Q fever immunology: the quest for a safe and effective vaccine

Abstract

Q fever is an infectious zoonotic disease, caused by the Gram-negative bacterium Coxiella burnetii. Transmission occurs from livestock to humans through inhalation of a survival form of the bacterium, the Small Cell Variant, often via handling of animal parturition products. Q fever manifests as an acute self-limiting febrile illness or as a chronic disease with complications such as vasculitis and endocarditis. The current preventative human Q fever vaccine Q-VAX poses limitations on its worldwide implementation due to reactogenic responses in pre-sensitized individuals. Many strategies have been undertaken to develop a universal Q fever vaccine but with little success to date. The mechanisms of the underlying reactogenic responses remain only partially understood and are important factors in the development of a safe Q fever vaccine. This review provides an overview of previous and current experimental vaccines developed for use against Q fever and proposes approaches to develop a vaccine that establishes immunological memory while eliminating harmful reactogenic responses.

Fig. 1. Cellular effector responses to C. burnetii.

T cell responses are initiated upon peptide-MHC recognition by T cell receptor. Activated T cells differentiate to CD4⁺ helper T cells that secrete cytokines that activate B cells, macrophages, and inflammation. Activated B cells differentiate to plasma cell that produce antibodies. Antibody effector mechanisms include opsonization and Fc receptor mediated phagocytosis and complement activation.

Fig. 2. Programming T cell responses by targeted antigen delivery to dendritic cells (antigen-presenting cell).

a Administration of anti-CD205 or CLEC9A with antigens, induces DC maturation and enhanced cross-presentation. b Anti-CD40 induces DC maturation, expression of costimulatory molecules and cytokines for T cell differentiation. c Co-delivery of TLR ligands with antigens: TLR9 present on the endosomal membrane detects unmethylated CpG DNA, TLR4 present on the cell membrane detects bacterial LPS. This innate recognition by pattern recognition receptors, in conjunction with antigen stimulation drives T cell activation.

Fig. 3. Programming B cell responses by driving germinal center (GC) reaction via potent B cell activation.

a Multivalent antigens cause B cell receptor clustering that initiates signal transduction, which combined with costimulation from cognate T cells, amplifies B cell activation. b Nanocarriers help to unload antigen cargo in lymph nodes, they can be bioengineered for controlled release of antigens; glycosylated antigens activate the mannose-binding lectin complement pathway, that produces C3b, for antigen opsonization, which eventually binds to complement receptors in follicular dendritic cells. These cells display the antigens for recognition by B cells during the process of affinity maturation in the germinal centers.