Chapter 5: Major Multi-Stakeholder Initiatives — Defining the Future of COVID-19 Observational Research

Vaccine Monitoring Collaboration for Europe (VAC4EU)


Brief description of the VAC4EU initiative and data

VAC4EU, a not-for-profit international association, is a research driven infrastructure (RI) that is creating a major and highly necessary leap in advancing knowledge about vaccines after licensure in the EU market by using novel and existing real-world data. Its governance and sustainability solutions are built on the blueprint that was written by the European Center for Disease Control as part of the European Commission funded ADVANCE project (2013–2019). The ADVANCE project was funded by the European Commission and comprised 47 organizations including EMA.

The influenza A/H1N1 pandemic in 2009 lessons showed that the monitoring of vaccine benefits and risks in Europe had potential for improvement if different public and private stakeholders would collaborate better.62 Stakeholders recognized that there were clear benefits for an EU collaborative approach, and the ADVANCE project showed this was possible. During the project, the foundations of the VAC4EU legal entity were established, and the entity was established in October 2019 and signed by the King of Belgium in in January 2020.

As of January 2022, VAC4EU has 25 organizations as members and provides access to a large network of experts in the area of vaccinology, medicine, data science, public health, pharmacovigilance, and data and regulatory science. As members, these experts have access to routine health data on more than 150 million European citizens, as well as access to the tools to analyze these data in a federated manner for a wide variety of questions. The mission of VAC4EU is to access, characterize, and analyze available and newly collected health data to allow for evidence-based decisions by people who need to regulate, advise, prescribe, or decide on vaccines.

VAC4EU uses the ConcePTION common data model63 as a basis, a generic common data model that was designed by ConcePTION and VAC4EU partners after 10 years of lessons learned around collaborative studies in Europe.64 It requires syntactic harmonization of local data through an extraction transformation load process (ETL). The data analytics pipeline conducts semantic harmonization in a transparent manner.

VAC4EU creates standards, builds community, facilitates sharing knowledge and conducting studies, and provides tools and infrastructures. Its governance is described in statutes and bylaws. VAC4EU is a partner in the EU Pharmacoepidemiology & Pharmacovigilance research network (EU PE &PV) and has boosted much of the EMA-tendered research into the COVID-19 vaccines. EU PE&PV is a consortium of more than 20 ENCePP centers coordinated by Utrecht University that holds framework service contracts with EMA since 2015 for the conduct of pharmacoepidemiological studies.

VAC4EU works according to a federated system in which data stay local, and open source analytics, developed in R programming language by its members, are sent to participating data partners. The organization allows for rotation and flexibility of roles and responsibilities across studies, which allows for scaling up and sharing of knowledge. Access to the infrastructure and tools is provided by the VAC4EU secretariat.

VAC4EU and COVID-19 observational research

The ACCESS (vACcine Covid-19 monitoring readinESS) project under VAC4EU was funded by EMA through the EU PE & PV research network to ensure that a European infrastructure was in place to effectively monitor COVID-19 vaccines in the real world, once these were authorized in the European Union. The project started May 2020 and ended July 2021. The ACCESS project produced the following deliverables which went through EMA and stakeholder review:

  • A list of 37 events of interest with definitions, ICD-9, ICD-10, Read, International Classification of Primary Care (ICPC), and Systemized Nomenclature of Medicine (SNOMED) codes (available on VAC4EU Zenodo community (
  • Background rates of 41 adverse events of special interest (AESI), including the AESI Background rates of AESI protocol (EUPAS 37273), results of background rate calculations (, and report with 41 AESI plus data65 on 10 data sources across 7 countries in Europe
  • Eight template protocols for different types of studies to be adapted for full implementation to local situation: (
  • Signal detection based on cohort event monitoring
    • Cohort event monitoring to assess safety of COVID-19 vaccines using patient-reported events, a protocol template from the ACCESS project
  • Rapid assessment of new safety signals based on electronic health record data
    • Rapid assessment of COVID-19 vaccine safety concerns through electronic health records: a protocol template from the ACCESS project
  • Safety signal evaluation studies (EHR or hospital based)
    • Safety evaluation of COVID-19 vaccines through electronic health records: a protocol template from the ACCESS project
    • Safety Protocol for Hospital Case-Based Monitoring of Specific Adverse Events Following COVID-19 Vaccines: A Protocol Template from the ACCESS project
  • Effectiveness studies (EHR or hospital based)
    • Protocol for COVID-19 vaccine effectiveness studies (test-negative design studies): a protocol from the ACCESS project
    • Assessment of effectiveness of COVID-19 vaccines through electronic health record: a protocol template from the ACCESS project
  • Coverage study (EHR/registry based)
    • Estimation of COVID-19 vaccine coverage using registers and EHR: a protocol template from the ACCESS project
  • Feasibility assessment of countries to participate in studies, including a final report

VAC4EU also organized monthly scientific webinars to discuss different aspects of the ACCESS work which were open to the public. Webinars are publicly available from the VAC4EU website Early-Covid- Vaccine-Monitoring.  .

VAC4EU case studies

The Early-Covid-Vaccine-Monitor project under VAC4EU was funded by EMA through the EU PE & PV research network from November 2020–November 2021 and monitored COVID-19 vaccines in 8 countries using 2 complementary methodologies which have been described in the EU PAS register:

  • A prospective cohort event in which more than 100,000 vaccinated persons across 6 countries were included and monitored through apps/internet
  • A retrospective cohort study in 4 countries with short lag-time, monitoring the incidence rates of adverse events of special interest and COVID-19 prior to vaccination and post vaccination (

The project was focused on monitoring of incidence, and not signal detection nor signal evaluation. VAC4EU provided expertise and tools.

In addition, VAC4EU leads a COVID-19 Vaccine Monitoring Study (CVM) project funded by EMA through the EU PE & PV research network from April 2021–April 2023. This project aims to:

  • Conduct prospective cohort event monitoring across 10 countries, focusing on special populations (children, immunocompromised, pregnant), general population, and booster doses
  • Conduct retrospective cohort studies and self-controlled studies in 10 data sources ready to assess safety signals. Studies on Multi-Inflammatory Syndrome and Myocarditis have been conducted (
  • Conduct methodological research on comparators and designs related to COVID-19 vaccine studies

VAC4EU is a member of the Global Vaccine Data Network (GVDN) and participates in dedicated studies on associations of COVID-19 vaccines and myocarditis, Thrombosis with Thrombocytopenia Syndrome

(TTS), and Guillain-Barré syndrome (GBS) funded by the US Centers for Disease Control and Preventtion (CDC).

Finally, VAC4EU supports its members to contract and implement post-authorization safety studies on COVID-19 vaccines for several manufacturers using the VAC4EU tools and governance, the ConcePTION data model and pipeline, and the VAC4EU member organizations.66–69

VAC4EU impact and perspective

Lessons from the 2009 pandemic led to the initiation of a collaboration in Europe, which was designed, tested, and implemented by the VAC4EU. VAC4EU was established as an entity just before the 2019 pandemic was declared, and was able to start its work to support the European PE & PV network and the European Medicines Agency in time to prepare for large scale collaborative studies. VAC4EU member organizations form a vibrant community leveraging the expertise and knowledge from all of its member organizations. VAC4EU supports more than 10 official post-authorization safety studies on COVID-19 vaccines, protocols, and materials, which are all in the public domain.