09:34pm Friday 17 November 2017

Vaccine for neglected disease ready for testing

Vaccine for neglected disease ready for testing

Several vaccine candidates work well in mice and are ready for further testing on blood of patients; one is ready for testing in mice. Scientists of the Antwerp Institute of Tropical Medicine play an important role in this endeavour.

Buruli ulcer is a neglected disease that is mainly endemic in Central and West Africa, where it typically affects poor rural communities – that never will be able to pay back the commercial development of a treatment. The culprit is Mycobacterium ulcerans, a relative of the bacteria that cause tuberculosis and leprosy. It mostly affects children. It produces massive skin ulcers and scars, ending in mutilation and severe disability. Treatment is difficult and often requires surgery. Antibiotics must be taken for a long time, which is impractical and carries the risk of drug resistance, while daily injections are difficult, painful and carry a risk for transmission of blood-borne infection. A vaccine would not only protect persons at risk, but could potentially be used to shorten treatment and to prevent relapses.

The BuruliVac project started because to date there is no vaccine against this mutilating disease, and market forces alone most probably would not lead to the development of a vaccine. BuruliVac is a three-year collaborative project funded by the European Commission under the 7th Framework Programme of the European Union. The scientists want to find novel vaccine candidates, and develop them for translation into clinical application.

The scientists work on three different vaccine candidates: mycolactone-directed vaccines; attenuated live vaccines; and subunit protein vaccines. Mycolactone is a toxin of the mycobacterium; live vaccines evoke reaction against the complete mycobacterium; subunit vaccines attack well-chosen parts of the mycobacterium.
As M. ulcerans causes harm through its toxin mycolactone, a vaccine directed against this toxin may provide protection. Several constructs are under development and confer some protection in mice. The recent identification of molecular targets of mycolactone  has been a big step forward in our understanding of the mechanisms by which mycolactone mediates its biological effects in the skin. In collaboration, research groups from Ghana and France demonstrated that mycolactone concentration dramatically decreases in skin lesions after treatment with antibiotics.

Groups in Belgium, Portugal and Germany tested several strains of mycolactone-deficient (and thus harmless) M. ulcerans for use as a vaccine in a mouse model. This way the mouse gets time to develop weapons against the harmless intruder, and so has its weapons ready when a normal strain of the Mycobacterium ulcerans comes along. Without vaccine, the mycobacterium has installed itself and inflicted harm before the weapon production of our body kicks in. The most promising strains are currently being characterized and further modified to increase their safety for use in humans.

Based on a multi-dimensional selection process, a group from Switzerland chose four target proteins for inclusion into a protein subunit vaccine. This kind of vaccine uses ‘typical’ parts of the mycobacterium as target for the immune systems, instead of complete mycobacteria. This is safer (there are no ‘harmless’ mycobacteria that can mutate back to a dangerous form), but not always as effective. For the assessment of the protective efficacy of test vaccines an experimental mouse infection model was established and optimized. The selected targets were produced with gene technology, purified and put into vaccine formulations. The protective efficacy of these vaccines can now be evaluated.

Yet other groups are setting up field studies that include blood collection from patients and their household contacts, to search for biomarkers that make it possible to follow the effects of the vaccine in humans. Two years after the start of the project all 4 African partner sites were equipped, trained and started the work. Currently the immune response of confirmed Buruli ulcer patients is being followed during and after administration of antibiotics for treatment. The scientists also follow several biomarkers in these patients, to see if they correlate with healing and treatment responses. The immune response to the vaccine candidates will be tested on white blood cells isolated from these patients.

Another group of scientists from Benin, Belgium, the Democratic Republic of Congo, Germany, Ghana, and Togo focused on patient management and put in place different quality assurance procedures and standard operating procedures. They organized diagnostic sample collection and laboratory confirmation in all 4 African countries. Extensive training workshops were held and PCR laboratories were installed at l’Institut National d’Hygiene in Lomé, Togo and at l’Institut National de Recherche Biomédicale in Kinshasa, Congo. In addition, a community-based case control study on the protective effect of the live attenuated vaccine against tuberculosis that was developed almost a century ago (known as the BCG vaccine) was launched in Ghana, Togo and DRC. Finally, a trial in which early versus deferred surgical intervention is compared started recruitment of study participants in Benin.

Picture
A typical Buruli wound. Wounds can be much worse. © Stop Buruli initiative funded by the UBS Optimus Foundation

Institute of Tropical Medicine


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