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Vaccines are vital for public health, but concerns about adverse effects, particularly myocarditis and pericarditis linked to COVID-19 vaccines-, persist. This study investigates the application of Brighton Collaboration case definition to national vaccine safety data related to post-COVID-19 vaccine myo/pericarditis, utilizing claims under the Korea National Vaccine Injury Compensation Program (NIVCP). This study analyzed 190 medical records of individuals who claimed to have developed myo/pericarditis after receiving the COVID-19 vaccine, as reported to the NVICP between specified dates, categorizing cases based on the Brighton criteria for myocarditis or pericarditis. Between 2021–2022, NVICP received 190 cases meeting the Brighton criteria for myocarditis or pericarditis at levels 1, 2, or 3. Most cases fell into Level 2 (70%), followed by Level 1 (29%), and one at Level 3 (1%), with Level 1 cases showing a higher hospitalization rate (87.3%) and a notable proportion requiring admission to the Intensive Care Unit (25.5%). Chest pain and Troponin-I/T elevation were common findings in Level 1 cases, while Level 2 cases exhibited similar patterns but at a slightly lower frequency. Electrocardiogram and echocardiography findings differed between the two levels. The Brighton Collaboration case definition proved valuable for classifying and assessing AEFI data, enhancing our understanding of the potential relationship between myocarditis and the COVID-19 vaccine. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the possible extent of bias due to violation of a core assumption (event-dependent exposures) when using self-controlled designs to analyse the association between COVID-19 vaccines and myocarditis. We used data from five European databases (Spain: BIFAP, FISABIO VID, and SIDIAP; Italy: ARS-Tuscany; England: CPRD Aurum) converted to the ConcePTION Common Data Model. Individuals who experienced both myocarditis and were vaccinated against COVID-19 between 1 September 2020 and the end of data availability in each country were included. We compared a self-controlled risk interval study (SCRI) using a pre-vaccination control window, an SCRI using a post-vaccination control window, a standard SCCS and an extension of the SCCS designed to handle violations of the assumption of event-dependent exposures. We included 1,757 cases of myocarditis. For analyses of the first dose of the Pfizer vaccine, to which all databases contributed information, we found results consistent with a null effect in both of the SCRI and extended SCCS, but some indication of a harmful effect in a standard SCCS. For the second dose, we found evidence of a harmful association for all study designs, with relatively similar effect sizes (SCRI pre = 1.99, 1.40 – 2.82; SCRI post 2.13, 95 %CI – 1.43, 3.18; standard SCCS 1.79, 95 %CI 1.31 – 2.44, extended SCCS 1.52, 95 %CI = 1.08 – 2.15). Adjustment for calendar time did not change these conclusions. Findings using all designs were also consistent with a harmful effect following a second dose of the Moderna vaccine. In the context of the known association between COVID-19 vaccines and myocarditis, we have demonstrated that two forms of SCRI and two forms of SCCS led to largely comparable results, possibly because of limited violation of the assumption of event-dependent exposures. [ABSTRACT FROM AUTHOR]

• Rare cases of myocarditis/pericarditis after vaccination with COVID-19 vaccine NVX-CoV2373 have been documented. • This analysis provides a benefit-risk assessment for vaccination with NVX-CoV2373 based on data from clinical studies and recent real-world burden of disease data. • Results indicate that the benefits of vaccination with NVX-Cov2373 outweigh the risks of myocarditis/pericarditis. A benefit–risk assessment of NVX-CoV2373, a vaccine to prevent COVID-19, was conducted to determine if the benefits of vaccination outweigh the risks of myocarditis/pericarditis. This analysis used data on myocarditis/pericarditis cases observed in the NVX-CoV2373 clinical studies, real-world data of mRNA COVID vaccine effectiveness against predominant SARS-CoV-2 strains in early 2023, and recent COVID-19 burden of disease data from the United States. The benefits of NVX-CoV2373 vaccination were estimated as the number of COVID-19 cases, hospitalizations, and deaths prevented. The risks of myocarditis/pericarditis cases and related hospitalizations and deaths occurring within 7 days of vaccination were also estimated. In our analysis, vaccination with NVX-CoV2373, per 100,000 vaccinated, resulted in an estimated 1805 COVID-19 cases prevented compared with an estimated 5.3 excess myocarditis/pericarditis cases. The number of COVID-19 hospitalizations and deaths prevented were also greater than vaccine-associated myocarditis/pericarditis hospitalizations and deaths. Our analysis indicates a positive benefit–risk balance for NVX-CoV2373. [ABSTRACT FROM AUTHOR]

• The third dose of the BNT162b2 vaccine increases the risk of myocarditis, particularly in adolescent males. • The risk of myocarditis from BNT162b2, whether as an initial or booster dose following the BBIBP-CorV series, is close. • The risk of myocarditis after vaccination is less marked in children aged 5–11. Due to the data scarcity in low- and middle-income countries, we aimed to examine the incidence rate of myocarditis and pericarditis within 30 days after each dose of homologous (3 × BNT162b2) and heterologous prime-boost (2 × BBIBP-CorV/BNT162b2) vaccine regimen among individuals younger than 40 years. We conducted a historical control cohort using routinely recorded data from Thai national vaccine and insurance claims databases. Sex-specific incidence rate ratios (IRRs) for myocarditis and pericarditis were calculated for each vaccination strategy and contrasted with incidence rates among the non-immunised population in the pre-COVID-19 period. From August 2021 to September 2022, we tracked the incidence of myocarditis and pericarditis within 30 days after vaccinations using < 40-year-old national population databases. Our reference was the average monthly incidence of these conditions in the non-immunised population from August to October 2019. The exposure of interest was immunisation against the SARS-CoV-2 virus, incorporating the following vaccination strategies: three-dose 3 × BNT162b2 regimen, three-dose 2 × BBIBP-CorV/BNT162b2 regimen, and non-immunisation. For myocarditis, a total of 215 cases were identified among 7,594,965 individuals in the 3 × BNT162b2 cohort, 5 cases among 2,914,643 individuals in the 2 × BBIBP-CorV/BNT162b2 cohort, and 115 cases among 32,424,780 non-immunised individuals. The sex-specific IRRs (95 % confidence intervals) of myocarditis and pericarditis after the homologous vaccination were 3.09 (1.61, 5.93) and 1.84 (0.72, 4.73) for females and 7.43 (3.11, 17.73) and 10.48 (3.90, 28.15) for males, respectively. Conversely, the IRRs of myocarditis after the heterologous vaccination were not significant (females: 2.24 (0.70, 7.17); males: 1.99 (0.48, 8.21)). IRRs could not be obtained for pericarditis after the heterologous vaccination because of the small number of observed events. The study observed a significantly increased risk of myocarditis and pericarditis following homologous 3 × BNT162b2 vaccination but had insufficient power to confirm an increased risk for myocarditis following the heterologous prime-boost 2 × BBIBP-CorV/BNT162b2 vaccination. The incidence of pericarditis following the heterologous vaccination was too rare to evaluate. [ABSTRACT FROM AUTHOR]

• Myocarditis is a well known adverse events of special interest following COVID-19 vaccines. • Limited information has been published regarding medium and longer term outcomes. • This clinical survey study found around half of patients still experience symptoms at 6 months. • There are distinct phenotypic differences between genders and age groups. Myocarditis and myopericarditis are well described adverse events of special interest (AESI) following COVID-19 vaccinations. Although reports are reassuring regarding initial clinical outcomes, information about longer term outcomes remains limited. We aimed to further this knowledge and report outcomes to 6 months post diagnosis from a single population cohort. Reports of myocarditis following COVID-19 vaccination were followed up by SAEFVIC (Surveillance of Adverse Events Following Vaccination in the Community), the state-wide vaccine safety service for Victoria, Australia. Confirmed myocarditis cases (Brighton Collaboration Criteria levels 1–3) were followed up via surveys at 1, 3 and 6 months post symptom onset. Responses received between 22 February 2021 and 30 September 2022 were analysed. 87.5 % (N = 182) of eligible participants completed at least 1 survey report. 377 reports were analysed. 76.9 % of completed reports were from male patients. The median age of patients was 21 years [IQR: 16 to 32]. 54.8 % (n = 74) of survey reports at 6 months, reported ongoing symptoms. At all follow-up time points, females were significantly more likely to have ongoing symptoms. At 6 months, 51.9 % of male respondents reported symptom resolution compared to 22.6 % of female patients (p = 0.002). Females were also more likely to continue medication and have ongoing exercise restrictions. However, males were significantly more likely to have higher initial peak troponin results and abnormal initial cardiac imaging investigations. There appears to be a significant proportion of patients who experience ongoing symptoms to 6 months post onset amongst patients that experience these AESI. Male patients were more likely to report earlier and more complete symptom recovery, despite significantly higher average initial peak troponin. This difference in phenotypic presentation in females compared to males warrants further investigation and there is a need for longer term follow up data. [ABSTRACT FROM AUTHOR]

• 1883 vaccinated and unvaccinated post-COVID patients evaluated by echocardiogram. • 2.92% presented pathological TTE findings consistent with post-COVID cardiac injury. • Unvaccinated patients presented more cardiac injury than vaccinated (4.1% vs 1.3%) • 15% of the patients reported persistent symptoms at the post-COVID control. • Complete vaccination was associated with 48% reduction in risk of long-COVID symptoms. After the acute infection, COVID-19 can produce cardiac complications as well as long-COVID persistent symptoms. Although vaccination against COVID-19 represented a clear reduction in both mortality and ICU admissions, there is very little information on whether this was accompanied by a decrease in the prevalence of post-COVID cardiac complications. The aim of this study was to analyze the relationship between COVID-19 vaccination and the prevalence of post-COVID cardiac injury assessed by echocardiogram, and long-COVID persistent cardiac symptoms. Methods : All patients who consulted for post-COVID evaluation 14 days after discharge from acute illness were included. Patients with heart disease were excluded. The relationship between complete vaccination scheme (at least two doses applied with 14 days or more since the last dose) and pathological echocardiographic findings, as well as the relationship of vaccination with persistent long-COVID symptoms, were evaluated by multivariate analysis, adjusting for age, sex and clinical variables that would have shown significant differences in univariate analysis. Results : From 1883 patients, 1070 patients (56.8%) suffered acute COVID-19 without a complete vaccination scheme. Vaccination was associated with lower prevalence of cardiac injury (1.35% versus 4.11%, adjusted OR 0.33; 95% CI 0.17–0.65, p=0.01). In addition, vaccinated group had a lower prevalence of persistent long-COVID symptoms compared to unvaccinated patients (10.7% versus 18.3%, adjusted OR 0.52; 95% CI 0.40–0.69, p<0.001). Conclusion: Vaccination against COVID-19 was associated with lower post-COVID cardiac complications and symptoms, reinforcing the importance of fully vaccinating the population. [ABSTRACT FROM AUTHOR]

Evidence indicates that mRNA COVID-19 vaccination is associated with risk of myocarditis and possibly pericarditis, especially in young males. It is not clear if risk differs between mRNA-1273 versus BNT162b2. We assessed if risk differs using comprehensive health records on a diverse population. Members 18–39 years of age at eight integrated healthcare-delivery systems were monitored using data updated weekly and supplemented with medical record review of myocarditis and pericarditis cases. Incidence of myocarditis and pericarditis events that occurred among vaccine recipients 0 to 7 days after either dose 1 or 2 of a messenger RNA (mRNA) vaccine was compared with that of vaccinated concurrent comparators who, on the same calendar day, had received their most recent dose 22 to 42 days earlier. Rate ratios (RRs) were estimated by conditional Poisson regression, adjusted for age, sex, race and ethnicity, health plan, and calendar day. Head-to-head comparison directly assessed risk following mRNA-1273 versus BNT162b2 during 0–7 days post-vaccination. From December 14, 2020 – January 15, 2022 there were 41 cases after 2,891,498 doses of BNT162b2 and 38 cases after 1,803,267 doses of mRNA-1273. Cases had similar demographic and clinical characteristics. Most were hospitalized for ≤1 day; none required intensive care. During days 0–7 after dose 2 of BNT162b2, the incidence was 14.3 (CI: 6.5–34.9) times higher than the comparison interval, amounting to 22.4 excess cases per million doses; after mRNA-1273 the incidence was 18.8 (CI: 6.7–64.9) times higher than the comparison interval, amounting to 31.2 excess cases per million doses. In head-to-head comparisons 0–7 days after either dose, risk was moderately higher after mRNA-1273 than after BNT162b2 (RR: 1.61, CI 1.02–2.54). Both vaccines were associated with increased risk of myocarditis and pericarditis in 18–39-year-olds. Risk estimates were modestly higher after mRNA-1273 than after BNT162b2. [ABSTRACT FROM AUTHOR]

• Myocarditis/pericarditis is a rare adverse event observed following COVID-19 mRNA vaccination. • Myocarditis/pericarditis risk is higher after mRNA-1273 than after BNT162b2. • The product-specific difference is highest in young males within 7 days after the second dose. Canadian 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. This 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). Reporting 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. In 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. The 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. [ABSTRACT FROM AUTHOR]

• Benefits/risks of Comirnaty vaccine evaluated, groups under 30, to inform decisions. • Disease prevention from vaccine compared to risks, such as myocarditis/pericarditis. • Model demonstrates benefits of Comirnaty clearly outweigh risks for analyzed groups. • Higher COVID-19 incidence associated with greater vaccine benefits and vice versa. Since authorization of the Pfizer-BioNTech COVID-19 Vaccine, mRNA (Comirnaty), real-world evidence has indicated the vaccines are effective in preventing COVID-19 cases and related hospitalizations and deaths. However, increased cases of myocarditis/pericarditis have been reported in the United States associated with vaccination, particularly in adolescents and young adults. FDA conducted a benefit-risk assessment to determine whether the benefits of vaccination outweigh the risks among various age (16–17, 18–24, 25–29) and sex (M/F) subgroups being considered for approved use of the vaccine. We conducted a simulation study with sensitivity analysis of the benefits and risks of the vaccine across possible pandemic scenarios. The model results show benefits outweigh the risks for all scenarios including the high-risk subgroup, males 16–17 years old. Our worst-case scenario used sex and age subgroup-specific incidences for COVID-19 cases (47–98 per million per day) and hospitalizations (1–4 per million per day) which are the US COVID-19 incidences as of July 10, 2021, vaccine efficacy of 70% against COVID-19 cases and 80% against hospitalization, and unlikely, pessimistic, non-zero vaccine-attributable myocarditis death rate. For males 16–17 years old, the model predicts prevented COVID cases, hospitalizations, ICUs, and deaths of 13577, 127, 41, and 1, respectively; while the predicted ranges for excess myocarditis/pericarditis cases, hospitalizations, and deaths attributable to the vaccine are [98–196], [98–196], and 0, respectively, for the worst-case scenario. Considering the different clinical implications of hospitalization due to COVID-19 infection versus vaccine-attributable myocarditis/pericarditis cases, we determine the benefits still outweigh the risks even for this high-risk subgroup. Our results demonstrate that the benefits of the vaccine outweigh its risks for all age and sex subgroups we analyze in this study. Uncertainties exist in this assessment as both benefits and risks of vaccination may change with the continuing evolution of the pandemic. [ABSTRACT FROM AUTHOR]

• Myocarditis affects mainly young males after the second mRNA vaccine dose. • Clinical course is typically mild, following complete symptom resolution. • Signs of heart failure are predictive of subsequent critical illness. • Late gadolinium enhancement is invariably observed in cardiac magnetic resonance. Post-marketing surveillance studies have raised concerns of increased myocarditis rates following coronavirus disease-19 (Covid-19) mRNA vaccines. The present study aims to accumulate the published mRNA Covid-19 vaccine-associated myocarditis cases, describe their clinical characteristics and determine the factors predisposing to critical illness. Medline, Scopus, Web of Science, CENTRAL and Google Scholar were systematically searched from inception. Studies reporting adult myocarditis cases following BNT162b2 or mRNA-1273 vaccination were included. Individual participant data coming from case reports/series were pooled. Proportional random-effects meta -analysis was conducted by combining the pooled cohort and observational studies with aggregated data. Overall, 39 studies were included with a total of 129 patients. Most cases occurred in young males after the second vaccine dose. Myocarditis after the first dose was significantly associated with prior Covid-19 (p-value : 0.025). The most common electrocardiographic finding was ST-segment elevation, while late gadolinium enhancement was invariably observed in cardiac magnetic reasoning. Logistic regression analysis demonstrated that signs of heart failure were predictive of subsequent critical illness (Odds ratio: 19.22, 95% confidence intervals-CI: 5.57–275.84). Proportion meta -analysis indicated that complete resolution of symptoms is achieved in 80.5% of patients (95% CI: 59.3–92.1), while the proportion of participants necessitating intensive care unit admission is 7.0% (95% CI: 3.8–12.9). Myocarditis following mRNA Covid-19 vaccination is typically mild, following an uncomplicated clinical course with rapid improvement of symptoms. Future research is needed to define its exact incidence, clarify its pathophysiology and determine the optimal management plan depending on its severity. Protocol registration: dx.https://doi.org/10.17504/protocols.io.bxwtppen. [ABSTRACT FROM AUTHOR]

Myocarditis and/or pericarditis (also known as myopericarditis) are inflammatory diseases involving the myocardium (with non-ischemic myocyte necrosis) and/or the pericardial sac. Myocarditis/pericarditis (MPC) may present with variable clinical signs, symptoms, etiologies and outcomes, including acute heart failure, sudden death, and chronic dilated cardiomyopathy. Possible undiagnosed and/or subclinical acute myocarditis, with undefined potential for delayed manifestations, presents further challenges for diagnosing an acute disease and may go undetected in the setting of infection as well as adverse drug/vaccine reactions. The most common causes of MPC are viral, with non-infectious, drug/vaccine associated hypersensitivity and/or autoimmune causes being less well defined and with potentially different inflammatory mechanisms and treatment responses. Potential cardiac adverse events following immunization (AEFIs) encompass a larger scope of diagnoses such as triggering or exacerbating ischemic cardiac events, cardiomyopathy with potential heart failure, arrhythmias and sudden death. The current published experience does not support a potential causal association with vaccines based on epidemiologic evidence of relative risk increases compared with background unvaccinated incidence. The only evidence supporting a possible causal association of MPC with a vaccine comes from case reports. Hypersensitivity MPC as a drug/vaccine induced cardiac adverse event has long been a concern for post-licensure safety surveillance, as well as safety data submission for licensure. Other cardiac adverse events, such as dilated cardiomyopathy, were also defined in the CDC definitions for adverse events after smallpox vaccination in 2006. In addition, several groups have attempted to develop and improve the definition and adjudication of post-vaccination cardiovascular events. We developed the current case definitions for myocarditis and pericarditis as an AEFI building on experience and lessons learnt, as well as a comprehensive literature review. Considerations of other etiologies and causal relationships are outside the scope of this document. [ABSTRACT FROM AUTHOR]

• 7 cases of myocarditis with symptoms in the first week after the second dose of COVID-19 Pfizer-BioNTech vaccine. • The incidence of myocarditis in the week following a second dose of the vaccine was 5.07/100,000 in the time of follow up, but due to the nature of this report no causality could be established. • Clinicians should be aware of the possibility of myocarditis following the COVID-19 Pfizer-BioNTech vaccination. There have been reports of myocarditis following COVID-19 vaccination. We surveyed all hospitalized military personnel in the Isareli Defense Forces during the period of the COVID-19 vaccination operation (12/28/2021–3/7/2021) for diagnosed myocarditis. We identified 7 cases of myocarditis with symptoms starting in the first week after the second dose of COVID-19 Pfizer-BioNTech vaccine. One case of myocarditis diagnosed 10 days after the second dose of the vaccine was not included. These 8 cases comprise of all events of myocarditis diagnosed in military personnel during this time period. All patients were young and generally healthy. All had mild disease with no sequalae. The incidence of myocarditis in the week following a second dose of the vaccine was 5.07/100,000 people vaccinated. Due to the nature of this report no causality could be established. Clinicians should be aware of the possibility of myocarditis following Pfizer-BioNTech vaccination. True incidence rates should be further investigated. [ABSTRACT FROM AUTHOR]

• Military medical records were searched electronically for myopericarditis. • The rate of myopericarditis after ACAM2000 smallpox vaccine was 20.06/100,000. • Myopericarditis rates were 21.1/100,000 for those < 40 years vs 6.3/100,000 for 40 +. • Myopericarditis rates were 21.8/100,000 for males vs 8.5/100,000 for females. To evaluate the rates of myopericarditis (primary objective) and rates of cardiovascular and neurological adverse events (secondary objectives) in temporal association with ACAM2000® smallpox vaccine. Observational cohort study conducted through monthly surveillance from 2009 to 2017 of electronic medical records of military service members (SM) for pre-specified cardiac and neurological International Classification of Diseases (ICD) codes reported in the 30 days following smallpox vaccination. ICD codes potentially predictive of myopericarditis and codes for encephalitis, Guillain-Barré syndrome, and sudden death were classified into Group 1. All other cardiovascular and neurological ICD codes were classified into Group 2. Medical records containing Group 1 codes were individually reviewed to confirm coding accuracy and to seek additional data in support of myopericarditis adjudication, which was performed by an independent clinical panel. Chart reviews were not performed for Group 2 codes, which were reported in aggregate only. 897,227 SM who received ACAM2000 smallpox vaccine and 450,000 SM who received Dryvax smallpox vaccine were included in the surveillance population. The rate of adjudicated myopericarditis among ACAM2000 smallpox vaccine recipients was 20.06/100,000 and was significantly higher for males (21.8/100,000) than females (8.5/100,000) and for those < 40 years of age (21.1/100,000) than for those 40 years or older (6.3/100,000). Overall rates for any cardiovascular event (Group 1 plus Group 2) were 113.5/100,000 for ACAM2000 vaccine and 439.3/100,000 for Dryvax vaccine; rate ratio, 0.26 (95% CI, 0.24–0.28). The rates of subjects with one or more defined neurological events were 2.12/100,000 and 1.11/100,000 for ACAM2000 and Dryvax vaccines respectively; rate ratio, 1.91 (95% CI, 0.71–5.10). Electronic records surveillance of the entire vaccinated SM population over a ten-year period found rates of myopericarditis, of defined neurological events, and of overall cardiac events that were consistent with those of prior passive surveillance studies involving Dryvax or ACAM2000 smallpox vaccines. Clinical trials registration: ClinicalTrials.gov NCT00927719. [ABSTRACT FROM AUTHOR]

Clinical trials of the BNT162b2 vaccine, revealed efficacy and safety. We report six cases of myocarditis, which occurred shortly after BNT162b2 vaccination. Patients 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. Five 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. Our 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. [ABSTRACT FROM AUTHOR]

• Smallpox vaccine is provided by CDC and DOD for use in specified circumstances. • The risk of myopericarditis following smallpox vaccine is not well defined. • The odds of myopericarditis after smallpox vaccine was 1.3 (not significant) • Careful screening to exclude those at risk appeared to be a successful strategy. To compare rates of myopericarditis, severe and serious dermatological or neurological events, and other adverse events in deploying US military personnel who received or did not receive ACAM2000® (Smallpox [Vaccinia] Vaccine, Live) vaccine and to evaluate potential risk factors for development of myopericarditis. Prospective observational cohort study enrolling up to 15,000 ACAM2000 recipients (Cohort 1) and up to 5000 persons otherwise eligible for ACAM2000 vaccination but not vaccinated due to recency of vaccination or characteristics of their contacts (Cohort 2). Data and specimens were collected initially and 10 (6–17) days later. Those with clinical or laboratory evidence of possible myopericarditis were referred for further evaluation and adjudication by a blinded independent review committee. The adjusted odds ratio for myopericarditis was determined by a logistic regression model controlling for age, race, gender, and exercise regimen. 14,667 subjects provided initial data and specimens (Cohort 1, 10,825; Cohort 2, 3842); 12,110 (Cohort 1, 8945; Cohort 2, 3165) completed Visit 2 per-protocol. A total of 125 (Cohort 1, 111; Cohort 2, 14) were referred for myopericarditis adjudication, yielding 54 (Cohort 1, 44, Cohort 2, 10) subclinical myopericarditis, 5 suspected myocarditis, 1 confirmed myocarditis, and 1 suspected pericarditis. Unadjusted myopericarditis rates were: Cohort 1, 5.7/1000 (95% CI, 4.3–7.5); Cohort 2, 3.2/1000 (95% CI, 1.7–5.8). Unadjusted and adjusted odds ratios for myopericarditis were 1.8 (95% CI: 0.9–3.6) and 1.3 (95% CI: 0.6–2.6), respectively. One hundred seventeen subjects (1.1%) in Cohort 1 and 13 (0.3%) in Cohort 2 experienced at least 1 serious adverse event. No instances of serious and severe neurological or dermatological adverse events were reported. In this carefully screened, generally young and healthy service-member population, ACAM2000 vaccination was associated with modest non-significant increases in the risk of myopericarditis (adjusted OR, 1.3; unadjusted OR, 1.8); all but seven cases were subclinical. Clinical trials registration: ClinicalTrials.gov NCT00928577. [ABSTRACT FROM AUTHOR]

Reports of myocarditis and pericarditis following smallpox vaccination in adults suggested a need to assess inflammatory cardiac disease risk among adults who receive live viral vaccinations. From 1996 through 2007, among 416,629 vaccinated adults in the Vaccine Safety Datalink, we identified one probable pericarditis case and no cases of myocarditis in the 42 days following a live viral vaccination. Our self-controlled risk interval analysis found that, based on one case identified during the risk interval and 10 cases during the control interval, there is no increased risk of myopericarditis in the 42 days following vaccination (IRR, 0.57; 95% CI, 0.07, 4.51). Our study suggests that the occurrence of myopericarditis following live viral vaccination is rare with an estimated incidence of 0.24 per 100,000 vaccinated, which is not higher than the background rate and is much lower than the incidence rates reported following smallpox vaccination. [ABSTRACT FROM AUTHOR]

An Adverse Event Following Immunization (AEFI) is an adverse reaction to a vaccination that goes above and beyond the usual side effects associated with vaccinations. One serious AEFI related to the smallpox vaccine is myopericarditis. Metabolomics involves the study of the low molecular weight metabolite profile of cells, tissues, and biological fluids, and provides a functional readout of the phenotype. Metabolomics may help identify a particular metabolic signature in serum of subjects who are predisposed to developing AEFIs. The goal of this study was to identify metabolic markers that may predict the development of adverse events following smallpox vaccination. Serum samples were collected from military personnel prior to and following receipt of smallpox vaccine. The study population included five subjects who were clinically diagnosed with myopericarditis, 30 subjects with asymptomatic elevation of troponins, and 31 subjects with systemic symptoms following immunization, and 34 subjects with no AEFI, serving as controls. Two-hundred pre- and post-smallpox vaccination sera were analyzed by untargeted metabolomics using 1 H nuclear magnetic resonance (NMR) spectroscopy. Baseline (pre-) and post-vaccination samples from individuals who experienced clinically verified myocarditis or asymptomatic elevation of troponins were more metabolically distinguishable pre- and post-vaccination compared to individuals who only experienced systemic symptoms, or controls. Metabolomics profiles pre- and post-receipt of vaccine differed substantially when an AEFI resulted. This study is the first to describe pre- and post-vaccination metabolic profiles of subjects who developed an adverse event following immunization. The study demonstrates the promise of metabolites for determining mechanisms associated with subjects who develop AEFI and the potential to develop predictive biomarkers. [ABSTRACT FROM AUTHOR]

Background The Vaccine Adverse Event Reporting System (VAERS) is a passive reporting system, used for monitoring the safety of all US licensed vaccines. In March 2008, ACAM2000® replaced Dryvax® as the only licensed smallpox vaccine and is administered to all persons entering military service and certain civilian researchers. In 2011, routine data mining of VAERS identified a vaccine safety concern resulting in acute ischemic cardiac events (ICE) following ACAM2000®. Methods During March 1, 2008 through June 30, 2013, we reviewed all serious reports received following ACAM2000®and classified them by diagnostic category. We identified possible ICE cases by searching the Medical Dictionary for Regulatory Affairs (MedDRA®) terms for "myocardial ischaemia," "acute myocardial infarction," "myocardial infarction," and "ischaemia," and applied standardized surveillance case definitions. Results VAERS received 1149 reports following ACAM2000® administration; 169 (14.7%) were serious (resulting in permanent disability, hospitalization or prolongation of hospitalization, life-threatening illness or death), including one death. The two most frequent diagnostic categories for serious reports were cardiovascular and other infectious conditions. The MedDRA® search found 31 reports of possible ICE after receipt of ACAM2000® vaccine. Of a total 30 possible ICE cases with demographic information, all but one was male; the age range was 20-45 years (median 32) and median interval to onset of symptoms was 12 days. On clinical review there were 16 cases of myocarditis/pericarditis and 15 ICE cases. Conclusions Our review of the data mining signal did not substantiate the concerns about ICE after ACAM2000®. Our study also suggests that with current pre-vaccination screening, cardiac morbidity in generally healthy vaccinated populations remains uncommon. [ABSTRACT FROM AUTHOR]

Efficient delivery of antigen to mucosal associated lymphoid tissue is a first and critical step for successful induction of mucosal immunity by vaccines. Considering its potential transcytotic capability, M cell has become a more and more attractive target for mucosal vaccines. In this research, we designed an M cell-targeting strategy by which mucosal delivery system chitosan (CS) was endowed with M cell-targeting ability via conjugating with a CPE30 peptide, C terminal 30 amino acids of clostridium perfringens enterotoxin (CPE), and then evaluated its immune-enhancing ability in the context of coxsackievirus B3 (CVB3)-specific mucosal vaccine consisting of CS and a plasmid encoding CVB3 predominant antigen VP1. It had shown that similar to CS-pVP1, M cell-targeting CPE30-CS-pVP1 vaccine appeared a uniform spherical shape with about 300nm diameter and +22mV zeta potential, and could efficiently protect DNA from DNase I digestion. Mice were orally immunized with 4 doses of CPE30-CS-pVP1 containing 50μg pVP1 at 2-week intervals and challenged with CVB3 4 weeks after the last immunization. Compared with CS-pVP1 vaccine, CPE30-CS-pVP1 vaccine had no obvious impact on CVB3-specific serum IgG level and splenic T cell immune responses, but significantly increased specific fecal SIgA level and augmented mucosal T cell immune responses. Consequently, much milder myocarditis and lower viral load were witnessed in CPE30-CS-pVP1 immunized group. The enhanced immunogenicity and immunoprotection were associated with the M cell-targeting ability of CPE30-CS-pVP1 which improved its mucosal uptake and transcytosis. Our findings indicated that CPE30-CS-pVP1 may represent a novel prophylactic vaccine against CVB3-induced myocarditis, and this M cell-targeting strategy indeed could be applied as a promising and universal platform for mucosal vaccine development. [ABSTRACT FROM AUTHOR]

Highlights: [•] Immunization with VSV-based vaccine is able to generate strong mucosal immunity. [•] VSV-based vaccine can induce significant higher polyfunctional T cells. [•] VSV-based vaccine significantly alleviates CVB3-induced viral myocarditis. [Copyright &y& Elsevier]

Highlights: [•] Dendritic cell-based vaccination strategy to protect from autoimmune diseases. [•] Flt3L induces maturation of CD8α+ DC. [•] CD8α+ DC vaccination promotes protective CD4+ Th1 cells. [•] Protection conferred by CD8α+ DC vaccination is IFN-γ dependent. [ABSTRACT FROM AUTHOR]

Abstract: Coxsackievirus B3 (CVB3), along with other enteroviruses, is involved in about 50% of myocarditis cases and in the pathogenesis of dilated cardiomyopathy. Prevention of CVB3 infection is therefore highly desirable. Virus-like particles (VLPs) are structurally similar to native virus particles and therefore are far better immunogens than any other subunit vaccines. Recombinant baculoviruses carrying either the intact, entire coding region of CVB3 or the four individual coding regions for virus proteins 1–4 (VP1–4) were constructed. Expression of CVB3 capsid proteins in insect cells infected with recombinant baculovirus was detected by immunofluorescence and Western blot analysis. Sucrose gradient ultracentrifugation fractions of the infected cell lysates contained peaks of CVB3 antigen with an approximate density of 1.14g/ml. Electron microscopy demonstrated the presence of VLP in these sucrose fractions. The CVB3 VLP was non-infectious in tissue culture. SWR (H-2q) mice vaccinated with CVB3 VLP developed antibodies to CVB3 capsid proteins after the first boost. Antibody titre was comparable to the level induced by an attenuated CVB3 vaccine. Vaccinated animals were protected from myocarditis when subsequently challenged with cardiovirulent CVB3 (chimera-2). Vaccination with VLP produced from the complete CVB3 coding region gave a greater immune response and afforded better protection than with VLP from the quadruple expression vector. These results demonstrate that CVB3 capsid proteins expressed in insect cells have the intrinsic capacity to assemble into non-infectious VLP, which afforded protection from CVB3 infection to mice when used as a vaccine. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: This study explores adverse events severe enough to warrant hospitalization that may have been associated with receiving the smallpox vaccine in conjunction with military service. Cox proportional hazards modeling was used to identify the risk of hospitalization among US active-duty military personnel during a 1-year period following receipt of the smallpox vaccine. The reference group consisted of active-duty military personnel who also received the smallpox vaccine after the conclusion of their health care observation period, allowing for comparison to a temporally and demographically similar population. The risk of hospitalization was slightly elevated among the postvaccine group for any-cause hospitalization and for hospitalization in several broad diagnostic categories. Hospitalizations for asthma, autoimmune diseases, and myopericarditis, were more likely in the postvaccine group. The increased risk of hospitalization for varied outcomes does not necessarily imply a cause–effect relationship, but it does offer areas for more focused study, using longitudinal data to explore the long-term impact of smallpox vaccination on the health of young adults. [Copyright &y& Elsevier]

Abstract: Coxsackievirus (CVB) 3 induces viral myocarditis and ultimately dilated cardiomyopathy (DCM). However, there is no vaccine in clinical use. We constructed recombinant CVB3 plasmids using a highly effective mammalian expression vector and evaluated their immunogenicity in vivo on the basis of survival rate. Four recombinant plasmids were constructed, which encode CVB3 capsid proteins (VP1 or VP3) or VP1 partial proteins (VP1-1 or VP1-2), and used to immunize BALB/c mice by electroporation. Although VP1, VP3, VP1-1, and VP1-2 induced specific antibodies against the corresponding proteins in mice, neutralizing antibodies were not present in the sera. These recombinant plasmids, except VP1-1 (12.5%), dramatically increased the survival rate in mice at 46 days after challenge (42.9–75.0%, p<0.05). VP3 (75.0%) protected mice against viral infection and the middle regions of VP1 (VP1-2, 50.5%) conferred a protective effect like that conferred by VP1 (42.9%), suggesting that the epitopes in VP3 as well as in the middle of VP1 protect against CVB3 infection in vivo. In conclusion, some recombinant CVB3 plasmids used in this study reduced the destruction of myocytes and improved the survival rates in mice immunized and challenged compared with the control. Thus, pCA-VP3 as well as pCA-VP1 are good candidates for a CVB3 DNA vaccine. [Copyright &y& Elsevier]

Purpose To identify algorithms that can capture incident cases of myocarditis and pericarditis in administrative and claims databases; these algorithms can eventually be used to identify cardiac inflammatory adverse events following vaccine administration. Methods We searched MEDLINE from 1991 to September 2012 using controlled vocabulary and key terms related to myocarditis. We also searched the reference lists of included studies. Two investigators independently assessed the full text of studies against pre-determined inclusion criteria. Two reviewers independently extracted data regarding participant and algorithm characteristics as well as study conduct. Results Nine publications (including one study reported in two publications) met criteria for inclusion. Two studies performed medical record review in order to confirm that these coding algorithms actually captured patients with the disease of interest. One of these studies identified five potential cases, none of which were confirmed as acute myocarditis upon review. The other study, which employed a search algorithm based on diagnostic surveillance (using ICD-9 codes 420.90, 420.99, 422.90, 422.91 and 429.0) and sentinel reporting, identified 59 clinically confirmed cases of myopericarditis among 492,671 United States military service personnel who received smallpox vaccine between 2002 and 2003. Neither study provided algorithm validation statistics (positive predictive value, sensitivity, or specificity). Conclusions A validated search algorithm is currently unavailable for identifying incident cases of pericarditis or myocarditis. Several authors have published unvalidated ICD-9-based search algorithms that appear to capture myocarditis events occurring in the context of other underlying cardiac or autoimmune conditions. [ABSTRACT FROM AUTHOR]