9 September 2021

Why outsmarting gonorrhoea is so difficult

Clinical Sex Vaccination

While most STI clinical trials focus on HIV and HSV immunisations, gonorrhoea is proving a wily adversary for vaccine developers – but Australian researchers believe they may be on the verge of a breakthrough.

Of the eight microbes which account for most sexually transmitted infections, half are curable (syphilis, gonorrhoea, chlamydia, trichomoniasis) and two of the incurable viral infections have vaccines (hepatitis B, HPV) while clinical trials are under way for vaccines which will prevent, HIV and HSV.

Despite developments in disease management, Griffith University microbiologist Professor Kate Seib believes that finding vaccines, even for those infections that are currently curable, is the only sustainable path forward.

“The majority of STIs have no symptoms, or only mild symptoms that may not be recognised as an STI,” Professor Seib told attendees at the Joint Australasian Sexual Health + HIV & AIDS Conferences.

With an absence of symptoms, treatment may be delayed or missed entirely, leading to long-term consequences including fertility issues.

In addition, there are concerns about increasing antibiotic resistance stalling curability in the future.

Currently, vaccines for trichomoniasis and syphilis are still in the basic research phase, but some chlamydia and gonorrhoea immunisation projects have progressed to preclinical development.

Neisseria gonorrhoea can really be used as a case study for some of the challenges and gaps that we have in developing vaccines for STIs,” Professor Seib said.

A major spoke in the wheel has been the fact that humans are the bacteria’s only natural host.

“It has all sorts of mechanisms to avoid our immune system – it has molecular mimicry of host structures, it can inhibit activation of our immune system and it also has highly variable surface structures,” Professor Seib said.

“There’s also lots of different strains out there and even though we’re understanding some of the details through genome sequencing, there’s still a lot of variability within strains.”

Even in studies where human subjects were inoculated with a relatively homogenous strain of gonorrhoea, after just a few days of infection the samples collected from participants were “expressing all sorts of different surface structures”, Professor Seib said.

“Unfortunately, a lot of the really early-stage vaccine development for gonorrhoea was targeting some of these major outer membrane proteins, and these were the really variable ones, so that that led to a lot of the failures in the early clinical trials,” said Professor Seib.

Given that the bacterium can completely change the appearance of certain proteins and sugars on its surface, most contemporary research has focussed on identifying antigens which are not only common between strains, but also stable within strains.

But this approach has also been littered with problems, as there is no natural immunity after a gonorrhoea infection. Unlike with viruses such as covid, researchers can’t easily identify antibodies that would underpin an effective vaccine.

“Essentially, there’s no mechanism of protection on which to base antigen discovery and development and we have no correlative protection to use in the lab to try and drive these antigens forward,” Professor Seib said.

Compounding this issue is the fact that there are no animal models which accurately mimic infection and transmission, which has then made it difficult to get the strong data needed for pharmaceutical companies and industry to invest in clinical trials.

However, progress has been made in other areas of vaccine development, with two large-scale Australian trials set to investigate why people who receive the 4CMenB meningococcal vaccine (Bexsero) are significantly less likely to get gonorrhoea.

“4CMenB has the same outer membrane vesicles as meningococcal serogroup B, but additional proteins,” said Professor Seib.

“We found that humans vaccinated with 4CMenB do elicit antibodies that recognise gonorrhoea, so now there are lots of different clinical trials under way.”

Findings from two of these studies – Kirby Institute’s GoGoVax and Griffith University’s MenGO – are set to be published around 2024.

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