaccination with liposomes. Thus, PLGA was chosen as the material platform for antigen delivery and surface-modified with two Toll-like receptor (TLR) agonists: bacterial lipopolysaccharides (LPS) and CpG oligodeoxynucleotides (ODNs), specific for TLR4 and TLR9, respectively. Surface-modified nanoparticles were readily endocytosed by antigen-presenting cells, leading to their activation and the enhanced expression of pro-inflammatory cytokines and co-stimulatory molecules. Interestingly, LPS-modified, but not CpG ODN-modified, nanoparticles were found to trigger the NLRP3 inflammasome, which has been shown recently to be the target of aluminum-based adjuvants.;When administered to mice, LPS- and CpG ODN- modified nanoparticles generated potent Th1-polarized humoral and cellular immune responses, resulting in a distinctly different response than vaccination with aluminum adjuvants, which favors Th2 and humoral responses. Vaccination of mice deficient for TLR4 and TLR9 afforded modified nanoparticles no advantage over unmodified nanoparticles, confirming that indeed TLR recognition was mostly, if not completely, responsible for observed immune responses. Lastly, we demonstrated the clinical relevance of this approach by encapsulating recombinant antigen from the West Nile virus. Mice vaccinated with modified nanoparticles and subsequently challenged with live virus demonstrated strong protection exceeding that of aluminum hydroxide. |
