Nine years ago, a serendipitous finding at sexual health clinics raised hopes for the prevention of gonorrhea, one of the world’s most widespread sexually transmitted infections (STIs). Researchers in New Zealand discovered that patients had a 31% reduced risk of infection if they had previously been vaccinated against meningococcal group B, suggesting that the vaccine might also help in the fight against gonorrhea. In the years that followed, several other observational studies saw a 33% to 47% reduction in gonorrhea cases in people vaccinated against meningococcus B.
But a randomized controlled trial (RCT) published today in The New England Journal of Medicine has dampened those hopes. The study showed that a meningococcal vaccine named 4CMenB did not prevent gonorrhea in men who have sex with men (MSM) at high risk of STIs.
However, researchers still hold out hope the vaccine might work in other groups at lower risk of gonorrhea—and multiple ongoing trials could yield further insights into the nuances of who may be protected.
Gonorrhea, caused by the bacterium Neisseria gonorrhoeae, increases the risk of contracting HIV and can lead to infertility if not treated properly. There are some 82 million cases worldwide every year, and the microbe has a knack for developing resistance against antibiotics. But developing a vaccine has proved difficult, in part because N. gonorrhoeae rapidly alters its surface proteins to evade detection by the human immune system.
That’s why the discovery that the meningococcal group B vaccine appeared to offer some protection was welcome. And this “cross-protection” made sense, because N. meningitidis, the meningococcal bacterium, is closely related to N. gonorrhoeae, meaning some antibodies might work against both.
The first RCT of the strategy was carried out in France, as part of a broader study that also looked at providing the antibiotic doxycycline after unprotected sex, a strategy known as doxyPEP. That trial showed the vaccine reduced the risk of gonorrhea by 22%, but the finding was not statistically significant, possibly because the study was accidentally ended prematurely as a result of errors in data processing, as the researchers explained in their 2024 paper.
Participants in the new trial, named GoGoVax and conducted in Australia, were primarily cisgender men, but also some trans men, trans women, and nonbinary people, who had at least one sexual encounter with a man within the 6 months preceding the study and a diagnosis of gonorrhea or syphilis in the preceding 18 months. They received either two injections of the 4CMenB vaccine or a saline placebo 3 months apart and were regularly tested for gonorrhea afterward.
During a 20-month period after vaccination, 160 of the 296 people who received 4CMenB had at least one gonorrhea infection, as did 155 of the 291 people who received a placebo—meaning the vaccine had no effect. (The total number of infections during the same period did not differ significantly either.)
The observational studies that showed a benefit were largely done in populations at lower risk for gonorrhea, notes trial leader Kate Seib, a molecular biologist at Griffith University who was also involved in 4CMenB’s development. She thinks prior gonorrhea infections may have reduced vaccine protection in the high-risk RCT participants. An infection can trigger production of antibodies against a N. gonorrhoeae protein named Rmp, which don’t attack the bacteria but can block other antibodies, including those triggered by a vaccine, from doing their work. People who have not had gonorrhea before lack Rmp antibodies and as a result may have a better chance of benefiting from the vaccine. “Although the outcome of the trial was not what we had hoped for, the study provides valuable insights into the complexity of gonorrhoea immunity and vaccine cross‑protection,” Seib says.
Epidemiologist Connie Celum of the University of Washington agrees and also holds out hope for a better outcome in other groups. Celum is the lead investigator of a placebo-controlled trial of 4CMenB for gonorrhea prevention in 1100 cis women in South Africa that will conclude in January 2027. Yet another trial, in 2200 men and women at high risk of STIs in the United States, Malawi, and Thailand, expects to complete its analysis by this October.
But Jean Michel-Molina, an infectious diseases scientist at the University of Paris Cité who led the French study, notes that the 4CMenB vaccine primarily prevents N. meningitidis from spreading through the bloodstream; it has no effect on the bacteria in the throat. So perhaps it’s not surprising that the vaccine fails to prevent gonorrhea infections where it matters: in the oral and genital mucosal regions.
Based on previous data, England’s National Health Service last year began offering 4CMenB to gay and bisexual men who have recently had an STI or report having multiple sexual partners. Galicia, a region in Spain, does the same for adults deemed at high risk of an STI, regardless of their gender or sexual orientation. Given the new data, GoGoVax co-author Andrew Grulich, a medical epidemiologist at the University of New South Wales, suggested in an interview in March that those recommendations should be revisited.
But Mary Ramsay, an epidemiologist at the UK Health Security Agency, disagrees. “It is important to consider a range of evidence rather than a single trial,” Ramsay told Science in an interview in April, noting that the Australian participants may have had a different risk profile than the men being vaccinated in England. She added that England’s 4CMenB program “will provide more robust data on vaccine effectiveness and the findings will be published in due course.”