The clinical development of an effective Chlamydia vaccine requires in-depth understanding of how well protective pre-clinical immune signatures translate to humans. Here we report the first comparative immunological characterization of CTH522/CAF®01 in mice and humans. We find a range of immune signatures that translate from mouse to humans, including a Th1/Th17 cytokine profile and antibody functionality. Interestingly, we identified vaccine-induced T cell epitopes, conserved among serovars and previously found in infected individuals. Using the mouse model, we show that the common immune signature protected against ascending infection in mice and vaccine induced antibodies could delay bacterial ascension to the oviduct, as well as development of pathology, in a T cell depleted mouse model. Finally, we demonstrate long-lasting immunity and protection of mice one year after vaccination. Based on the results obtained in the present study, we propose to further investigate CTH522/CAF®01 in a phase IIb study.