A Mucosal Vaccine Against Chlamydia Trachomatis

Vaccination by nonmucosal routes often induces poor protection at mucosal surfaces, presumably because those vaccines do not induce mucosa-tropic memory lymphocytes. However, only few mucosal vaccines are currently available for use in humans, and most of these vaccines consist of replicating microorganisms, having potential safety risks. Chlamydia trachomatis (Ct) causes mucosal infections of the eye and genital tract and infects > 100 million people worldwide without any approved vaccines available to date. In our study we describe a Ct vaccine composed of UV-inactivated Ct (UV-Ct) conjugated to charge-switching synthetic adjuvant nanoparticles (cSAPs) that elicited long-lived protection in conventional and humanized mice. In contrast, uterine exposure to UV-Ct generated tolerogenic Ct-specific regulatory T cells, resulting in exacerbated bacterial burden upon Ct infection. This differential effect was due to two different uterine mucosal dendritic cell populations, namely CD103⁺CD11b^– DCs and CD103^–CD11b⁺ DC, targeted by UV-Ct and UV-Ct-cSAP, respectively. Regardless of the vaccination route, UV-Ct-cSAP always induced a robust circulating memory T cell response. However, only mucosal vaccination evoked a first wave of effector T cells that seeded the uterine mucosa under steady state conditions during the fist week after immunization and established mucosa-resident memory T cells. Optimal protection depended on the synergistic action of tissue-resident memory cells and infection-induced recruitment of a second wave of circulating memory T cells. We propose that the cSAP technology offers a platform for efficient mucosal immunization that may also be applicable to other mucosal pathogens.