Pharmacovigilance signals from active surveillance of mRNA platform vaccines (tozinameran and elasomeran)

Introduction: Two severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines, tozinameran/BNT162b2 (Comirnaty®, Pfizer-BioNTech) and elasomeran/mRNA-1273 (Spikevax®, Moderna), were approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) at the end of 2020, less than a year after the start of the coronavirus disease 2019 (COVID-19) pandemic. In France, the health authorities have requested an intensive vaccination campaign, accompanied by a reinforced and active pharmacovigilance surveillance. This surveillance and analysis of real-life data, based on spontaneous reports received by the French Network of Regional PharmacoVigilance Centers (RFCRPV), has enabled to identify numerous pharmacovigilance signals. Some of them, such as myocarditis and heavy menstrual bleeding, have been confirmed as adverse effects of these vaccines. Method: We propose a descriptive review of the main pharmacovigilance signals identified by the RFCRPV concerning vaccines from the mRNA platform. Results: Most pharmacovigilance signals were common to both mRNA vaccines: myocarditis, menstrual disorders, acquired haemophilia, Parsonage-Turner syndrome, rhizomelic pseudo-polyarthritis and hearing disorders. Other signals were more specific, such as arterial hypertension with tozinameran or delayed reaction site injection with elasomeran. Conclusion: This non-exhaustive review illustrates the experience of RFCRPV in identifying and monitoring pharmacovigilance signals related to mRNA vaccines in France during the COVID-19 pandemics, and the crucial role of pharmacological and clinical expertise in this area. It also highlights the predominant contribution of spontaneous reporting in the generation of pharmacovigilance signals, particularly for serious and rare adverse events not detected before marketing.

Role of spontaneous reporting in investigating the relationship between mRNA COVID-19 vaccines and myocarditis: the French perspective

Aim of the study: Post-mRNA coronavirus diseases 2019 (COVID-19) vaccines myocarditis emerged as a rare adverse effect, particularly in adolescents and young adults, and was labeled as such for both vaccines in the summer of 2021. This study aims to summarize the timeline and process of signal detection, substantiation, and quantification of myocarditis cases related to mRNA vaccines in France. Methods: The intensive monitoring plan for COVID-19 vaccine safety was based on case-by-case analysis of all cases collected in the French spontaneous reporting database (base nationale de pharmacovigilance, BNPV). Cases were evaluated by drug safety medical professionals and discussed at a national level for signal detection purposes. Reported cases were compared to the number of vaccine-exposed persons up to September 30, 2021. Reporting rates (Rr) of myocarditis per 100,000 injections were calculated and stratified according to age, gender, and injection rank of BNT162b2 and mRNA-1273 vaccines. Poisson distribution was used to compute Rrs 95% Confidence Interval (95% CI). Results.- The case-by-case analysis detected a possible cluster of myocarditis in April 2021 (5 cases, 4 after the 2nd injection). In June 2021, the signal was substantiated with 12 cases (9 related to BNT162b2, and 3 to mRNA-1273). As of September 2021, almost 73 million BNT162b2 and 10 million mRNA-1273 doses had been injected. The Rr per 100,000 injections was 0.5 (0.5-0.6) for BNT162b2 and 1.1 (95% CI 0.9-1.3) for mRNA-1273. The difference among vaccines was more pronounced after the second injection, particularly in men aged 18-24 years (4.3 [3.4-5.5] for BNT162b2 vs. 13.9 [9.2-20.1] for mRNA-1273) and aged 25-29 years (1.9 [1.2-2.9] vs. 7.0 [3.4-12.9]). Conclusion: The study highlighted the role of the spontaneous reporting system in the detection, assessment, and quantification of myocarditis related to m-RNA vaccines. It suggested from September 2021 that mRNA-1273 was reasonably related to a higher risk of myocarditis than BNT162b2 in people under 30, particularly after the second injection.

Role of spontaneous reporting in investigating the relationship between mRNA COVID-19 vaccines and myocarditis: The French perspective.

AIM OF THE STUDY: Post-mRNA coronavirus diseases 2019 (COVID-19) vaccines myocarditis emerged as a rare adverse effect, particularly in adolescents and young adults, and was labeled as such for both vaccines in the summer of 2021. This study aims to summarize the timeline and process of signal detection, substantiation, and quantification of myocarditis cases related to mRNA vaccines in France. METHODS: The intensive monitoring plan for COVID-19 vaccine safety was based on case-by-case analysis of all cases collected in the French spontaneous reporting database (Base nationale de pharmacovigilance, BNPV). Cases were evaluated by drug safety medical professionals and discussed at a national level for signal detection purposes. Reported cases were compared to the number of vaccine-exposed persons up to September 30th, 2021. Reporting rates (Rr) of myocarditis per 100,000 injections were calculated and stratified according to age, gender, and injection rank of BNT162b2 and mRNA-1273 vaccines. Poisson distribution was used to compute Rrs 95% Confidence Interval (95% CI). RESULTS: The case-by-case analysis detected a possible cluster of myocarditis in April 2021 (5 cases, 4 after the 2nd injection). In June 2021, the signal was substantiated with 12 cases (9 related to BNT162b2, and 3 to mRNA-1273). As of September 2021, almost 73 million BNT162b2 and 10 million mRNA-1273 doses had been injected. The Rr per 100,000 injections was 0.5 (0.5-0.6) for BNT162b2 and 1.1 (95% CI 0.9-1.3) for mRNA-1273. The difference among vaccines was more pronounced after the second injection, particularly in men aged 18-24 years (4.3 [3.4-5.5] for BNT162b2 vs. 13.9 [9.2-20.1] for mRNA-1273) and aged 25-29 years (1.9 [1.2-2.9] vs. 7.0 [3.4-12.9]). CONCLUSION: The study highlighted the role of the spontaneous reporting system in the detection, assessment, and quantification of myocarditis related to m-RNA vaccines. It suggested from September 2021 that mRNA-1273 was reasonably related to a higher risk of myocarditis than BNT162b2 in people under 30, particularly after the second injection.

Pharmacovigilance signals from active surveillance of mRNA platform vaccines (tozinameran and elasomeran).

INTRODUCTION: Two severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines, tozinameran/BNT162b2 (Comirnaty®, Pfizer-BioNTech) and elasomeran/mRNA-1273 (Spikevax®, Moderna), were approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) at the end of 2020, less than a year after the start of the coronavirus disease 2019 (COVID-19) pandemic. In France, the health authorities have requested an intensive vaccination campaign, accompanied by a reinforced and active pharmacovigilance surveillance. This surveillance and analysis of real-life data, based on spontaneous reports received by the French Network of Regional PharmacoVigilance Centers (RFCRPV), has enabled to identify numerous pharmacovigilance signals. Some of them, such as myocarditis and heavy menstrual bleeding, have been confirmed as adverse effects of these vaccines. METHOD: We propose a descriptive review of the main pharmacovigilance signals identified by the RFCRPV concerning vaccines from the mRNA platform. RESULTS: Most pharmacovigilance signals were common to both mRNA vaccines: myocarditis, menstrual disorders, acquired haemophilia, Parsonage-Turner syndrome, rhizomelic pseudo-polyarthritis and hearing disorders. Other signals were more specific, such as arterial hypertension with tozinameran or delayed reaction site injection with elasomeran. CONCLUSION: This non-exhaustive review illustrates the experience of RFCRPV in identifying and monitoring pharmacovigilance signals related to mRNA vaccines in France during the COVID-19 pandemics, and the crucial role of pharmacological and clinical expertise in this area. It also highlights the predominant contribution of spontaneous reporting in the generation of pharmacovigilance signals, particularly for serious and rare adverse events not detected before marketing.

Correction to "Hyper inflammatory syndrome following COVID-19 mRNA vaccine in children: A national post-authorization pharmacovigilance study".

[This corrects the article DOI: 10.1016/j.lanepe.2022.100393.].

A UPLC-MS/MS Method for Plasma Biological Monitoring of Nirmatrelvir and Ritonavir in the Context of SARS-CoV-2 Infection and Application to a Case.

Nirmatrelvir/ritonavir association has been authorized for conditional use in the treatment of COVID-19, especially in solid-organ transplant recipients who did not respond to vaccine and are still at high risk of severe disease. This combination remains at risk of drug interactions with immunosuppressants, so monitoring drug levels seems necessary. After a simple protein precipitation of plasma sample, analytes were analyzed using an ultrahigh performance liquid chromatography system coupled with tandem mass spectrometry in a positive ionization mode. Validation procedures were based on the guidelines on bioanalytical methods issued by the European Medicine Agency. The analysis time was 4 min per run. The calibration curves were linear over the range from 10 to 1000 ng/mL for ritonavir and 40 to 4000 ng/mL for nirmatrelvir, with coefficients of correlation above 0.99 for all analytes. Intra-/interday imprecisions were below 10%. The analytical method also meets criteria of matrix effect, carryover, dilution integrity, and stability. In the context of a SARS-CoV-2 infection in a renal transplant recipient, we present a case of tacrolimus overdose with serious adverse events despite discontinuation of nirmatrelvir and ritonavir. The patient had still effective concentrations of nirmatrelvir and tacrolimus 4 days after drug discontinuation. This method was successfully applied for therapeutic drug monitoring in clinical practice.

Validation of Artificial Intelligence to Support the Automatic Coding of Patient Adverse Drug Reaction Reports, Using Nationwide Pharmacovigilance Data.

INTRODUCTION: Adverse drug reaction reports are usually manually assessed by pharmacovigilance experts to detect safety signals associated with drugs. With the recent extension of reporting to patients and the emergence of mass media-related sanitary crises, adverse drug reaction reports currently frequently overwhelm pharmacovigilance networks. Artificial intelligence could help support the work of pharmacovigilance experts during such crises, by automatically coding reports, allowing them to prioritise or accelerate their manual assessment. After a previous study showing first results, we developed and compared state-of-the-art machine learning models using a larger nationwide dataset, aiming to automatically pre-code patients' adverse drug reaction reports. OBJECTIVES: We aimed to determine the best artificial intelligence model identifying adverse drug reactions and assessing seriousness in patients reports from the French national pharmacovigilance web portal. METHODS: Reports coded by 27 Pharmacovigilance Centres between March 2017 and December 2020 were selected (n = 11,633). For each report, the Portable Document Format form containing free-text information filled by the patient, and the corresponding encodings of adverse event symptoms (in Medical Dictionary for Regulatory Activities Preferred Terms) and seriousness were obtained. This encoding by experts was used as the reference to train and evaluate models, which contained input data processing and machine-learning natural language processing to learn and predict encodings. We developed and compared different approaches for data processing and classifiers. Performance was evaluated using receiver operating characteristic area under the curve (AUC), F-measure, sensitivity, specificity and positive predictive value. We used data from 26 Pharmacovigilance Centres for training and internal validation. External validation was performed using data from the remaining Pharmacovigilance Centres during the same period. RESULTS: Internal validation: for adverse drug reaction identification, Term Frequency-Inverse Document Frequency (TF-IDF) + Light Gradient Boosted Machine (LGBM) achieved an AUC of 0.97 and an F-measure of 0.80. The Cross-lingual Language Model (XLM) [transformer] obtained an AUC of 0.97 and an F-measure of 0.78. For seriousness assessment, FastText + LGBM achieved an AUC of 0.85 and an F-measure of 0.63. CamemBERT (transformer) + Light Gradient Boosted Machine obtained an AUC of 0.84 and an F-measure of 0.63. External validation for both adverse drug reaction identification and seriousness assessment tasks yielded consistent and robust results. CONCLUSIONS: Our artificial intelligence models showed promising performance to automatically code patient adverse drug reaction reports, with very similar results across approaches. Our system has been deployed by national health authorities in France since January 2021 to facilitate pharmacovigilance of COVID-19 vaccines. Further studies will be needed to validate the performance of the tool in real-life settings.

Hyper inflammatory syndrome following COVID-19 mRNA vaccine in children: A national post-authorization pharmacovigilance study.

Background: Multisystem inflammatory syndrome in children (MIS-C) is the most severe clinical entity associated with pediatric SARS-CoV-2 infection with a putative role of the spike protein into the immune system activation. Whether COVID-19 mRNA vaccine can induce this complication in children is unknown. We aimed to assess the risk of hyper-inflammatory syndrome following COVID-19 mRNA vaccine in children. Methods: We conducted a post-authorization national population-based surveillance using the French enhanced pharmacovigilance surveillance system for COVID-19 vaccines. All cases of suspected hyper-inflammatory syndrome following COVID-19 mRNA vaccine in 12-17-year-old children between June 15th, 2021 and January 1st, 2022, were reported. Cases were reviewed according to WHO criteria for MIS-C. The reporting rate of this syndrome was compared to the MIS-C rate per 1,000,000 12-17-year-old children infected by SARS-CoV-2. Findings: Up to January 2022, 8,113,058 COVID-19 mRNA vaccine doses were administered to 4,079,234 12-17-year-old children. Among them, 12 presented a hyper-inflammatory syndrome with multisystemic involvement. Main clinical features included male predominance (10/12, 83%), cardiac involvement (10/12, 83%), digestive symptoms (10/12, 83%), coagulopathy (7/12, 58%), cytolytic hepatitis (6/12, 50%), and shock (5/12, 42%). 4/12 (33%) required intensive care unit transfer, and 3/12 (25%) hemodynamic support. All cases recovered. In eight cases, no evidence of previous SARS-CoV-2 infection was found. The reporting rate was 1.5 (95%CI [0.8; 2.6]) per 1,000,000 doses injected, i.e. 2.9 (95%CI [1.5; 5.1]) per 1,000,000 12-17-year-old vaccinated children. As a comparison, 113 MIS-C (95%CI [95; 135]) occurred per 1,000,000 12-17-year-old children infected by SARS-CoV-2. Interpretation: Very few cases of hyper-inflammatory syndrome with multi-organ involvement occurred following COVID-19 mRNA vaccine in 12-17-year-old children. The low reporting rate of this syndrome, compared to the rate of post-SARS-CoV-2 MIS-C in the same age-group, largely supports the vaccination in a context of an important circulation of SARS-CoV-2. Funding: ESPID Fellowship Award; Grandir-Fonds de Solidarité Pour L'enfance.

Association study between herpes zoster reporting and mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273).

Several cases of herpes zoster (HZ) following mRNA COVID-19 vaccination (BNT162b2 and mRNA-1273) have been reported, and the first epidemiological evidence suggests an increased risk. We used the worldwide pharmacovigilance database VigiBase to describe HZ cases following mRNA COVID-19 vaccination. We performed disproportionality analyses (case/non-case statistical approach) to assess the relative risk of HZ reporting in mRNA COVID-19 vaccine recipients compared to influenza vaccine recipients and according to patient age. To 30 June 2021, of 716 928 reports with mRNA COVID-19 vaccines, we found 7728 HZ cases. When compared to influenza vaccines, mRNA COVID-19 vaccines were associated with a significantly higher reporting of HZ (reporting odds ratio 1.9, 95% CI 1.8-2.1). Furthermore, we found a reduced risk of reporting HZ among under 40-year-old persons compared to older persons (reporting odds ratio 0.39, 95% CI 0.36-0.41). Mild and infrequent HZ reactions may occur shortly after mRNA COVID-19 vaccination, at higher frequency than reported with influenza vaccination, especially in patients over 40 years old. Further analyses are needed to confirm this risk.

Features of Inflammatory Heart Reactions Following mRNA COVID-19 Vaccination at a Global Level.

Myocarditis and pericarditis may constitute adverse reactions of mRNA coronavirus disease 2019 (COVID-19) vaccines. This study aimed to document these reactions and to assess the association with patient sex and age. This is as an observational retrospective study using a case-non-case design (also called disproportionality study) on inflammatory heart reactions reported with mRNA COVID-19 vaccines within the World Health Organization (WHO) global safety database (VigiBase), up to June 30, 2021. Results are expressed using reporting odds ratios (RORs) and their 95% confidence interval (95% CI). Of 716,576 reports related to mRNA COVID-19 vaccines, 2,277 were cases of inflammatory heart reactions, including 1241 (55%) myocarditis and 851 (37%) pericarditis. The main age group was 18-29 years (704, 31%), and mostly male patients (1,555, 68%). Pericarditis onset was delayed compared with myocarditis with a median time to onset of 8 (3-21) vs. 3 (2-6) days, respectively (P = 0.001). Regarding myocarditis, an important disproportionate reporting was observed in adolescents (ROR, 22.3, 95% CI 19.2-25.9) and in 18-29 years old (ROR, 6.6, 95% CI 5.9-7.5) compared with older patients, as well as in male patients (ROR, 9.4, 95% CI 8.3-10.6). Reporting rate of myocarditis was increased in young adults and adolescents. Inflammatory heart reactions may rarely occur shortly following mRNA COVID-19 vaccination. Although an important disproportionate reporting of myocarditis was observed among adolescents and young adults, particularly in male patients, reporting rates support a very rare risk, that does not seem to compromise the largely positive benefit-risk balance of these vaccines. Furthermore, this study confirmed the value of disproportionality analyses for estimation of relative risks among subgroups of patients.

Myocarditis and pericarditis in adolescents after first and second doses of mRNA COVID-19 vaccines.

AIMS: While some concerns about vaccination-related pericarditis and/or myocarditis have been raised, no published data are available on pericarditis and/or myocarditis with mRNA COVID-19 vaccines in the age group of adolescents, particularly 12-15 years. The objective of this study was to determine whether the risk of reporting pericarditis and/or myocarditis with mRNA COVID-19 vaccines varied according to dose of vaccination, age, sex, and type of pericarditis and/or myocarditis in adolescents between 12 and 17 years. METHODS AND RESULTS: We performed an observational study reviewing all reports of adolescents vaccinated with mRNA COVID-19 vaccines and recorded in VigiBase®, the World Health Organization global database of individual case safety reports. We included all reports registered between 1 January 2021 and 14 September 2021. Reporting odds ratios (RORs) with their 95% confidence interval (CI) were calculated to estimate the risk of reporting pericarditis and/or myocarditis. Among 4942 reports with mRNA COVID-19 vaccines in adolescents, we identified 242 pericarditis and/or myocarditis. Compared with the first dose of mRNA COVID-19 vaccines, the second dose was associated with an increased risk of reporting pericarditis and/or myocarditis (ROR 4.95; 95% CI 3.14, 7.89). The risk of reporting pericarditis and/or myocarditis was 10 times higher in boys than in girls and no difference between the two types of vaccines could be demonstrated. CONCLUSION: This investigation including only adolescent data suggests for the first time that the second dose of mRNA COVID-19 vaccines increases the risk of reporting myocarditis/pericarditis compared with the first dose particularly in boys without significant difference between tozinameran and elasomeran.

Early extubation with immediate non-invasive ventilation versus standard weaning in intubated patients for coronavirus disease 2019: a retrospective multicenter study.

In patients intubated for hypoxemic acute respiratory failure (ARF) related to novel coronavirus disease (COVID-19), we retrospectively compared two weaning strategies, early extubation with immediate non-invasive ventilation (NIV) versus standard weaning encompassing spontaneous breathing trial (SBT), with respect to IMV duration (primary endpoint), extubation failures and reintubations, rate of tracheostomy, intensive care unit (ICU) length of stay and mortality (additional endpoints). All COVID-19 adult patients, intubated for hypoxemic ARF and subsequently extubated, were enrolled. Patients were included in two groups, early extubation followed by immediate NIV application, and conventionally weaning after passing SBT. 121 patients were enrolled and analyzed, 66 early extubated and 55 conventionally weaned after passing an SBT. IMV duration was 9 [6-11] days in early extubated patients versus 11 [6-15] days in standard weaning group (p = 0.034). Extubation failures [12 (18.2%) vs. 25 (45.5%), p = 0.002] and reintubations [12 (18.2%) vs. 22 (40.0%) p = 0.009] were fewer in early extubation compared to the standard weaning groups, respectively. Rate of tracheostomy, ICU mortality, and ICU length of stay were no different between groups. Compared to standard weaning, early extubation followed by immediate NIV shortened IMV duration and reduced the rate of extubation failure and reintubation.

French organization for the pharmacovigilance of COVID-19 vaccines: A major challenge.

In this special issue, we present the main highlights of the first weeks of pharmacovigilance monitoring of coronavirus disease 2019 (COVID-19) vaccines in this unprecedented situation in France: the deployment of a vaccination during an epidemic period with the aim of vaccinating the entire population and the intense pharmacovigilance and surveillance of these vaccines still under conditional marketing authorizations. In this unprecedented situation, the cross approach and interaction between the French pharmacovigilance network and French National Agency for the Safety of Medicines and Health Products (ANSM) has been optimized to provide a real-time safety related to COVID-19 vaccines. Every week, pair of regional pharmacovigilance centers gathered safety data from the French pharmacovigilance network, to acutely expertise all the adverse drug reactions (ADRs) reported with each COVID-19 vaccine within a direct circuit with ANSM. Results of this expertise are presented and discussed with ANSM in order to raise safety signals and take appropriate measures if necessary. These reports are then published online. At the 25th of March 2021, more than 9 815 000 doses were injected and 20,265 ADRs were reported, mostly non-serious (76%). Several potential or confirmed signals were raised at the european level for those vaccines and others ADRs are under special attentions. This underlines the adaptiveness of the French pharmacovigilance system to both the identification of new patient profiles experiencing ADRs and the evolution of the vaccine strategy. Such an efficiency is necessary to manage a careful and acute surveillance of these new COVID-19 vaccines for and to face the pandemic at the same time.