Periodic Reporting for period 1 - ReCHISVac (Experimental vaccinology, revealing unnatural signatures of protection by repeat controlled human schistosome infection.)
Période du rapport: 2022-06-01 au 2024-11-30
Schistosomiasis is a neglected tropical disease afflicting over 200 million people and causing 300,000 deaths in Africa alone. Whilst infections can be cleared with schistosomocidal drugs, individuals will become rapidly re-infected upon exposure to contaminated water. Partial immunity only develops naturally only after decades of constant infection, and there is no vaccine.
Previous schistosome vaccine studies have had limited success, due to a lack of understanding of what constitutes a protective immune response and a lack of pharmaceutical industry support or expertise for development. Here, I proposed to use unique samples from repeat Schistosoma mansoni controlled human infection (Sm-CHI) models to reveal novel antigens and corresponding cellular and cytokine responses that are protective against schistosomiasis. To evaluate how well this protective signature will translate to endemic countries, I performed matched analyses on samples from naturally schistosome infected Ugandan individuals. Antigen-specific antibody and cellular immunology data were combined utilising bioinformatic tools, with the intention of revealing a signatures associated with protection from schistosomiasis.
Finally, in a non-academic placement at Batavia Biosciences I performed a systematic review of pre-clinical schistosome vaccines. This review aimed to identify the key parameters of vaccine formulation (such as adjuvant and platform) as well as study design (including challenge dose and timing) that were critical for vaccine efficacy.
Together the work aimed to advance immunology of schistosome infection, with the intention of guiding the next generation of schistosome vaccine studies.
Previous schistosome vaccine studies have had limited success, due to a lack of understanding of what constitutes a protective immune response and a lack of pharmaceutical industry support or expertise for development. Here, I proposed to use unique samples from repeat Schistosoma mansoni controlled human infection (Sm-CHI) models to reveal novel antigens and corresponding cellular and cytokine responses that are protective against schistosomiasis. To evaluate how well this protective signature will translate to endemic countries, I performed matched analyses on samples from naturally schistosome infected Ugandan individuals. Antigen-specific antibody and cellular immunology data were combined utilising bioinformatic tools, with the intention of revealing a signatures associated with protection from schistosomiasis.
Finally, in a non-academic placement at Batavia Biosciences I performed a systematic review of pre-clinical schistosome vaccines. This review aimed to identify the key parameters of vaccine formulation (such as adjuvant and platform) as well as study design (including challenge dose and timing) that were critical for vaccine efficacy.
Together the work aimed to advance immunology of schistosome infection, with the intention of guiding the next generation of schistosome vaccine studies.
During this project we have elucidated antibody and cellular responses in repeated controlled human Schistosoma mansoni infection (reSm-CHI) studies. Antibody responses were elucidated using large protein/glycan microarrays (200+targets), produced for this project. Probing of arrays with reSm-CHI serum was performed as well as data extraction, processing and analysis. Dynamics of the IgG and IgM antibody response to proteins and glycans during reSm-CHI were determined.
Cytokine responses in serum of both reSm-CHI and endemic samples were performed using Luminex. Finally, bulk antigen preparations were produced from different stages of Sm, with these antigens used to stimulate cells to identify antigen-specific T cell responses. Cytokines produced by antigen-specific T cells were measured by flow cytometry. The dynamics of the antigen-specific T cell response in reSm-CHI were analysed, and compared to responses seen in endemic (Uganda) infection.
Finally, at Batavia Biosciences a systematic review of pre-clinical Schistosoma mansoni vaccine studies was performed. Inclusion and exclusion criteria for articles was specified within the review. Key parameters of vaccine formulation, study design and efficacy were extracted from the analyses. Each parameter was graphically displayed to display how vaccine experiments are commonly performed. A linear model was used to extract key parameters that contributed to higher vaccine efficacy. Results from this manuscript are in the process of being transferred to an online portal, which will be kept up to date with new studies.
Cytokine responses in serum of both reSm-CHI and endemic samples were performed using Luminex. Finally, bulk antigen preparations were produced from different stages of Sm, with these antigens used to stimulate cells to identify antigen-specific T cell responses. Cytokines produced by antigen-specific T cells were measured by flow cytometry. The dynamics of the antigen-specific T cell response in reSm-CHI were analysed, and compared to responses seen in endemic (Uganda) infection.
Finally, at Batavia Biosciences a systematic review of pre-clinical Schistosoma mansoni vaccine studies was performed. Inclusion and exclusion criteria for articles was specified within the review. Key parameters of vaccine formulation, study design and efficacy were extracted from the analyses. Each parameter was graphically displayed to display how vaccine experiments are commonly performed. A linear model was used to extract key parameters that contributed to higher vaccine efficacy. Results from this manuscript are in the process of being transferred to an online portal, which will be kept up to date with new studies.
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.
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.