Update: cardiac-related events during the civilian smallpox vaccination program--United States, 2003

During the pre-event smallpox vaccination program, the U.S. Department of Defense (DOD) and CDC have received reports of cardiac events after vaccination. A case definition for myo/pericarditis as a smallpox vaccine--associated adverse event has been developed in conjunction with DOD, the joint Smallpox Vaccine Safety Working Group of the Advisory Committee on Immunization Practices (ACIP) and the Armed Forces Epidemiology Board (AFEB), and consulting cardiologists, immunologists, and epidemiologists. The term myo/pericarditis is used for surveillance purposes to refer to patients who have myocarditis, pericarditis, or both (myopericarditis). Myo/pericarditis cases are classified into suspected, probable, and confirmed categories. Suspected cases include those that are investigated and reported, although the level of certainty for the diagnosis is lower. These definitions were used to categorize all cardiac-related reports among civilian vaccinees received through May 9, 2003; a total of 21 cases of myo/pericarditis were ascertained. All have been reported previously; however, some have been reclassified. In addition, nine cases of ischemic cardiac events (i.e., myocardial infarction [MI] or angina) among civilian vaccinees have been reported previously. This report includes the case definition of myo/pericarditis and updates information on all reports of cardiac adverse events among 36,217 civilian vaccinees since the beginning of the civilian smallpox vaccination program reported through May 9 to CDC from the Vaccine Adverse Event Reporting System (VAERS).     

Cardiomyopathy during clozapine therapy

A 45-year-old woman of Moroccan origin developed a dilated cardiomyopathy during clozapine treatment for a psychosis that did not respond to conventional antipsychotics. The onset of her illness was acute with chest pain. She subsequently developed shortness of breath and oedema of the face and legs. The cardiomyopathy appeared to be partially reversible after the clozapine was halted. Cardiomyopathy during the use of clozapine is rarely described in the literature, although myocarditis is a known complication. The cause of cardiomyopathy during the use of clozapine is not known. Myocarditis might evolve into cardiomyopathy. There are indications that myocarditis is caused by an allergic reaction to clozapine. It is advised that clozapine treatment should only be initiated under the close supervision of a psychiatrist, and that during the use of clozapine one should be alert to the risk of cardiac complications.     

Background incidence rates of adverse events of special interest related to COVID-19 vaccines in Ontario,Canada, 2015 to 2020, to inform COVID-19 vaccine safety surveillance

BackgroundBackground incidence rates are critical in pharmacovigilance to facilitate identification of vaccine safety signals. We estimated background incidence rates of 11 adverse events of special interest related to COVID-19 vaccines in Ontario, Canada.MethodsWe conducted a population-based retrospective observational study using linked health administrative databases for hospitalizations and emergency department visits among Ontario residents. We estimated incidence rates of Bell’s palsy, idiopathic thrombocytopenia, febrile convulsions, acute disseminated encephalomyelitis, myocarditis, pericarditis, Kawasaki disease, Guillain-Barré syndrome, transverse myelitis, acute myocardial infarction, and anaphylaxis during five pre-pandemic years (2015–2019) and 2020.ResultsThe average annual population was 14 million across all age groups with 51% female. The pre-pandemic mean annual rates per 100,000 population during 2015–2019 were 191 for acute myocardial infarction, 43.9 for idiopathic thrombocytopenia, 28.8 for anaphylaxis, 27.8 for Bell’s palsy, 25.0 for febrile convulsions, 22.8 for acute disseminated encephalomyelitis, 11.3 for myocarditis/pericarditis, 8.7 for pericarditis, 2.9 for myocarditis, 2.0 for Kawasaki disease, 1.9 for Guillain-Barré syndrome, and 1.7 for transverse myelitis. Females had higher rates of acute disseminated encephalomyelitis, transverse myelitis and anaphylaxis while males had higher rates of myocarditis, pericarditis, and Guillain-Barré syndrome. Bell’s palsy, acute disseminated encephalomyelitis, and Guillain-Barré syndrome increased with age. The mean rates of myocarditis and/or pericarditis increased with age up to 79 years; males had higher rates than females: from 12 to 59 years for myocarditis and ≥12 years for pericarditis. Febrile convulsions and Kawasaki disease were predominantly childhood diseases and generally decreased with age.ConclusionsOur estimated background rates will permit estimating numbers of expected events for these conditions and facilitate detection of potential safety signals following COVID-19 vaccination.     

Myocarditis following COVID-19 mRNA vaccination

BackgroundClinical trials of the BNT162b2 vaccine, revealed efficacy and safety. We report six cases of myocarditis, which occurred shortly after BNT162b2 vaccination.MethodsPatients were identified upon presentation to the emergency department with symptoms of chest pain/discomfort. In all study patients, we excluded past and current COVID-19. Routine clinical and laboratory investigations for common etiologies of myocarditis were performed. Laboratory tests also included troponin and C-reactive protein levels. The diagnosis of myocarditis was established after cardiac MRI.FindingsFive patients presented after the second and one after the first dose of the vaccine. All patients were males with a median age of 23 years. Myocarditis was diagnosed in all patients, there was no evidence of COVID-19 infection. Laboratory assays excluded concomitant infection; autoimmune disorder was considered unlikely. All patients responded to the BNT162b2 vaccine. The clinical course was mild in all six patients.InterpretationOur report of myocarditis after BNT162b2 vaccination may be possibly considered as an adverse reaction following immunization. We believe our information should be interpreted with caution and further surveillance is warranted.     

A broad assessment of covid-19 vaccine safety using tree-based data-mining in the vaccine safety datalink

BackgroundExcept for spontaneous reporting systems, vaccine safety monitoring generally involves pre-specifying health outcomes and post-vaccination risk windows of concern. Instead, we used tree-based data-mining to look more broadly for possible adverse events after Pfizer-BioNTech, Moderna, and Janssen COVID-19 vaccination.MethodsVaccine Safety Datalink enrollees receiving ≥1 dose of COVID-19 vaccine in 2020–2021 were followed for 70 days after Pfizer-BioNTech or Moderna and 56 days after Janssen vaccination. Incident diagnoses in inpatient or emergency department settings were analyzed for clustering within both the hierarchical ICD-10-CM code structure and the post-vaccination follow-up period. We used the self-controlled tree-temporal scan statistic and TreeScan software. Monte Carlo simulation was used to estimate p-values; p = 0.01 was the pre-specified cut-off for statistical significance of a cluster.ResultsThere were 4.1, 2.6, and 0.4 million Pfizer-BioNTech, Moderna, and Janssen vaccinees, respectively. Clusters after Pfizer-BioNTech vaccination included: (1) unspecified adverse effects, (2) common vaccine reactions, such as fever, myalgia, and headache, (3) myocarditis/pericarditis, and (4) less specific cardiac or respiratory symptoms, all with the strongest clusters generally after Dose 2; and (5) COVID-19/viral pneumonia/sepsis/respiratory failure in the first 3 weeks after Dose 1. Moderna results were similar but without a significant myocarditis/pericarditis cluster. Further investigation suggested the fifth signal group was a manifestation of mRNA vaccine effectiveness after the first 3 weeks. Janssen vaccinees had clusters of unspecified or common vaccine reactions, gait/mobility abnormalities, and muscle weakness. The latter two were deemed to have arisen from confounding related to practices at one site.ConclusionsWe detected post-vaccination clusters of unspecified adverse effects, common vaccine reactions, and, for the mRNA vaccines, chest pain and palpitations, as well as myocarditis/pericarditis after Pfizer-BioNTech Dose 2. Unique advantages of this data mining are its untargeted nature and its inherent adjustment for the multiplicity of diagnoses and risk intervals scanned.     

Cardiac adverse events following smallpox vaccination--United States, 2003

During January 24-March 21, smallpox vaccine was administered to 25,645 civilian health-care and public health workers in 53 jurisdictions as part of an effort to prepare the United States in the event of a terrorist attack using smallpox. Seven cases of cardiac adverse events have been reported among civilian vaccinees since the beginning of the smallpox vaccination program. In addition, 10 cases of myopericarditis have been reported among military vaccinees. This report summarizes data on the seven cases reported among civilians and provides background information on recent military vaccinees. Although a causal association between vaccination and adverse cardiac events in the civilian population is unproven, as a precautionary measure, CDC recommends that persons with physician-diagnosed cardiac disease with or without symptoms (e.g., previous myocardial infarction, angina, congestive heart failure, or cardiomyopathy) be excluded from vaccination during this smallpox preparedness program.     

Myocarditis and/or pericarditis risk after mRNA COVID-19 vaccination: A Canadian head to head comparison of BNT162b2 and mRNA-1273 vaccines

BackgroundCanadian and international data suggest the risk of myocarditis and/or pericarditis is elevated during the week after mRNA COVID-19 vaccination, particularly in younger age groups, in males, and after second doses.ObjectivesThis article examines whether there is a product-specific difference in the risk for myocarditis and/or pericarditis between the two mRNA vaccines administered in Canada: BNT162b2 (Pfizer-BioNTech Comirnaty) and mRNA-1273 (Moderna Spikevax).Materials and methodsReporting rates of myocarditis and/or pericarditis were calculated from reports received by the Canadian Adverse Events Following Immunization Surveillance System from December 2020-March 2022. Excess cases and attributable incidence among individuals aged 18–39 were estimated for each vaccine in comparison with background rates from 2015 to 2019. Head-to-head comparisons used Poisson regression, conditioned on week of vaccine administration, to estimate rate ratios for the week after mRNA-1273 vaccination versus the week after BNT162b2, by age and sex as well as overall. Analyses were restricted to May 30–March 13, 2021, when heightened media awareness was unlikely to have affected reporting rates for the two products differentially.ResultsIn 18–29 year-old males who received a second dose of mRNA COVID-19 vaccine, attributable risk of myocarditis and/or pericarditis was found to be 5.69 (95% CI: 4.07 – 7.95; p < 0.001) times higher among mRNA-1273 recipients (n = 106) as compared to BNT162b2 recipients (n = 33). In the same group, Poisson regression modelling estimated that the risk of myocarditis and/or pericarditis was 4.72 (p-value = <0.001) times higher after mRNA-1723 compared to BNT162b2 vaccination.ConclusionsThe risk of myocarditis and/or pericarditis is higher after mRNA-1723 vaccination than BNT162b2 vaccination in those aged 18–39 years, especially in males aged 18–29 years, where the risk is several times higher.     

Update: adverse events following smallpox vaccination--United States, 2003

During January 24-March 28, 2003, smallpox vaccine was administered to 29,584 civilian health-care and public health workers in 54 jurisdictions as part of an effort to prepare the United States for a terrorist attack using smallpox virus. This report summarizes data on ten cases of cardiac adverse events reported among civilian vaccinees since the beginning of the smallpox vaccination program, including three new cardiac adverse events reported to CDC from the Vaccine Adverse a fall Event Reporting System (VAERS) during March 24-30. Fourteen cases of myocarditis and one fatal myocardial infarction have been reported among military personnel. This report summarizes data on the three new cases of cardiac adverse events, updates data on seven previously reported cases among civilian vaccinees (Table 1), summarizes selected cases of cardiac adverse events among military vaccinees, and updates information on all adverse events reported in the civilian vaccination program as of March 30.     

Near real-time surveillance of safety outcomes in US COVID-19 vaccine recipients aged 12 to 64 years

BackgroundActive monitoring of safety outcomes following COVID-19 vaccination is critical to understand vaccine safety and can provide early detection of rare outcomes not identified in pre-licensure trials. We present findings from an early warning rapid surveillance system in three large commercial insurance databases including more than 16 million vaccinated individuals.MethodsWe evaluated 17 outcomes of interest following COVID-19 vaccination among individuals aged 12–64 years in Optum, HealthCore, and CVS Health databases from December 11, 2020, through January 22, 2022, January 7, 2022, and December 31, 2021, respectively. We conducted biweekly or monthly sequential testing and generated rate ratios (RR) of observed outcome rates compared to historical (or expected) rates prior to COVID-19 vaccination.FindingsAmong 17 outcomes evaluated, 15 did not meet the threshold for statistical signal in any of the three databases. Myocarditis/pericarditis met the statistical threshold for a signal following BNT162b2 in two of three databases (RRs: 1.83–2.47). Anaphylaxis met the statistical threshold for a signal in all three databases following BNT162b2 vaccination (RRs: 4.48–10.86) and mRNA-1273 vaccination (RRs: 7.64–12.40).DiscussionConsistent with published literature, our near-real time monitoring of 17 adverse outcomes following COVID-19 vaccinations identified signals for myocarditis/pericarditis and anaphylaxis following mRNA COVID-19 vaccinations. The method is intended for early detection of safety signals, and results do not imply a causal effect. Results of this study should be interpreted in the context of the method’s utility and limitations, and the validity of detected signals must be evaluated in fully adjusted epidemiologic studies.     

Safety monitoring of COVID-19 vaccination among adolescents aged 12 to 17 years old in the Republic of Korea

ObjectivesThis study aimed to disseminate information on coronavirus disease 2019 (COVID-19) vaccine safety among adolescents aged 12 to 17 years in the Republic of Korea.Methods Two databases were used to assess COVID-19 vaccine safety in adolescents aged 12 to 17 years who completed the primary Pfizer-BioNTech vaccination series. Adverse events reported to the web-based COVID-19 vaccination management system (CVMS) and collected in the text message-based system were analyzed.Results From March 5, 2021 to February 13, 2022, 12,216 adverse events among 12- to 17-year-olds were reported to the CVMS, of which 97.1% were non-serious adverse events and 2.9% were serious adverse events, including 85 suspected cases of anaphylaxis, 74 suspected cases of myocarditis and/or pericarditis, and 2 deaths. From December 13, 2021 to January 26, 2022, 10,389 adolescents responded to a text message survey, and local/systemic adverse events were more common after dose 2 than after dose 1. The most commonly reported events following either vaccine dose were pain at the injection site, headache, fatigue/tiredness, and myalgia.ConclusionThe overall results are consistent with previous findings; the great majority of adverse events were non-serious, and serious adverse events were rare among adolescents aged 12 to 17 years following Pfizer-BioNTech COVID-19 vaccination.     

Vaccinovigilance in Europe--need for timeliness, standardization and resources

OBJECTIVE: To identify gaps in the systems for reporting adverse events following immunization (AEFI) in Europe by means of an interactive database constructed using a standardized approach. METHODS: A comparative survey was conducted in 1999-2000, using structured questionnaires addressed to the government authorities responsible for national immunization programmes and drug safety surveillance in all European Union (EU) Member States and in Norway and Switzerland. FINDINGS: The reporting of adverse vaccine reactions (AVRs) is covered by regulations in 13 of the 17 countries. Four countries have a specialized expert group with responsibility for vaccine safety. Only six professionals work full-time on vaccine safety in the 17 countries; in four of these countries the person is medically qualified. Fourteen countries have centralized reporting systems; in 14 countries the responsible authority is the drug regulatory agency. AEFI are reported using the procedure used for adverse drug reactions (ADRs) in all except four countries. The reporting form is not usually designed for vaccines and important details may therefore not be requested. Clinical definitions for vaccine reactions are not available. Twelve countries have appropriate official definitions for events or reactions, but the list of reportable events varies considerably between countries. The assessment of adverse vaccine reactions (AVRs) is hampered by lack of exact denominator data. Feedback to the rapporteurs was provided in 13 countries, but its quality was highly variable. CONCLUSION: The database facilitated a simple comparison of vaccinovigilance systems across participating countries. Most of the problems identified related to the reporting and analysis of AEFI could be solved through standardization and intensified international collaboration. On a national level, functional vaccinovigilance systems should be the shared responsibility of the drug regulatory authority and the national immunization programme. The resources for development and management of vaccine safety systems should be urgently improved.     

Suspected vasculitis in an adolescent female with cardiomyopathy,myocardial infarction,and heart failure requiring heart transplantation

A 15-year-old girl presented with dilated cardiomyopathy, positive cardiac markers, and electrocardiogram changes suggestive of acute coronary syndrome. Coronary angiography showed giant dilated coronary arteries. Pathological evidence for cardiomyopathy with acute myocardial infarction was present in the explanted heart. Further investigation suggested evidence for a systemic vasculitis: polyangiitis overlap syndrome.     

A case series of acute pericarditis following COVID-19 vaccination in the context of recent reports from Europe and the United States

BackgroundCOVID-19 vaccines were efficacious and safe in clinical trials. We report nine events of acute pericarditis (AP) in eight patients following COVID-19 vaccination with BNT162b2 (6/9), AZD1222 (2/9) and mRNA-1273 (1/9).MethodsAll patients were referred for AP temporally linked with COVID-19 vaccination. Chest pain was the most common clinical manifestation. Alternative etiologies were excluded upon thorough diagnostic work up. AP diagnosis was established according to ESC guidelines.FindingsFive events occurred after the first vaccine dose and four after the second. The mean age in this cohort was 65.8 ± 10.2 years and the men/women ratio 3/5. All events resolved without sequelae; two events were complicated by cardiac tamponade requiring emergent pericardial decompression. Hospitalization was required in four cases.InterpretationAlthough causality cannot be firmly established, AP has emerged as a possible complication following COVID-19 vaccination. Further investigation is indispensable to fully characterize this new entity.     

Attenuation of coxsackievirus B3 by VP2 mutation and its application as a vaccine against virus-induced myocarditis and pancreatitis

Coxsackievirus B3 (CVB3) is a common agent of viral myocarditis, a major cause of sudden cardiac death, and ultimately dilated cardiomyopathy. However, there is no vaccine in clinical use. In this study, we identified the conserved amino acid sequences in the C-terminal region of the VP2 of the coxsackievirus B group and some echoviruses. The mutant virus, YYFF, with phenylalanines substituted for two tyrosines in these conserved sequences was highly attenuated in vivo and could induce a high neutralizing antibody titer and a cytotoxic T-lymphocyte response against CVB3. Thereby, mutant-virus-immunized mice showed a 100% survival rate and protection against inflammation of the heart and pancreas after lethal dose challenge. Thus, this mutant virus is a good candidate for an attenuated CVB3 vaccine.     

Generation of protective immune responses against coxsackievirus B3 challenge by DNA prime-protein boost vaccination

Coxsackievirus B3 (CVB3) causes viral myocarditis and can ultimately result in dilated cardiomyopathy. However, there is no vaccine available for clinical use. In this study, we assessed the protection provided by three immunization strategies against CVB3 infection. Vaccination was performed with a DNA vaccine expressing the cloned capsid gene VP1 or a vaccine developed from purified VP1 protein. Third, a strategy of vaccination was attempted with the DNA vaccine followed by two boosts with the recombinant protein vaccine (DNA prime-protein boost vaccine). Followed immunization, mice were challenged with CVB3 infection. Improved induction of CVB3-specific antibodies and neutralizing antibodies were found in mice immunized by the DNA prime-protein boost regimen. Furthermore, virus-specific cytotoxic activity of spleen cells derived from DNA prime-protein boost vaccinated mice was elicited. In addition, the DNA prime-protein boost vaccine resulted in protection of 75% of mice from lethal CVB3 challenge and a significant reduction of viral load in sera of immunized mice after acute CVB3 infection. There was a significant reduction in myonecrosis and infiltrating myocardial immune cells indicating reduced severity of myocarditis in surviving mice. These findings demonstrated that a DNA prime-protein boost immunization strategy, but not a DNA vaccine or protein vaccine alone, was effective in eliciting both humoral and cell-mediated immune responses against CVB3 infection in mice and might be a promising vaccine candidate.     

Risk of serious adverse events after the BNT162b2, CoronaVac,and ChAdOx1 vaccines in Malaysia: A self-controlled case series study

BackgroundRapid deployment of COVID-19 vaccines is challenging for safety surveillance, especially on adverse events of special interest (AESIs) that were not identified during the pre-licensure studies. This study evaluated the risk of hospitalisations for predefined diagnoses among the vaccinated population in Malaysia.MethodsHospital admissions for selected diagnoses between 1 February 2021 and 30 September 2021 were linked to the national COVID-19 immunisation register. We conducted self-controlled case-series study by identifying individuals who received COVID-19 vaccine and diagnosis of thrombocytopenia, venous thromboembolism, myocardial infarction, myocarditis/pericarditis, arrhythmia, stroke, Bell’s Palsy, and convulsion/seizure. The incidence of events was assessed in risk period of 21 days postvaccination relative to the control period. We used conditional Poisson regression to calculate the incidence rate ratio (IRR) and 95% confidence interval (CI) with adjustment for calendar period.ResultsThere was no increase in the risk for myocarditis/pericarditis, Bell’s Palsy, stroke, and myocardial infarction in the 21 days following either dose of BNT162b2, CoronaVac, and ChAdOx1 vaccines. A small increased risk of venous thromboembolism (IRR 1.24; 95% CI 1.02, 1.49), arrhythmia (IRR 1.16, 95% CI 1.07, 1.26), and convulsion/seizure (IRR 1.26; 95% CI 1.07, 1.48) was observed among BNT162b2 recipients. No association between CoronaVac vaccine was found with all events except arrhythmia (IRR 1.15; 95% CI 1.01, 1.30). ChAdOx1 vaccine was associated with an increased risk of thrombocytopenia (IRR 2.67; 95% CI 1.21, 5.89) and venous thromboembolism (IRR 2.22; 95% CI 1.17, 4.21).ConclusionThis study shows acceptable safety profiles of COVID-19 vaccines among recipients of BNT162b2, CoronaVac, and ChAdOx1 vaccines. This information can be used together with effectiveness data for risk-benefit analysis of the vaccination program. Further surveillance with more data is required to assess AESIs following COVID-19 vaccination in short- and long-term.     

Myocarditis in a 72-year-old woman with late onset systemic lupus erythematous

A 72-year-old female with late onset systemic lupus erythematosus (SLE) was admitted with chest pain and dyspnoea, and was submitted to investigation by echocardiogram, cardiovascular magnetic resonance(CMR) and serology panel. Morphological and functional studies of the heart revealed conspicuous inflammatory signs and moderate effusion compatible with myocarditis and pericarditis. Myocarditis is an uncommon manifestation of SLE. The additional burden posed by myocarditis in the management and outcome of elderly patients with SLE is also emphasized.     

Cardiomyopathies in adolescents: dilated, hypertrophic, and restrictive

Three major types of cardiomyopathies affect adolescents: dilated, hypertrophic, and restrictive. At the present time the etiologies of the majority of these cardiomyopathies in children remain elusive. Treatment of these diseases is generally directed toward improving symptoms, survival, myocardial performance, and hemodynamics. Most treatment strategies are extrapolated from studies in adults with these types of cardiomyopathies, although prospective, randomized therapeutic trials are currently underway in children. All three types of cardiomyopathy can be associated with a wide range of symptoms (from none to severe) and also are associated with sudden death. For those in whom medical management fails, heart transplantation is a therapeutic option with an excellent intermediate-term success rate.     

Development of case definitions for acute encephalopathy,encephalitis, and multiple sclerosis reports to the vaccine: Adverse Event Reporting System

The Vaccine Adverse Event Reporting System (VAERS), administered by the FDA and CDC, is the U.S. system for surveillance of vaccine adverse events (AE). Acute encephalopathy age <18 months (EO < 18), age > or =18 months (EO > or = 18), encephalitis (EI), and multiple sclerosis (MS) after vaccination have been reported to VAERS, but reports often contain insufficient information to validate diagnoses. Standardized case definitions would enhance the utility of VAERS reports for AE surveillance. We developed practical case definitions for classification of VAERS reports, and three neurologists independently applied the definitions to reports submitted in 1993. Inter-observer agreement was assessed, and non-concordant classifications were reviewed in a follow-up conference call. Reports of EO < 18 (n = 8), EO > or = 18 (n = 20), EI (n = 15), and MS (n = 16) were classified as "definite" in 7% to 30% of the cases, while 26% to 51% of reports were thought to have insufficient information to make a classification. Agreement among reviewers was good to excellent, (kappa: 0.65 to 0.85) except for EO < 18 m for which it was marginal (kappa: 0.37). It is possible to develop reproducible case definitions for acute encephalopathy, encephalitis, and multiple sclerosis using a standardized approach. Application of standardized case definitions to VAERS reports documents the limited information in many reports, specifies data for supplemental collection, and indicates that VAERS reports should be cautiously interpreted. Development and application of case definitions for other adverse events reported after vaccination should enhance the value of vaccine safety databases. Published by Elsevier Science Inc.