Background rates of 41 adverse events of special interest for COVID-19 vaccines in 10 European healthcare databases - an ACCESS cohort study.

BACKGROUND: In May 2020, the ACCESS (The vACCine covid-19 monitoring readinESS) project was launched to prepare real-world monitoring of COVID-19 vaccines. Within this project, this study aimed to generate background incidence rates of 41 adverse events of special interest (AESI) to contextualize potential safety signals detected following administration of COVID-19 vaccines. METHODS: A dynamic cohort study was conducted using a distributed data network of 10 healthcare databases from 7 European countries (Italy, Spain, Denmark, The Netherlands, Germany, France and United Kingdom) over the period 2017 to 2020. A common protocol (EUPAS37273), common data model, and common analytics programs were applied for syntactic, semantic and analytical harmonization. Incidence rates (IR) for each AESI and each database were calculated by age and sex by dividing the number of incident cases by the total person-time at risk. Age-standardized rates were pooled using random effect models according to the provenance of the events. FINDINGS: A total number of 63,456,074 individuals were included in the study, contributing to 211.7 million person-years. A clear age pattern was observed for most AESIs, rates also varied by provenance of disease diagnosis (primary care, specialist care). Thrombosis with thrombocytopenia rates were extremely low ranging from 0.06 to 4.53/100,000 person-years for cerebral venous sinus thrombosis (CVST) with thrombocytopenia (TP) and mixed venous and arterial thrombosis with TP, respectively. INTERPRETATION: Given the nature of the AESIs and the setting (general practitioners or hospital-based databases or both), background rates from databases that show the highest level of completeness (primary care and specialist care) should be preferred, others can be used for sensitivity. The study was designed to ensure representativeness to the European population and generalizability of the background incidence rates. FUNDING: The project has received support from the European Medicines Agency under the Framework service contract nr EMA/2018/28/PE.

Acquired Hemophilia A and COVID19 Vaccines: A Possible Safety Signal or a Notoriety/Detection Bias?

Introduction: Acquired hemophilia A (AHA) is a rare autoimmune hemorragic condition (1-2 cases/million person/year)1. Several cases of AHA diagnosed following the administration of the COVID19 vaccines were described. Incidence of AHA diagnoses possibly higher than expected was also reported2,3. Indeed, higher attention to, and/or screening for, coagulation disorders during the vaccination campaign (i.e. notoriety/detection bias) might have increased the probability of AHA diagnosis and reporting compared to the past. Objective(s): To observe the utilization of AHA laboratory tests and incidence of AHA cases in Tuscany region during 2017-2021 and compare the rate of AHA in patients tested for AHA during COVID19 immunization campaign (2021) with that observed in 2019-2017. Method(s): A retrospective cohort study was performed using population- based administrative data from Tuscany region (3.7million inhab), Italy. Per each year between 2017 and 2021, patients active into the database at 1st January, with >= 5 years of age and 2 years of look-back were included. Subjects with >= 1 laboratory tests used for diagnosing AHA1 were identified. Due to the absence of a AHA ICD9CM codes, possible AHA cases were identified combining information from different databanks. Cumulative annual incidence of both patients tested for AHA and possible AHA cases was respectively calculated. The rates of incident AHA cases on patients tested for AHA observed in 2021 and in 2017-2019 were calculated. All estimates were standardized by age and sex (std.). 95% confidence intervals (95% CIs) were estimated with Poissons method (statistical difference = no 95% CIs overlap). Result(s): A total of 126 possible AHA cases and 1.081.878 incident patients with >= 1 laboratory test for AHA were identified between 2017 and 2021. Calendar year 2020 was clearly non-representative of the pre-immunizazion campaign period due to pandemic waves, thus it was excluded from the analyses. In 2021, std. incidence of tested patients (6067/million inhab/year;95% CI 60412-60913) and std. Incidence of possible AHA cases (5.6/million inhab/year;95% CI 3.4-8.7) showed the lowest point estimates, though only the former was statistically significant compared to any other year of the observation period. The std. rate of possible AHA cases on patients tested for AHA in 2021 was 5,6/100milion (95% CI 3.4-8.7) was not statistically different from that observed in 2017-2019 (7.6/100milion;95% CI 5-11). Conclusion(s): No increased incidence of possible AHA cases during the COVID19 immunization campaign was observed in Tuscany. Findings from this study do not suggest neither a possible detection bias nor a possible safety signal. Notority of other known vaccineinduced coagulation disorders may explain the increased reporting of AHA following COVID19 vaccines.

Association between SARS-CoV-2 Vaccines and Myoand Pericarditis, a Large Observational Study Using Electronic Healthcare Data from Four European Countries

Introduction: Some COVID-19 vaccines (Moderna and Pfizer) have been associated with an elevated risk of myocarditis in younger adults. However, observational studies were unable to stratify by dose and had limited ability to evaluate the effect of adenovirus-based COVID-19 vaccines due to the limited distribution of these in their study populations [1-4]. Objective(s): Estimate the incidence rates (IR), rate differences (RD) and incidence rate ratios (IRR) of myocarditis and pericarditis before and after each dose of mRNA (Pfizer and Moderna) and adenovirusplatform (AstraZeneca and Janssen) COVID-19 vaccines. Method(s): We conducted a population-based cohort design with nested self-controlled risk interval (SCRI) study. Participants were followed from 1st January 2020 to 31st December 2021. Data were derived from healthcare data from five population-based data sources in four European countries: Italy, the Netherlands, the United Kingdom (UK), and Spain. The main outcome was first occurrence of myocarditis or pericarditis. RD and IR before COVID-19 disease and after each COVID-19 vaccine dose in those without COVID-19 were calculated. The SCRI calculated IRR with 60-day control period prior to vaccination and 28-day risk windows, with adjustment for seasonality. All analyses were stratified by age (<30 and >= 30 years) and in the cohorts refined age-bands for<30 were utilised. Result(s): The study cohort comprised 35,365,669 persons with median age between 39-49 years, 57.4% received at least one COVID-19 vaccine dose and 77.6% of these received two. Myocarditis background rates were highest in persons 18-29 years (IR 2.8, 95% CI [1.5-4.1] to 6.4 [3.8-9.0] across UK, the Netherlands and Spain, and for 12-17 years in Italy (IR = 9.9 [5.3-14.4]). Pericarditis rates were higher in persons>30 years (standardised IR from 11.6 [10.9-12.4] to 29.7 [19.8-22.1] across databases). RD of myocarditis were significantly elevated after Moderna dose 2 in persons between 18-29 years in Italy. Significantly reduced RD of pericarditis in the age group above 30 years was seen for Pfizer, Moderna and AstraZeneca. The SCRI showed significantly higher myocarditis IRR after dose 1 of Pfizer (IRR = 3.3 [1.2-9.4]), and also after dose 2 of Pfizer and Moderna in persons 12-29 years (IRR of 7.8 [2.6-23.5] and 6.1 [1.1-33.5], respectively). No association was observed between COVID-19 vaccination and pericarditis in the SCRI. In a sensitivity analysis, occasional significant association was seen for AstraZeneca dose 2 and myocarditis. Conclusion(s): Myocarditis is rare, but rates were increased significantly after both doses of Pfizer and the second dose of Moderna vaccines in persons below 30 years of age. This was not seen for pericarditis.

VAC4EU: A Pan-European Research Network for Collaborative Post-authorization Vaccine Safety and Benefit Monitoring

Introduction: VAC4EU (Vaccine monitoring Collaboration for Europe) is a not-for profit international association with 24 member organizations specialised in the collaborative generation of real-world evidence on coverage, safety, and efficacy of vaccines in Europe. VAC4EU was established as a result of the IMI-ADVANCE project with the aim to enable, coordinate and accelerate the creation of the best evidence at European level on vaccine effects. In the past two years, VAC4EU has proven preparedness and efficiency in designing post-authorization monitoring for COVID-19 vaccines responding to the requests of both the European Medicines Agency (EMA) and vaccine manufacturers Objective: To describe the VAC4EU organization, data, tools and the accomplishments made towards the generation of real-world evidence on vaccine benefit-risk evaluation. Method(s): Not applicable. Result(s): Since its creation in October 2019, VAC4EU has established a large research network composed of 24 institutions from 9 European countries (BE, DE, DK, FR, IT, NL, NO, ES, UK) providing access to different health care data sources covering more than 150 million European citizens. VAC4EU has implemented a research infrastructure including a catalogue, a codemapper tool, a sharepoint, Github, digital research environment (DRE), a phenotype library of more than 100 variables with definitions and a Zenodo community to facilitate collaboration, transparency, and federated data analysis. VAC4EU has adopted the ConcePTION common data model as a basis for the structural harmonization of electronic health data, but it also allows for primary data collection. VAC4EU has consolidated its governance structure for implementation of pharmacovigilance studies on vaccines and successfully participated in four public tenders regarding vaccines safety and effectiveness launched by the European Medicines Agency (EMA) [1-3] as well as four required post-authorization safety studies on COVID-19 vaccines sponsored by vaccine manufacturers [4-8], and other studies promoted by the Global Vaccine Data Network. All protocols developed within VAC4EU are registered in the EU PAS register, and results are published in the open science VAC4EU Zenodo community. Conclusion(s): We know already from the H1N1 pandemic that collaboration is needed to study vaccine effects. This collaboration was designed and tested in the IMI-ADVANCE project and implemented in VAC4EU. VAC4EU has demonstrated readiness of its research framework making a key difference in COVID-19 vaccine monitoring in Europe. Research and public health organizations can join the initiative.

Acquired Hemophilia A and COVID19 Vaccines: A Possible Safety Signal or a Notoriety/Detection Bias?: An International Journal of Medical Toxicology and Drug Experience

Introduction: Acquired hemophilia A (AHA) is a rare autoimmune hemorragic condition (1-2 cases/million person/year)1. Several cases of AHA diagnosed following the administration of the COVID19 vaccines were described. Incidence of AHA diagnoses possibly higher than expected was also reported2,3. Indeed, higher attention to, and/or screening for, coagulation disorders during the vaccination campaign (i.e. notoriety/detection bias) might have increased the probability of AHA diagnosis and reporting compared to the past. Objective: To observe the utilization of AHA laboratory tests and incidence of AHA cases in Tuscany region during 2017-2021 and compare the rate of AHA in patients tested for AHA during COVID19 immunization campaign (2021) with that observed in 2019-2017. Methods: A retrospective cohort study was performed using population-based administrative data from Tuscany region (3.7million inhab), Italy. Per each year between 2017 and 2021, patients active into the database at 1st January, with > 5 years of age and 2 years of look-back were included. Subjects with > 1 laboratory tests used for diagnosing AHA1 were identified. Due to the absence of a AHA ICD9CM codes, possible AHA cases were identified combining information from different databanks. Cumulative annual incidence of both patients tested for AHA and possible AHA cases was respectively calculated. The rates of incident AHA cases on patients tested for AHA observed in 2021 and in 2017-2019 were calculated. All estimates were standardized by age and sex (std.). 95% confidence intervals (95% CIs) were estimated with Poissons method (statistical difference = no 95% CIs overlap). Results: A total of 126 possible AHA cases and 1.081.878 incident patients with > 1 laboratory test for AHA were identified between 2017 and 2021. Calendar year 2020 was clearly non-representative of the pre-immunizazion campaign period due to pandemic waves, thus it was excluded from the analyses. In 2021, std. incidence of tested patients (6067/million inhab/year;95% CI 60412-60913) and std. Incidence of possible AHA cases (5.6/million inhab/year;95% CI 3.4-8.7) showed the lowest point estimates, though only the former was statistically significant compared to any other year of the observation period. The std. rate of possible AHA cases on patients tested for AHA in 2021 was 5,6/100milion (95% CI 3.4-8.7) was not statistically different from that observed in 2017-2019 (7.6/100milion;95% CI 5-11). Conclusion: No increased incidence of possible AHA cases during the COVID19 immunization campaign was observed in Tuscany. Findings from this study do not suggest neither a possible detection bias nor a possible safety signal. Notority of other known vaccineinduced coagulation disorders may explain the increased reporting of AHA following COVID19 vaccines.

Association between SARS-CoV-2 Vaccines and Myoand Pericarditis;a Large Observational Study Using Electronic Healthcare Data from Four European Countries: An International Journal of Medical Toxicology and Drug Experience

Introduction: Some COVID-19 vaccines (Moderna and Pfizer) have been associated with an elevated risk of myocarditis in younger adults. However, observational studies were unable to stratify by dose and had limited ability to evaluate the effect of adenovirus-based COVID-19 vaccines due to the limited distribution of these in their study populations [1-4]. Objective: Estimate the incidence rates (IR), rate differences (RD) and incidence rate ratios (IRR) of myocarditis and pericarditis before and after each dose of mRNA (Pfizer and Moderna) and adenovirusplatform (AstraZeneca and Janssen) COVID-19 vaccines. Methods: We conducted a population-based cohort design with nested self-controlled risk interval (SCRI) study. Participants were followed from 1st January 2020 to 31st December 2021. Data were derived from healthcare data from five population-based data sources in four European countries: Italy, the Netherlands, the United Kingdom (UK), and Spain. The main outcome was first occurrence of myocarditis or pericarditis. RD and IR before COVID-19 disease and after each COVID-19 vaccine dose in those without COVID-19 were calculated. The SCRI calculated IRR with 60-day control period prior to vaccination and 28-day risk windows, with adjustment for seasonality. All analyses were stratified by age (< 30 and > 30 years) and in the cohorts refined age-bands for < 30 were utilised. Results: The study cohort comprised 35,365,669 persons with median age between 39-49 years, 57.4% received at least one COVID-19 vaccine dose and 77.6% of these received two. Myocarditis background rates were highest in persons 18-29 years (IR 2.8, 95% CI [1.5-4.1] to 6.4 [3.8-9.0] across UK, the Netherlands and Spain, and for 12-17 years in Italy (IR = 9.9 [5.3-14.4]). Pericarditis rates were higher in persons > 30 years (standardised IR from 11.6 [10.9-12.4] to 29.7 [19.8-22.1] across databases). RD of myocarditis were significantly elevated after Moderna dose 2 in persons between 18-29 years in Italy. Significantly reduced RD of pericarditis in the age group above 30 years was seen for Pfizer, Moderna and AstraZeneca. The SCRI showed significantly higher myocarditis IRR after dose 1 of Pfizer (IRR = 3.3 [1.2-9.4]), and also after dose 2 of Pfizer and Moderna in persons 12-29 years (IRR of 7.8 [2.6-23.5] and 6.1 [1.1-33.5], respectively). No association was observed between COVID-19 vaccination and pericarditis in the SCRI. In a sensitivity analysis, occasional significant association was seen for AstraZeneca dose 2 and myocarditis. Conclusion: Myocarditis is rare, but rates were increased significantly after both doses of Pfizer and the second dose of Moderna vaccines in persons below 30 years of age. This was not seen for pericarditis.

VAC4EU: A Pan-European Research Network for Collaborative Post-authorization Vaccine Safety and Benefit Monitoring: An International Journal of Medical Toxicology and Drug Experience

Introduction: VAC4EU (Vaccine monitoring Collaboration for Europe) is a not-for profit international association with 24 member organizations specialised in the collaborative generation of real-world evidence on coverage, safety, and efficacy of vaccines in Europe. VAC4EU was established as a result of the IMI-ADVANCE project with the aim to enable, coordinate and accelerate the creation of the best evidence at European level on vaccine effects. In the past two years, VAC4EU has proven preparedness and efficiency in designing post-authorization monitoring for COVID-19 vaccines responding to the requests of both the European Medicines Agency (EMA) and vaccine manufacturers Objective: To describe the VAC4EU organization, data, tools and the accomplishments made towards the generation of real-world evidence on vaccine benefit-risk evaluation. Methods: Not applicable. Results: Since its creation in October 2019, VAC4EU has established a large research network composed of 24 institutions from 9 European countries (BE, DE, DK, FR, IT, NL, NO, ES, UK) providing access to different health care data sources covering more than 150 million European citizens. VAC4EU has implemented a research infrastructure including a catalogue, a codemapper tool, a sharepoint, Github, digital research environment (DRE), a phenotype library of more than 100 variables with definitions and a Zenodo community to facilitate collaboration, transparency, and federated data analysis. VAC4EU has adopted the ConcePTION common data model as a basis for the structural harmonization of electronic health data, but it also allows for primary data collection. VAC4EU has consolidated its governance structure for implementation of pharmacovigilance studies on vaccines and successfully participated in four public tenders regarding vaccines safety and effectiveness launched by the European Medicines Agency (EMA) [1-3] as well as four required post-authorization safety studies on COVID-19 vaccines sponsored by vaccine manufacturers [4-8], and other studies promoted by the Global Vaccine Data Network. All protocols developed within VAC4EU are registered in the EU PAS register, and results are published in the open science VAC4EU Zenodo community. Conclusion: We know already from the H1N1 pandemic that collaboration is needed to study vaccine effects. This collaboration was designed and tested in the IMI-ADVANCE project and implemented in VAC4EU. VAC4EU has demonstrated readiness of its research framework making a key difference in COVID-19 vaccine monitoring in Europe. Research and public health organizations can join the initiative.

Post-marketing safety evaluation of flu vaccine during the 2020-2021 flu vaccination campaign in Italy: a Self-Controlled Case Series study of Guillain-Barre syndrome

Introduction: The Istituto Superiore di Sanita and the Agenzia Italiana del Farmaco coordinate the project TheShinISS-Vax, Flu, a post-marketing "active" surveillance of influenza vaccines. We report the results of the investigation using the Self- Controlled Case Series (SCCS) design on influenza vaccine and Guillain-Barre syndrome in vaccinated population aged over than 6 months, during the influenza vaccine campaign 2020-2021 in Italy. Materials and methods: A SCCS multi-regional study was carried out using linked data from Regional Health Care Registries of Valle d'Aosta, Friuli Venezia Giulia, Emilia-Romagna, Toscana, Lazio, Campania, and Puglia. Relative incidence of Guillain-Barre syndrome was estimated, comparing the exposure risk periods (0-41 days from the vaccination day, subdivided in six intervals) with the unexposed period.

Risk of COVID-19 hospitalization/mortality in patients with rheumatic disease treated with chloroquine/hydroxychloroquine or other conventional DMARDs in Italy: A large-scale nested casecontrol study

Objective: Chloroquine (CLQ)/hydroxychloroquine (HCQ) are two of the most studied drugs for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There are very limited data on the effect of treatment of patients affected by rheumatic diseases with HCQ/CLQ and other conventional disease-modifying anti-rheumatic drugs (cDMARDs) on COVID-19. The aim of this study is to investigate the hypothesis that treatment of rheumatic diseases with hydroxychloroquine (HCQ)/chloroquine (CLQ) as compared to other conventional disease-modifying anti-rheumatic drugs (cDMARDs) might decrease the COVID-19-related risk of hospitalization and mortality. Methods: This large-scale case-control study nested within a cohort of cDMARD users was conducted in the Lombardy, Veneto, Tuscany and Lazio regions and Reggio Emilia (Emilia Romagna) Local Health Unit, covering a total of 25.1 million inhabitants. Claims databases were linked to loco-regional COVID-19 surveillance registries from the same catchment area through unique fully-anonymized patient identifiers. Risk of COVID-19-related outcomes was estimated as odds ratios (ORs) along with 95% confidence intervals (CIs), using a multivariate conditional logistic regression analysis, by comparing HCQ/CLQ vs methotrexate (primary comparator) and other cDMARDs (secondary comparator). In addition, the same risk for HCQ/CLQ, methotrexate and other cDMARDs separately vs nonuse of these drugs as well as for presence of rheumatic diseases vs. absence in a non-nested population was investigated. Results: From the cohort of cDMARD users, 1275 cases who were hospitalized due to COVID-19 were identified and matched to 12,734 controls. When compared to recent use of methotrexate, no statistically significant association between recent HCQ/CLQ monotherapy with COVID-19 hospitalization (OR 0.83 [95% CI, 0.69 to 1.00]) or mortality (OR 1.19 [95% CI, 0.85 to 1.67]) was observed. A statistically significant lower risk was found when comparing recent use of HCQ/CLQ to treatment with other cDMARDs and glucocorticoids concomitantly. In the sensitivity analysis in the non-nested population, HCQ/CLQ was not associated with COVID-19 hospitalization as compared with non-use, whereas a mild statistically significant increased risk for recent use of both methotrexate as monotherapy (OR 1.19 [95% CI, 1.05 to 1.34]) or other cDMARDs (OR 1.21 [95% CI, 1.08 to 1.36]) vs non-use was found. Finally, the presence of rheumatoid arthritis or systemic lupus erythematosus was not associated with COVID-19 hospitalization (OR 0.98 [95% CI, 0.89 to 1.07]) or mortality (OR 0.88 [95% CI, 0.74 to 1.05]). Conclusion: Prior exposure to HCQ/CLQ in rheumatic patients was not associated with a protective effect against COVID-19-related hospitalization and mortality. On the contrary, an increased risk in patients receiving other cDMARDs was observed when compared to non-use, especially in those patients concomitantly treated with glucocorticoids. This is likely attributable to a synergistic immunosuppressive effect, leading to increased risk of severe SARS-CoV-2 infection.