Sexually transmitted infections (STIs) are on the rise in Spain,1 particularly due to an increase in bacterial STIs. Cisgender men who have sex with men (MSM), transgender women, and sex workers are disproportionately affected.2 The incidence of venereal infections is particularly high among individuals who engage in condomless sex. Condom use has declined dramatically in recent years, especially among certain groups such as users of HIV pre-exposure prophylaxis (PrEP), which protects against HIV but not against other STIs.

In addition to condom promotion, which is helpful but insufficient,3 the traditional strategy for controlling venereal infections has relied on screening and treatment of STIs in patients with high-risk sexual practices.4 In high-resource countries, quarterly serologies for syphilis and molecular testing for chlamydia and gonorrhea (and treatment if needed) form the basis of bacterial STI control in people at elevated risk.5 However, in lower-resource settings, diagnosis tends to be syndromic and treatment empirical, due to lack of access to sensitive, rapid diagnostic tests. This empirical approach leaves asymptomatic patients – whose screening is crucial for controlling these infections – out of reach.6

In recent years, new strategies for primary and secondary STI prevention are being explored in high-risk populations. Of particular interest due to emerging evidence are the use of doxycycline and meningococcal B vaccines. We believe that dermatology and venereology specialists should be aware of these developments, which are already impacting the global management of venereal infections.

Definition: Preventive intake of doxycycline before (Doxy-PrEP), during, or after (Doxy-PEP) high-risk sexual events, without prior sexual contact with someone diagnosed with an STI.

Usage: For Doxy-PEP,7,8 a single dose of 200mg doxycycline is taken within the first 24h – and no later than 72h – after unprotected oral/anal/vaginal sex. Doxy-PrEP9,10 refers to continuous intake (100mg every 24h) of doxycycline to prevent STI acquisition.

Advantages: Doxycycline is a second-generation tetracycline with moderate spectrum, easy access, rapid absorption, and high bioavailability. It has a solid safety profile and is generally well tolerated.12 It is the first-line therapy for Chlamydia trachomatis, second-line for syphilis, and shows activity against Neisseria gonorrhoeae in areas with low tetracycline resistance. Contraindications and drug interactions are limited.

Five randomized controlled trials7–11 (RCTs) have been published on STI prevention with doxycycline in MSM, and in some cases, transgender women. Participants were either using HIV PrEP (PrEP-HIV) or had confirmed HIV infection (PLHIV).

Bolan et al.9 presented a preliminary study with 30 PLHIV randomized into Doxy-PEP vs control. Molina et al.7 published a 2018 study with 232 patients randomized to Doxy-PEP vs no intervention, allowing up to three doses of 200mg doxycycline per week. Zhu et al.10 conducted a dual-treatment study in 2021. The “immediate group” received HIV PrEP+Doxy-PrEP; the “deferred group”, HIV PrEP and added Doxy-PrEP on week 25. Afterwards, Luetkemeyer et al.8 enrolled a total of 501 participants categorized into two cohorts: HIV PrEP users and PLHIV. Ultimately, 374 were in the Doxy-PEP group vs 180 controls. Molina et al.11 published 2023 open-label RCT results with 2:1 randomization (Doxy-PEP vs no prophylaxis) and 1:1 (2-dose meningococcal B vaccine vs no intervention), including 362 in Doxy-PEP vs 183 controls.

Efficacy against syphilis: Syphilis incidence decreased in all studies among Doxy-PEP users, with reductions between 73 and 87% vs controls. In the PLHIV subgroup, reductions of 73% and 77% were not statistically significant. Zhu et al.10 reported a decrease from 8.2 to 0 per 100 person-years, though not statistically significant due to few syphilis diagnoses. In all PrEP-HIV cohorts,7,8,11 the syphilis incidence reduction was statistically significant.

Efficacy against C. trachomatis: Incidence was significantly reduced in all studies7,8,10,11 among doxycycline users vs controls, with reductions between 70% and 89%. This was observed in both PrEP-HIV and PWH users. None of the studies differentiated between D–K and L1–L3 C. trachomatis serovars.

Efficacy against N. gonorrhoeae: Gonorrhea incidence declined in all studies, though data were more heterogeneous. Reductions ranged between 17% and 57%, with statistical significance in only a few studies.8,11 These results may reflect regional susceptibility of gonococci to tetracyclines.

Overall efficacy in bacterial STI prevention: Across all studies, a combined reduction in bacterial STI incidence was noted. Molina et al.11 reported an 83% combined reduction in syphilis and chlamydia. Other studies showed combined reductions ranging from 47% to 82%.

Adverse effects (AEs): GI AEs (nausea, vomiting, diarrhea) were among the most common in the RCTs7–11 (Table 1 and supplementary data). However, no statistically significant differences were found regarding serious AEs between doxycycline and control groups.7–11 Photosensitivity, a classic tetracycline-related AE, is a potential risk. Although specific evidence for doxycycline is limited, sun protection is recommended during its use.13 Although hematological, liver, and kidney alterations are rare, analytical monitoring is advised for prolonged use.

Efficacy in cisgender women: The only study14 that has investigated STI prevention with doxycycline in cisgender women did not observe a significant reduction in the incidence of venereal infections, which could be due to a different pattern of antibiotic resistance, as the study was conducted in Kenya (Africa). However, the authors also point to a possible low adherence to doxycycline by the participating women, which should be taken into consideration. Therefore, more studies are needed to evaluate the efficacy profile of this preventive measure in cisgender women.

Will patients adhere to doxycycline? In Luetkemeyer et al.,8 a total of 86% of participants reported consistent Doxy-PEP adherence. A total of 71% said they never missed a dose during the study, with a median of 4 monthly doses (range, 1–10). It is unknown whether such adherence would be sustained long-term or if 4 monthly doses are sufficient in our populations.

What about antibiotic resistance? From a public health standpoint, the main concern about preventive doxycycline use is the potential to promote antimicrobial resistance – not only among STI pathogens but also in other bacteria or users’ microbiomes:

• •

  N. gonorrhoeae: In Luetkemeyer et al.,8 26.7% of baseline isolates showed tetracycline resistance. During the study, tetracycline resistance was higher in the Doxy-PEP vs the control (38.5% vs 12.5%). Molina et al.7 found tetracycline resistance in all isolates (initial and during follow-up), with MIC >8mg/L in 33.3% of Doxy-PEP isolates vs 18.9% in controls.

• •

  M. genitalium: Molina et al.7 (n=14) reported no resistance differences across the groups.

• •

  C. trachomatis: No resistance was detected, but prolonged use may risk strain selection.15

• •

  Staphylococcus aureus: In the Molina et al.7 study, the presence of methicillin-resistant S. aureus (MRSA) was investigated in pharyngeal swabs among participants. During the study, the two groups experienced an increase in MRSA detections, though the differences were nonsignificant. However, in the Luetkemeyer et al.7 study, there were statistically significant differences and higher rates in the doxycycline group (month 6: 21.6% [doxycycline group] vs 10.3% [control group]; month 12: 16.1% vs 8.3%).

• •

  Escherichia coli carrying extended-spectrum beta-lactamase (E. coliESBL): In the Molina et al.7 study, an increase in anorrectal E. coli ESBL was observed in the two groups, with no differences detected between them.

• •

  Microbiota: Prolonged doxycycline intake seems to have moderate and transient effects on oral, respiratory, and GI flora; however, data on this topic are limited, mainly due to the relatively small size of the studies.15

The International Union against Sexually Transmitted Infections (IUSTI)16 issued a 2024 statement acknowledging the evidence supporting Doxy-PEP but noting concerns regarding resistance, public health impact, etc. IUSTI advises individualized decisions, considering the infection to be prevented, local health care capacity, ability to conduct public health surveillance, and patient engagement. Crucially, users must be informed about limitations in evidence and potential AEs. Other societies17–19 oppose general prophylactic doxycycline use in sexually active individuals but allow Doxy-PEP in select cases.

The Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC)20 has stated that doxycycline is not approved for STI prevention and is thus considered off-label. SEIMC recommends individualized Doxy-PEP prescription in MSM or transgender women with repeated STIs in the past year, following shared decision-making with the patient.

A hard-to-control bacterium: N. gonorrhoeae has developed resistance to all antibiotic classes.21 Pharyngeal and rectal infections are often asymptomatic,22,23 facilitating resistance and transmission. In response to rising incidence, WHO aims to reduce gonorrhea by 90% by 2030.24 Gonorrhea does not confer protective immunity,25 and humans are its only natural host. There are no suitable animal models, complicating vaccine development. Four candidate vaccines failed to protect against gonorrhea in clinical trials.25-28 However, recent epidemiological data29–37 suggest that meningococcal B vaccines may provide cross-protection against gonorrhea.

Twelve serogroups of Neisseria meningitidis exist, based on polysaccharide capsules. Six (MenA, MenB, MenC, MenW, MenX, MenY) cause most invasive disease globally.38 Conjugate vaccines are available for MenA, MenC, MenW, MenY. The Spanish Pediatric Association recommends routine vaccination against MenB, MenC, and MenACWY. Currently in Spain, eight inactivated meningococcal vaccines are available39: three monovalent vaccines against serogroup C; three tetravalent vaccines against serogroups A, C, W, and Y (MenACWY); and two monovalent vaccines against serogroup B.39

Two vaccines are available for invasive MenB disease39:

• •

  Bivalent vaccine (fHbp, Trumenba®, Pfizer): Composed of two variants of factor H binding protein (fHbp). fHbp is a subcapsular protein essential for evading the host's immune response. It is expressed in almost all meningococcal B strains and can generate an antibody response in humans.

• •

  Tetravalent vaccine (4CMenB, Bexsero®, GSK): Contains three subcapsular antigens from meningococcus B (N. meningitidis adhesin A or NadA, fHbp, and the Neisseria heparin-binding antigen or NHBA) combined with outer membrane vesicles (OMV) from the N. meningitidis strain NZ 98/254.

N. meningitidis and N. gonorrhoeae belong to the same genus and share 80–90% genome sequence identity.38 This similarity suggests that there might be cross-protection between serogroup B meningococcal vaccines and N. gonorrhoeae. A bioinformatics analysis has identified that a homolog of 20 out of 22 main meningococcal OMV proteins in the 4CMenB vaccine are present in N. gonorrhoeae (16 proteins have >90% identity and two proteins have >80% identity with the meningococcal vaccine antigen), and the 4CMenB antigen NHBA shares >67% identity with the NHBA of N. gonorrhoeae strains.40

Several real-world studies were conducted from 2009 through 202329–37 in countries such as Cuba, New Zealand, Norway, Canada, and the United States (Table 2). Most available results come from retrospective cohort studies, case–control studies, and ecological data from national epidemiological surveillance reports. The efficacy data for the meningococcal B vaccine are based on the reduction in the incidence rates of reported N. gonorrhoeae infections after vaccinating specific populations with OMV-containing vaccines (MeNZB™ from New Zealand, VA-MENGOC-BC from Cuba) or by comparing N. gonorrhoeae incidence rates after vaccination with 4CMenB vs MenACWY. Compared to other STSs, complete vaccination efficacy for gonorrhea prevention in the post-vaccination period went from 31% to 44%. The Paynter et al.30 study showed that the efficacy rate of the MeNZB™ vaccine against gonorrhea hospitalization was 24%. Conversely, the Wang et al.34 study observed lower vaccine efficacy rates after 36 months (23.2%; 95%CI, 0–47.5%) vs 6–36 months (34.9%; 95%CI, 15.0–50.1%) post-vaccination, and a reduced vaccine efficacy in patients with repeated gonococcal infections.

To date, data from two studies11,41 have been published (Table 2). The study by Raccagni et al.,41 an unmatched case–control study, evaluated the vaccine effectiveness (VE) of the 4CMenB vaccine against gonorrhea in PLHIV with a previous diagnosis of venereal infections. The study included a total of 1051 PLHIV (103 cases and 948 controls); 349 of 1051 (33%) received two doses of the 4CMenB vaccine. The median follow-up was 3.8 years (2.1–4.3 years). The unadjusted estimate of VE vs gonorrhea was 42% (95%CI, 6–64%; p=0.027). Logistic regression showed that VE against gonorrhea remained significant (44%; 95%CI, 9–65%; p=0.020) after adjusting for some factors.

Recently, the results of the DOXYVAC study from France11 have been published. This is a multicenter, randomized, placebo-controlled, double-blind, phase 3 study to evaluate the efficacy of two doses of 4CMenB in preventing N. gonorrhoeae infection (whether symptomatic or asymptomatic), serum bactericidal activity vs meningococcus B and gonococcus, as well as vaccine tolerance. The study included a total of 720 participants aged 18–40, MSM on HIV PrEP who had been diagnosed with a bacterial STI in the previous 12 months. They were randomized in a 1:1 ratio to 4CMenB vs placebo. No statistically significant differences were observed in the cumulative incidence rates of gonorrhea at any site (anal, pharyngeal, or urethral).

Currently, several studies42–46 are underway that will be able to provide better answers on the real efficacy (Table 2 of the additional data) in these populations in the near future.

How often should patients be revaccinated? A probable short duration of vaccine-induced protection is assumed, calculated to be between 6 and 12 months.36 Therefore, booster doses would be essential. In this regard, the group by Hui et al.47 suggests a booster dose administered on average every 3 years.

Will it be effective vs asymptomatic infection? Studies on vaccines designed to protect vs meningococcal B disease have shown that they are very effective vs symptomatic invasive disease but do not have a real impact on carriers. If vaccination only reduces symptomatic N. gonorrhoeae infection, it could lead to fewer MSM seeking control/treatment for these infections, which would be counterproductive for transmission control.48–50 It will be interesting to observe the impact of the vaccine on asymptomatic N. gonorrhoeae infection.51

Will it be effective against all strains? As with all vaccines, if the vaccine is not equally effective vs all N. gonorrhoeae strains, vaccination could introduce selective pressure favoring strains that are more difficult to prevent or treat.48 This possibility makes close monitoring of N. gonorrhoeae strains essential if vaccination is implemented.

To whom should we offer the vaccine? Whittles et al.52 recommended considering 4CMenB vaccination for MSM in sexual health clinics in England based on their individual risk. While this strategy might seem like the logical first step to radically reduce N. gonorrhoeae cases, this approach excludes many people who could benefit from the vaccine. An alternative approach would be to vaccinate adolescents, ideally before their sexual debut, which could contribute to protection vs gonorrhea and increase herd immunity vs N. meningitidis. However, this second strategy might have a lower impact on population-level gonorrhea diagnosis and would also be less efficient.53

Although evidence continues to grow, long-term consequences of prophylactic doxycycline and 4CMenB vaccination for N. gonorrhoeae prevention remain uncertain. In Spain, both measures are off-label.

Leading institutions suggest that Doxy-PEP prescription should be considered on an individualized basis for MSM or transgender women who’ve experienced repeated venereal infections in the last year. This decision needs to be supported by appropriate monitoring and research activities. It's also recommended to monitor the impact of antibiotic prophylaxis regarding the emergence of antimicrobial resistance, potential changes in the microbiome, and possible shifts in the epidemiological dynamics of STIs.

On the other hand, current evidence indicates that vaccinating at-risk populations with the 4CMenB vaccine could significantly impact gonorrhea incidence in these groups, even if protection is only partial. However, we still need more information on the vaccine potential differential impact on asymptomatic vs symptomatic infection, as well as on its effectiveness at various infection sites.

Given these points, we believe that the suitability of using both measures should be individually assessed for selected users at high risk of acquiring venereal infections, such as some PrEP users.

None declared.