Frequency and timing of adverse reactions to COVID-19 vaccines; A multi-country cohort event monitoring study

Monika Raethke; Florence van Hunsel; Nicoletta Luxi; Thomas Lieber; Chiara Bellitto; Erik Mulder; Francesco Ciccimarra; Fabio Riefolo; Nicolas H. Thurin; Debabrata Roy; Kathryn Morton; Felipe Villalobos; Francisco Batel Marques; Andreea Farcas; Simona Sonderlichová; Svetlana Belitser; Olaf Klungel; Gianluca Trifirò; Miriam C. Sturkenboom

doi:10.1016/j.vaccine.2024.03.001

Frequency and timing of adverse reactions to COVID-19 vaccines; A multi-country cohort event monitoring study

Monika Raethke
, Florence van Hunsel^*
, Nicoletta Luxi
, Thomas Lieber
, Chiara Bellitto
, Erik Mulder
, Francesco Ciccimarra
, Fabio Riefolo
, Nicolas H. Thurin
, Debabrata Roy
, Kathryn Morton
, Felipe Villalobos
, Francisco Batel Marques
, Andreea Farcas
, Simona Sonderlichová
, Svetlana Belitser
, Olaf Klungel
, Gianluca Trifirò
, Miriam C. Sturkenboom

^*Corresponding author for this work

's
University of Groningen
University of Verona
Lareb
Partnerships
Université de Bordeaux
Drug Safety Research Unit
University of Portsmouth
Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol)
CLPP Vaccines Network
Iuliu Hatieganu University of Medicine and Pharmacy
P. J. Safarik University
Utrecht University

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Introduction: During the COVID-19 pandemic, EMA set-up a large-scale cohort event monitoring (CEM) system to estimate incidence rates of patient-reported adverse drug reactions (ADRs) of different COVID-19 vaccines across the participating countries. This study aims to give an up to date and in-depth analysis of the frequency of patient-reported ADRs after the 1st, 2nd, and booster vaccination, to identify potential predictors in developing ADRs and to describe time-to-onset (TTO) and time-to-recovery (TTR) of ADRs. Methods: A CEM study was rolled out in a period ranging from February 2021 to February 2023 across multiple European countries; The Netherlands, Belgium, France, the United Kingdom, Italy, Portugal, Romania, Slovakia and Spain. Analysis consisted of a descriptive analyses of frequencies of COVID-19 vaccine-related ADRs for 1st, 2nd and booster vaccination, analysis of potential predictors in developing ADRs with a generalized linear mixed-effects model, analysis of TTO and TTR of ADRs and a sensitivity analysis for loss to follow-up (L2FU). Results: A total of 29,837 participants completed at least the baseline and the first follow-up questionnaire for 1st and 2nd vaccination and 7,250 participants for the booster. The percentage of participants who reported at least one ADR is 74.32% (95%CI 73.82–74.81). Solicited ADRs, including injection site reactions, are very common across vaccination moments. Potential predictors for these reactions are the brand of vaccine used, the patient's age, sex and prior SARS-CoV-2 infection. The percentage of serious ADRs in the study is low for 1st and 2nd vaccination (0.24%, 95%CI 0.19––0.31) and booster (0.26%, 95%CI 0.15, 0.41). The TTO was 14 h (median) for dose 1 and slightly longer for dose 2 and booster dose. TTR is generally also within a few days. The effect of L2FU on estimations of frequency is limited. Conclusion: Despite some limitations due to study design and study-roll out, CEM studies can allow prompt and almost real-time observations of the safety of medications directly from a patient-centered perspective, which can play a crucial role for regulatory bodies during an emergency setting such as the COVID-19 pandemic.

Original language	English
Pages (from-to)	2357-2369
Number of pages	13
Journal	Vaccine
Volume	42
Issue number	9
DOIs	https://doi.org/10.1016/j.vaccine.2024.03.001
Publication status	Published - 2 Apr 2024

Bibliographical note

Publisher Copyright:
© 2024

Funding

The research leading to these results was conducted as part of the activities of the EU PE&PV (Pharmacoepidemiology and Pharmacovigilance) Research Network which is a public academic partnership coordinated by the Utrecht University, The Netherlands. Scientific work for this project was coordinated by the University Medical Center Utrecht, in collaboration with the Vaccine Monitoring Collaboration for Europe network (VAC4EU). The project has received support from the European Medicines Agency under the Framework service contract nr EMA/2018/23/PE. The content of this paper expresses the opinion of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties. The Dutch part of the study was funded by a grant from the Dutch Ministry of Health, Welfare and Sport. The Dutch Ministry of Health, Welfare and Sport had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Funders	Funder number
European Medicines Agency	EMA/2018/23/PE
Dutch Ministry of Health, Welfare and Sport

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Adverse drug reactions
Cohort event monitoring
COVID-19 vaccination
Pandemic
SARS-CoV-2 infection

Access to Document

10.1016/j.vaccine.2024.03.001Licence: CC BY

1-s2.0-S0264410X24002731-mainFinal published version, 2.4 MBLicence: CC BY

Cite this

Raethke, M., van Hunsel, F., Luxi, N., Lieber, T., Bellitto, C., Mulder, E., Ciccimarra, F., Riefolo, F., Thurin, N. H., Roy, D., Morton, K., Villalobos, F., Batel Marques, F., Farcas, A., Sonderlichová, S., Belitser, S., Klungel, O., Trifirò, G., & Sturkenboom, M. C. (2024). Frequency and timing of adverse reactions to COVID-19 vaccines; A multi-country cohort event monitoring study. Vaccine, 42(9), 2357-2369. https://doi.org/10.1016/j.vaccine.2024.03.001

@article{859d2326f2ec4819a52424b0c7a4c38b,

title = "Frequency and timing of adverse reactions to COVID-19 vaccines; A multi-country cohort event monitoring study",

abstract = "Introduction: During the COVID-19 pandemic, EMA set-up a large-scale cohort event monitoring (CEM) system to estimate incidence rates of patient-reported adverse drug reactions (ADRs) of different COVID-19 vaccines across the participating countries. This study aims to give an up to date and in-depth analysis of the frequency of patient-reported ADRs after the 1st, 2nd, and booster vaccination, to identify potential predictors in developing ADRs and to describe time-to-onset (TTO) and time-to-recovery (TTR) of ADRs. Methods: A CEM study was rolled out in a period ranging from February 2021 to February 2023 across multiple European countries; The Netherlands, Belgium, France, the United Kingdom, Italy, Portugal, Romania, Slovakia and Spain. Analysis consisted of a descriptive analyses of frequencies of COVID-19 vaccine-related ADRs for 1st, 2nd and booster vaccination, analysis of potential predictors in developing ADRs with a generalized linear mixed-effects model, analysis of TTO and TTR of ADRs and a sensitivity analysis for loss to follow-up (L2FU). Results: A total of 29,837 participants completed at least the baseline and the first follow-up questionnaire for 1st and 2nd vaccination and 7,250 participants for the booster. The percentage of participants who reported at least one ADR is 74.32\% (95\%CI 73.82–74.81). Solicited ADRs, including injection site reactions, are very common across vaccination moments. Potential predictors for these reactions are the brand of vaccine used, the patient's age, sex and prior SARS-CoV-2 infection. The percentage of serious ADRs in the study is low for 1st and 2nd vaccination (0.24\%, 95\%CI 0.19––0.31) and booster (0.26\%, 95\%CI 0.15, 0.41). The TTO was 14 h (median) for dose 1 and slightly longer for dose 2 and booster dose. TTR is generally also within a few days. The effect of L2FU on estimations of frequency is limited. Conclusion: Despite some limitations due to study design and study-roll out, CEM studies can allow prompt and almost real-time observations of the safety of medications directly from a patient-centered perspective, which can play a crucial role for regulatory bodies during an emergency setting such as the COVID-19 pandemic.",

keywords = "Adverse drug reactions, Cohort event monitoring, COVID-19 vaccination, Pandemic, SARS-CoV-2 infection",

author = "Monika Raethke and \{van Hunsel\}, Florence and Nicoletta Luxi and Thomas Lieber and Chiara Bellitto and Erik Mulder and Francesco Ciccimarra and Fabio Riefolo and Thurin, \{Nicolas H.\} and Debabrata Roy and Kathryn Morton and Felipe Villalobos and \{Batel Marques\}, Francisco and Andreea Farcas and Simona Sonderlichov{\'a} and Svetlana Belitser and Olaf Klungel and Gianluca Trifir{\`o} and Sturkenboom, \{Miriam C.\}",

note = "Publisher Copyright: {\textcopyright} 2024",

year = "2024",

month = apr,

day = "2",

doi = "10.1016/j.vaccine.2024.03.001",

language = "English",

volume = "42",

pages = "2357--2369",

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Raethke, M, van Hunsel, F, Luxi, N, Lieber, T, Bellitto, C, Mulder, E, Ciccimarra, F, Riefolo, F, Thurin, NH, Roy, D, Morton, K, Villalobos, F, Batel Marques, F, Farcas, A, Sonderlichová, S, Belitser, S, Klungel, O, Trifirò, G & Sturkenboom, MC 2024, 'Frequency and timing of adverse reactions to COVID-19 vaccines; A multi-country cohort event monitoring study', Vaccine, vol. 42, no. 9, pp. 2357-2369. https://doi.org/10.1016/j.vaccine.2024.03.001

TY - JOUR

T1 - Frequency and timing of adverse reactions to COVID-19 vaccines; A multi-country cohort event monitoring study

AU - Raethke, Monika

AU - van Hunsel, Florence

AU - Luxi, Nicoletta

AU - Lieber, Thomas

AU - Bellitto, Chiara

AU - Mulder, Erik

AU - Ciccimarra, Francesco

AU - Riefolo, Fabio

AU - Thurin, Nicolas H.

AU - Roy, Debabrata

AU - Morton, Kathryn

AU - Villalobos, Felipe

AU - Batel Marques, Francisco

AU - Farcas, Andreea

AU - Sonderlichová, Simona

AU - Belitser, Svetlana

AU - Klungel, Olaf

AU - Trifirò, Gianluca

AU - Sturkenboom, Miriam C.

PY - 2024/4/2

Y1 - 2024/4/2

N2 - Introduction: During the COVID-19 pandemic, EMA set-up a large-scale cohort event monitoring (CEM) system to estimate incidence rates of patient-reported adverse drug reactions (ADRs) of different COVID-19 vaccines across the participating countries. This study aims to give an up to date and in-depth analysis of the frequency of patient-reported ADRs after the 1st, 2nd, and booster vaccination, to identify potential predictors in developing ADRs and to describe time-to-onset (TTO) and time-to-recovery (TTR) of ADRs. Methods: A CEM study was rolled out in a period ranging from February 2021 to February 2023 across multiple European countries; The Netherlands, Belgium, France, the United Kingdom, Italy, Portugal, Romania, Slovakia and Spain. Analysis consisted of a descriptive analyses of frequencies of COVID-19 vaccine-related ADRs for 1st, 2nd and booster vaccination, analysis of potential predictors in developing ADRs with a generalized linear mixed-effects model, analysis of TTO and TTR of ADRs and a sensitivity analysis for loss to follow-up (L2FU). Results: A total of 29,837 participants completed at least the baseline and the first follow-up questionnaire for 1st and 2nd vaccination and 7,250 participants for the booster. The percentage of participants who reported at least one ADR is 74.32% (95%CI 73.82–74.81). Solicited ADRs, including injection site reactions, are very common across vaccination moments. Potential predictors for these reactions are the brand of vaccine used, the patient's age, sex and prior SARS-CoV-2 infection. The percentage of serious ADRs in the study is low for 1st and 2nd vaccination (0.24%, 95%CI 0.19––0.31) and booster (0.26%, 95%CI 0.15, 0.41). The TTO was 14 h (median) for dose 1 and slightly longer for dose 2 and booster dose. TTR is generally also within a few days. The effect of L2FU on estimations of frequency is limited. Conclusion: Despite some limitations due to study design and study-roll out, CEM studies can allow prompt and almost real-time observations of the safety of medications directly from a patient-centered perspective, which can play a crucial role for regulatory bodies during an emergency setting such as the COVID-19 pandemic.

AB - Introduction: During the COVID-19 pandemic, EMA set-up a large-scale cohort event monitoring (CEM) system to estimate incidence rates of patient-reported adverse drug reactions (ADRs) of different COVID-19 vaccines across the participating countries. This study aims to give an up to date and in-depth analysis of the frequency of patient-reported ADRs after the 1st, 2nd, and booster vaccination, to identify potential predictors in developing ADRs and to describe time-to-onset (TTO) and time-to-recovery (TTR) of ADRs. Methods: A CEM study was rolled out in a period ranging from February 2021 to February 2023 across multiple European countries; The Netherlands, Belgium, France, the United Kingdom, Italy, Portugal, Romania, Slovakia and Spain. Analysis consisted of a descriptive analyses of frequencies of COVID-19 vaccine-related ADRs for 1st, 2nd and booster vaccination, analysis of potential predictors in developing ADRs with a generalized linear mixed-effects model, analysis of TTO and TTR of ADRs and a sensitivity analysis for loss to follow-up (L2FU). Results: A total of 29,837 participants completed at least the baseline and the first follow-up questionnaire for 1st and 2nd vaccination and 7,250 participants for the booster. The percentage of participants who reported at least one ADR is 74.32% (95%CI 73.82–74.81). Solicited ADRs, including injection site reactions, are very common across vaccination moments. Potential predictors for these reactions are the brand of vaccine used, the patient's age, sex and prior SARS-CoV-2 infection. The percentage of serious ADRs in the study is low for 1st and 2nd vaccination (0.24%, 95%CI 0.19––0.31) and booster (0.26%, 95%CI 0.15, 0.41). The TTO was 14 h (median) for dose 1 and slightly longer for dose 2 and booster dose. TTR is generally also within a few days. The effect of L2FU on estimations of frequency is limited. Conclusion: Despite some limitations due to study design and study-roll out, CEM studies can allow prompt and almost real-time observations of the safety of medications directly from a patient-centered perspective, which can play a crucial role for regulatory bodies during an emergency setting such as the COVID-19 pandemic.

KW - Adverse drug reactions

KW - Cohort event monitoring

KW - COVID-19 vaccination

KW - Pandemic

KW - SARS-CoV-2 infection

UR - https://www.scopus.com/pages/publications/85186944755

U2 - 10.1016/j.vaccine.2024.03.001

DO - 10.1016/j.vaccine.2024.03.001

M3 - Article

C2 - 38448322

AN - SCOPUS:85186944755

SN - 0264-410X

VL - 42

SP - 2357

EP - 2369

JO - Vaccine

JF - Vaccine

IS - 9

ER -

Frequency and timing of adverse reactions to COVID-19 vaccines; A multi-country cohort event monitoring study

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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