Moderna Spikevax® Post-Authorisation Safety Study

Background: The Moderna mRNA-1273 vaccine was developed in response to the coronavirus disease 2019 (COVID-19) pandemic and included in vaccination programmes in Europe. This post-authorisation safety study aimed to evaluate the safety profile of the mRNA-1273 vaccine.

Objectives: To examine whether the mRNA-1273 vaccine was associated with increased rates of 39 pre-specified adverse events of special interest (AESI).

Methods: This multi-database, VAC4EU study utilized data from population-based health registries in Denmark and Norway, and primary-care databases in Spain (SIDIAP –Catalonia region) and the United Kingdom (CPRD Aurum). Data were harmonised using the ConcePTION common data model and analysed with a federated approach. The exposure was the mRNA-1273 vaccine (any dose, by dose, or within designated risk windows after vaccination). Signal detection observed/expected analyses compared AESI rates among mRNA-1273 vaccinees with historical rates using a threshold of standardized morbidity ratio ≥2 with a minimum of 5 exposed cases. When the threshold was reached, signal evaluation was conducted using self-controlled or cohort designs. Country-specific estimates were combined using random-effects meta-analysis.

Results: For signal detection, the number of eligible individuals with at least one dose of mRNA-1273 vaccine was 564,080 in Denmark, 531,172 in Norway, 621,871 in Spain, and 273,254 in the United Kingdom.

Self-controlled case series analyses were used for signal evaluation of anaphylaxis, myocarditis, and pericarditis. For anaphylaxis 0-2 days post mRNA-1273 vaccination, the combined incidence rate ratios (IRRs) (95% confidence interval [CI]) were 4.74 (2.06-10.9) after the first dose and 2.66 (1.09-6.49) after the second dose in individuals ≥12 years. For myocarditis, the combined IRRs (95% CI) were 16.8 (6.86-41.3) 0-7 days after the second dose and 9.24 (3.77-22.6) 0-14 days after the second dose in males 12-39 years. The corresponding IRRs (95% CI) for pericarditis were 8.56 (3.01-24.4) and 4.55 (1.80-11.5).

Our findings did not indicate an association between the mRNA-1273 vaccine and the remaining 36 AESIs. Among AESIs with country-specific results available for all countries, the combined association measures ranged from an adjusted IRR (95% CI) for deep vein thrombosis of 0.87 (0.70-1.09) for the risk window 1-42 days after any dose of mRNA-1273 vaccine to an adjusted hazard ratio (95% CI) for single organ cutaneous vasculitis of 1.28 (0.73-2.25) comparing mRNA-1273 recipients with age and sex matched historical comparators.

Conclusions: We confirmed previously identified associations between the mRNA-1273 COVID-19 vaccine and anaphylaxis, myocarditis, and pericarditis. However, no additional safety concerns were observed.

The novel coronavirus SARS-CoV-2 caused a pandemic and subsequently brought about a mass vaccination
campaign involving several vaccines. The scale and speed of this campaign necessitated unprecedented
collaboration to overcome challenges for large scale European multinational post-authorization studies of
vaccines.

Objectives:
To explore optimal approaches to harmonize multinational observational studies of adverse events of
special interest (AESIs) in vaccinees of mRNA-1273 in Europe.

Methods:
This study, conducted by the Vaccine monitoring Collaboration for Europe (VAC4EU) association, relies on
secondary routinely collected data from 5 countries selected based on availability of specific data elements.
The databases included national registers (Denmark and Norway), regional administrative databases (Italy’s
Agenzia Regionale di Sanita’ della Toscana [ARS]; Spain’s Sistema d’Informació per al Desenvolupament de la
Investigació en Atenció Primaria [IDIAP]), and the Clinical Practice Research Datalink (CPRD), in the UK.
Source data was extracted and transformed into the standardized format of the ConcepTION common data
model, consisting of semantically harmonized tables of persons, observation periods, vaccines, drugs, and
diagnoses. AESI-defining algorithms, based on diagnoses and/or drug proxies, were developed using cross-
mapping with the automated tool Codemapper, published algorithms, and clinical expertise.
We created scripts to define study variables and populations and perform prespecified analyses. Results
from the analyses were output aggregated data, enabling their transfer to a cloud-based centralized Digital
Research Environment where the report tables are generated, while preserving data privacy.

Results:
We programmed 127 scripts which aimed at ultimately generating 23 report tables covering population
selection, population description, and results from seven different epidemiological designs spanning 5
countries and 38 AESIs. Our federated approach identified 4.7M people who received at least one dose of
mRNA-1273. Over 2.1M individuals met the eligibility criteria for the statistical analyses.

Conclusions:
Combining heterogeneous data sources from 5 European countries, this project used and further developed
a successful analysis pipeline, serving as a model for conducting multinational post-authorization
observational studies of vaccine safety. Comparing and harmonizing outcomes of interest without violating
privacy regulations, our solution automates documentation to ensure reproducibility.