Gonorrhoea is a sexually transmitted infection which has afflicted human populations for at least 2,000 years. Early treatments, which included bleeding and the use of mercury, were largely ineffective. The advent of antibiotics revolutionized the treatment of gonorrhoea and sharp declines in the incidence of infection were reported from the 1950s. It seemed as though the scourge of sexually transmitted infections, which is reported to have afflicted historical figures as diverse as Henry VIII and Napoleon, were an unpleasant feature of the past. However, almost as soon as antibiotics were introduced, resistance to them started to be reported. Unfortunately, development of new antibiotics has not kept pace with the incidence of resistance in the infectious bacterium, Neisseria gonorrhoeae (Ng). The World Health Organization now lists drug-resistance Ng as a major public health concern worldwide. 

Early attempts to develop a vaccine against Ng were unsuccessful, for several reasons. The Ng bacterium has a variable genome- gene transfer is a highly effective mechanism for generating thousands of different strains. The same genetic mechanisms which give rise to antibiotic resistance also create problems for vaccine developers- finding a vaccine which induces immunity against most strains is a challenge. A second problem is that the immune response in infected individuals is not adequate to ensure protection against reinfection. The bacterium has a range of mechanisms to dampen immune responses, meaning that there is insufficient immunological ‘memory’ following convalescence to combat infection. Attempts to use purified proteins from the bacterium as vaccine components were ineffective in clinical trials. 

For many years, the prospect of a comprehensively effective vaccine against gonorrhoea seemed remote. However, in 2017 some encouragement came from an unexpected source. A retrospective study showed that introduction of a vaccine against the related bacterium Neisseria meningitidis (Nm) had led to a reduction in the incidence of gonorrhoea infections. Nm is the causative agent of meningococcal meningitis and a very similar organism to Ng, although they cause different infections. Meningococcal meningitis is mainly found in children and young adults and is, fortunately, rare. Rates of incidence of the disease have been reduced substantially in recent decades, as a result of the introduction of several vaccines. Immune responses to Nm are less muted than is the case for Ng, and development of vaccines against it has been more successful. Although the efficacy of the Nm vaccine against Ng is lower than we would like, it provided an important clue as to which direction we should pursue for a comprehensive Ng vaccine.  

This raises the obvious, important question: how does the Nm vaccine protection against Ng infection? Working with colleagues in Oxford and Kenya, we examined the immune responses in a population of individuals who are at high risk of gonorrhoea (Stejskal et al 2024). This is a difficult task, because the Nm vaccine is a complex mixture of many different components- trying to work out which ones are likely to be responsible for protection is a difficult problem to unpick. We made use of two powerful technologies- the first is a collection of individual antigens on a small device which allows us to profile the complex antibody responses in vaccine recipients. Rather than simply measuring antibodies to one or two antigens, we were able to look at nearly 100 in a single sample. We married this complex dataset with machine learning- a type of AI which allows us to pick out complex patterns in the antibody responses. We were able to map how the Nm vaccine induced a complex family of antibodies against Ng antigens, and also examine how they compared with individuals who had gonorrhoea. This work takes us an important step along the road to developing an improved Ng vaccine- we now have a better idea of which direction to take. The study also has wider implications- we can start to think about revisiting vaccine design for other bacterial pathogens using these new methods, including those where antimicrobial resistance is a problem. We have a long way to go, but these technologies are offering some hope.

Stejskal et al 2024 ‘Profiling IgG and IgA antibody responses during vaccination and infection in a high-risk gonorrhoea population’ 
https://doi.org/10.1038/s41467-024-51053-x 

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