Evaluation of adverse event clusters following immunization with mRNA COVID-19 vaccines: a real-world analysis using EudraVigilance data

Study type

• Study topic:
  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Drug utilisation
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Name of medicine:
  COMIRNATY

  SPIKEVAX
• Anatomical Therapeutic Chemical (ATC) code:
  (J07) VACCINES

  VACCINES

  (J07BN01) covid-19, RNA-based vaccine

  covid-19, RNA-based vaccine

Population studied

• Short description of the study population:
  This study will include individuals aged 18 years and older who have been recipients of at least one dose of an mRNA COVID-19 vaccine (Pfizer/BioNTech or Moderna) within the European Economic Area. ; The population will comprise all cases reported to EudraVigilance between 1 January 2020 and 31 December 2023 that include at least one suspected adverse event following immunization (AEFI). ; No exclusions based on demographic characteristics or comorbidities will be applied. ; The study population is expected to reflect a wide range of real-world vaccine recipients, including younger adults (18–45 years), middle-aged adults (46–64 years), and elderly individuals (65 years and older), thus allowing subgroup analyses across distinct age ranges and seriousness profiles of AEFI.
• Age groups:
  Adults (18 to < 46 years)

  Adults (46 to < 65 years)

  Adults (65 to < 75 years)

  Adults (75 to < 85 years)

  Adults (85 years and over)
• Special population of interest:
  Hepatic impaired

  Immunocompromised

  Pregnant women

  Renal impaired
• Estimated number of subjects:
  1430

Study design details

• Study design:
  Retrospective observational study using individual case safety reports (ICSRs) from EudraVigilance, analysing adverse event patterns following mRNA COVID-19 vaccination in adults, through co-occurrence and correspondence analysis.
• Main study objective:
  To characterize and identify clusters of adverse events following immunization (AEFI) with mRNA COVID-19 vaccines in real-world settings, using EudraVigilance data, and to assess the variability in safety profiles between different vaccine versions and across population subgroups.
• Setting:
  This study will be conducted using anonymized Individual Case Safety Reports (ICSRs) submitted to the EudraVigilance Post-Authorization Module (EVPM), covering all European Economic Area countries. ; The dataset includes reports related to mRNA COVID-19 vaccines (Pfizer/BioNTech and Moderna), received between 1 January 2020 and 31 December 2023. ; All ICSRs with at least one suspected adverse event following immunization (AEFI) will be included, regardless of reporter type, seriousness, or patient demographics. ; No exclusion criteria will be applied to ensure the comprehensiveness of real-world data. Subgroup analyses will explore variations in AEFI patterns by age, seriousness, and vaccine version.
• Comparators:
  No formal control group will be used. However, internal comparisons will be made between vaccine brands (Pfizer/BioNTech vs. Moderna) and across different vaccine versions. ; Stratified analyses will also compare AEFI profiles by patient age groups and seriousness classification. ; These internal comparators will enable indirect assessment of differences in safety profiles across products and population subgroups.
• Outcomes:
  Primary outcomes include the identification and characterization of adverse event clusters following mRNA COVID-19 vaccination, based on co-occurrence patterns of AEFI. ; Secondary outcomes involve assessing differences in AEFI profiles between vaccine brands and versions, seriousness classification (serious vs. non-serious), and specific populations of interest (e.g., older adults, immunocompromised, pregnant women). ; Outcomes will be measured using frequency counts, co-occurrence networks, and correspondence analysis.
• Data analysis plan:
  Descriptive statistics will be used to summarize the distribution of ICSRs by year, vaccine version, age group, and seriousness. Co-occurrence analysis will identify frequently co-reported AEFI pairs using hypergeometric testing. Statistically significant associations will be visualized through network plots. ; Correspondence analysis will explore relationships between vaccine versions and AEFI patterns. Analyses will be performed globally and within relevant subgroups (e.g., age, seriousness). ; Statistical analyses will be conducted using R software, following STROBE and ENCePP methodological guidance.
• Summary results:
  We retrieved 993,199 ICSR (Moderna: 394,484; Pfizer: 605,794), with most reports related to women patients (69%) and non-healthcare professionals (65%). A total of 10,804 distinct AEFI terms were described across the retrieved ICSR, with a cumulative occurrence frequency of 3,558,219 (Moderna: 1,555,638; Pfizer: 2,031,828). The most prominent serious clusters included headache, fatigue, pyrexia, myalgia, arthralgia, malaise, nausea, and chills, which frequently co-occurred with vaccination failure. Specific AEFI like fever, chills, malaise, arthralgia, injection site pain, inflammation, and warmth were more often linked to Moderna, while Pfizer was more commonly associated with vaccination failure, menstrual disorders (heavy menstrual bleeding and dysmenorrhea), and hypoesthesia. ; In older adults, serious clusters included confusional states, cerebrovascular accidents, and myocardial infarctions, while myocarditis and pericarditis were noted in younger males. Although rare, serious systemic AEFI, like anaphylactic reactions, were identified but require further causality evaluation.; The overall safety of mRNA COVID-19 vaccines for mass vaccination is supported, but continuous pharmacovigilance remains essential. ; Identified clusters of AEFI, particularly serious and systemic ones, although rare and potentially influenced by other underlying causes, underscore the need for continuous monitoring and further epidemiological investigations to explore potential causal relationships.