The Untold Story of Gonorrhoea: How People Chose to be Infected for Science
Would you volunteer to get a gonorrhoea infection?
Whether your instinct is yes or no, our scientific understanding of this infection has been greatly advanced by people who’ve said yes.
Last year, I was called to consult on a young man who had hobbled into the emergency department, supported by his mother — I’ll call him Al*.
Over the preceding few days his right knee had ballooned to the size of a melon and was hot and painful. He also had pain in the small joints of his fingers and a high fever, with signs of inflammation on his blood tests. The emergency doctors were concerned about septic arthritis, where bacteria get inside a joint. Without prompt treatment, the joint can be destroyed.
When I saw Al in the hospital bed, mother at his side, I needed to work out which bacteria had got into his knee. This would help determine the best tests and most effective treatments. He didn’t have any cuts or bruises, no recent injuries, no sports activities, no recent surgeries — no obvious way a bacteria could have gotten in.
But there was one other thing I needed to know. I asked his mum to leave the room, which she was not happy about, and with careful questioning, Al told me that he had had unprotected sex with several male partners in the preceding months. He was extremely anxious that his mother would find out, as he was not yet out to his family. I assured him of confidentiality and recommended some further tests to see if a gonorrhoea might be the cause of his knee infection.
Human intimacy
Humans and gonorrhoea have had an intimate relationship for thousands of years. The eminent 2nd-century Greek physician Galen gave gonorrhoea its awkward name, a combination of gonos (seed/semen) and rhoea (flow) — the disease of unwanted seed flow. Descriptions compatible with gonorrhoea are present in the Biblical story of Moses and Aaron (see Leviticus 15:1–3) as well as in ancient Egyptian papyri.
Gonorrhoea spreads between sexual partners and can cause a wide range of symptoms. In men, the most common is penile pain and discharge (urethritis), but other symptoms can include sore throat (pharyngitis), vaginal and rectal pain and discharge, or testicular pain and swelling (orchitis). Two in five gonorrhoea infections in women don’t cause any symptoms, but, if left untreated, can result in infertility.
In rare cases, like Al’s, the bacteria can spread into the blood and onto other sites in the body, leading to joint, tendon and skin inflammation. More rarely, gonorrhoea can cause bone infections, meningitis, and endocarditis. If someone is pregnant and contracts gonorrhoea, the bacteria can be passed from mother to baby during childbirth.
These complications were common before antibiotics were widely available. However, with advances in testing and treatment, these have become rarer in many countries. Unfortunately, lack of access to testing and antibiotics means that gonorrhoea still causes a huge amount of disease — 90% of the 80 million cases globally each year occur in poorer countries.
Social ills
Some groups of people have more gonorrhoea infections, particularly those who have higher rates of sexual contact. This includes men who have sex with men (MSM), sex workers, and (male) military personnel. Having lots of gonorrhoea infectious in soldiers was a huge problem during World War 2 with propaganda produced to reduce risk and encourage treatment (pictured above).
Following the discovery and commercialisation of penicillin in the 1940s, gonorrhoea suddenly had an effective treatment for the first time in history. However, the Neisseria gonorrhoeae bacteria (named after Dr Albert Neisser) is masterful at developing resistance to antibiotics. It can produce enzymes to break down drugs, produce pores to pump molecules out, or even alter structures within the cell to make them resistant to antibiotic effects.
Penicillins had completely stopped working by the 1980s. Treatment moved to fluoroquinolone antibiotics (particularly ciprofloxacin), but by the late 1990s, resistance was already widespread. By the 2010s, only ceftriaxone (a 3rd generation cephalosporin) and the macrolide antibiotic azithromycin remained effective.
However, strains that are resistant to one or other of these antibiotics are now circulating widely. More worryingly, bacteria that are resistant to both are becoming increasingly common. These infections are untreatable and there is an urgent need for both new treatments and preventative vaccines.
An exclusive relationship
“In whatever manner it arose, it certainly began in the human race, as we know no other animal that is capable of being infected with this poison”
— John Hunter, 1788
Neisseria gonorrhoeae belongs to a special class of bacteria called obligate human pathogens, which are bacteria that are adapted to only infect humans. Other examples include Salmonella enterica typhi (causing typhoid fever) and Mycobacterium tuberculosis.
For me, as an infectious diseases researcher, studying these bacteria has both advantages and disadvantages. It’s simpler to study an infection that only circulates in humans — I can ask patients about their symptoms, discuss their behaviours and exposures, request and prescribe treatments, and measure the results.
However, most new therapies need to be tested on animals to make sure they are safe before they are given to humans. But for obligate human pathogens, this is extremely difficult. In the case of gonorrhoea, scientists developed a model in mice that involved giving females additional oestrogen to extend their reproductive cycle as well as antibiotics to reduce the overgrowth of bacteria in the genital tract. But this does not have all the nuances of human-gonorrhoea interactions that have developed over thousands of years of co-evolution.
Challenging times
Ultimately, researchers have resorted to the only animal model left — deliberately infecting humans (also known as human challenge studies). In the 1980s and 90s, two strains of N. gonorrhoeae were used to infect volunteers, both of which were isolated from patients in the 1970s. Neither strain had been genetically modified, as is common with bacteria and viruses used in more recent human challenge studies. Only males were recruited into this study due to the risk of infertility in females.
To infect trial participants, the researchers took a small number of colonies of the bacteria suspended in liquid, inserted a catheter about 5cm into a volunteer’s urethra, and then injected a tiny amount (<0.5ml) of the bacterial suspension inside. Then they waited, watched and measured.
These early studies looked at how signs and symptoms developed in participants. From this, we learned that men shed bacteria in their urine from almost the moment they are infected, with evidence of urethral inflammation shortly afterwards; pain and discharge develop at around 1–6 days post-infection. Surprisingly, the time to symptoms was not related to how many bacteria a participant was exposed to.
Maximum inflammation levels measured in the blood happen at the same time symptoms of urethritis occur. However, this returns to normal very quickly (within 2 days) after treatment. Importantly, of the several hundred volunteers infected as part of these studies, none suffered serious side effects or complications.
These studies also found that volunteers who developed an antibody response to a cell membrane component called lipooligosaccharide (LOS) were less likely to become re-infected if exposed to the bacteria again, which raised the prospect of the development of a gonorrhoea vaccine.
Vaccine quest
There have been many attempts to develop a gonorrhoea vaccine using a wide range of technologies. In the 1970s and 80s, several were trialled in population groups with high rates of gonococcal infections (including military personnel). Unfortunately, rates in vaccinated and unvaccinated participants were not different in any of these studies, showing that these early vaccine candidates were not effective.
Trials in communities are complex and expensive, especially if the vaccines end up not working. This is when a human challenge study can be extremely useful. In 1985, Dr Peter Rice and colleagues tested a vaccine made from small bubbles (vesicles) formed from the outer membrane of a gonorrhoea bacteria. These vesicles were designed to stimulate the immune system with a range of antigens at the same time. They vaccinated 63 male volunteers with the vaccine or a placebo, and four weeks later, they used a catheter to insert some gonorrhoea bacteria into the volunteers’ urethras and waited to see how many in each group developed symptoms. Unfortunately, this study also found no difference between the groups, suggesting this vaccine was also not effective.
Despite these failures, one of the most valuable insights into N. gonorrhoeae from these studies is that this bacteria can change proteins in its outer membrane. This makes it more difficult for the immune system to spot and remove it. Imagine the police trying to chase down a burglar wearing a red coat and black hat, but the criminal has quickly changed into a green jacket and blue hat, enabling them to sneak right past the police officer.
This effect can happen within a single person with a single infection and, as the infection progresses, different groups of bacteria end up wearing a great mix of different clothes. Soon the room is filled with fashionistas competing to become the dominant trend. The result of this is that informing the police to search for one person (through vaccination) may not stop the fashion show from getting underway.
Meningitis magic
In the mid-2000s, Quebec province in Canada was suffering from an outbreak of cases of meningitis, caused by the uncommon B strain. In 2006, the health department launched a vaccination campaign for people under the age of 20 with a new vaccine called 4CMenB.
After the meningitis outbreak had been brought under control, they started to notice that there were far fewer cases of gonorrhoea in young people aged 14–20. Other regions started looking for this effect and similar reductions in gonorrhoea have since been observed in populations in Norway and Cuba following meningitis vaccination.
Inspired by these signals, Dr Helen Petousis-Harris and colleagues in New Zealand conducted a study to compare diagnoses of gonorrhoea in young people attending sexual health clinics by whether they had received a meningitis B vaccine called MeNZB. This was a more advanced outer membrane vesicle (OMV) vaccine than the one trialled in the military in the 1980s. They found that vaccinated young people had a 31% reduced risk of gonorrhoea.
Although they cause very different diseases, the bacteria responsible for many cases of meningitis is also a member of the Neisseria — N. meningitidis. The magic of using OMVs as immunizing agents is that they contain a wide range of proteins present in the bacterial outer membrane, which are common to several Neisseria species.
This means that if you stimulate the immune system against some strains of N. meningitidis, the immune system also recognises N. gonorrhoeae. There are many other vaccines now in development, including those designed specifically for N. gonorrhoea. This raises the prospect of finally being able to prevent gonorrhoea in people at risk, like Al.
Glimmer of hope
Back in the hospital, I recommended that Al be started on ceftriaxone while we waited for the test results. I hoped with my fingers crossed that it wouldn’t be a resistant strain. To rescue his joint, the orthopaedic surgeons took him to the theatre to wash out the pus that was causing him so much pain. Fortunately, he recovered well, and a few days later, the final results were in — an antibiotic-sensitive strain of N. gonorrhoeae was found in his knee. He was lucky.
If it had been a drug-resistant strain, I don’t know what I would have done. There have been declining levels of research into new antibiotics to treat these new strains of antibiotic-resistant bacteria, including N. gonorrhoeae. One of the first new antibiotics to be developed in recent decades, zoliflodacin, has been shown to be effective in treating gonorrhoea, which is a great beacon of hope. However, it is not yet widely available.
A month after his discharge, Al came to see me in the clinic, walking normally and smiling broadly, his mother in tow. He was relieved that it was over and spoke openly about his sexuality, having now come out to his family. I was glad that Al had been cured and had felt confident enough to talk to his family, but wished that this infection could have been prevented. We need more research into this common and potentially devastating disease, so if you see an opportunity to get a voluntary gonorrhoea infection, I hope you will think about signing up.
*Name and some details changed to preserve anonymity.
