A systems biology approach to understand immunity and pathogenesis of malaria in children
Lead Research Organisation:
University of Oxford
Department Name: Tropical Medicine
Abstract
Malaria is a major health problem, with approximately half of the world's population at risk. Most malaria cases and deaths occur in sub-Saharan Africa and are caused by the species "Plasmodium falciparum", with an annual mortality rate of up to 700,000, mostly among children.. Despite many years of work and investment, we still do not have a highly effective vaccine. One reason for this is that we have an incomplete understanding of the interaction between malaria parasites and immunity. Immune responses to Plasmodium are complex, and protective immunity in malaria endemic areas develops only after several years of exposure. We know from our long-term studies of longitudinal cohorts that the outcome of malaria infection in children is extremely variable such that some children have two or three clinical episodes while others have very frequent clinical episodes or severe episodes without apparently becoming immune. Malaria can have a profound suppressive impact on immune responses. Our hypothesis is that these children with frequent and symptomatic malaria infections are caught in a causal "loop" (or "vicious cycle") whereby malaria episodes lead to impaired immunity to malaria, which in turn leads to further episodes of malaria.
In our first phase of analysis, we will investigate immune responses in a cohort of children developing immunity to P.falciparum malaria, for whom we have detailed life histories of malaria exposure. We will compare those immune responses of children with a history of repeated and clinical malaria episodes with those of children with a normal number of clinical malaria episodes (matching age, location and malaria exposure). We will also examine responses in a third group of children who live nearby, but are not exposed to malaria. This first phase of analysis will establish the analytical methodology, determine patterns of responses, and generate models and hypotheses that can be tested in the second phase (see below). We will combine transcriptomic, flow-cytometric, cytokine analyses, and malaria-specific B cell/antibody responses to compare as comprehensively as possible the features of the host response in the two groups.
A single "snap shot" of immune responses may represent only the endpoint of immune processes and may not reflect those that are causally related to differences in malaria outcome. Therefore, in a second phase of testing, we will collect and store samples from the whole cohort prior to surveillance for clinical malaria episodes. Samples will be stored, and then tested and analysed when parallel groups to those describe for the first phase above can be identified (i.e. multiple episodes vs normal episodes). These samples will be analysed by the laboratory and analytical teams blinded to epidemiological data, and the association between the signatures identified in the first phase and malaria episodes in prospect will be examined. We will undertake a further cross-sectional assessment of the children in this cohort in the second year, in order to assess the stability of these markers over time.
Our studies will identify immune response patterns that can be used as predictive markers of the child's ability to develop immunity to clinical malaria, and will be of great value in informing rational vaccine design, and monitoring vaccine efficacy and therapeutics. We will establish a set of robust analytical and modeling tools, which can be used in further studies, which will combine genetic variation in parasite and host, and which will inform mechanistic studies in animal models. Our unique dataset will be available for other researchers, and the expertise acquired will help establish a systems immunology expertise in the UK.
In our first phase of analysis, we will investigate immune responses in a cohort of children developing immunity to P.falciparum malaria, for whom we have detailed life histories of malaria exposure. We will compare those immune responses of children with a history of repeated and clinical malaria episodes with those of children with a normal number of clinical malaria episodes (matching age, location and malaria exposure). We will also examine responses in a third group of children who live nearby, but are not exposed to malaria. This first phase of analysis will establish the analytical methodology, determine patterns of responses, and generate models and hypotheses that can be tested in the second phase (see below). We will combine transcriptomic, flow-cytometric, cytokine analyses, and malaria-specific B cell/antibody responses to compare as comprehensively as possible the features of the host response in the two groups.
A single "snap shot" of immune responses may represent only the endpoint of immune processes and may not reflect those that are causally related to differences in malaria outcome. Therefore, in a second phase of testing, we will collect and store samples from the whole cohort prior to surveillance for clinical malaria episodes. Samples will be stored, and then tested and analysed when parallel groups to those describe for the first phase above can be identified (i.e. multiple episodes vs normal episodes). These samples will be analysed by the laboratory and analytical teams blinded to epidemiological data, and the association between the signatures identified in the first phase and malaria episodes in prospect will be examined. We will undertake a further cross-sectional assessment of the children in this cohort in the second year, in order to assess the stability of these markers over time.
Our studies will identify immune response patterns that can be used as predictive markers of the child's ability to develop immunity to clinical malaria, and will be of great value in informing rational vaccine design, and monitoring vaccine efficacy and therapeutics. We will establish a set of robust analytical and modeling tools, which can be used in further studies, which will combine genetic variation in parasite and host, and which will inform mechanistic studies in animal models. Our unique dataset will be available for other researchers, and the expertise acquired will help establish a systems immunology expertise in the UK.
Technical Summary
We will examine immune response profiles of children developing immunity to Plasmodium falciparum malaria, in order to define a response pattern that distinguishes children who have suffered very frequent clinical malaria episodes from those who have an average number of clinical. We will then sample a cohort prior to surveillance, store the samples, and then test once clinical data are available to examine whether these profiles can prospectively predict multiple clinical episodes and failure to acquire immunity.
Using RNA sequencing we will determine the transcriptome profile of the immune response. This will be combined with flow cytometric analyses on leukocytes in whole blood, and measurements of cytokines, chemokines and P. falciparum specific B cell/antibody responses.
At each analytical step we will identify potentially important 'predictors', which could be individual up- or down-regulated genes, gene clusters, regulatory pathways etc. These will be collated and iteratively used to build up our predictive model. We will concentrate on the most significant pathways for more in depth analysis by developing mathematical descriptions for pathways and then predict the effects of perturbations in the study population. Detailed cytometric analyses (CyTOF and Flow) and functional B-cell and T-cell assays will be performed, and will inform mechanistic animal model studies. During this study we will develop novel analytical tools and train scientists in systems immunology, build up large databases of childrens' immune responses, and define biomarkers that will predict frequent malaria episodes in children.
Using RNA sequencing we will determine the transcriptome profile of the immune response. This will be combined with flow cytometric analyses on leukocytes in whole blood, and measurements of cytokines, chemokines and P. falciparum specific B cell/antibody responses.
At each analytical step we will identify potentially important 'predictors', which could be individual up- or down-regulated genes, gene clusters, regulatory pathways etc. These will be collated and iteratively used to build up our predictive model. We will concentrate on the most significant pathways for more in depth analysis by developing mathematical descriptions for pathways and then predict the effects of perturbations in the study population. Detailed cytometric analyses (CyTOF and Flow) and functional B-cell and T-cell assays will be performed, and will inform mechanistic animal model studies. During this study we will develop novel analytical tools and train scientists in systems immunology, build up large databases of childrens' immune responses, and define biomarkers that will predict frequent malaria episodes in children.
Planned Impact
This project seeks to use a systems approach to define the characteristics of protective immunity to the malaria parasite, Plasmodium falciparum, and to understand how the host response contributes to severe malaria in children. We believe our studies will be the first comprehensive dataset obtained from children in an endemic area of P. falciparum transmission that will link epidemiological and clinical data on malaria to a large range of immune parameters such as the gene expression of immune-related genes, cytokine and chemokine production, the breadth of B-cell/antibody responses and functional capacity of immune cells.
Our data set will be of great value, and will be available to other Malaria immunologists, epidemiologists, and vaccine developers, who will be able to interrogate the data for their particular areas of immunological or other interest. The data set can also be used by any interested parties to define pathways, cells and molecules of interest that can be then investigated in mechanistic studies in experimental models. This would be an excellent way to bridge the gap between experimental models and human infection and disease by focussing on those responses that are directly relevant to human malaria.
The plasma remaining from this study will be available to colleagues, who are already in the process of developing various P. falciparum proteomes for screening for vaccine candidate antigens and developing protein micro-arrays targeting blood-stage merozoite and variable surface antigens, respectively, and will be able to link the resultant data sets with the results of this study.
We will collect samples such as P. falciparum DNA and RNA as well as human DNA in addition to the human RNA, peripheral blood cells and plasma to be used in our immunological studies. These samples will then be integrated into existing and planned large-scale studies funded by other sources such as Malariagen (www.malariagen.net), a network that integrates malaria epidemiology with genome studies on both the host and the malaria. This will enable us to expand our systems approach to bring together genetics with gene expression, functional immune responses and parasite variation.
This has huge potential for identifying markers for protective immunity and for identifying risk factors for severe disease. The data from this study will identify potential immune modulatory pathways that can be interrogated by interested immunologists from anywhere in the world. Furthermore the studies will provide important novel information on the relationships between genetic variability, gene expression and functional responses. Within the time scale of this project we will train young postgraduate and postdoctoral scientists in bioinformatics, predictive modeling and systems approaches to study human immunology and thereby establish a cohort of scientists who will further and expand this type of research in the UK and in Africa.
Identification of patterns of immune responses that can be used as predictive markers of the child's ability or not to develop immunity will be of great value in informing rational vaccine design, monitoring vaccine efficacy and determining indicators for children at risk of severe disease. Our findings will aid in designing vaccines to target the most protective responses can be used by those organisations such as WHO, MVI, Gates Foundation, MRC, Wellcome Trust and pharmaceutical companies involved in furthering development of vaccines and therapeutic interventions.
Information that would accelerate malaria vaccine development against an infection to which half of the world's population are exposed would have a significant impact on the educational and economic development of those affected countries, and therefore in the longer term also on the global economy and British economy.
Our data set will be of great value, and will be available to other Malaria immunologists, epidemiologists, and vaccine developers, who will be able to interrogate the data for their particular areas of immunological or other interest. The data set can also be used by any interested parties to define pathways, cells and molecules of interest that can be then investigated in mechanistic studies in experimental models. This would be an excellent way to bridge the gap between experimental models and human infection and disease by focussing on those responses that are directly relevant to human malaria.
The plasma remaining from this study will be available to colleagues, who are already in the process of developing various P. falciparum proteomes for screening for vaccine candidate antigens and developing protein micro-arrays targeting blood-stage merozoite and variable surface antigens, respectively, and will be able to link the resultant data sets with the results of this study.
We will collect samples such as P. falciparum DNA and RNA as well as human DNA in addition to the human RNA, peripheral blood cells and plasma to be used in our immunological studies. These samples will then be integrated into existing and planned large-scale studies funded by other sources such as Malariagen (www.malariagen.net), a network that integrates malaria epidemiology with genome studies on both the host and the malaria. This will enable us to expand our systems approach to bring together genetics with gene expression, functional immune responses and parasite variation.
This has huge potential for identifying markers for protective immunity and for identifying risk factors for severe disease. The data from this study will identify potential immune modulatory pathways that can be interrogated by interested immunologists from anywhere in the world. Furthermore the studies will provide important novel information on the relationships between genetic variability, gene expression and functional responses. Within the time scale of this project we will train young postgraduate and postdoctoral scientists in bioinformatics, predictive modeling and systems approaches to study human immunology and thereby establish a cohort of scientists who will further and expand this type of research in the UK and in Africa.
Identification of patterns of immune responses that can be used as predictive markers of the child's ability or not to develop immunity will be of great value in informing rational vaccine design, monitoring vaccine efficacy and determining indicators for children at risk of severe disease. Our findings will aid in designing vaccines to target the most protective responses can be used by those organisations such as WHO, MVI, Gates Foundation, MRC, Wellcome Trust and pharmaceutical companies involved in furthering development of vaccines and therapeutic interventions.
Information that would accelerate malaria vaccine development against an infection to which half of the world's population are exposed would have a significant impact on the educational and economic development of those affected countries, and therefore in the longer term also on the global economy and British economy.
Publications
Kimenyi KM
(2024)
Distinct transcriptomic signatures define febrile malaria depending on initial infective states, asymptomatic or uninfected.
in BMC infectious diseases
Bediako Y
(2016)
The effect of declining exposure on T cell-mediated immunity to Plasmodium falciparum - an epidemiological "natural experiment".
in BMC medicine
Bediako Y
(2019)
Repeated clinical malaria episodes are associated with modification of the immune system in children.
in BMC medicine
Recker M
(2018)
Recent advances in the molecular epidemiology of clinical malaria
in F1000Research
Kamuyu G
(2018)
KILchip v1.0: A Novel Plasmodium falciparum Merozoite Protein Microarray to Facilitate Malaria Vaccine Candidate Prioritization.
in Frontiers in immunology
Boyle MJ
(2017)
Recent insights into humoral immunity targeting Plasmodium falciparum and Plasmodium vivax malaria.
in International journal for parasitology
Brugat T
(2017)
Antibody-independent mechanisms regulate the establishment of chronic Plasmodium infection.
in Nature microbiology
Valletta J
(2017)
Identification of immune signatures predictive of clinical protection from malaria
in PLOS Computational Biology
Harrison TE
(2020)
Structure of the Plasmodium-interspersed repeat proteins of the malaria parasite.
in Proceedings of the National Academy of Sciences of the United States of America
Talavera-López C
(2019)
Comparison of whole blood and spleen transcriptional signatures over the course of an experimental malaria infection.
in Scientific reports
Holding T
(2018)
Multiscale Immune Selection and the Transmission-Diversity Feedback in Antigenically Diverse Pathogen Systems.
in The American naturalist
Mogeni P
(2017)
Detecting Malaria Hotspots: A Comparison of Rapid Diagnostic Test, Microscopy, and Polymerase Chain Reaction
in The Journal of Infectious Diseases
Nkumama IN
(2017)
Changes in Malaria Epidemiology in Africa and New Challenges for Elimination.
in Trends in parasitology
Addy JWG
(2021)
10-year longitudinal study of malaria in children: Insights into acquisition and maintenance of naturally acquired immunity.
in Wellcome open research
Addy J
(2021)
10-year longitudinal study of malaria in children: Insights into acquisition and maintenance of naturally acquired immunity
in Wellcome Open Research
Valletta J
(2022)
Individual-level variations in malaria susceptibility and acquisition of clinical protection
in Wellcome Open Research
Valletta JJ
(2021)
Individual-level variations in malaria susceptibility and acquisition of clinical protection.
in Wellcome open research
Valletta J
(2021)
Individual-level variations in malaria susceptibility and acquisition of clinical protection
in Wellcome Open Research
Addy J
(2021)
10-year longitudinal study of malaria in children: Insights into acquisition and maintenance of naturally acquired immunity
in Wellcome Open Research
Description | EDCTP Senior Fellowship - This award is to the ARL (Francis Ndungu) rather than the PI (me). |
Amount | € 500,000 (EUR) |
Organisation | Sixth Framework Programme (FP6) |
Department | European and Developing Countries Clinical Trials Partnership |
Sector | Public |
Country | Netherlands |
Start | 07/2018 |
End | 09/2023 |
Description | Sofja Kovalevskaja Award |
Amount | € 1,600,000 (EUR) |
Funding ID | 3.2 - 1184811 - KEN - SKP |
Organisation | Alexander von Humboldt Foundation |
Sector | Public |
Country | Germany |
Start | 11/2015 |
End | 10/2021 |
Description | Strategic Award |
Amount | £4,500,000 (GBP) |
Organisation | Wellcome Trust |
Department | Wellcome Trust Strategic Award |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2015 |
End | 11/2020 |
Title | A Proposed Method for Assessing Cluster Heterogeneity |
Description | A membership matrix and the degree of membership matrix is suggested to determine the homogeneity of a cluster fit. Maximisation of the ratio of the overall degree of membership at cluster number lag 1 is also suggested as a method to optimise the number of clusters in a dataset. A threshold factor upon the degree of membership is also suggested for homogeneous clusters. Cluster simulations were given to compare how well the proposed method compares against established methods. This method may be applied to the output of both hierarchical and k-means clustering. arXiv:2001.09996v1 |
Type Of Material | Model of mechanisms or symptoms - human |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | The application of classifying a dataset into optimal meaningful clusters is a dif- ficult process dependent on the sampled data, method of clustering and method of optimising used. This work presents that considerations of the heterogeneity of each cluster through cluster membership should be acknowledged. The method gives consideration of how membership of a cluster should also be considered along with the cluster fit itself. |
Title | A Proposed Method for Assessing Cluster Heterogeneity |
Description | A membership matrix and the degree of membership matrix is suggested to determine the homogeneity of a cluster fit. Maximisation of the ratio of the overall degree of membership at cluster number lag 1 is also suggested as a method to optimise the number of clusters in a dataset. A threshold factor upon the degree of membership is also suggested for homogeneous clusters. Cluster simulations were given to compare how well the proposed method compares against established methods. This method may be applied to the output of both hierarchical and k-means clustering. arXiv:2001.09996v1 |
Type Of Material | Model of mechanisms or symptoms - human |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | The application of classifying a dataset into optimal meaningful clusters is a dif ficult process dependent on the sampled data, method of clustering and method of optimising used. This paper presents that considerations of the heterogeneity of each cluster through cluster membership should be acknowledged. The method gives con- sideration of how membership of a cluster should also be considered along with the cluster fit itself |
Title | CyTOF panels |
Description | deveoplement of panels of antibodies for Mass cytometry, including isotyope labelling of certin purtified antibodies |
Type Of Material | Technology assay or reagent |
Provided To Others? | No |
Impact | This panel will enable a very detailed analysis of PBMC responses to Plasmodium falciparum-infected red blood cells from exposed children in Kilifi, Kenya. The panel will be used to determine the phenotype of responding cells from selected children in the next longitudinal blled |
Title | CytoF Panels |
Description | developed panels for antibodies for mass cytometry, including isotope labelling of selected Abs |
Type Of Material | Technology assay or reagent |
Provided To Others? | No |
Impact | this panel will enable a detailed investigation of PBMC responses to Plasmodium falciparum infected red blood cells of exposed children in Kilifi , Kenya using Mass Cytometry, |
Title | FLow cytometry deconvolution panel for human whole blood |
Description | flow cytometry panel to detemine the major cellular components of human peripheral blood for later deconvoultion studies |
Type Of Material | Technology assay or reagent |
Year Produced | 2015 |
Provided To Others? | Yes |
Impact | this enables us to detemine cell specific signatures from whole blood RNA seq data |
Title | FLow cytometry deconvoution panel for whole blood |
Description | wehave developed a flow cytometry panels to deterine the cellaur components of peripheral blood, whic can be used to detemine cell specific signatures from RNA sequencing. |
Type Of Material | Technology assay or reagent |
Year Produced | 2015 |
Provided To Others? | Yes |
Impact | we will now be able to deconvolute our RNA seq data and assign cell specific signatures. |
Title | High throughput extraction of RNA from 1ml of blood |
Description | Development of a high-throughput protocol for extraction of RNA from 1ml of blood in Tempus tubes, building on our low throughput approach described previously |
Type Of Material | Technology assay or reagent |
Year Produced | 2018 |
Provided To Others? | No |
Impact | We are able to process many more samples, e.g. for the longitudinal part of our study |
Title | Human PBMC |
Description | human peripheral blood mononuclear cells from exposed individuals in Kilfi Kenya after re-exposure to P. falciparum |
Type Of Material | Biological samples |
Provided To Others? | No |
Impact | data are not yet analysed |
Title | RNA extraction from 1ml Blood |
Description | Protocol developed and optimised for extraction from 1ml of blood in Tempus tubes. (Manufacturers protocol requires 3 ml) |
Type Of Material | Biological samples |
Provided To Others? | No |
Impact | This is a critical step in enabling transcriptome analysis from blood samples of infants |
Title | bar coding of PBMC samples for Cytof |
Description | bar coding allows multiplexing samples for Cytof analysis |
Type Of Material | Technology assay or reagent |
Provided To Others? | No |
Impact | this allows us to save money of reagents and analysis time as multiple samples can be analysed in a single tube |
Title | cellular deconvolution |
Description | we have developed a computational method to identify cell-specific transcriptomic signatures of cells in human peripheral blood |
Type Of Material | Model of mechanisms or symptoms - human |
Year Produced | 2017 |
Provided To Others? | No |
Impact | this method allows us to define the transcriptome of specific subpopulations of cells within peripheral blood without having to isolate individual populations. Cell signatures can be compared between blood samples of different groups of samples using small volumes of blood. This has has wide application for immunology studies in which only small volumes of whole blood can be collected , eg children. The method will be available to others in 2018 |
Title | Additional file 10: of Repeated clinical malaria episodes are associated with modification of the immune system in children |
Description | Table S4. Results of GSEA analysis of CD8+ T cell deconvolution signature associated with high-episode children. (XLSX 13 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | None |
URL | https://springernature.figshare.com/articles/Additional_file_10_of_Repeated_clinical_malaria_episode... |
Title | Additional file 10: of Repeated clinical malaria episodes are associated with modification of the immune system in children |
Description | Table S4. Results of GSEA analysis of CD8+ T cell deconvolution signature associated with high-episode children. (XLSX 13 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | None |
URL | https://springernature.figshare.com/articles/Additional_file_10_of_Repeated_clinical_malaria_episode... |
Title | Additional file 1: of Repeated clinical malaria episodes are associated with modification of the immune system in children |
Description | Table S1. Flow cytometry antibody panel. (XLSX 9 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | None |
URL | https://springernature.figshare.com/articles/Additional_file_1_of_Repeated_clinical_malaria_episodes... |
Title | Additional file 1: of Repeated clinical malaria episodes are associated with modification of the immune system in children |
Description | Table S1. Flow cytometry antibody panel. (XLSX 9 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | None |
URL | https://springernature.figshare.com/articles/Additional_file_1_of_Repeated_clinical_malaria_episodes... |
Title | Additional file 4: of Repeated clinical malaria episodes are associated with modification of the immune system in children |
Description | Table S2. k-means clustering of differentially expressed genes between low- and high-episode children. (XLSX 10 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | None |
URL | https://springernature.figshare.com/articles/Additional_file_4_of_Repeated_clinical_malaria_episodes... |
Title | Additional file 4: of Repeated clinical malaria episodes are associated with modification of the immune system in children |
Description | Table S2. k-means clustering of differentially expressed genes between low- and high-episode children. (XLSX 10 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | None |
URL | https://springernature.figshare.com/articles/Additional_file_4_of_Repeated_clinical_malaria_episodes... |
Title | Additional file 6: of Repeated clinical malaria episodes are associated with modification of the immune system in children |
Description | Table S3. Mean levels of detectable plasma cytokines. (XLSX 11 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | None |
URL | https://springernature.figshare.com/articles/Additional_file_6_of_Repeated_clinical_malaria_episodes... |
Title | Additional file 6: of Repeated clinical malaria episodes are associated with modification of the immune system in children |
Description | Table S3. Mean levels of detectable plasma cytokines. (XLSX 11 kb) |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | None |
URL | https://springernature.figshare.com/articles/Additional_file_6_of_Repeated_clinical_malaria_episodes... |
Title | RNA-Seq analysis of first cross-sectional bleed |
Description | This reports provides an overview of the RNA-Seq data analysis pipeline from the first cross-sectional bleed (X1) using open-source software R |
Type Of Material | Data analysis technique |
Provided To Others? | No |
Impact | The report, and the the pipeline described therein, constitutes a major part of the general, data analytic methodology of this project. It is being described a general as possible to facilitate similar analysis on unrelated data sets in the future (both for this project and others). |
Title | Replication Data for: Individual-level variations in malaria susceptibility and acquisition of clinical protection |
Description | Replication Data for: Individual-level variations in malaria susceptibility and acquisition of clinical protection |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | data underlying analyses reported in published manuscript "Individual-level variations in malaria susceptibility and acquisition of clinical protection" (Valletta et al, Wellcome Open Research, 2022) |
URL | https://dataverse.harvard.edu/dataset.xhtml?persistentId=doi:10.7910/DVN/WQCKJJ |
Title | SIMS LabKey |
Description | Broad-based collaborations are becoming increasingly common among disease researchers. This is true for the SIMS project, where several partners are generating data ranging from clinical, RNA-Seq, proteomics and immunological data sets. To enable the researchers to organize and integrate these heterogeneous data early in the discovery process, standardize processes are needed to manage and integrate the data to gain new insights into pooled data and collaborate securely. We are implementing the open source LabKey server (www.labkey.org), a web-based data integration platform, to meet the needs of the project to manage the multi-dimensional data being generated in the SIMS project. The SIMS LabKey instance is hosted and managed by KWTRP. |
Type Of Material | Data handling & control |
Provided To Others? | No |
Impact | Is providing a shared platform for all participants in the project to gain access to all the data being generated including SOPs and other relevant documents. Also server as a communication tool for the project collaborators. |
URL | http://labkey.kemri-wellcome.org:8080/labkey |
Title | analysis of protein microarray data |
Description | Generic pipeline to analyse antibody profiles based on protein microarray data and develop predictive models of clinical infections using random forests machine learning algorithm |
Type Of Material | Data analysis technique |
Provided To Others? | No |
Impact | Powerful technique to (i) identify important variables from high dimensional data sets, and (ii) develop predictive models of infection outcomes based on individual antibody profiles |
Title | cluster analysis of gene expression data in R |
Description | Pipeline to perform rudimentary cluster analysis of gene expression data |
Type Of Material | Computer model/algorithm |
Provided To Others? | No |
Impact | Speedup of performaing cluster analysis using generic R script |
Title | differentail gene expression analysis in R |
Description | R-based pipeline to perform differential gene expression analysis; currently based on microarray data but can be used as generic tool |
Type Of Material | Computer model/algorithm |
Provided To Others? | No |
Impact | This pipeline should speed-up process of performing rudimentary gene expression analysis using opensource statistical software package R |
Description | CyTOf analysis |
Organisation | King's College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | a member of the Langhporne lab will work on the Cytof |
Collaborator Contribution | DR Susanne Heck at Knigs will provide advice and train gin on the cytof |
Impact | noe yet it only started this year |
Start Year | 2014 |
Description | Cytof analysis of human PBMC responding to malaria |
Organisation | Guy's and St Thomas' NHS Foundation Trust |
Country | United Kingdom |
Sector | Public |
PI Contribution | multiparameter mass cytometry to investigate leukocyte responses to Plasmodium falciparum. design of study and optimisation of of cell preparation, completed testing of panel of reagents and analysed subpopulations of PBMC in malaria naive donors |
Collaborator Contribution | advised on design and testing a panel of markers to delineate different populations of PBMC in P. falciparum- infected children. Training in the use of the Cytof and Cytobank. |
Impact | a panel of tested reagents suitable to investigate PBMC responses in malaria |
Start Year | 2015 |
Description | PBMC and blood |
Organisation | Wellcome Trust |
Department | KEMRI-Wellcome Trust Research Programme |
Country | Kenya |
Sector | Academic/University |
PI Contribution | KEMRI send samples from children with a characterised history of malaria CRICK performed in vitro stimulation assays, Mass Cytometry and RNA seq |
Collaborator Contribution | KEMRI provided field samples for human immune responses and RNA preparation |
Impact | papers in preparation |
Start Year | 2015 |
Description | Pwani University |
Organisation | Pwani University |
Country | Kenya |
Sector | Academic/University |
PI Contribution | This underlies the MRC-ARL award, and is a partnership between Oxford/Pwani and KEMRI-Wellcome. We are developing a shared programme referred to as PUBREC, which includes a developing laboratory facility in Pwani University, several staff working across projects, a PG Diploma course and a recent EDCTP award. Masters course now in preparation. Collaboration began prior to MRC-ARL, but strengthened substantially by the award. |
Collaborator Contribution | Support and development of a laboratory, successful National Research Fund application (Government of Kenya) Masters course with Francis Ndungu as lead. |
Impact | Developing infrastructure for a new laboratory, post-graduate diploma course |
Start Year | 2017 |
Description | Towards a highly effective multi-component vaccine against Plasmodium falciparum malaria |
Organisation | Heidelberg University Hospital |
Country | Germany |
Sector | Hospitals |
PI Contribution | Acquired new funding from the Alexander Humboldt Foundation to build on the existing work |
Collaborator Contribution | Provided transgenic parasites to test potential vaccine candidates discovered in the "antigen discovery" part of the ongoing project. |
Impact | Work ongoing |
Start Year | 2016 |
Description | BioMal Par 2021 poster |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | An improved method of modelling malaria history data for understanding malarial immunity Poster presentation by: J. W. G. Addy, Y. Bediako, F. M. Ndungu, J. Mwacharo, J. M. Ngoi, J. Wambua, K. Said, E. Otieno, E. P. de Villers, JJ Valletta, A. J. Reid, M. Recker, C. Newbold, M. Berriman, P. Bejon, K. Marsh, J. Langhorne. |
Year(s) Of Engagement Activity | 2021 |
Description | Community Liaison Meetings in Kenya |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | A series of meetings have been held in the research programme taking 100 community representatives at a time and describing individual research studies with a question and answer session. Recruitment to further studies has been facilitated and communication regarding our research in the field is easier. |
Year(s) Of Engagement Activity | 2012,2013,2014 |
Description | Crick Annual Autumn science meeting 2022 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Other audiences |
Results and Impact | JL gave a talk to the Crick Institute at its annual autumn science meet reviewing the immuno-epidemiology of plasmodium falciparum infections in the Kenyan cohorts used for the SIMS study |
Year(s) Of Engagement Activity | 2022 |
Description | F, Osier attended Women in Science event, University of Warwick |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | We had a lively debate where we discussed the challenges and successes of women in science, engineering and mathematics. The audience were engaged and participated actively. they were mostly young women in social sciences and basic laboratory sciences who were all interested in developing research careers. It id too early to tell the impact of the meeting but the initial feedback from attendees was encouraging and the discussions showed that these were issues they were thinking about as they went about their studies |
Year(s) Of Engagement Activity | 2017 |
URL | https://www2.warwick.ac.uk/research/priorities/internationaldevelopment/research/annualthemes/gender... |
Description | Radio Programme |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | I discussed malaria research in an interview and call-in radio programme. |
Year(s) Of Engagement Activity | 2016 |
URL | http://barakafm.org/ |
Description | World malaria day at Mill Hill |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Other audiences |
Results and Impact | we had an exhibition at the Mill Hill laboratory for world malaria day together with the other malaria groups. It was very well received within the institute and in 2017 it is planned to extend this to Midland rd site and for a Crick Late for the general public. |
Year(s) Of Engagement Activity | 2016 |
Description | autumn science meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | talk on epidemiology of p. falciparum malaria in Kenya |
Year(s) Of Engagement Activity | 2022 |
Description | community sensitization (systems immunology study) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | They medical officers in charge of health provision for the study population that we will recruit from are now aware of the systems immunology for malaria susceptibility that is just about to start. This meeting opened up the process for community engagement and will be followed by several meetings of sensitizing the potential study participants of the new study. The Kilifi County health provision team are happy to be involved in the new study, and happy to support our community engagement activities. |
Year(s) Of Engagement Activity | 2014,2015 |
Description | crick Autumn Science meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Investigating Phenotypes from Ten-Years of Clinical Active Surveillance Data- a poster John W. G. Addy, Yaw Bediako, Francis M. N'dungu, John Joseph Valetta, Adam. J. Reid, Jedida Mwacharo, Joyce Mwongeli Ngoi, J. Wambua, E. Otieno, Mario Recker, Chris Newbold, Matthew Berriman, Kevin Marsh, Philip Bejon and Jean Langhorne |
Year(s) Of Engagement Activity | 2021 |
Description | world malaria day 2017 |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Other audiences |
Results and Impact | World malaria day for the Crick |
Year(s) Of Engagement Activity | 2017 |