Identifying cellular and molecular features of protective anti-malaria B cell response

Project Information

Bmem-Malaria

Grant agreement ID: 101109084

DOI

10.3030/101109084

Project closed

EC signature date 26 April 2023

Start date 1 September 2023

End date 31 August 2025

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 187 624,32

Coordinated by

ACADEMISCH ZIEKENHUIS LEIDEN
Netherlands

Periodic Reporting for period 1 - Bmem-Malaria (Identifying cellular and molecular features of protective anti-malaria B cell response)

Reporting period: 2023-09-01 to 2025-08-31

Summary of the context and overall objectives of the project

Malaria is one of the major infectious diseases that causes high disease burden worldwide. According to World malaria Report 2024, 263 million cases and 597,000 deaths are related to malaria in 2023. Most of the disease incidences are observed in low- and middle-income countries (LMICs) in sub-Saharan Africa, South America and Southeast Asia. Importantly, the deaths related to malaria disease are observed mainly in children. In the last two decades, two malaria vaccines have been approved by WHO and implemented in several countries in Africa. Even with low protective efficacy, the vaccines is making major differences in the vaccinees. Howeve, the disease is not eradicated and vaccine-induced protective efficacy wanes, highlighting the need to develop highly efficacious malaria vaccines.
In this project, I proposed to perform an in-depth immunological analysis of B cell response to malaria, making use of the unique clinical trial samples from controlled human malaria infection studies. To that end, I characterized cellular and humoral immunity against two distinct genetically attenuated parasite exposures in malaria-naive individuals. This thorough analysis revealed a broad convergence between the two arms of adaptive immunity to the parasites. Furthermore, this study also uncovered malaria antigens targeted by the antibody response, that are unique to late- but not early-liver stage arresting parasites. Additionally, from the samples, I isolated B cells and characterized the evolution of their response over repeated parasite exposure.
Collectively, this work advanced our understanding on different components of adaptive immunity that contribute to protection against malaria and thereby help develop efficacious vaccines.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

This project was performed by using the clinical trial samples collected at multiple time points during repeated malaria infection by genetically attenuated parasites in naive volunteers. Initially, antibody responses to the predominant malaria antigens were measured using Enzyme Linked ImmunoSorbent Assays (ELISAs). By comparing the antibody levels from pre- and post-parasite exposure the overall levels and specificity of antibodies were discovered. Additionally, cellular immunity against malaria antigens was characterized exactly on the same samples to discover the synergy between the two arms of immunity.
Due to a technical advantage over ELISAs, we next studied the humoral immunity against a large number of malaria antigens (n=224), covering different parasite development stages, using microarrays. This helped uncover the antigens that are uniquely targeted by the immune response against late-liver stage arresting malaria parasites in humans. As the next step, we isolated malaria-antigen binding B cells and profiled their features at the level of single B cells using multi-omics approaches. We developed a bioinformatics pipeline and data analysis strategy to define the cellular and molecular features of B cells. Using monoclonal antibodies derived from the B cells, we defined their antigen binding specificity and affinity. Results from this work are already featured in two publications and additional work is currently in the process of being written as a manuscript.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The study is the first to characterize antibody and cellular responses against genetically attenuated malaria parasites in naïve individuals. By selecting broad set of antigens to study, we identified key antigens from the liver stage that are targeted by the antibodies. By following the immune response over repeated parasite exposure, we observed a general boosting of the immune response against the antigens over time. This indicates memory formation and participation of the formed memory cells in future parasite exposure. Moreover, by performing in depth cellular immune analysis, we observed a broad correlation between both cellular and humoral immunity. Our study collectively provides a thorough overview of the quality of adaptive immunity elicited in individuals exposed to genetically attenuated malaria parasites.
To gain deeper understanding, we developed a multi-omics single cell profiling platform to study malaria antigen-binding B cells. Accompanied by the bioinformatic analysis, we are able to dissect the B cell response at a high-resolution for the first time in humans. Importantly, our findings will help understand B cell response against not just malaria but also other infectious diseases, auto-immunity and cancer.

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