Coxiella burnetii is an obligate intracellular bacterium which, in humans, causes the disease Q fever. Although Q fever is most often a mild, self-limiting respiratory disease, it can cause a range of severe syndromes including hepatitis, myocarditis, spontaneous abortion, chronic valvular endocarditis, and Q fever fatigue syndrome. This agent is endemic worldwide, except for New Zealand and Antarctica, transmitted via aerosols, persists in the environment for long periods, and is maintained through persistent infections in domestic livestock. Because of this, elimination of this bacterium is extremely challenging and vaccination is considered the best strategy for prevention of infection in humans. Many vaccines against C. burnetii have been developed, however, only a formalin-inactivated, whole cell vaccine derived from virulent C. burnetii is currently licensed for use in humans. Unfortunately, widespread use of this whole cell vaccine is impaired due to the severity of reactogenic responses associated with it. This reactogenicity continues to be a major barrier to access to preventative vaccines against C. burnetii and the pathogenesis of this remains only partially understood. This review provides an overview of past and current research on C. burnetii vaccines, our knowledge of immunogenicity and reactogenicity in C. burnetii vaccines, and future strategies to improve the safety of vaccines against C. burnetii.

T cell-mediated immunity plays a central role in the control and clearance of intracellular Coxiella burnetii infection, which can cause Q fever. Therefore, we aimed to develop a novel T cell-targeted vaccine that induces pathogen-specific cell-mediated immunity to protect against Q fever in humans while avoiding the reactogenicity of the current inactivated whole cell vaccine. Human HLA class II T cell epitopes from C. burnetii were previously identified and selected by immunoinformatic predictions of HLA binding, conservation in multiple C. burnetii isolates, and low potential for cross-reactivity with the human proteome or microbiome. Epitopes were selected for vaccine inclusion based on long-lived human T cell recall responses to corresponding peptides in individuals that had been naturally exposed to the bacterium during a 2007-2010 Q fever outbreak in the Netherlands. Multiple viral vector-based candidate vaccines were generated that express concatemers of selected epitope sequences arranged to minimize potential junctional neo-epitopes. The vaccine candidates caused no antigen-specific reactogenicity in a sensitized guinea pig model. A subset of the vaccine epitope peptides elicited antigenic recall responses in splenocytes from C57BL/6 mice previously infected with C. burnetii. However, immunogenicity of the vaccine candidates in C57BL/6 mice was dominated by a single epitope and this was insufficient to confer protection against an infection challenge, highlighting the limitations of assessing human-targeted vaccine candidates in murine models. The viral vector-based vaccine candidates induced antigen-specific T cell responses to a broader array of epitopes in cynomolgus macaques, establishing a foundation for future vaccine efficacy studies in this large animal model of C. burnetii infection.