We sought to evaluate microenvironmental factors in the vagina that drive protection against STIs. We conducted a nested case control study in the Longitudinal Study of Vaginal Flora to assess the vaginal microenvironment of 397 cases at the visit before an incident genital STI (Chlamydia trachomatis, Neisseria gonorrhea, or Trichomonas vaginalis) and 1,794 STI-negative controls. Controls were matched to cases on age, race and follow-up time. Vaginal lavages and surveys were collected every three months for one year. Vaginal microbiota, metagenomes, metabolites, and lactic acid isomers were assessed as factors associated with incident STI. Bacterial community state types (CSTs) were assigned by hierarchical clustering of vaginal microbiota. Metagenomes of 708 participants were characterized using VIRGO. We used conditional logistic regression with covariate adjustment (partner concurrency, number of sex partners, condom use). Women with a CST-IV-A profile, low-Lactobacillus with high relative abundance of BVAB-1, had the highest odds of incident STI. CST-I (L. crispatus-dominated), CST-II (L. gasseri-dominated), CST-III-A, and CST-III-C (both L iners-dominated; the latter has other Lactobacillus spp.) had >50% lower odds of STI than women in CST IV-A (all p<0.01). CST-II had the lowest point estimate (72% lower odds, p=0.02). Metagenomic analyses confirmed these findings and revealed a cluster of G. vaginalis sub-species with 40% lower odds of STI than the BVAB-1 dominated cluster (p=0.02). Higher bacterial absolute abundance had lower odds of STI in each CST (p<0.001). High D-lactic acid concentration was associated with lower STI, irrespective of L-concentration (p<0.05). Of the 185 metabolites that were significantly associated with incident STI (q-value<0.05), 13 metabolites, including taurine and kynurenine (microbial metabolites with immunomodulating properties), were associated with ≥20% lower odds of STI per fold change. Multi-omic interrogation revealed protection against STI acquisition was associated with vaginal microenvironments containing immunomodulatory metabolites, as well as Lactobacillus spp. that produce D-lactic acid.

Disclosure No significant relationships.