Elucidating the Mechanisms of Protective Immune Responses against Coxiella burnetii Infection

Coxiella burnetii is an obligate intracellular bacterium that causes human Q fever. Despite the availability of a formalin-inactivated whole-cell vaccine (Q-VAX) in Australia, there is currently no FDA-approved vaccine for broad usage due to the high occurrence of adverse events in already sensitized persons. The unavailability of a licensed vaccine and the possibility of C. burnetii being weaponized highlights the crucial need for creating a safe and effective Q fever vaccine. To develop a vaccine, it is essential to understand the immunological mechanism of protective immunity against C. burnetii infection. This thesis seeks to fill knowledge gaps in our understanding of the immunological mechanisms for protective immunity against C. burnetii infection. Coxiella has two phase variations, Phase-I (PI, has full length LPS), Phase-II (PII, lacks O-antigen and Outer core). The work shows that primary PI C. burnetii infection elicits strong, dose- and route-independent protective immunity that includes both humoral responses and T cell-mediated immunity, with CD8⁺ T cells playing a more critical role than CD4⁺ T cells. Furthermore, the adoptive transfer of dendritic cells pulsed with phase I (PIV) or phase II (PIIV) formalin whole-cell vaccine antigens provides equivalent protection despite the failure of the PIIV vaccine alone, implying that directing antigens to dendritic cells may improve vaccine efficacy. Notably, dendritic cells stimulated with PIIV antigens can elicit protective immunity through T cell-dependent and T cell-independent antibody responses. Finally, investigations using animals lacking Bruton's tyrosine kinase (BTK^xid), which has B cell deficiency, show that among the two subsets of B cells B2 cells might play an essential role in the immune response against C. burnetii infection as evident by reduced B2 cell response after infection in these mice. Overall, this thesis sheds new light on the complex immunological responses that mediate protection against C. burnetii and proposes viable options for rational vaccine design, bringing us closer to developing a safer and more effective Q fever vaccine.