The goal of this open-label, randomized trial is to assess the efficacy of doxycycline prophylaxis in reducing incidences of bacterial sexually transmitted infections (STIs) among adolescent and young adult females while also evaluating acceptability and antimicrobial resistance in order to inform public health policy.

Participants will be randomized to receive on-demand doxycycline post-exposure prophylaxis (doxyPEP), weekly doxycycline, or standard of care (SOC) and will be followed quarterly to assess the impact of doxycycline use on the quarterly incidence of STIs (gonorrhea [GC], chlamydia [CT], and early syphilis), and within the doxycycline arms adherence and acceptability of weekly versus on-demand dosing.

Approximately 760 females will be randomized 1:1:1 to (1) on-demand doxyPEP (doxycycline 200 mg as soon as possible and within 72 hours after any condomless oral, vaginal, and/or anal sex), (2) weekly doxycycline (doxycycline 200 mg weekly regardless of sexual activity), or (3) SOC (quarterly STI testing/treatment and sexual health counseling). Participants will complete quarterly study visits over the course of 1 year during which they will receive STI testing (GC, CT, and syphilis), complete surveys, undergo safety monitoring, provide specimens for objective markers of doxycycline adherence and other laboratory assessments, and provide specimens (vaginal and rectal swabs [participant self-collected or staff-collected if the participant prefers]) for future testing, such as microbiome analysis. Resistance testing will be conducted on Staphylococcus (S.) aureus and Neisseria (N.) gonorrhoeae isolates to evaluate for doxycycline and tetracycline resistance, respectively. Participants will also complete weekly assessments of sexual activity and doxycycline adherence via the HealthMpowerment (HMP) application (app).

Inclusion Criteria:

• Age 13-29 years, inclusive;
• Self-reports GC, CT, and/or early syphilis diagnosis in the 12 months prior to screening;
• Self-reports condomless (oral, vaginal, and/or anal) intercourse at least once in the 30 days prior to screening
• Is at least 45 kilograms (99.2 pounds) in weight
• Fluent in English (able to read, speak, and understand English);
• Willing to undergo all required study procedures; and
• Willing to provide written informed consent to participate in the study.

Exclusion Criteria:

• Is male;
• Is pregnant, breastfeeding, or planning to become pregnant in the next 12 months;
• Documented history of tetracycline allergy or self-reports an allergy to tetracyclines;
• Current or anticipated use of a medication (e.g., barbiturates, phenytoin, lithium, carbamazepine, systemic retinoids, warfarin) with a contraindicated interaction to doxycycline ;
• Current or planned use of doxycycline for a prolonged period (> 2 weeks) in the 30 days prior to enrollment, including current prescription for doxycycline for STI prophylaxis;
• Prolonged antibiotic use (> 2 weeks) within the last 30 days prior to enrollment;
• Co-enrollment in any other concurrent interventional research or studies that may interfere with this study, such as an STI prevention trial, unless approved by Protocol Team in writing;
• Does not have consistent access (or anticipated weekly access for 52 weeks of survey completion) to smartphone that can access the HMP app; or
• Any other medical condition, medical/behavioral intervention, or other conditions that, in the opinion of the clinical site Project Lead (PL)/Investigator of Record (IoR) or designee, could interfere with adherence to study procedures or compromise interpretation of study results.