This study is the first time repeat controlled human infection models (reSm-CHI) have been used to understand immune responses in schistosomiasis. Use of reSm-CHI has significant advantages over prior murine models as well as cross sectional endemic studies. Specifically, immunological insights can be understood in the context of infectious dose, timing, and exposure history of the participant.
Using this model we have been able to greatly extend our understanding of antibody and cellular/cytokine responses in schistosomiasis. Specifically, production and probing of an innovative protein/glycan schistosome microarray has revealed the dynamics of IgG and IgM antibody responses. Responses to glycan antigens were robust and IgM dominated, whilst proteins had reduced reactivity and provoked mainly IgG responses. Only a few proteins showed reactivity prior to praziquantel treatment, showing the importance of worm killing and antigen release in exposing worm antigens. Our identification of immunogenic proteins using this array is currently being used to guide vaccine antigen choice. Additionally the microarray produced will be used in further projects with international collaborators, furthering the impact of this work.
We were able to show that worm antigen-specific T cells develop during schistosome infection, plateauing during the second infection/treatment cycle. These responses were diverse, encompassing a broad range of Th2/Th1 and regulatory associated cytokinesand similar in magnitude to those observed in endemic infection. Responses to cercarial antigen were minimal in reSm-CHI participants, with lack of recognition of this infectious stage perhaps contributing to the lack of immune protection observed. An unexpected impact of our project was further insight into schistosomiasis morbidity. Acute schistosomiasis morbidity is observed in non-endemic individuals, but rarely in endemic individuals. In our study we observed a reduction in acute schsitosomiasis symptoms after multiple rounds of reSm-CHI. By studying cytokine responses we were able to provide a potential mechanism for this, observing that the pro-inflammatory serum cytokines associated with acute schistosomiasis were seen to a lesser extent after reSm-CHI.
In the final part of the project we were able to perform the first systematic review of pre-clinical schistosome vaccine experiments. This manuscript used a data-driven approach to provide guidance on suggested parameters for vaccine models and assessing the current state of the field.
