Date of Award
Doctor of Philosophy
Veterinary Microbiology and Preventive Medicine
Michael J. Wannemuehler
The worldwide impact of vaccines on human health through the prevention of death, disease, and suffering caused by infectious disease cannot be overstated. The use of inactivated or live-attenuated microbes, as wells as alum or oil-in-water adjuvanted vaccines has been successful in limiting or eradicating disease across the world. However, each of these existing vaccine formulations carries its own shortcomings and limitations associated with their use. These deficiencies will need to be addressed and overcome through the identification and development of new vaccine adjuvants and/or delivery platforms. It would also be beneficial to those populations of individuals who exhibit increased susceptibility to infectious disease or who respond poorly to vaccination to identify adjuvants capable of enhancing efficacy in these immunologically deficient groups. While providing for antigen delivery, the studies described herein demonstrate that polyanhydride nanoparticles are capable activation of innate immune cells, particularly dendritic cell populations, in a manner that avoids induction of an overtly proinflammatory environment. These effects are associated with improved induction of cytotoxic CD8+ T cell memory, as compared to the inflammatory TLR ligand CpG, and resultant decreased tumor progression. The stimulation of the STING pathway using cyclic dinucleotides also demonstrated differential activation of the innate immune system as compared to TLR ligands. STING mediated stimulation of innate immune cells results in a differential activation phenotype that avoids production of innate, antimicrobial effector molecules. This led to increased BAFF production which was associated with higher vaccine-induced antibody titers in healthy adult mice, as well as in aged animals. This is potentially a unique outcome given the fact that aged individuals often respond poorly to TLR ligand adjuvanted vaccine formulations. This suggests that by leveraging pathways and/or materials that avoid undesirable aspects associated with innate inflammatory response against microbial infection leads to a more hospitable inflammatory environment that results in a better adaptive immune response following vaccination.
Darling, Ross, "The STING of inflammatory adjuvants: Is the Toll too high?" (2019). Graduate Theses and Dissertations. 17432.