Safety Monitoring of COVID-19 Vaccines in Persons with Prior SARS-CoV-2 Infection: A European Multi-Country Study
by
, , , , , , and
Francesco Ciccimarra
1,†,
Nicoletta Luxi
2,†,
Chiara Bellitto
1,
Luca L’Abbate
1,
Monika Raethke
3,
Florence van Hunsel
3,4,
Thomas Lieber
3,
Erik Mulder
3,
Fabio Riefolo
5,
Caroline Dureau-Pournin
6,
Andreea Farcas
7,
Francisco Batel Marques
8,
Kathryn Morton
9,10,
Debabrata Roy
9,10,
Simona Sonderlichová
11,
Nicolas H. Thurin
6
,
Felipe Villalobos
12
,
Miriam C. Sturkenboom
13 and
Gianluca Trifirò
1,* 1
Department of Diagnostics and Public Health, University of Verona, 37134 Verona, Italy
2
Department of Medicine, University of Verona, 37134 Verona, Italy
3
Netherlands Pharmacovigilance Centre Lareb, Goudsbloemvallei 7, 5237 MH ‘s-Hertogenbosch, The Netherlands
4
Department of PharmacoTherapy, Epidemiology & Economics, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9712 CP Groningen, The Netherlands
5
Teamit Institute, Partnerships, Barcelona Health Hub, 08025 Barcelona, Spain
6
University of Bordeaux, INSERM CIC-P 1401, Bordeaux PharmacoEpi, 146 rue Léo Saignat, 33076 Bordeaux, France
7
Pharmacovigilance Research Center, Iuliu Hatieganu University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania
8
Laboratory of Social Pharmacy and Public Health, School of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
9
Drug Safety Research Unit, Southampton SO31 1AA, UK
10
University of Portsmouth, Portsmouth PO1 2UP, UK
11
Faculty of Medicine, SLOVACRIN, Pavol Jozef Šafárik University in Košice, 040 01 Košice, Slovakia
12
Fundació Institut Universitari per a la Recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), 08007 Barcelona, Spain
13
Department of Data Science and Biostatistics, Julius Global Health, University Medical Centre Utrecht, 3584 CG Utrecht, The Netherlands
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Vaccines 2024, 12(3), 241; https://doi.org/10.3390/vaccines12030241
Submission received: 5 January 2024
/
Revised: 7 February 2024
/
Accepted: 21 February 2024
/
Published: 26 February 2024
(This article belongs to the Special Issue 2nd Edition: Safety and Autoimmune Response to SARS-CoV-2 Vaccination)
Abstract
:In all pivotal trials of COVID-19 vaccines, the history of previous SARS-CoV-2 infection was mentioned as one of the main exclusion criteria. In the absence of clinical trials, observational studies are the primary source for evidence generation. This study aims to describe the patient-reported adverse drug reactions (ADRs) following the first COVID-19 vaccination cycle, as well as the administration of booster doses of different vaccine brands, in people with prior SARS-CoV-2 infection, as compared to prior infection-free matched cohorts of vaccinees. A web-based prospective study was conducted collecting vaccinee-reported outcomes through electronic questionnaires from eleven European countries in the period February 2021–February 2023. A baseline questionnaire and up to six follow-up questionnaires collected data on the vaccinee’s characteristics, as well as solicited and unsolicited adverse reactions. Overall, 3886 and 902 vaccinees with prior SARS-CoV-2 infection and having received the first dose or a booster dose, respectively, were included in the analysis. After the first dose or booster dose, vaccinees with prior SARS-CoV-2 infection reported at least one ADR at a higher frequency than those matched without prior infection (3470 [89.6%] vs. 2916 [75.3%], and 614 [68.2%] vs. 546 [60.6%], respectively). On the contrary side, after the second dose, vaccinees with a history of SARS-CoV-2 infection reported at least one ADR at a lower frequency, compared to matched controls (1443 [85.0%] vs. 1543 [90.9%]). The median time to onset and the median time to recovery were similar across all doses and cohorts. The frequency of adverse reactions was higher in individuals with prior SARS-CoV-2 infection who received Vaxzevria as the first dose and Spikevax as the second and booster doses. The frequency of serious ADRs was low for all doses and cohorts. Data from this large-scale prospective study of COVID-19 vaccinees could be used to inform people as to the likelihood of adverse effects based on their history of SARS-CoV-2 infection, age, sex, and the type of vaccine administered. In line with pivotal trials, the safety profile of COVID-19 vaccines was also confirmed in people with prior SARS-CoV-2 infection.
1. Background
All COVID-19 vaccines authorized by the European Medicines Agency (EMA) showed a good benefit–risk profile in pivotal clinical trials [1]. The most commonly reported local and systemic adverse reactions in these studies were injection site pain, fatigue, headache, erythema, and induration; a smaller percentage of participants reported injection site redness or swelling. The incidence of serious adverse events was low, and similar in the vaccine and placebo groups [2,3]. However, vulnerable populations/higher-risk-people, and special cohorts, such as those with prior SARS-CoV-2 infection, have not been included in these trials [4].
Assessing the benefit–risk profile of COVID-19 vaccines in the real-world setting, especially in those categories not recruited in clinical trials, is crucial to ensuring that they perform as intended, rapidly identifying any potential safety signal and providing insights into whether vaccination strategies need to be adapted.
Vaccination policies for people with prior SARS-CoV-2 infection evolved due to rapidly accumulated evidence on the vaccines’ benefit–risk profiles, and also because of the growing number of subjects that have been infected over time [5,6,7]. Observational studies showed that increased time between infection and vaccination might result in improved immune responses to vaccination and a lower risk of reinfections [8]. In Europe, to administer any COVID-19 vaccine, a minimum of three months of lag time after infection has been recommended [9]. In addition, the World Health Organization (WHO) and other public health agencies recommended implementing intensive post-marketing safety monitoring for these vaccinees [10].
In the absence of data from clinical trials, observational studies are the primary source for evidence generation [11,12] about the safety of COVID-19 vaccines in patients with prior SARS-CoV-2 infection.
Recently published post-marketing studies showed that COVID-19 vaccines may induce higher immunogenicity in previously infected individuals, as documented by higher anti-spike antibody titers, as compared to those without prior SARS-CoV-2 infection [13,14,15,16].
From a clinical perspective, this translates into a higher reactogenicity of COVID-19 vaccines among individuals previously infected with SARS-CoV-2, as reported in both prospective and retrospective observational studies published so far (Supplementary Table S1).
However, most of these observational studies were conducted in single countries and assessed the safety of only one or, at most, two vaccine brands; were restricted to either the first vaccination cycle or a booster dose only; and monitored a short follow-up period. To date, no observational studies assessing the comparative safety of all COVID-19 vaccines authorized by the EMA across different vaccine brands and doses in persons with prior SARS-CoV-2 infection, as compared to SARS-CoV-2 infection-history naïve vaccinees, have been published.
The EMA funded the European multi-country project “Covid Vaccine Monitor” (CVM), a large-scale cohort event monitoring system aimed at collecting vaccinee-reported outcomes on the safety of all EMA-approved COVID-19 vaccines through web-based questionnaires within the general population, as well as in special categories, including those with prior SARS-CoV-2 infection.
As part of the CVM project, this study aims to investigate the safety profiles of different doses and brands of all EMA-licensed COVID-19 vaccines in people with previous SARS-CoV-2 infection, matched 1:1 to prior infection-free persons, from eleven European countries.
2. Methods
2.1. Setting and Study Population
This was a prospective cohort study based on electronic questionnaires collecting vaccinee-reported characteristics and outcomes from 11 European countries.
All vaccinees, who provided informed consent to participation in the study, registered on the web app within 48 h after receiving the first or a booster dose of any EMA-authorized COVID-19 vaccine (Vaxzevria, Comirnaty, Spikevax, or Jcovden vaccines) in a period ranging from February 2021 to February 2023 and reported a prior SARS-CoV-2 infection before vaccination.
Applying the same inclusion criteria, as the control group, a random sample of vaccinees participating in the CVM project and who did not report prior SARS-CoV-2 infection at the vaccination time was selected.
Controls were 1:1 matched to vaccinees with prior SARS-CoV-2 infection by gender, age, and vaccine dose and brand at the study entry. The matching procedure was performed based on the propensity score values, using the nearest-neighbor procedure for the age variable and exact matching for gender, dose, and vaccine brand.
In each country, the study protocol was approved by the respective Ethics Committee, and the study was carried out in line with the General Data Protection Regulation (GDPR) and the Data Protection Impact Assessment (DPIA). The study protocol has been submitted to the EU-PAS register (EUPAS42504).
2.2. Data Collection
Data were collected by partners of the CVM project, a large European network including pharmacovigilance centers, universities, hospitals, and local health units, as well as the EMA. Vaccinees were invited to participate in the cohort event-monitoring study through ad hoc dissemination materials (e.g., flyers, posters, animation videos, and infographics), which were distributed through different channels, such as print magazines, online journals, scientific society web pages, social networks, and vaccination centers.
Two specific and harmonized web-based apps were developed for data collection, the Lareb-managed Intensive Monitoring (LIM) and Research Online (RO), which were built specifically for vaccinee-reported outcomes, and questionnaires were translated into local languages [17,18].
In the baseline questionnaire, information on vaccinees’ characteristics, including demographics, medical history (i.e., cardiovascular disorder, diabetes mellitus, hypertension, liver disorder, lung disorder, mental disorder, malignant tumor, nervous system disorder, and renal disorder), concomitant drug use, and administered COVID-19 vaccine dose and brand, were collected. In addition, for people with prior SARS-CoV-2 infection, information on the dates and symptoms relevant to the infection was collected. Moreover, vaccinees filled out a total of six follow-up questionnaires (FU-Qs) during the six months after the first dose of COVID-19 vaccines, and five follow-up questionnaires over a 3-month follow-up period were provided for those recruited at the booster dose (Figure 1). Participants could register for the booster dose via the web app until 30 November 2022. FU-Qs were stored until 28 February 2023.
FU-Qs collected information on patient-reported short-/medium-/long-term adverse reactions experienced following the COVID-19 vaccines. Specifically, FU-Qs collected data on solicited local reactions (injection site hematoma, induration, inflammation, pain, pruritus, swelling, and warmth) and systemic adverse drug reactions (ADRs) (arthralgia, chills, fatigue, headache, malaise, myalgia, nausea, and fever), based on the most frequently reported adverse events in pivotal trials [2,3]. Information on unsolicited ADRs, adverse events of special interest (AESI), and serious ADRs was also collected. Serious ADRs were assessed and coded by pharmacovigilance-trained personnel according to the Council for International Organizations of Medical Sciences (CIOMS criteria) [19]. Adverse events of special interest were defined according to a list provided by the Brighton Collaboration [20]. All patient-reported adverse reactions were coded using Medical Dictionary for Regulatory Activities (MedDRA) terminology 23.0 and 24.0 [21] and ultimately sent to EudraVigilance. For each ADR, time of onset, outcome, duration of symptoms (if recovered), and severity/impact of symptoms (including medical assistance and hospitalization) were topics of inquiry [22].
2.3. Data Analysis
Data from 11 European countries (Belgium, France, Italy, Ireland, Portugal, Romania, Slovakia, Spain, Switzerland, the Netherlands, and the United Kingdom), were collected through two comparable tools and standardized using a common data model (CDM) and then pooled and analyzed centrally. Only vaccinees who filled out the baseline and at least the first follow-up questionnaire were included in the analyses.
First, a descriptive analysis of the demographics and clinical characteristics of people with prior SARS-CoV-2 infection versus the matched control was conducted and stratified by first/booster dose as well as vaccine brands.
Second, the proportion of subjects with at least one ADR in general, as well as specifically solicited/unsolicited/serious ADRs, was also evaluated, using as denominator the total number of recruited vaccinees receiving the first dose, second dose, or a booster dose of any vaccine brand, and who filled in (baseline plus) at least the first FU-Q. In addition, the frequency of local and systemic solicited ADRs reported after the first, second, or booster doses of any vaccine, for people with prior SARS-CoV-2 infection versus matched controls, was measured. To investigate a potential interaction effect of medical history on the association between previous SARS-CoV-2 infection and the occurrence of at least one ADR, logistic regression models were utilized. The estimated interaction effect was represented in a forest plot. In addition, to explore the occurrence of ADRs in relation to SARS-CoV-2 variants of concern, participants who reported the date of symptom onset in the web app were divided into two groups based on date periods. Based on a previous study [23], we estimated the prevalence of SARS-CoV-2 variants using the WHO periodic bulletin, identifying two periods (i.e., Alpha and Delta). The occurrence of ADRs in relation to the severity of COVID-19 symptoms reported in the baseline questionnaire (i.e., no symptoms, symptoms similar to cold, many symptoms, or admitted to hospital) was also analyzed.
Third, heatmaps of the proportions of participants who reported at least one solicited ADR, stratified by gender and age categories, were generated. In addition, heatmaps of the percentages of vaccinees who reported local and systemic solicited ADRs, stratified by vaccine brand, dose, gender, and age categories, were also produced.
Fourth, the time to onset (TTO) and the time to recovery (TTR) of reported ADRs were analyzed and visualized with a combination of violin plots and box-plots, with median, first quartile, third quartile, minimum, and maximum observed values rendered in hours. Participants could report the TTO and TTR of an ADR as the number of seconds, minutes, hours, days, weeks, or months, or with a specific calendar date. For this analysis, only subjects who reported both TTO and TTR for a specific ADR were included.
All of the heatmaps and TTO and TTR analyses for vaccinees with prior SARS-CoV-2 infections versus matched controls were separately generated. Finally, we explored whether the frequency of ADR reporting among subjects with prior SARS-CoV-2 infection varied based on the time elapsed between infection and vaccination, using four different timeframes (i.e., 0–90 days, 91–180 days, 181–360 days, and >360 days).
Categorical variables were reported as absolute frequencies and percentages, while continuous variables were reported as median (interquartile range), as appropriate. A Chi-square test or Fisher’s exact test was performed to compare categorical variables, while a Wilcoxon test was performed to compare medians, as appropriate. A p-value < 0.05 denoted statistical significance. All analyses were performed using R statistical software (version 4.3.1). For heatmaps, violin plots, box-plots, and random forest analysis, the ggplot2 R package was used.
3. Results
Overall, between February 2021 and November 2022, 37,170 subjects from 11 European countries registered for the Covid Vaccine Monitor study and completed both the baseline questionnaire and the FU-Q1. Of them, 30,186 (81.2%) registered after receiving the first vaccination cycle and 6984 (18.9%) after receiving the booster dose.
From this study population, overall, 12.9% of vaccinees recruited at the first vaccination cycle (N = 3886) and at the booster dose (N = 902) reported a prior SARS-CoV-2 infection at the time of vaccination. These vaccinees were included in the analyses and 1:1 matched to a cohort of vaccinees without a prior SARS-CoV-2 infection by age, gender, and vaccine brand.
Regarding subjects included in the analyses, after the first vaccination cycle, 50.8% of the vaccinees with prior SARS-CoV-2 infection and 56.6% of the matched controls filled out all six FU-Qs, while only 41.2% of the vaccinees with prior SARS-CoV-2 infection and 50.6% of the matched controls completed all five FU-Qs after the booster dose (Figure 2).
Most of the participants with prior SARS-CoV-2 infection received Vaxzevria (N = 1410; 36.3%) at the first vaccination cycle, a percentage followed by Comirnaty (N = 1372; 35.6%), Spikevax (N = 668; 17.2%), and Janssen (N = 422; 10.9%). The female/male (F/M) ratio was equal to 2.8 (Table 1).
As for the booster dose, most of the participants (F/M ratio = 1.9) received Comirnaty (N = 521; 57.8%), a percentage followed by Spikevax (N = 376; 41.2%), while only three received Vaxzevria (0.3%) (Table 2). The median ages of participants who received the first and the booster doses were 46 years (interquartile range: 33–56 years) and 42 years (interquartile range: 31–53 years), respectively. In general, no statistically significant differences in terms of medication use and medical history were observed among subjects with prior SARS-CoV-2 infection and matched controls, for both the first vaccination cycle and booster dose (Table 1 and Table 2).
After the first and the booster dose, vaccinees with prior SARS-CoV-2 infection reported at least one ADR with higher frequencies than those matched without prior infection (3470 [89.6%] vs. 2916 [75.3%], and 614 [68.2%] vs. 546 [60.6%], respectively). On the contrary side, after the second dose, vaccinees with a history of SARS-CoV-2 infection reported at least one ADR with a lower frequency compared to matched controls (1443 [85.0%] vs. 1543 [90.9%]) (Figure 3, Supplementary Tables S2–S4).
In more detail, the proportion of vaccinees with prior SARS-CoV-2 infection reporting at least one ADR was higher for those who received Vaxzevria for the first dose and for those who received Spikevax for the second or booster doses (Supplementary Tables S2–S4). As shown in Supplementary Figure S3, for the first dose and the booster dose, no statistically significant interaction effect of comorbidities on the association between previous SARS-CoV-2 infection and the occurrence of ADRs was observed, except for hypertension at the first dose. However, for both the first and the booster dose, a trend of increased risk for diabetes was observed, although it does not reach the point of significance (Supplementary Figure S3).
In both cohorts, irrespective of vaccine dose and brand, injection site pain was the most frequently reported local solicited ADR, while fatigue, headache, malaise, and myalgia were the most reported systemic solicited ADRs (Figure 4).
Regarding the booster dose, arthralgia, chills, malaise, increased body temperature, and pyrexia were significantly more reported among subjects with prior SARS-CoV-2 infection who received Comirnaty as compared with their matched controls (p < 0.05 for each comparison) (Supplementary Table S4).
Among all doses and brands of vaccines, the frequency of AESIs was low, ranging from 0.1% to 1.2%. A similar trend was also observed for serious ADRs, with frequencies ranging from 0.1% to 0.3% (Supplementary Tables S2–S4). The total numbers of reported serious ADR and AESI (n = 85 in total), stratified by vaccine brand, dose, and cohort, are shown in Table 3 and Table 4.
When stratifying by different timeframes between SARS-CoV-2 infection and vaccine administration, no significant differences in the frequency of reported ADRs were observed (Supplementary Table S7). However, a statistically significant difference was observed in the frequency of reported ADRs by stratifying the analysis by variants of concern following the first dose (p-value = 0.006) (Supplementary Table S8).
The frequency of people with prior SARS-CoV-2 infection reporting at least one ADR, stratified by different severity of symptoms, showed a statistically significant difference for both first and booster doses (p-value < 0.001) (Supplementary Table S9).
Overall, across all doses, women and younger subjects were more likely to report at least one solicited ADR, despite no sex-related differences being found in the distribution of systemic ADRs observed (Supplementary Tables S5 and S6, and Figure 5).
As shown in the violin plots in Figure 6A, the median time to onset for all reported ADRs following the first dose was 12.9 (interquartile range: 7.4–22.7) hours among vaccinees with prior SARS-CoV-2 infection and 11.7 (interquartile range: 6.2–23.1) hours among the matched controls. Likewise, a similar time to recovery in people with prior SARS-CoV-2 infection (37.9 h; interquartile range 21.3–64.3 h) versus matched controls (37.3 h; interquartile range 19.8–57.8 h) was reported (Figure 6B).
Following the second dose, a similar time to onset was observed among infected and matched controls (Figure 6C), whilst the time to recovery was higher for matched controls (37.2 h; interquartile range 20.1–59.3), as compared with participants with previous SARS-CoV-2 infection (28.3 h; interquartile range 19.8–53.5) (Figure 6D).
Lastly, regarding the booster dose, people with prior SARS-CoV-2 infection showed a slightly lower median TTO (13.5 h; interquartile 1.8–20.0), than that of the matched controls (15.5 h; interquartile 2.9–20.9) (Figure 6E). Time to recovery demonstrated the same trend as that observed for the second dose (Figure 6F). A statistically significant difference for the TTO and TTR of individuals with prior SARS-CoV-2 infection and participants without prior infection in each dose was observed, except for that for the TTO of individuals who received the second dose.
4. Discussion
To our knowledge, this is the first active surveillance study that explored the safety of COVID-19 vaccines through patient-reported outcomes, collected via electronic questionnaires, in people with prior SARS-CoV-2 infection, as compared to a matched cohort of not previously infected vaccinees, across different vaccine doses and brands from multiple European countries, with a long study period. In addition, as compared to previously published observational studies that focused exclusively on single vaccine brands or doses, our evidence provided a broader overview of different COVID-19 vaccine brands and doses authorized by the EMA.
This study documented that the safety profile of COVID-19 vaccines in people with prior SARS-CoV-2 infection is favorable, with extremely low frequencies of serious adverse reactions/AESI following each vaccine dose. Overall, subjects with prior SARS-CoV-2 infection were more likely to experience at least one ADR, as compared to those without a history of SARS-CoV-2 infection, after the first dose or the booster dose, confirming already-existing evidence coming from several observational studies [24,25]. In particular, for both cohorts, the most frequently reported local solicited ADR following both the first vaccination cycle and the booster dose was injection site pain. As for systemic solicited ADRs, fatigue, headache, malaise, and myalgia were the most commonly reported; such findings are in line with previously published articles [26,27,28].
Furthermore, as already reported in the scientific literature, our study demonstrated that, for all vaccine brands, the frequency of ADRs among individuals with prior SARS-CoV-2 infection was higher following the first dose than the second dose [24,25]. This finding is also confirmed by a longitudinal study conducted on health workers in the Johns Hopkins Health System, which reported that people with previous SARS-CoV-2 infection were associated with an increased risk of experiencing clinically significant symptoms following a first dose of Spikevax or Comirnaty vaccines, as compared to the second dose [29]. It has been shown that COVID-19 vaccines have increased immunogenicity in individuals with past infection due to higher antibody titers than found in those without previous infection [30,31,32]. In particular, Krammer et al. documented that individuals with pre-existing immunity have relevant spike antibody responses and experience more severe reactogenicity after the first dose, as compared to naïve individuals [33]. In addition, no increase in antibody titers in individuals with a history of COVID-19 was observed following the second vaccine dose, thus potentially explaining the lower frequency of ADRs reported [33]. Moreover, a U.K. prospective cohort study collecting information through an ad hoc developed app on self-reported ADRs following COVID-19 vaccination reported higher reactogenicity after the first dose of the Vaxzevria vaccine [34]. Additionally, an active-surveillance cohort study conducted in Canada found a greater reactogenicity among subjects with prior SARS-CoV-2 infection following the administration of both the second and the booster dose of Spikevax vaccine, as compared to Comirnaty and Vaxzevria [35]. In a longitudinal study, Debes et al. observed that Spike IgG antibody measurements were higher in individuals who received the Spikevax vaccine, had prior SARS-CoV-2 infection, and reported clinically significant reactions [29]. Such evidence supports our findings concerning the vaccine brands associated with a higher frequency of ADRs, as reported following both the first vaccination cycle and the booster dose. Overall, based on these observations, the association between more severe symptomatology and a higher reported frequency of ADRs could be related to an increase in antibody titers. Furthermore, the variant analysis of SARS-CoV-2 also suggests a likely change in antibody titer and, consequently, a variation in reported ADR frequencies. As expected, most ADRs were reported by women and younger subjects, in both study cohorts. Specific sex-related immunological, hormonal, and genetic differences in immune responses are widely documented in the scientific literature [36], and it is also well-known that antibody titers tend to decrease as age increases [37]. The lower frequency of ADRs reported after the booster dose, as compared to the first vaccination cycle, may be related to the lower number of follow-up questionnaires scheduled for this dose. Consequently, this might have allowed a lower frequency of ADRs to be captured. However, as reported in previous studies [20,31], and in line with our results, the majority of reported ADRs occur within 8 days of vaccination. In addition, following the first vaccination cycle, there has been a growing awareness of adverse events associated with the administration of COVID-19 vaccines, which could have made people less motivated to participate in the study or report ADRs. The high frequency of ADRs reported following the first vaccination cycle, as compared to the booster dose, could be explained by the heterogeneity of the vaccines administered during the first vaccination cycle. In particular, although Vaxzevria showed a high frequency of ADRs reported after the first and second doses, it was excluded from the analysis of the booster dose, since only three participants received this vaccine brand. Consequently, the overall lower frequency of ADRs reported after the booster dose could be related to the absence of data related to this vaccine brand. Furthermore, our study shows that people with previous SARS-CoV-2 infection and a history of hypertension are more likely to report at least one ADR than those without a history of hypertension. One of the main strengths of this study is that it included patient-level data from eleven European countries, which were collected and analyzed using a CDM. Moreover, the adaptability of the LIM and RO web apps in integrating information that became available after the study started and in adapting to changing regulatory frameworks (e.g., variations in vaccination regimens) should also be acknowledged. It was possible to directly and promptly update the questionnaires by adding new questions or modifying questions to capture data to test emerging hypotheses about COVID-19-related signs and symptoms. In addition, the large sample number of vaccinees enrolled allowed us to investigate vaccine safety and to compare safety outcomes among subjects with and without prior SARS-CoV-2 infection. Another strength of our study is the duration of the study period as well as the follow-up period. Previously published studies examining the safety of the COVID-19 vaccine in persons with previous SARS-CoV-2 infection were conducted for a period ranging from 1 month to 12 months, and their follow-up periods ranged from 7 days to 4 months. Only one study with a 12-month follow-up period was identified (Supplementary Table S1). Lastly, unlike passive surveillance studies conducted using spontaneous reporting system databases, the availability of a denominator allowed for the assessment of the frequency of specific ADRs as well as the stratification and adjustment of the analyses. However, some limitations warrant caution. First, particularly serious ADRs, e.g., those leading to hospitalization or severe disability, might have been missed if vaccinees experiencing such ADRs were unable to use the web-based apps to report them. As a consequence, the frequency of serious ADRs could have been underestimated. However, a study on surveillance of adverse events following immunization shows that self-reported data described more serious events than those reported by healthcare professionals [38]. In addition, participants whose reminder emails for the completion of the follow-up questionnaire ended up in spam or who did not experience any ADRs may have contributed to the loss to follow-up. Furthermore, after the first vaccination cycle, there was an increasing consciousness of the safety of these vaccines, which may have made vaccinees less motivated to continue filling out the FU-Qs, contributing to the loss of follow-up data. Second, considering that self-reporting of health-related events may be subject to recall bias, people with previous SARS-CoV-2 infections may be more likely to report them. Such bias may concern both symptomatic (especially if they have had a more severe infection) and asymptomatic patients. The latter may indeed have been worried about their own health, and thus tending to recall events more precisely. Third, it should be considered that there may be periods of overlap between variants of concern, and this could affect the analysis, as stratified by variant type. In addition, since information on ethnicity was not recorded, our findings might not be entirely applicable to certain groups. Fourth, it should be taken into account that self-reported information is subjective in nature and participants may have misinterpreted or misreported information. However, the coding of ADRs and their seriousness was assessed by trained pharmacovigilance personnel who could contact the participant if further information were needed, in cases in which the participant agreed during registration on the web app to be recontacted. In addition, the prior SARS-CoV-2 infection was not confirmed by a clinician, although the majority of included vaccinees reported a diagnosis of SARS-CoV-2 infection confirmed with a positive polymerase chain reaction (PCR) test. Lastly, the individuals who utilized the web app were self-selected and may not adequately represent the general population.
5. Conclusions
This large-scale prospective study of COVID-19 vaccinees allowed the comparison between different brands and doses of vaccines in people previously infected with SARS-CoV-2 and individuals without a history of infection, by administering the same survey to all participants in eleven European countries. Adverse reactions were reported more frequently by those with a previous SARS-CoV-2 infection than those without a history of SARS-CoV-2 infection; this was observed in both cohorts. The frequency of reported ADRs was higher in young subjects and women. The frequency of serious ADRs was low for all doses and cohorts. Overall, post-vaccinal symptoms (both systemic and local) resolved within a few days after administration of the first, second, or booster doses.
Supplementary Materials
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/vaccines12030241/s1, Figure S1: Heatmaps with the frequency of reported local solicited ADRs following the first, second and the booster dose of any vaccine in people with SARS-CoV-2 infection vs. matched control, stratified by gender. Figure S2: Heatmaps with the frequency of reported systemic solicited ADRs following the first, second and the booster dose of any vaccine in people with SARS-CoV-2 infection vs. matched control, stratified by gender. Figure S3: Forest plot relating medical history to the occurrence of at least one ADR in people with prior SARS-CoV-2 infection for the first and the booster dose. Table S1: Experimental and observational studies related to COVID-19 vaccines in clinicaltrials.gov and PubMed, as of November 21, 2023. Table S2. Frequency of reported local and systemic solicited ADRs following the first dose, stratified by vaccine brands, in people with SARS-CoV-2 infection vs. matched control. Table S3. Frequency of reported local and systemic solicited ADRs following the second dose, stratified by vaccine brands, in people with SARS-CoV-2 infection vs. matched control. Table S4. Frequency of reported local and systemic solicited ADRs following the booster dose, stratified by vaccine brands, in people with SARS-CoV-2 infection vs. matched control. Table S5. Frequency of reported local and systemic solicited ADRs following the first vaccination cycle of any vaccine, stratified by gender, in people with SARS-CoV-2 infection vs. matched control. Table S6. Frequency of reported local and systemic solicited ADRs following the booster dose of any vaccine, stratified by gender for people with SARS-CoV-2 infection and the matched control. Table S7. Frequency of people with prior SARS-CoV-2 infection reporting at least one ADR, stratified by different timeframes between SARS-CoV-2 infection and vaccine administration, and vaccine dose. Table S8. Frequency of people with prior SARS-CoV-2 infection reporting at least one ADR, stratified by different variants of concern. Table S9. Frequency of people with prior SARS-CoV-2 infection reporting at least one ADR, stratified by different severity of symptoms. Table S10. People with prior SARS-CoV-2 infection stratified by country.
Author Contributions
Conceptualization, G.T.; Formal analysis, C.B., L.L., T.L. and E.M.; Investigation, F.C., N.L., C.B., M.R., F.v.H., F.R., C.D.-P., A.F., F.B.M., K.M., D.R., S.S., N.H.T., F.V. and M.C.S.; Data curation, M.R., F.v.H., F.R., C.D.-P., A.F., F.B.M., K.M., D.R., S.S., N.H.T., F.V. and M.C.S.; Writing—original draft, F.C., N.L. and G.T.; Writing—review & editing, M.R., F.v.H., F.R., C.D.-P., A.F., F.B.M., K.M., D.R., S.S., N.H.T., F.V. and M.C.S.; Visualization, F.C. and C.B.; Supervision, M.C.S. and G.T. All authors have read and agreed to the published version of the manuscript.
Funding
This research was supported by the European Medicines Agency, grant number: S01-FWC EMA/2018/23/PE. 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 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). This document expresses the opinion of the authors of the paper 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.
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki, and approved by Ethics Committee: THE NETHERLAND (LAREB): If a study in the Netherlands is subject to the Medical Research Involving Human Subjects Act (WMO), it must undergo a review by an accredited Medical Research Ethics Committee or the central committee on research involving human subjects (CCMO). After submission to an accredited review committee (METC Brabant), this study was deemed not to fall under the WMO act. SPAIN (SIDIAP): The study was approved by the Comitè Ètic d’Investigació amb medicaments (CEIm) de l’IDIAP Jordi Gol Approval Number 21/208-PCV. FRANCE (BPE): The study in France was approved by the Comité de Protection des personnes (CPP—21.00821.210217) and the Commission nationale de l’informatique et des libertés (CNIL—DR-2021-209) under the name EVANESCO. PORTUGAL: The study in Portugal was approved by the COMISSÃO ÉTICA PARA A SAÚDE (24/09/2021, Number 74/2021). ROMANIA: The study was approved by The Ethics Committee of the ‘Iuliu Hatieganu’ University of Medicine and Pharmacy Cluj-Napoca, Romania, No 246/ 30.06.2021 (Amendment 08/11/2021, Number AVZ6). SLOVAKIA: The study was approved by the ethics committee of Children Hospital in Kosice according to ICH GCP 135/95 in date 1/12/2021 (Number: not applicable). UK: The study was approved by the London Brent Research Ethics Committee (25/05/2021, Number 21/HRA/2077). ITALY: The study was approved by the Ethical Committee of the Spallanzani Hospital (Rome), the unique national committee for the investigation on COVID-19, with protocol number 463.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
Data are contained within the article and Supplementary Materials.
Acknowledgments
The authors acknowledge Giele-Eshuis Janneke (UMCU); Cecile Droz-Perroteau, Estelle Guiard, Pauline Bosco, Pauline Diez and Stéphanie Lamarque (University of Bordeaux); Brigitte Keller-Stanislawski and Dirk Mentzer (Paul-Ehrlich Institut); Fergal O’Shaughnessy, Brian Cleary (Rotunda Hospital Dublin); Ana Paula Martins, Ana Penedones, Ana Silva, Carla Torre, Carlos Miguel Costa Alves, Diogo Mendes, Inês Vaz, Jorge Polonia, Paula Barao and Renato Ferreira da Silva (CLPP Vaccines Network); Camelia Busca (University of Medicine and Pharmacy ‘Iuliu Hatieganu’ Cluj-Napoca); Beata Čečetková, Daniel Pella and Radka Troníčková (SLOVACRIN, Medical faculty of Pavol Jozef Šafárik University in Košice); Alice Panchaud, Émeline Maisonneuve and Guillaume Favre (University of Bern); Agnes Kant, Jasper Schmitz and Loes Ruijs (Lareb); Hester de Melker (RIVM); Derek Hall, Elizabeth Lynn, Saad Shakir, Vicki Osborne, Samantha Lane and Shane Freemantle (UK DSRU); the Primary Care Centres from the Catalan Institute of Health (for their support and the recruitment of vaccines), namely, Amposta, Tortosa, Barberà del Vallés, Mataró, Pineda de Mar and Salou; Ugo Moretti, Laura Augusta Gonella, Giuliana Petrelli, Cristiano Chiamulera and Elena Arzenton (University of Verona, Department of Diagnostics and Public Health—Section of Pharmacology, Verona, Italy); Riccardo Lora, David Bellantuono and Alberto Sabaini (MedBrains); Alberto Firenze, Donatella Zodda, Fabrizia Guidotti, Maria Zappone and Bernardo Alagna (Struttura Commissariale per l’Emergenza COVID della città metropolitana di Messina/Messina Local Health Unit, Messina, Italy); Paola Maria Cutroneo and Claudia Minore (Sicilian Regional Pharmacovigilance Centre, University Hospital of Messina, Messina, Italy); Claudio Costantino and Francesco Vitale (University of Palermo, Palermo, Italy—Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties “G. D’Alessandro”, Hygiene section); Ilaria Morreale—Sicilian Regional Center of Pharmacovigilance, Azienda Ospedaliera Universitaria Policlinico P. Giaccone, Internal Medicine, Pharmacovigilance and Clinical Pharmacology Unit; Laura Marsala, Desirè Farinella and Silvana Bavetta (Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione (ARNAS) “Civico”, Palermo, Italy); Maria Pia Fantini, Chiara Reno, Emanuel Raschi and Elisabetta Poluzzi (Alma Mater Studiorum-University of Bologna, Italy—Department of Medical and Surgical Sciences); Ester Sapigni, Annamaria Potenza, Debora Podetti, Victoria Nikitina, Rita Ricciardelli, Nazanin Mogheiseh, Silvia Croce and Barbara Paltrinieri (Emilia-Romagna Pharmacovigilance Regional Centre, Bologna—Italy); Sofa Castellani, Elisa Sangiorgi, Margherita Selleri, Simona Lucchesi and Giuseppe Catucci (Ferrara Local Health Unit, Ferrara, Italy); Denis Savini, Chiara Sacripanti, Marco Faccioli, Maria Silvia Romio and Laura Rossi (Bologna Local Health Unit, Bologna, Italy); Simonetta Radici—Piacenza Local Health Unit, Piacenza, Italy; Giovanna Negri—Parma Local Health Unit, Parma, Italy; Lidia Fares—Reggio Emilia Local Health Unit, Reggio Emilia, Italy; Chiara Ajolfi—Modena Local Health Unit, Modena, Italy; Antonella Fadda, Antonella Chiarello—Imola Local Health Unit, Imola, Italy; Fabio Pieraccini, Barbara Gavioli, Simonetta Palazzi—Romagna Local Health Unit, Romagna, Italy; Marco Tuccori—Tuscany Region, Italy—Unit of Adverse Drug Reactions Monitoring, University Hospital of Pisa, Pisa, Italy; Alfredo Vannacci, Roberto Bonaiuti, Claudia Ravaldi, Niccolò Lombardi, Giada Crescioli—PeaRL—Perinatal Research Laboratory, NEUROFARBA Department, University of Florence and CiaoLapo Foundation for Perinatal Health, Florence, Italy; Francesco Gori—Firenze Local Health Unit, Florence, Italy; Roberto Tessari (IRCCS Ospedale Sacro Cuore Don Calabria—Hospital Pharmacy, Negrar di Valpolicella, Italy); Emanuela Zandonà (University Hospital of Verona, Italy—Medical Coordination Unit); Maria Angiola Crivellaro—University Hospital of Padua, Padova, Italy—Occupational Health Unit and Allergology Unit, Department of Cardiac Thoracic Vascular and Public Health Sciences University of Padova; Mauro Cancian—University Hospital of Padua, Departmental Allergy Unit, Padua, Italy; Francesca Venturini—University Hospital of Padua, Pharmacy Department, Padua, Italy; Marina Ferri and Luca Leonardi (Trento Local Health Unit, Trento, Italy); Paolo Baldo, Sabrina Orzetti and Elisabetta Caccin (Centro di Riferimento Oncologico (CRO) di Aviano, IRCCS—Pharmacy Unit, National Cancer Institute, Aviano, Italy); Annalisa Capuano and Concetta Rafaniello (Regional Centre of Pharmacovigilance and Pharmacoepidemiology, Naples, Italy); Claudia Pagliaro, Mariangela Mercaldo, Annalisa Di Giorgio, Sonia Manna, Giuseppina Farina, Cristina Di Mauro and Michele Tari (Caserta Local Health Unit, Caserta, Italy); Ilenia De Carlo (Abruzzo Region, Pharmacovigilance Regional Centre, Italy); Ilenia De Carlo, Ilenia Senesi—Abruzzo Region, Pharmacovigilance Regional Centre, Italy; Claudia Pileggi, Caterina Palleria, Luca Gallelli, Caterina De Sarro, Chiara Verduci, Rosa Papadopoli and Giovambattista De Sarro (Department of Health Sciences, University of Catanzaro “Magna Græcia”/Regional Centre for Pharmacovigilance of Calabria, Catanzaro, Italy); Mariagrazia Morgese, Stefania Schiavone, Paolo Tucci, Maria Bove and Luigia Trabace (University of Foggia, Foggia, Italy); Francesco Lapi and Claudio Cricelli—Italian Society of General Practitioners; Giorgio Racagni (Italian Society of Pharmacology); Silvia Tonolo (Association of Patients with Rheumatic Diseases); Giusi Fava, Sandro Giufrida and Vincenza Amato (Reggio Calabria Local Health Unit, Reggio Calabria, Italy); Marco Gambera and Valentina Montresor (Ospedale Pederzoli—Hospital Pharmacy, Peschiera del Garda, Italy); and Dario Mastropasqua—Croce Verde Verona, Verona, Italy for their contribution to the Italian part of the ECVM study, as the “ilmiovaccinoCOVID19 collaborating group”.
Conflicts of Interest
Miriam Sturkenboom is head of a department that conducts studies for regulatory agencies and pharmaceutical companies, with research grants to the institution; this includes Pfzer, Janssen and AstraZeneca. All studies are conducted using the ENCePP code of conduct. Gianluca Trifrò has served in the last three years on advisory boards/seminars funded by SANOFI, Eli Lilly, AstraZeneca, Abbvie, Servier, Mylan, Gilead, Amgen; he was the scientifc director of a Master’s program on pharmacovigilance, pharmacoepidemiology and real-world evidence which has received a non-conditional grant from various pharmaceutical companies; he coordinated a pharmacoepidemiology team at the University of Messina until October 2020, which has received funding for conducting observational studies from various pharmaceutical companies (Boehringer Ingelheim, Daichii Sankyo, PTC Pharmaceuticals). He is also the scientifc coordinator of the academic spin-of “INSPIRE srl” which has received funding for conducting observational studies from contract research organizations (RTI Health Solutions, Pharmo Institute N.V.). None of these listed activities is related to the topic of the manuscript. Francesco Ciccimarra, Nicoletta Luxi, Chiara Bellitto, Luca L’Abbate, Monika Raethke, Florence van Hunsel, Thomas Lieber, Erik Mulder, Fabio Riefolo, Caroline Dureau-Pournin, Andreea Farcas, Francisco Batel Marques, Kathryn Morton, Debabrata Roy, Simona Sonderlichová, Nicolas H. Thurin, Felipe Villalobos have no conficts of interest that are directly relevant to the content of this article.
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Figure 1.
Questionnaire scheduling scheme over time. Abbreviations: FU-Q = Follow-up questionnaire.
Figure 2.
Flowchart of recruited people with prior SARS-CoV-2 infection and matched control who were recruited at either first or booster dose and who filled out different questionnaires.
Figure 2.
Flowchart of recruited people with prior SARS-CoV-2 infection and matched control who were recruited at either first or booster dose and who filled out different questionnaires.
Figure 3.
Frequency of at least one ADR reported, stratified by vaccine brand and dose, for persons with previous SARS-CoV-2 infection and matched controls.
Figure 3.
Frequency of at least one ADR reported, stratified by vaccine brand and dose, for persons with previous SARS-CoV-2 infection and matched controls.
Figure 4.
Heatmaps of the frequency of vaccinee-reported local and systemic solicited ADRs following the first, second, or booster doses, stratified by vaccine brands, for people with prior SARS-CoV-2 infection and the matched control.
Figure 4.
Heatmaps of the frequency of vaccinee-reported local and systemic solicited ADRs following the first, second, or booster doses, stratified by vaccine brands, for people with prior SARS-CoV-2 infection and the matched control.
Figure 5.
Heatmaps of the frequency of vaccinee-reported solicited ADRs following the first, second, or booster doses of any vaccine, for people with SARS-CoV-2 infection and the matched control, stratified by age categories.
Figure 5.
Heatmaps of the frequency of vaccinee-reported solicited ADRs following the first, second, or booster doses of any vaccine, for people with SARS-CoV-2 infection and the matched control, stratified by age categories.
Figure 6.
Combination of violin plots and box-plots of the median time to onset and the median time to recovery (in hours) of vaccinee-reported ADRs following a first vaccination cycle or a booster dose, in people with prior SARS-CoV-2 infection vs. matched controls. (A) Median time to ADR onset (in hours) following the first dose. (B) Median time to recovery (in hours) following the first dose. (C) Median time to ADR onset (in hours) following the second dose. (D) Median time to recovery (in hours) following the second dose. (E) Median time to ADR onset (in hours) following the booster dose (F) Median time to recovery (in hours) following the booster dose. Abbreviations: * = statistically significant.
Figure 6.
Combination of violin plots and box-plots of the median time to onset and the median time to recovery (in hours) of vaccinee-reported ADRs following a first vaccination cycle or a booster dose, in people with prior SARS-CoV-2 infection vs. matched controls. (A) Median time to ADR onset (in hours) following the first dose. (B) Median time to recovery (in hours) following the first dose. (C) Median time to ADR onset (in hours) following the second dose. (D) Median time to recovery (in hours) following the second dose. (E) Median time to ADR onset (in hours) following the booster dose (F) Median time to recovery (in hours) following the booster dose. Abbreviations: * = statistically significant.
Table 1.
Demographic and clinical characteristics of people with prior SARS-CoV-2 infection and the matched control, following the administration of the first COVID-19 vaccination cycle, stratified by vaccine brand.
Table 1.
Demographic and clinical characteristics of people with prior SARS-CoV-2 infection and the matched control, following the administration of the first COVID-19 vaccination cycle, stratified by vaccine brand.
| First Vaccination Cycle | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Vaxzevria (ChAdOx1-S) N = 1410 (%) | Comirnaty (BioNTech/Pfizer) N = 1372 (%) | Spikevax (Moderna) N = 668 (%) | Jcovden (Ad26.COV2-S) N = 422 (%) | |||||||||
| Prior SARS-CoV-2 Infection | Matched Control | p-Value | Prior SARS-CoV-2 Infection | Matched Control | p-Value | Prior SARS-CoV-2 Infection | Matched Control | p-Value | Prior SARS-CoV-2 Infection | Matched Control | p-Value | |
| Gender | ||||||||||||
| Female | 1230 (87.2) | 1230 (87.2) | Matching factor | 840 (61.2) | 840 (61.2) | Matching factor | 490 (73.4) | 490 (73.4) | Matching factor | 326 (77.3) | 326 (77.3) | Matching factor |
| Male | 180 (12.8) | 180 (12.8) | 532 (38.8) | 532 (38.8) | 178 (26.6) | 178 (26.6) | 96 (22.7) | 96 (22.7) | ||||
| Median, years (IQR) | 47 (35–57) | 47 (35–57) | 45 (31–56) | 45 (31–56) | 43 (32–51) | 43 (32–51) | 48 (36–48) | 48 (36–48) | ||||
| Age Categories | ||||||||||||
| 5–17 | 2 (0.1) | 1 (0.1) | Matching factor | 109 (7.9) | 109 (7.9) | Matching factor | 2 (0.3) | 2 (0.3) | Matching factor | 0 (0.0) | 0 (0.0) | Matching factor |
| 18–39 | 463 (32.8) | 464 (32.9) | 482 (35.2) | 482 (35.2) | 253 (37.9) | 253 (37.9) | 127 (30.1) | 127 (30.1) | ||||
| 40–69 | 945 (67.1) | 945 (67.0) | 442 (32.2) | 442 (32.2) | 411 (61.5) | 411 (61.5) | 294 (69.7) | 294 (69.7) | ||||
| ≥70 | 0 (0.0) | 0 (0.0) | 339 (24.7) | 339 (24.7) | 2 (0.3) | 2 (0.3) | 1 (0.2) | 1 (0.2) | ||||
| Medication Use | ||||||||||||
| Use of any medication | 684 (48.5) | 689 (48.9) | 0.131 | 651 (47.4) | 664 (48.4) | 0.647 | 308 (46.1) | 306 (45.8) | 0.956 | 157 (37.2) | 169 (40) | 0.437 |
| Use of painkillers/fever reducing medicines # | 347 (24.6) | 306 (21.7) | 0.0742 | 174 (12.7) | 124 (9.0) | 0.00264 * | 114 (17.1) | 95 (14.2) | 0.175 | 112 (26.5) | 96 (22.7) | 0.231 |
| Medical History | ||||||||||||
| Cardiovascular diseases | 43 (3) | 50 (3.5) | 0.527 | 110 (8) | 89 (6.5) | 0.141 | 14 (2.1) | 20 (3.0) | 0.385 | 8 (1.9) | 5 (1.2) | 0.576 |
| Diabetes | 32 (2.3) | 38 (2.7) | 0.545 | 50 (3.6) | 50 (3.6) | 1.000 | 11 (1.6) | 9 (1.3) | 0.822 | 1 (0.2) | 1 (0.2) | 1.000 ^ |
| Hypertension | 134 (9.5) | 120 (8.5) | 0.392 | 164 (12) | 165 (12) | 1.000 | 35 (5.2) | 43 (6.4) | 0.414 | 27 (6.4) | 26 (6.2) | 1.000 |
| Liver diseases | 32 (2.3) | 29 (2.1) | 0.796 | 23 (1.7) | 22 (1.6) | 1.000 | 9 (1.3) | 23 (3.4) | 0.02 * | 6 (1.4) | 2 (0.5) | 0.287 ^ |
| Lung diseases | 2 (0.1) | 3 (0.2) | 1.000 ^ | 5 (0.4) | 3 (0.2) | 0.723 ^ | 3 (0.4) | - | 0.248 ^ | 1 (0.2) | 1 (0.2) | 1.000 ^ |
| Psychological disorders | 124 (8.8) | 113 (8) | 0.497 | 109 (7.9) | 97 (7.1) | 0.426 | 70 (10.5) | 70 (10.5) | 1.000 | 18 (4.3) | 22 (5.2) | 0.627 |
| Malignant tumors | 50 (3.5) | 60 (4.3) | 0.381 | 50 (3.6) | 69 (5) | 0.0916 | 30 (4.5) | 29 (4.3) | 1.000 | 23 (5.5) | 22 (5.2) | 1.000 |
| Neurological diseases | 5 (0.4) | 13 (0.9) | 0.458 ^ | 14 (1) | 15 (1.1) | 1.000 | 4 (0.6) | 5 (0.7) | 1.000 ^ | 3 (0.7) | 7 (1.7) | 0.340 ^ |
| Kidney diseases | 14 (1.0) | 13 (0.9) | 1.000 | 15 (1.1) | 18 (1.3) | 0.726 | 5 (0.7) | 6 (0.9) | 1.000 ^ | 5 (1.2) | 2 (0.5) | 0.448 ^ |
| Immunosuppression | 10 (0.7) | 8 (0.6) | 0.813 | 14 (1) | 13 (0.9) | 1.000 | 5 (0.7) | 3 (0.4) | 1.000 ^ | - | 1 (0.2) | 1.000 ^ |
# Taken within a few hours before COVID-19 vaccine administration. Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities; PT = preferred term; * = statistically significant; ^ = Fisher’s exact test. A total of 13 vaccinees who reported an unknown vaccine brand and 1 vaccinee reporting Novavax were excluded.
Table 2.
Demographic and clinical characteristics of people with prior SARS-CoV-2 infection and the matched control, following the administration of COVID-19 vaccine booster dose, stratified by vaccine brand.
Table 2.
Demographic and clinical characteristics of people with prior SARS-CoV-2 infection and the matched control, following the administration of COVID-19 vaccine booster dose, stratified by vaccine brand.
| Booster Dose | ||||||
|---|---|---|---|---|---|---|
| Comirnaty (BioNTech/Pfizer) N = 521 (%) | Spikevax (Moderna) N = 376 (%) | |||||
| Prior SARS-CoV-2 Infection | Matched Control | p-Value | Prior SARS-CoV-2 Infection | Matched Control | p-Value | |
| Gender | ||||||
| Female | 347 (66.6) | 347 (66.6) | Matching factor | 243 (64.6) | 243 (64.6) | Matching factor |
| Male | 174 (33.4) | 174 (33.4) | 133 (35.4) | 133 (35.4) | ||
| Median, years (IQR) | 41 (28–53) | 41 (28–53) | 43 (35–54) | 43 (35–54) | ||
| Age Categories, Years | ||||||
| 5–17 | 17 (3.3) | 17 (3.3) | Matching factor | 1 (0.3) | 1 (0.3) | Matching factor |
| 18–39 | 231 (44.3) | 231 (44.3) | 140 (37.2) | 140 (37.2) | ||
| 40–69 | 259 (49.7) | 259 (49.7) | 226 (60.1) | 226 (60.1) | ||
| ≥70 | 14 (2.7) | 14 (2.7) | 9 (2.4) | 9 (2.4) | ||
| Medication Use | ||||||
| Any medication | 226 (43.4) | 202 (38.8) | 0.148 | 158 (42) | 130 (34.6) | 0.428 * |
| Use of painkillers/fever reducing medicines # | 82 (15.7) | 171 (32.8) | <0.0001 * | 89 (23.7) | 84 (22.3) | 0.729 |
| Medical History (MedDRA PT) | ||||||
| Cardiovascular diseases | 15 (2.9) | 10 (1.9) | 0.418 | 8 (2.1) | 7 (1.9) | 1.000 |
| Diabetes | 8 (1.5) | 11 (2.1) | 0.674 | 10 (2.7) | 10 (2.7) | 1.000 |
| Hypertension | 35 (6.7) | 42 (8.1) | 0.477 | 28 (7.4) | 25 (6.6) | 0.776 |
| Liver diseases | 17 (3.3) | 13 (2.5) | 0.578 | 5 (1.3) | 4 (1.1) | 1.000 ^ |
| Lung diseases | 1 (0.2) | 1 (0.2) | 1.000 ^ | 1 (0.3) | 1 (0.3) | 1.000 ^ |
| Psychological disorders | 37 (7.1) | 33 (6.3) | 0.806 | 26 (6.9) | 14 (3.7) | 0.0739 |
| Malignant tumors | 19 (3.6) | 24 (4.6) | 0.533 | 16 (4.3) | 11 (2.9) | 0.433 |
| Neurological diseases | 6 (1.2) | 5 (1.0) | 1.000 ^ | 2 (0.5) | 1 (0.3) | 1.000 ^ |
| Kidney diseases | 5 (1) | 4 (0.8) | 1.000 ^ | 2 (0.5) | 2 (0.5) | 1.000 ^ |
| Immunosuppression | 3 (0.6) | 5 (1.0) | 0.723 ^ | 1 (0.3) | 2 (0.5) | 1.000 ^ |
# Taken within a few hours before COVID-19 vaccine administration. Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities; PT = preferred term, * = statistically significant; ^ = Fisher’s exact test. A total of 2 vaccinees who reported an unknown vaccine brand and 3 vaccinees reporting Vaxzevria were excluded.
Table 3.
List of AESIs following the first, second, or booster doses of any vaccine.
| Dose | Cohort | Vaccine Brand | AESI | N. |
|---|---|---|---|---|
| First dose | Matched controls | Vaxzevria | Hypersensitivity | 1 |
| Hypersomnia | 1 | |||
| Acute myocardial infarction | 1 | |||
| Spikevax | Pancreatitis acute | 1 | ||
| Comirnaty | Pericarditis | 1 | ||
| Anaphylactoid reaction | 1 | |||
| Hypersensitivity | 1 | |||
| Prior SARS-CoV-2 infection | Vaxzevria | Hypersensitivity | 1 | |
| Comirnaty | Hypersensitivity | 1 | ||
| Hypersensitivity | 1 | |||
| Moderna | Hypersomnia | 1 | ||
| Second dose | Matched controls | Comirnaty | Seizure | 1 |
| Vaxzevria | Epilepsy | 1 | ||
| Myocardial infarction | 1 | |||
| Prior SARS-CoV-2 infection | Vaxzevria | Hypersensitivity | 1 | |
| Booster dose | Prior SARS-CoV-2 infection | Spikevax | Hypersensitivity | 1 |
Abbreviations: AESI = adverse events of special interest; N. = number.
Table 4.
List of serious ADRs following the first, second, or booster doses of any vaccine.
| Dose | Cohort | Vaccine Brand | Serious ADR | N. | CIOMS Criteria |
|---|---|---|---|---|---|
| First dose | Matched controls | Spikevax | Arthralgia | 1 | Other |
| Headache | 1 | Other | |||
| Myalgia | 1 | Other | |||
| Paresthesia | 1 | Other | |||
| Pyrexia | 1 | Other | |||
| Abortion, spontaneous | 2 | Other | |||
| Body temperature increased | 1 | Other | |||
| Vaxzevria | Atrial fibrillation | 1 | Other | ||
| Pyrexia | 1 | Other | |||
| Acute myocardial infarction | 1 | Hospital | |||
| Myocardial infarction | 1 | Hospital | |||
| Comirnaty | Urticaria | 1 | Other | ||
| Diarrhea | 1 | Hospital | |||
| Hyperpyrexia | 1 | Hospital | |||
| Vomiting | 1 | Hospital | |||
| Jcovden | Dyspnea | 1 | Other | ||
| Hypoesthesia | 1 | Threatening | |||
| Limb discomfort | 1 | Other | |||
| Pallor | 1 | Other | |||
| Palpitations | 1 | Other | |||
| Paresthesia, oral | 1 | Other | |||
| Restlessness | 1 | Other | |||
| Tremor | 1 | Other | |||
| Prior SARS-CoV-2 infection | Vaxzevria | Pulmonary pain | 1 | Other | |
| Retinal detachment | 1 | Other | |||
| Vitreous floaters | 1 | Other | |||
| Comirnaty | Abortion, spontaneous | 1 | Other | ||
| Aggravated condition | 1 | Other | |||
| Hypersensitivity | 1 | Threatening | |||
| Muscle spasms | 1 | Threatening | |||
| Depression | 1 | Other | |||
| Dyspnea | 1 | Other | |||
| Eye hemorrhage | 1 | Other | |||
| Fatigue | 1 | Other | |||
| Headache | 1 | Other | |||
| Hypersensitivity | 1 | Other | |||
| Nausea | 1 | Other | |||
| Pruritus | 1 | Other | |||
| Rash | 1 | Other | |||
| Spikevax | Dizziness | 1 | Threatening | ||
| Gait disturbance | 1 | Threatening | |||
| Hyperpyrexia | 1 | Other | |||
| Hypotension | 1 | Threatening | |||
| Loss of consciousness | 1 | Threatening | |||
| Vision blurred | 1 | Threatening | |||
| Second dose | Matched controls | Vaxzevria | Respiratory arrest | 1 | Other |
| Breast cancer | 1 | Other | |||
| Myocardial infarction | 1 | Other | |||
| Comirnaty | Hypertension | 1 | Hospital | ||
| Malaise | 1 | Hospital | |||
| Spikevax | Abortion, spontaneous | 2 | Hospital | ||
| Prior SARS-CoV-2 infection | Vaxzevria | Retinal detachment | 1 | Hospital | |
| Vitreous floaters | 1 | Hospital | |||
| Comirnaty | Depression | 1 | Other | ||
| Eye hemorrhage | 1 | Other | |||
| Fatigue | 1 | Other | |||
| Headache | 1 | Other | |||
| Nausea | 1 | Other | |||
| Spikevax | Dizziness | 1 | Threatening | ||
| Gait disturbance | 1 | Threatening | |||
| Hypotension | 1 | Threatening | |||
| Loss of consciousness | 1 | Threatening | |||
| Vision blurred | 1 | Threatening | |||
| Comirnaty | Hypothermia | 1 | Other | ||
| Booster dose | Matched controls | Comirnaty | Tachycardia | 1 | Other |
| Congenital anomaly | 1 | Other | |||
| Prior SARS-CoV-2 infection | Comirnaty | Hyperpyrexia | 1 | Threatening |
Abbreviations: ADR = adverse drug reaction; CIOMS = The Council for International Organizations and Medical Sciences.
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Ciccimarra, F.; Luxi, N.; Bellitto, C.; L’Abbate, L.; Raethke, M.; van Hunsel, F.; Lieber, T.; Mulder, E.; Riefolo, F.; Dureau-Pournin, C.; et al. Safety Monitoring of COVID-19 Vaccines in Persons with Prior SARS-CoV-2 Infection: A European Multi-Country Study. Vaccines 2024, 12, 241. https://doi.org/10.3390/vaccines12030241
AMA Style
Ciccimarra F, Luxi N, Bellitto C, L’Abbate L, Raethke M, van Hunsel F, Lieber T, Mulder E, Riefolo F, Dureau-Pournin C, et al. Safety Monitoring of COVID-19 Vaccines in Persons with Prior SARS-CoV-2 Infection: A European Multi-Country Study. Vaccines. 2024; 12(3):241. https://doi.org/10.3390/vaccines12030241
Chicago/Turabian StyleCiccimarra, Francesco, Nicoletta Luxi, Chiara Bellitto, Luca L’Abbate, Monika Raethke, Florence van Hunsel, Thomas Lieber, Erik Mulder, Fabio Riefolo, Caroline Dureau-Pournin, and et al. 2024. "Safety Monitoring of COVID-19 Vaccines in Persons with Prior SARS-CoV-2 Infection: A European Multi-Country Study" Vaccines 12, no. 3: 241. https://doi.org/10.3390/vaccines12030241
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