Schistosome vaccine development using the local immune response

2017-02-28T04:56:02Z (GMT) by McWilliam, Hamish Edwin Graham
Schistosomiasis is one of the most prevalent infectious diseases, and contributes to the persistence of poverty in endemic regions due to its high level of morbidity. It is caused by several related species of the parasitic flatworms, known as schistosomes or blood flukes. Despite control efforts, schistosomiasis is still widespread in many regions. It has proved difficult to control, particularly for the Asian zoonotic Schistosoma japonicum which has the additional problem of animal reservoirs such as the water buffalo. A vaccine for humans and/or buffaloes could significantly help in the control of schistosomiasis and has been a goal for schistosome research for decades. The aim of this thesis has been to contribute towards developing a vaccine against S. japonicum. The intramammalian larval stages are considered the targets of natural and experimental immunity and therefore were the focus of this research. Due to difficulties in working with this microscopic and transient developmental stage no larval specific vaccine candidates have been found. The antibody secreting cell (ASC)-probe technique has been used to identify larval vaccine targets for other helminths, therefore this promising method was applied here to study the immune response against the schistosome larvae as they penetrate, migrate and develop in the host. In this method, cells from lymph nodes draining the sites of larval migration (the skin and lungs) are cultured to allow the in vivo-induced ASC to release antibody into the culture media. This technique allows the capture of the local antibody response induced by the migrating larvae, effectively providing an immunological ‘spotlight’ on this transient developmental stage. Initially the ASC-probe technique was successfully implemented in a rat model of schistosomiasis, indicating the applicability of the method to this disease and providing valuable samples for antigen identification. Then the technique applied to the natural host, the water buffalo. The type of immune response induced against the migrating schistosome larvae was also investigated, in the first study of its kind in this important reservoir host. The captured local antibody response from the rat experiment was subsequently used to identify potentially novel vaccine targets using a newly-generated protein microarray. Several vaccine targets were identified, and one antigen in particular, S. japonicum Ly-6-like protein-1 (Sj-L6L-1), showed promise and was further characterised. It was found to be primarily transcribed in the developing larval stages, uniquely antigenic in the lung site in rats, present in the tegument and antigenic during early water buffalo infection. Finally, recombinant Sj-L6L-1 was tested with various adjuvant formulations, and a vaccine trial using a type-2 response-inducing adjuvant was performed. Although the antigen failed to protect mice against schistosomiasis, there is scope to try to improve the vaccine by optimising the formulation or recombinant production, and this is discussed. The research presented in this thesis provides a comprehensive investigation into the complex immunobiology of the migrating schistosome larvae, by investigating this developmental stage in both an experimental model and a natural host, and then identifying and characterising a novel larval vaccine target. It is hoped that this thesis will contribute towards developing an effective anti-schistosome vaccine.