Large 4.1m FDA Study Confirms small but significant Myocarditis/Pericarditis and Seizure Safety Signals in Young People

The results depend heavily on diagnostic accuracy, which can certainly not be assumed

Researchers from the Food and Drug Administration (FDA) as well as major pharmacy retail chains, payers and data-based companies investigated whether statistical signals detected health outcomes post-vaccination with ancestral COVID-19 vaccine in children aged 6 months to 17 years. Part of an active safety monitoring program involving COVID-19 vaccination, a bid to detect rare outcomes not identified in clinical trials involved researchers from the FDA, CVS Health/Aetna Blue Bell, Optum Epidemiology (part of UnitedHealthcare), IQVIA, Acumen LLC and Carelon Research led by Patricia C. Lloyd, Ph.D., ScM of the FDA.

An FDA-sponsored clinical trial with results published in the journal JAMA Network, the cohort study evaluated 21 prespecified health outcomes post-exposure before early 2023 to Pfizer (BNT162b2), Moderna (mRNA-1273), or Novavax (NVX-CoV2373) ancestral monovalent COVID-19 vaccines in children aged 6 months to 17 years by applying a near-real-time monitoring framework using healthcare data from three commercial claims databases in the US (Optum [through April 2023], Carelon Research [through March 2023], and CVS Health [through February 2023]).

Lloyd and colleagues analyzed and reported on increased rates of each outcome after vaccinations were compared with annual historical rates from January 1 to December 31, 2019, and January 1 to December 31, 2020, as well as between April 1 and December 31, 2020. The study involved 4,102,016 vaccinated enrollees aged 6 months to 17 years. 2,058,142 (50.2%) of the total were male, and 3,901,370 (95.1%) lived in an urban area.

Thirteen of 15 sequentially tested outcomes failed to meet the threshold for a statistical signal. However, as was reported on with the group’s preprint, statistical signals were detected for myocarditis or pericarditis after BNT162b2 vaccination in children aged 12 to 17 years plus seizure after vaccination with BNT162b2 and mRNA-1273 in children aged 2 to 4 or 5 years.

Conducting a post hoc sensitivity analysis, the study team reported that the statistical signal for seizure was observed only after exposure to the Moderna vaccine (mRNA-1273) when 2019 background rates were selected; no statistical signal was observed when 2022 rates were selected.

Real-Word Data

This study team tapped into what is known as a form of real-world data, from commercial administrative health claims including Optum (UnitedHealth and affiliated health plans), Carelon Research (Elevance Health, formerly Anthem, and affiliated health plans), and CVS Health (Aetna and affiliated health plans).

These databases contain longitudinal medical and pharmacy claims data supplemented with vaccination data from participating local and state Immunization Information Systems. Such sources are nationally representative of the commercially insured population aged 0 to 64 years and provide comprehensive capture of medical services submitted for insurance reimbursement.

Other factors make this a robust study. Broad geographical coverage across 3 commercial health insurance databases with vast representation across America. The commercial data (claims) were supplemented with immunization information systems data plus medical records reviews.

Findings

An FDA statistician since 2021, corresponding author Patricia C. Lloyd, and colleagues report on the study involving 4,102,016 vaccinated individuals aged 6 months to 17 years, with 3,920,563 (95.6%) receiving BNT162b2 vaccination, 174,427 (4.3%) receiving mRNA-1273, and 53 (<0.1%) receiving NVX-CoV2373.

As depicted above, a total of 8,444,?355 ancestral monovalent COVID-19 vaccine doses were administered to young people, including 8,121,591 BNT162b2 doses (dose 1: 3,843,778; dose 2: 3,235,442, dose 3 or monovalent booster: 1,033,036, and unknown or unclear: 9335), 322,628 mRNA-1273 doses (dose 1: 173,857; dose 2: 140,734; dose 3 or monovalent booster: 5284; and unknown or unclear: 2753) administered to children aged 6 months to 17 years, as well as 136 NVX-CoV2373 doses (dose 1: 63; dose 2: 43; dose 3 or monovalent booster and unknown or unclear: 30) administered to children aged 12 to 17 years.

Sequential Testing

Of the established 15 outcomes that the study team sequentially tested, two (2) outcomes met the statistical threshold for a signal, including myocarditis or pericarditis in children aged 12 to 15 years and 16 to 17 years, and seizure in children aged 2 to 4 or 5 years.

The study team found statistical signals for myocarditis or pericarditis during the primary analysis after Pfizer-BioNTech (BNT162b2) COVID-19 vaccination among children aged 12 to 15 years and 16 to 17 years in all three commercial databases.

The authors report dose-specific statistical signals for 1 or more definitions of the outcomes detected in children aged 12 to 17 years after dose 1, dose 2, and dose 3 of BNT162b2 vaccine in at least 1 of the 3 databases. See eTable 8 in Supplement 1.

According to Lloyd and colleagues:

“In the primary analysis, seizure met the statistical threshold for a signal in children aged 2 to 4 years after BNT162b2 vaccination in all 3 databases and in children aged 2 to 5 years after mRNA-1273 vaccination in 2 of the 3 databases. Dose-specific statistical signals for seizure were detected in 2 of the 3 databases after dose 1 and dose 2 BNT162b2 vaccination in children aged 2 to 4 years and after dose 2 of mRNA-1273 vaccination in children aged 2 to 5 years.” Again, see eTable 8.

Signal Characterization

The authors report 72 observed seizure cases among children aged 2 to 4 or 5 years; 51 (70.8%) of these cases met the definition of febrile seizures. Lloyd and the team found no differences in rates of seizure by sex. Based on the timing of cases, the team reports no indication of substantial clustering with cases distributed across the 0- to 7-day risk window; 23 (31.9%) of the seizure cases occurred within the 0- to 1-day period after COVID-19 vaccination. The median (IQR) time between vaccination and diagnosis of seizure was 2 (1-5) days.

Selection of comparator rates impacted statistical signals for seizure. For instance, when evaluating annual background rates of seizure demonstrates rates used in the primary analyses (2020) were lower than rates in 2022 and 2019.

“Background rates in 2022 and 2019 ranged from approximately 2.2 to 2.4 times and 1.7 to 1.9 times the 2020 rates, respectively, across 3 databases.”

As mentioned at the onset, “the post hoc sensitivity analysis, using 2022 background rates as the comparator in sequential testing, did not identify any statistical signals for seizure in any databases. Using 2019 background rates as the comparator resulted in a statistical signal for seizure after primary series vaccination with mRNA-1273 in 2 of the 3 databases and after dose 2 vaccination with mRNA-1273 in 1 of the 3 databases.”

Is the incidence of myocarditis considered rare?

Yes. The authors report a rate of reported mean incidence of 39.3 cases per 1 million vaccine doses administered in children aged 5 to 17 years within 7 days after BNT162b2 vaccination according to two CDC separate studies. However, TrialSite notes that some studies suggest the rates are higher.

What about the rate of myocarditis and pericarditis outcome measured in the inpatient and emergency department settings?

In the 1 to 7 days window post the COVID-19 jab, the team reports an observed rate of 27.0 inpatient or emergency department cases per million doses in days 1 to 7 after the primary series in children aged 12 to 15 years and 38.2 cases per million doses after the primary series in children aged 16 to 17 years. There was a lack of any myocarditis/pericarditis signal in children aged 12 and under.

A new seizure signal was reported.

Lloyd and co-authors report that such a seizure signal in children aged 2 to 4 or 5 years has not been previously reported for this age group in active surveillance studies of mRNA COVID-19 vaccines.

The authors point to reports in the Vaccine Adverse Events Reporting System (VAERS), which is a “passive reporting system” with “limitations,” hence the data there was all but ignored. TrialSite suggests there very well may be more signals buried in VAERS, but this must be proven in rigorous study.

But the authors point to only 8 identified seizures in VAERS after approximately 1 million mRNA vaccinations through August 2022, in children aged 6 months to 5 years. They note that out of all those, 8 of the seizures were afebrile.

Do the FDA-sponsored authors suggest interpreting the seizure data with caution?

Yes. They call for more robust epidemiologic study. We at TrialSite concur. How can the CDC relentlessly push for young people to continuously get the latest booster with such data available? Especially so, given the risk-benefit analyses continuously change given pre-existing infection, milder Omicron variants, etc.

Study Limitations

Like all such observational studies, the limitations must be understood. TrialSite bulletizes for summary.

Near-real-time surveillance method, which may be sensitive to comparator rate selection and does not include controlling for bias and confounding

The study only includes data from a commercially insured pediatric population and may not be nationally representative—meaning the generalizability could be quested despite the broad coverage

Here, small counts of NVX-CoV2373 prevented evaluation of most demographic factors due to privacy concerns

The authors report that they could not conduct medical record review for all outcomes included in the study due to resource, time, and legal constraints. For the myocarditis or pericarditis outcome, they reviewed medical records of a subset of identified cases of myocarditis or pericarditis that were obtained from the medical professionals.

2020 background rates as the historical comparator for the seizure analysis because this period was marked by behavioral shifts during the early pandemic that may have caused a sustained decrease in the underlying outcome rates. Hence the study team compared both prepandemic and peripandemic periods across data partners when selecting historical rates and generally selected the lower rate as the historical comparator.

For the Novavax vaccine, only 53 children aged 12 to 17 years who received at least 1 dose of NVX-CoV2373 and 4266 children aged 5 to 17 years who received at least 1 dose of mRNA-1273.

https://www.trialsitenews.com/a/large-4.1m-fda-study-confirms-myocarditispericarditis-and-seizure-safety-signals-in-young-peopleshould-boosters-continue-41e92005

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http://edwatch.blogspot.com (EDUCATION WATCH)

http://antigreen.blogspot.com (GREENIE WATCH)

http://pcwatch.blogspot.com (POLITICAL CORRECTNESS WATCH)

http://australian-politics.blogspot.com (AUSTRALIAN POLITICS)

http://snorphty.blogspot.com (TONGUE-TIED)

https://immigwatch.blogspot.com (IMMIGRATION WATCH)

https://awesternheart.blogspot.com (THE PSYCHOLOGIST)

http://jonjayray.com/blogall.html More blogs

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