UC Irvine

Coxiella burnetii is an intracellular Gram-negative bacterium responsible for Q fever, a zoonotic disease with significant global health implications courtesy of its endemic status worldwide. This tier 2 select agent has the potential for use as a bioweapon due to low infectious dose and aerosol transmissibility. The development of a vaccine against C. burnetii is of great interest, particularly for people who are in close contact with ruminants and military personnel who may be exposed to the pathogen in the field. The Q-VAX vaccine, an inactivated whole-cell vaccine, has shown efficacy in preventing Q fever and has been used in high-risk populations. However, challenges remain in its widespread implementation due to limited availability and adverse reactions.Immunological studies have demonstrated the crucial role of macrophages in the host's defense against C. burnetii, with these cells playing a central role in phagocytosis, antigen presentation, and the production of pro-inflammatory cytokines. Interferon gamma (IFNγ), a key cytokine produced by T lymphocytes and natural killer cells, plays a significant role in controlling C. burnetii infection by activating macrophages and enhancing their antimicrobial activity. The use of nanoparticles as chemically programmable scaffolds in bead design shows promise in C. burnetii vaccine development. These nanoparticles can be engineered to display multiple proteins and epitopes, increasing immunogenicity and broadening the immune response. We showcased a high-throughput method of capturing expressed proteins onto bead scaffolds, which were directly administered to animals for in vivo evaluation. Additionally, the bacterial sacculus, the highly ordered peptidoglycan structure of bacteria, was explored as a vaccine scaffold and adjuvant. Muramyl dipeptide (MDP), the main component of the sacculus, acts as a pathogen-associated molecular pattern (PAMP) and activates innate immune responses through recognition by NOD-like receptors. The sacculus’s immunogenicity as an adjuvant was also evaluated in vivo. Adjuvants, such as toll-like receptor (TLR) agonists, are investigated here to enhance the immunogenicity of Q fever vaccines by increasing Th1 responses and IFNγ production. Challenge studies were conducted to evaluate subunit vaccine formulations containing downselected antigen candidates combined with optimized adjuvant combinations, including C. burnetii lipopolysaccharide. In conclusion, understanding the immunology of C. burnetii infection and the challenges associated with vaccine development is essential for effectively combating Q fever. Continued research into novel vaccine strategies, adjuvants, and delivery systems holds promise for improving vaccine efficacy, reducing the global burden of Q fever, and protecting at-risk individuals.