Natural Chlamydia trachomatis Immunity Highlights CPAF as a Key Vaccine Target 2258359

Introduction Our previous studies identified Chlamydia trachomatis (CT)-specific IFNg-producing CD4+ T cells as correlates of protection from reinfection, whereas higher antibody titers marked exposure, and CPAF (CT858) emerged as an immunodominant T cell target. Methods We analyzed IFNg ELISPOT responses to seven CT antigens (CT005, CT372, CT486, CT529, CT681, CT858, CT871) in 79 women stratified as FU- (n = 48), who completed ≥3 of 4 follow-up visits and remained CT-negative, or FU + (n=31), who tested CT-positive at any visit within one year. Frequencies of positive responders and summed antigen responses were compared using Fisher’s exact or Chi-squared tests. Correlations between total antigen-specific IFNg responses and anti-CT IgG titers were assessed by Spearman analysis, and Wilcoxon tests compared response magnitudes by antibody titer (≤1:64 vs > 1:64). Antigen-specific antibody levels (CT529, CT681, CT858) were correlated with corresponding T cell responses, and CPAF-specific responses were further analyzed by anti-CPAF antibody levels (< 45% vs ≥ 45%). Results IFNg responses were most frequent to CT858 (n = 34) and CT529 (n = 34), followed by CT005 (n = 22), CT486 (n = 16), CT681 (n = 11), CT871 (n = 6), and CT372 (n = 4). Response frequencies and magnitudes did not differ between FU- and FU+ groups. In FU+ participants, IFNg responses correlated with anti-CT IgG titers (Rho=0.4, P = 0.03), a pattern not observed in FU- women. Among women with low anti-CT IgG titers, higher IFNg responses were detected in FU- compared with FU+ groups (P = 0.03), whereas no difference was seen among those with high titers. Among women with low anti-CPAF IgG, higher CPAF-specific IFNg responses showed a trend toward protection from reinfection (P = 0.19 for FU- vs FU+). Conclusion These findings indicate that natural infection elicits CT-specific IFNg T cell responses, yet reinfection still occurs. Stronger T cell responses, particularly to CPAF, were linked to lower reinfection risk, supporting CPAF as a key target for CT vaccine design.