Cross-omics integration to identify modulators for improving vaccine efficacy

Project Information

ModVaccine

Grant agreement ID: 948207

DOI

10.3030/948207

Project closed

EC signature date 14 December 2020

Start date 1 January 2021

End date 31 December 2025

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 499 871,00

EU contribution

€ 1 499 871,00

Coordinated by

HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH
Germany

Periodic Reporting for period 3 - ModVaccine (Cross-omics integration to identify modulators for improving vaccine efficacy)

Reporting period: 2024-01-01 to 2025-06-30

Summary of the context and overall objectives of the project

The problem being addressed
Seasonal influenza remains a major global health burden, causing 3–5 million severe cases and up to 650,000 deaths annually. Although vaccination is the most effective preventive measure, protection varies widely and is particularly reduced in elderly and immunocompromised populations. The molecular determinants underlying this variability remain poorly understood, as previous studies have focused on isolated factors rather than integrated, systems-level analyses of host immunity.

Why this is important for society
Understanding inter-individual differences in vaccine responsiveness is essential for public health. Identifying determinants of poor response enables early detection of vulnerable individuals, improved vaccine allocation, and development of targeted immunomodulatory strategies. Such precision vaccination approaches are increasingly important in aging societies and for populations with chronic diseases.

Overall objectives of the project
The ERC Starting Grant (ModVaccine) aimed to apply systems immunology to dissect host-specific determinants of influenza vaccine variability. Specifically, the project sought to:
1. Identify molecular determinants of vaccine responsiveness using longitudinal multi-omics profiling across diverse cohorts.
2. Develop predictive models based on pre-vaccination signatures to stratify individuals by likelihood of achieving seroprotection.
3. Identify actionable pathways to enhance vaccine efficacy in low responders.

Conclusions of the Action
ModVaccine established a systems immunology framework to investigate inter-individual variability in vaccine responses across four cohorts (~500 participants; >1,500 longitudinal samples).

Key achievements include:
• Large-scale multi-omics profiling across diverse populations
• Identification of a pre-vaccination IL-15–NK cell axis suppressing antibody responses
• Discovery of long-chain fatty acids linked to inflammatory non-responsiveness
• Identification of a genome-wide significant abQTL (rs67211229) associated with mitochondrial metabolism
• Development of predictive models achieving strong performance (AUC ≈ 0.8)
These findings demonstrate that vaccine responsiveness is governed by coordinated molecular networks and that pre-vaccination immune states can predict seroprotection. Beyond influenza, this framework advances precision vaccination and provides a broadly applicable model for understanding immune heterogeneity.

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

Work performed
During the ERC-ST project, we generated longitudinal multi-omics datasets to investigate inter-individual variability in influenza vaccine responses across diverse populations, including elderly individuals, patients with chronic inflammatory diseases, and healthy controls.
Across four vaccination cohorts (~500 participants; >1,500 longitudinal samples), we integrated genomics, transcriptomics, proteomics, metabolomics, epigenomics, and single-cell profiling with antibody titers and functional immune readouts.
The systems immunology framework developed in this project was further extended to additional vaccination and infectious disease contexts, enabling cross-pathogen comparisons of immune variability.

Main results achieved
The project generated several major advances:
Identification of a pre-vaccination IL-15–NK cell axis suppressing antibody responses in the elderly, validated experimentally
Discovery of long-chain fatty acids as modulators of inflammatory non-responsiveness
Identification of a genome-wide significant abQTL (rs67211229) linked to mitochondrial metabolism
Development of predictive models achieving strong performance (AUC ≈ 0.8)
Establishment of an improved framework to identify truly non-protected individuals
Overall, the ERC Starting Grant resulted in 54 peer-reviewed publications directly acknowledging the ERC grant, including 35 publications in which I served as senior or corresponding author, with papers in Nature Medicine, Nature Immunology, Nature Aging, Science Advances, and Cell Genomics.

Dissemination and exploitation
Results were disseminated through 54 peer-reviewed publications, 69 invited talks at national and international conferences, data deposition in public repositories (e.g. GEO, EGA, MetaboLights), and collaborations with clinical and translational partners.
To advance translation, we secured an ERC Proof of Concept (DiMoVac) and a Helmholtz Enterprise Field Study Fellowship. We are developing a diagnostic tool for pre-vaccination stratification, including a targeted 30-marker proteomic panel in collaboration with Olink Proteomics, forming the basis for a clinically translatable assay for precision vaccination.

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)

This project advances the field beyond the state of the art in several fundamental ways.
1. From isolated biomarkers to systems-level integration
We established a longitudinal multi-omics integration framework that identifies coordinated molecular networks governing vaccine responsiveness, moving beyond single-layer analyses.
2. Redefining vaccine response measurement
We developed a refined stratification concept integrating pre-existing antibody levels and vaccine-induced responses, enabling improved identification of truly non-protected individuals across age groups and seasons.
3. Mechanistic insight into immune regulation
We uncovered an IL-15–NK-cell axis that suppresses humoral immunity in the elderly, providing mechanistic insight and a candidate intervention pathway.
4. Integration of host genetics and metabolism
The identification of an abQTL linked to mitochondrial metabolism reveals a novel connection between genetic variation, metabolic regulation, and seroprotection.
5. Immune responses in chronic inflammatory disease
Cirrhotic patients demonstrated enhanced vaccine responses relative to healthy controls, suggesting that chronic inflammatory states may differentially shape adaptive immunity and immune resilience.
6. Predictive precision vaccination
By integrating multi-layer pre-vaccination signatures, we developed predictive models enabling stratification prior to vaccine administration, providing the foundation for precision vaccination strategies.

Long-term impact
Building on these advances, we are:
• Developing clinically applicable pre-vaccination diagnostic tools
• Advancing immune-function aging clocks to predict vaccine and infection responsiveness
• Translating identified modulators into preventive interventions
Collectively, this ERC-ST project substantially advances the field from descriptive immunology toward predictive and personalized immune modulation, with broad implications for vaccination strategies and infectious disease preparedness.

Summary figure