Periodic Reporting for period 1 - EBV-MS (Targeting Epstein-Barr Virus Infection for Treatment and Prevention of Multiple Sclerosis)
Reporting period: 2023-12-01 to 2024-11-30
Multiple Sclerosis (MS) is a chronic, immune-mediated neurological disease that affects over 1 million people in Europe and remains a leading cause of non-traumatic disability in young adults. Despite advances in treatment, the underlying causes of MS remain incompletely understood, and no curative therapies exist. A growing body of evidence has identified Epstein-Barr Virus (EBV) as a key environmental trigger in MS pathogenesis. Nearly all individuals with MS have a history of EBV infection, and recent studies have shown a strong temporal and mechanistic link between EBV infection and the onset of MS. However, EBV has not yet been directly targeted in MS treatment or prevention strategies.
The EBV-MS project addresses this critical gap by investigating whether targeting EBV can prevent, treat, or modify the course of MS. The project brings together a multidisciplinary consortium of clinical researchers, immunologists, virologists, data scientists, and patient organizations across Europe. Its overarching goal is to determine whether EBV is a viable therapeutic and preventive target in MS, and to develop the tools, data, and clinical evidence needed to support this approach.
The project’s objectives span seven key areas:
1. Conducting two clinical trials to test antiviral therapies targeting EBV in MS patients.
2. Investigating the role of EBV genome variation in MS risk and immune response.
3. Characterizing the timing between EBV infection and MS onset using epidemiological data.
4. Profiling immune cell signatures associated with EBV in MS patients.
5. Developing predictive models for MS risk and progression using machine learning.
6. Building mathematical models to simulate EBV-related immune dynamics and test therapeutic hypotheses in silico.
7. Ensuring responsible research and broad dissemination of findings to stakeholders and the public.
The project is strategically aligned with EU health priorities, particularly the Horizon Europe mission to improve understanding and treatment of complex diseases. By targeting a ubiquitous virus with known links to MS, the EBV-MS project has the potential to transform the prevention and management of MS. Its impact could be far-reaching: reducing disease burden, improving patient outcomes, and informing public health strategies for EBV vaccination and antiviral use. The integration of clinical, molecular, and computational approaches ensures a comprehensive pathway to impact, from mechanistic insight to therapeutic innovation.
The EBV-MS project addresses this critical gap by investigating whether targeting EBV can prevent, treat, or modify the course of MS. The project brings together a multidisciplinary consortium of clinical researchers, immunologists, virologists, data scientists, and patient organizations across Europe. Its overarching goal is to determine whether EBV is a viable therapeutic and preventive target in MS, and to develop the tools, data, and clinical evidence needed to support this approach.
The project’s objectives span seven key areas:
1. Conducting two clinical trials to test antiviral therapies targeting EBV in MS patients.
2. Investigating the role of EBV genome variation in MS risk and immune response.
3. Characterizing the timing between EBV infection and MS onset using epidemiological data.
4. Profiling immune cell signatures associated with EBV in MS patients.
5. Developing predictive models for MS risk and progression using machine learning.
6. Building mathematical models to simulate EBV-related immune dynamics and test therapeutic hypotheses in silico.
7. Ensuring responsible research and broad dissemination of findings to stakeholders and the public.
The project is strategically aligned with EU health priorities, particularly the Horizon Europe mission to improve understanding and treatment of complex diseases. By targeting a ubiquitous virus with known links to MS, the EBV-MS project has the potential to transform the prevention and management of MS. Its impact could be far-reaching: reducing disease burden, improving patient outcomes, and informing public health strategies for EBV vaccination and antiviral use. The integration of clinical, molecular, and computational approaches ensures a comprehensive pathway to impact, from mechanistic insight to therapeutic innovation.
During the first year of the EBV-MS project, the consortium advanced several key scientific and technical components across clinical, immunological, genomic, epidemiological, and computational domains:
Clinical Trials: The phase 2a clinical trial investigating the antiviral drug tenofovir alafenamide fumarate (TAF) in MS patients was initiated, with patient recruitment and randomization ongoing across multiple centers. The trial includes comprehensive clinical assessments, MRI imaging, and frequent saliva and blood sampling for EBV and immunological analyses. Preparations for the phase 2b trial were completed, including protocol development and integration of advanced biomarkers such as neurofilament light (NFL) in cerebrospinal fluid, MRI-based inflammation markers, and PET imaging.
Immunological Profiling: Extensive protocols were developed and implemented for flow cytometry, antigen stimulation, and multiomic analyses. Blood samples from MS patients treated with anti-CD20 therapies were collected and processed to assess immune cell activation and antigen-specific responses. Single-cell RNA sequencing and methylation profiling were performed on sorted memory B and T cells, and immunophenotyping of circulating immune cells was initiated using spectral cytometry.
EBV Genomics: Saliva and blood samples were collected from MS patients and controls across several European centers. DNA extraction and EBV genome enrichment protocols were optimized, and sequencing workflows were established. A bioinformatics pipeline was developed for processing viral sequences and identifying genetic variants, enabling future analyses of EBV-host interactions and viral genome-wide association studies.
Epidemiological Analysis: Applications for access to national health registries were submitted and approved to enable linkage of EBV infection data with MS onset and progression. Coordination among partners was established to prepare for analyses of the timing between EBV infection and MS onset, and to identify drugs that may influence this interval.
Computational Modeling: A mathematical model of the immune system was developed using ordinary differential equations to simulate interactions between effector and regulatory T cells, B cells, and natural killer cells in the context of EBV infection. The model supports in silico testing of hypotheses such as molecular mimicry, mistaken self, and impaired immune regulation. Simulations were conducted to explore immune dynamics from healthy states through EBV infection to MS-like inflammatory relapses. A complementary model of CNS damage is under development for integration with the immune system model.
Data Management and Integration: A comprehensive data management plan was implemented, including the development of a data dictionary and harmonization of clinical trial variables. Preparations were made for secure and interoperable data sharing across work packages, supporting future analyses and integration of clinical, immunological, and genomic data.
Clinical Trials: The phase 2a clinical trial investigating the antiviral drug tenofovir alafenamide fumarate (TAF) in MS patients was initiated, with patient recruitment and randomization ongoing across multiple centers. The trial includes comprehensive clinical assessments, MRI imaging, and frequent saliva and blood sampling for EBV and immunological analyses. Preparations for the phase 2b trial were completed, including protocol development and integration of advanced biomarkers such as neurofilament light (NFL) in cerebrospinal fluid, MRI-based inflammation markers, and PET imaging.
Immunological Profiling: Extensive protocols were developed and implemented for flow cytometry, antigen stimulation, and multiomic analyses. Blood samples from MS patients treated with anti-CD20 therapies were collected and processed to assess immune cell activation and antigen-specific responses. Single-cell RNA sequencing and methylation profiling were performed on sorted memory B and T cells, and immunophenotyping of circulating immune cells was initiated using spectral cytometry.
EBV Genomics: Saliva and blood samples were collected from MS patients and controls across several European centers. DNA extraction and EBV genome enrichment protocols were optimized, and sequencing workflows were established. A bioinformatics pipeline was developed for processing viral sequences and identifying genetic variants, enabling future analyses of EBV-host interactions and viral genome-wide association studies.
Epidemiological Analysis: Applications for access to national health registries were submitted and approved to enable linkage of EBV infection data with MS onset and progression. Coordination among partners was established to prepare for analyses of the timing between EBV infection and MS onset, and to identify drugs that may influence this interval.
Computational Modeling: A mathematical model of the immune system was developed using ordinary differential equations to simulate interactions between effector and regulatory T cells, B cells, and natural killer cells in the context of EBV infection. The model supports in silico testing of hypotheses such as molecular mimicry, mistaken self, and impaired immune regulation. Simulations were conducted to explore immune dynamics from healthy states through EBV infection to MS-like inflammatory relapses. A complementary model of CNS damage is under development for integration with the immune system model.
Data Management and Integration: A comprehensive data management plan was implemented, including the development of a data dictionary and harmonization of clinical trial variables. Preparations were made for secure and interoperable data sharing across work packages, supporting future analyses and integration of clinical, immunological, and genomic data.
During the first reporting period, the EBV-MS project has made significant technical and scientific progress toward its goal of evaluating Epstein-Barr Virus (EBV) as a therapeutic and preventive target in Multiple Sclerosis (MS). Key achievements include the launch of a phase 2a clinical trial investigating antiviral therapy in MS patients, the development of advanced immunological profiling protocols, and the collection of extensive biosamples for multiomic analysis. The project has also established a scalable pipeline for EBV genome sequencing and initiated computational modeling of immune responses to EBV, enabling in silico testing of disease mechanisms and therapeutic strategies.
These results lay the groundwork for impactful contributions to MS research and care. The project is expected to generate novel biomarkers, therapeutic insights, and predictive models that could inform future clinical practice and public health strategies. To ensure further uptake and success, continued clinical validation, integration with real-world data, and engagement with regulatory and industry stakeholders will be essential.
These results lay the groundwork for impactful contributions to MS research and care. The project is expected to generate novel biomarkers, therapeutic insights, and predictive models that could inform future clinical practice and public health strategies. To ensure further uptake and success, continued clinical validation, integration with real-world data, and engagement with regulatory and industry stakeholders will be essential.