Real-World Comparative Effectiveness of SARS-CoV-2 Primary Vaccination Campaigns Against SARS-CoV-2 Infections: A Federated Observational Study Emulating a Target Trial in Three Nations

Background:
To assess the impact of large-scale SARS-CoV-2 vaccination campaigns in uncontrolled settings across regions, we performed a reproducible cross-border comparison of the real-world effectiveness of primary vaccination in preventing SARS-CoV-2 infections across three sites: Aragon (Spain), Brussels and Wallonia (Belgium), and Finland.

Methods:
This observational study emulated a target trial by daily matching primary vaccinated individuals 1:1 to un- or partially vaccinated individuals based on a set of confounders from January to September 2021. Matched individuals were followed up until a SARS-CoV-2 infection was contracted or a censoring event occurred. Vaccine effectiveness in preventing infections was estimated by the difference in Restricted Mean Survival Time (RMST).

Findings:
Primary vaccination extended the mean time until contracting a SARS-CoV-2 infection on average by 35.9 (95% CI [34.9 - 37.0]), 59.6 (95% CI [59.3 - 60.0]), and 1.6 (95% CI [1.1 - 2.0]) days over 365 days in the population cohort of Aragon (Spain), Brussels and Wallonia (Belgium), and Finland, respectively.

Interpretation:
This federated population-based observational study showed the effectiveness of the SARS-CoV-2 primary vaccination campaign in prolonging the mean time to infection in the Aragon (Spain) and Brussels & Wallonia (Belgium) population cohorts. Only a minor difference over this time frame was found in Finland's population cohort.

Funding:
This research was supported by funds from the BY-COVID Project. BY-COVID (BeYond COVID) is a Horizon Europe funded project from the European Union (grant agreement HORIZON-INFRA-2021- EMERGENCY-01 101046203), launched in October 2021.

Declaration of Interest: Not applicable.

Ethical Approval:
Ethical approval was granted for linking different individual-level data sources to comply with the data requirements specified in the study in the sites Aragon (Spain), Brussels and Wallonia (Belgium), and Finland. In Aragon (Spain), the Research Ethics Committee of Aragon (CEICA) granted approval for linking the required data sources (the COVID-19 public health surveillance and monitoring information system of COVID-19 cases, the SARS-CoV-2 vaccination population registry, the health system users databases, and data from electronic health records), via BIGAN (https://bigan.iacs.es/en/home), in its ruling of 22 February 2023 (reference number C.I. EPA 23/008). In Brussels and Wallonia (Belgium), activities of this study and thus linkage of the required data sources (the vaccine registry VACCINNET+, the COVID-19 test result database, the COBRHA database, the Intermutualistic Agency (IMA) database, the STATBEL database) are covered by the existing deliberation of the Information Security Committee Social Security and Health (ISC-SSH) of the LINK-VACC project. The LINKVACC project was approved by the Medical Ethics Committee UZ Brussels–VUB on 3 February 2021 (reference number 2020/523), and authorization was granted from the ISC Social Security and Health (reference number IVC/KSZG/21/034). Informed consent was waived based on Art. 6 and 9 of the GDPR. The collection is allowed based on general interest (art. 6 GDPR) and regarding article 9 § 2 of the GDPR: processing is necessary for reasons of public interest in the area of public health, such as protecting against serious cross-border threats to health or ensuring high standards of quality and safety of health care and of medicinal products or medical devices, on the basis of Union or Member State law which provides for suitable and specific measures to safeguard the rights and freedoms of the data subject, in particular, professional secrecy.