FAME

The challenge

Onchocerciasis, an infection caused by the roundworm parasite Onchocerca volvulus, is a neglected tropical disease most commonly found in Central Africa. In addition to skin conditions, it can lead to visual impairment and blindness. The parasite is spread by blackflies, which reproduce in flowing water, so many cases of disease are found close to watercourses – hence the label ‘river blindness’.

Onchocerciasis has been targeted for elimination, predominantly through the use of mass drug administration campaigns with ivermectin. However, this is likely to take more than a decade even if high coverage is achieved. In addition, there are large areas of Central Africa where ivermectin cannot be used safely because of the risk of co-infection with another parasitic worm, Loa loa: killing L. loa can trigger a powerful inflammatory response that may lead to neurological damage and even death.

Recently, an alternative control strategy has begun to emerge. The parasite depends on a commensal bacterium Wolbachia for survival. Hence, targeting Wolbachia is an effective way of eliminating O. volvulus. Antibiotics such as doxycycline are highly effective against both microfilariae, larval stages transmitted between people via blackflies, and the adult worms that generate microfilariae. Furthermore, the killing effects of doxycycline are relatively slow, so there is less risk of triggering neurological damage in co-infections.

Despite these promising developments, doxycycline is unlikely to be a long-term solution: it needs to be given for extended periods and is not suitable for young children or pregnant women. 

The project

The FAME project is evaluating a possible alternative to doxycycline, fusidic acid, a naturally occurring antibiotic used in topical creams, which is off-patent and safe for use in children and pregnant women.

The first step is to establish a suitable dose for use in a large-scale field trial. A dose-finding study is being carried out in Cameroon, with effects on Wolbachia compared with a four-week course of doxycycline. This study is being conducted alongside community consultations to assess the approach's acceptability and any potential barriers to its introduction.

The project is also exploring ways to enhance the efficiency of clinical studies, for example, by evaluating a potential new method for assessing treatment responses. Current methods depend on biopsies of nodules containing adult parasites, which are then stained and examined by two different expert observers. Using an extensive library of slides, the project will develop and validate an AI tool to classify stained sections.

In addition, the project will evaluate an alternative method, based on a less invasive skin biopsy, to assess Wolbachia levels in microfilariae. The assumption is that changes in Wolbachia levels in microfilariae will likely mirror those occurring in adult parasites. This method would allow the efficacy of treatments to be assessed much more rapidly.

An additional goal is to refine a pharmacokinetic/pharmacodynamic model to provide a more accurate indication of the drug levels required to kill Wolbachia effectively. This would guide pre-clinical studies on Wolbachia killing and increase the likelihood that results from pre-clinical research translate to humans.

Impact

The FAME project will advance the development of an affordable compound that could make a significant contribution to onchocerciasis control. It will: 

• Provide an initial indication of the efficacy of fusidic acid and the optimal dose for human use.
• Generate new tools to accelerate the assessment of anti-Wolbachia disease control strategies.
• Enable a full clinical development plan to be created for fusidic acid. 

If studies confirm the early promise of fusidic acid, this would open the door to large-scale trials and ultimately provide a new approach to onchocerciasis control that could drive forward its elimination in Central Africa.