Review Reports - Comparison of COVID-19 Vaccine-Associated Myocarditis and Viral Myocarditis Pathology

Round 1

Reviewer 1 Report

In the manuscript of " Comparison of COVID Vaccine-Associated Myocarditis and Viral Myocarditis Pathology" authors showed the risk of myocarditis and decreased cardiac function later in life is important to consider in both CHD patients and the public, the risk of myocarditis and other serious sequelae from COVID infection far outweigh the risk of myocarditis from vaccine-associated myocarditis. This review provide useful insight into the risk of COVID vaccine, the following points may improve the quality of this review:1.Line 150 , 507 and 542 the author mentioned table15 , 1 and 5, but I didn't find it, please check it.

2.Line 162, figure 1 covers this line, please check.

3.Line 171 and l72, for ORF7 and ORF3a, both abbreviated and full names were mentioned earlier, so please use ORF7 and ORF3a to describe them directly,please check the full text.

4.Line 333,why is the first sentence bold, please change.

5.Please clarify whether COVID-19 refers specifically to COVID-19 or all coronaviruses.

Author Response

Dear Dr. Pang, Dr. Liu, and Review 1,

Thank you for giving us the opportunity to submit a revised draft of the manuscript “Comparison of COVID Vaccine-Associated Myocarditis and Viral Myocarditis Pathology” for publication in the journal Vaccines. We appreciate the time and effort that you and the reviewers dedicated to providing feedback on our manuscript and are grateful for the insightful comments on and valuable improvements to our paper.

We have all of the suggestions made by the reviewers. Those changes are marked by track changes within the manuscript. Due to difficulties with incorporating EndNote for new sources used, the edits were made in another document and reconciled with our resubmission paper. Because of this, most major changes in content have been marked by track changes in the paragraph in which they exist. When possible, individual changes have been marked with track changes. Please see below, in blue, for a point-by-point response to the reviewers’ comments and concerns. All page numbers refer to the revised manuscript file with tracked changes.

Reviewers' Comments to the Authors:

Reviewer 1

In the manuscript of ‘Comparison of COVID Vaccine-Associated Myocarditis and Viral Myocarditis Pathology’ authors showed the risk of myocarditis and decreased cardiac function later in life is important to consider in both CHD patients and the public, the risk of myocarditis and other serious sequelae from COVID infection far outweigh the risk of myocarditis from vaccine-associated myocarditis. This review provide useful insight into the risk of COVID vaccine, the following points may improve the quality of this review:

1.Line 150 , 507 and 542 the author mentioned table15 , 1 and 5, but I didn't find it, please check it.

Author response: This was an error caused when moving our text to the MDPI template. These references to tables have been removed as there are no tables in this paper, only figures.

2.Line 162, figure 1 covers this line, please check.

Author response: Thank you for pointing out this error. Figure 1 has been adjusted to ensure it is not blocking text.

3.Line 171 and l72, for ORF7 and ORF3a, both abbreviated and full names were mentioned earlier, so please use ORF7 and ORF3a to describe them directly,please check the full text.

Author response: Thank you for bringing this to our attention. I had redefined these there as they were in the body of a figure description, but I have removed the full names and left only the abbreviations. The rest of the text follows appropriate acronym definition and usage.

4.Line 333,why is the first sentence bold, please change.

Author response: This was an error caused when moving our text to the MDPI template. This has been corrected and is no longer bolded.

5.Please clarify whether COVID-19 refers specifically to COVID-19 or all coronaviruses.

Author response: We mean to refer specifically to COVID-19 and have added clarification that we hope will make this clear to readers at line 137-138.

Reviewer 2 Report

sequelae from COVID infection far outweigh the risk of myocarditis from vaccine-associated myocarditis." Such a sweeping, crucial assertion must be backed up with,at the very least, some type of actual data regarding the incidence of the condition in Covid patients! Furthermore, the authors claim that the case mortality rate of Covid is 1.2 percent (again with no evidence cited), which is rather vastly higher than most credible, recent estimates.

Author Response

Dear Dr. Pang, Dr. Liu, and Reviewer 2

Reviewers' Comments to the Authors:

Reviewer 2

The paper is well written and contains a wealth of physiological and other biomedical information. However, the entire premise/conclusion is fundamentally flawed, as there is - unbelievably- virtually no EPIDEMIOLOGICAL data presented, particularly regarding the central conclusion, in the very last sentence, that the"risk of myocarditis and other sequelae from COVID infection far outweigh the risk of myocarditis from vaccine-associated myocarditis." Such a sweeping, crucial assertion must be backed up with,at the very least, some type of actual data regarding the incidence of the condition in Covid patients! Furthermore, the authors claim that the case mortality rate of Covid is 1.2 percent (again with no evidence cited), which is rather vastly higher than most credible, recent estimates.

Lack of epidemiological data presented in the paper, particular concerning if the risk of myocarditis and other sequelae from COVID infection far outweigh the risk of myocarditis from vaccine-associated myocarditis.

Author response: Thank you for this valuable feedback regarding the central argument of our paper. We have added additional sources discussing the incidence and mortality rates of COVID infection-associated myocarditis and contrasting data for COVID vaccine-associated myocarditis in their respective sections. We have also added additional discussion regarding the data available for the effects of both types of myocarditis in congenital heart defect patients. These changes can be found at lines 292-382 and lines 680-726 respectively. We hope these additional discussions make a stronger case for our central argument.

The case mortality rate of Covid is 1.2 percent made without citation.

Author response: Thank you for bringing up this concern. Our original numbers were found on the WHO COVID dashboard, and we attempted to cite that as our source. Due to concern for the accuracy of this information, we have changed our reported information in lines 101-103 to reflect the global infection numbers and mortality rate reported in a report in The Lancet.

Round 2

Reviewer 2 Report

Unfortunately, the revisions do not really address the concerns from my previous review. First of all, the studies cited to back up the assertion of high levels of severe myocarditis in Covid patients are NOT actual EPIDEMIOLOGICAL data, but rather (as described) just small-sample indications from "some studies," clinical case studies of hosptialized or dead Covid patients, etc that do not, however, show HOW COMMON myocarditis is in people infected with Covid. This is a classic example of apples and oranges methods error: comparing the (low) frequency of the problem in persons vaccinated with the much higher prevalence among persons very ill with COvid (as opposed to merely infected). Also, nearly all the cited studies stem particularly from the early phase of the pandemic. The virus has mutated very much since then, hence the authors need to locate relevant data on this regarding the more current (omicron) variants.

Some clinicians and experts have suggested that problems like myocarditis due to Covid infection appear to be much much less common than was the case during the first two years of the pandemic. This is an absolutely crucial point, because while the risk of myocarditis from Covid may now be quite low, presumably the risk of myocarditis from Covid vaccines would remain essentially static.

By the way, this also seemingly conflicts with their conclusion: "This study also showed that the excess events of myocarditis after the second
dose of the mRNA-1273 vaccine were similar but higher than those observed in COVID infections." Please do not, however, simply delete tha

And once again the very inaccurate (and once again unsubstantiated) assertion is made re "The case-mortality rate in the US is estimated at 1.2%" for COvid-19, which is wildly higher than CURRENT estimates, and frankly I find it odd for the authors to have merely moved the location of the assertion to a different part of the paper, and attempting to claim in the authors' response that by adding the more accurate/updated WHO data that thereby they have now addressed the error? Furthermore, those 2 data assertions (case-mortality rate of 1.2% versus the MUCH lower WHO estimate) are contradictory!

Author Response

Dear Dr. Pang, Dr. Liu, and Reviewer 2

Thank you for giving us this second opportunity to revise the manuscript “Comparison of COVID Vaccine-Associated Myocarditis and Viral Myocarditis Pathology” for publication in the journal Vaccines. We are disappointed that our previous revisions were not sufficient and hope that these additional changes will adequately answer your concerns.

We have addressed all the suggestions made by the reviewers. Those changes are marked by track changes within the manuscript. Due to difficulties with incorporating EndNote for the new sources we used, the edits were made in another document and reconciled with our resubmission paper. Because of this, most major changes in content have been marked by track changes in the paragraph in which they exist. When possible, individual changes have been marked with track changes. Below, in blue, we have provided a point-by-point response to the reviewers’ comments and concerns. All page numbers refer to the revised manuscript file with tracked changes.

Reviewers Comments to the Authors:

Reviewer 2

The studies cited to back up the assertion of high levels of severe myocarditis in Covid patients are NOT actual EPIDEMIOLOGICAL data, but rather (as described) just small-sample indications from "some studies," clinical case studies of hospitalized or dead Covid patients, etc. that do not, however, show HOW COMMON myocarditis is in people infected with Covid.

Thank you for this clarification on the requisite data. We have included a meta-analysis that accounts for a significant number of patients including data from 58 million patients across many reviews, case studies, and databases, with 2.5 million patients who were part of the COVID-19 infection cohort. This study presents the relative risk for myocarditis from COVID-19 infection (14.82) and COVID-19 vaccines (3.6 for the Moderna vaccine, 2.7 for the Pfizer vaccine).[1] This discussed in lines 313-319. This was consistent with data presented from a CDC morbidity and mortality report discussed in lines 319-321.[2] Also included were some of the individual reviews from the previously mentioned meta-analysis, which specifically reported how often myocarditis was seen after COVID-19 infection in addition to the CDC morbidity and mortality report. Depending on the study, the risk of post-COVID-19 infection myocarditis was approximately 0.1%, though one study reported frequencies as high as 0.7%.[2-4] These are discussed in lines 327-334.

This is a classic example of apples and oranges methods error: comparing the (low) frequency of the problem in persons vaccinated with the much higher prevalence among persons very ill with COVID (as opposed to merely infected).

The reviewer brings up an excellent point that the comparisons are not adequate. To remedy this, we have included and differentiated the frequency of myocarditis in COVID-19 infection as accurately as possible to reflect the general infected population, particularly in lines 331-334. We continue to include the data from those with severe COVID-19 infection as presented in lines 322-327 and 337 as we believe they make a strong case for the importance of recognizing the effects myocarditis can have in the setting of severe COVID-19. This is also mentioned in lines 342-344.

Also, nearly all the cited studies stem particularly from the early phase of the pandemic. The virus has mutated very much since then, hence the authors need to locate relevant data on this regarding the more current (omicron) variants. Some clinicians and experts have suggested that problems like myocarditis due to Covid infection appear to be much much less common than was the case during the first two years of the pandemic. This is an absolutely crucial point, because while the risk of myocarditis from Covid may now be quite low, presumably the risk of myocarditis from Covid vaccines would remain essentially static.

We agree that using the latest data to reflect the current state of complications from COVID-19 infection is important. We endeavored to find references to this comment that earlier variants of COVID-19 were associated with higher rates of myocarditis. Unfortunately, no direct references could be found. We did find and include a case study of two patients with confirmed omicron COVID-19 infection hospitalized to demonstrate that even if the rate is lower, this complication can still occur in recent COVID-19 variants.[5] This case is discussed in lines 357-364. While we could not find references specific to the rate of myocarditis in omicron, we did cite several studies highlighting the increased transmission but decreased severity of the omicron variant located in lines 354-357.[6,7] We also cited, in lines 364-366, a comment made in a recent paper by Roy et al noting the lack of data concerning myocarditis in the omicron variant and the need for further reporting and study to determine if the decreased severity of omicron in accompanied by a decrease in the rate of myocarditis and other cardiac complications.[8]

By the way, this also seemingly conflicts with their conclusion: "This study also showed that the excess events of myocarditis after the second dose of the mRNA-1273 vaccine were similar but higher than those observed in COVID infections." Please do not, however, simply delete that.

This was not one of the conclusions of our paper. This data was presented as contrast to the other data presented that does support our conclusion that the risk of myocarditis from COVID-19 infection is higher than that from the COVID-19 vaccine.[1,9] This was also included for completeness in discussing different views regarding this subject, particularly in light of the recent vaccine guidance released by the Florida Surgeon General advocating against vaccination of healthy males between the ages of 18-39.[10,11] Regardless of our opinion of his recommendation, this is a concern for many as this data stands out; we feel it is important to include as contrast to the significant data indicating the safety and benefit of the COVID-19 vaccine. Additional wording has been added in lines 395-401 and 413-417 to indicate this data is at odds with the data we have found including the meta-analysis by Voleti et al.[1]

There were two places in the manuscript in which the data was used, only one of which was caught by us during the last round of revisions. We also discovered the miscalculation that resulted in significantly higher than normal results using the data from the WHO and Johns Hopkins COVID-19 dashboards.[12,13] We found a recent citation for WHO covid mortality estimates and have used those in both places where the data needed to be cited in lines 103-105 and 373-374.[14] The authors would like to point out, however, that no moving of assertions ever took place in the paper. The original submission shows where the data was used in error in two locations; the first revision made changes in the first location at lines 103-105 but not the second at lines 373-374 which was an oversight in our revision. However, nothing was ever moved from its original location. These errors in the data have now been corrected in both locations.

Voleti, N.; Reddy, S.P.; Ssentongo, P. Myocarditis in SARS-CoV-2 infection vs. COVID-19 vaccination: A systematic review and meta-analysis. Frontiers in Cardiovascular Medicine 2022, 9, doi:10.3389/fcvm.2022.951314.
Boehmer, T.K.; Kompaniyets, L.; Lavery, A.M.; Hsu, J.; Ko, J.Y.; Yusuf, H.; Romano, S.D.; Gundlapalli, A.V.; Oster, M.E.; Harris, A.M. Association Between COVID-19 and Myocarditis Using Hospital-Based Administrative Data - United States, March 2020-January 2021. MMWR Morb Mortal Wkly Rep 2021, 70, 1228-1232, doi:10.15585/mmwr.mm7035e5.
O’Gallagher, K.; Shek, A.; Bean, D.M.; Bendayan, R.; Papachristidis, A.; Teo, J.T.H.; Dobson, R.J.B.; Shah, A.M.; Zakeri, R. Pre-existing cardiovascular disease rather than cardiovascular risk factors drives mortality in COVID-19. BMC Cardiovascular Disorders 2021, 21, 327, doi:10.1186/s12872-021-02137-9.
Murk, W.; Gierada, M.; Fralick, M.; Weckstein, A.; Klesh, R.; Rassen, J.A. Diagnosis-wide analysis of COVID-19 complications: an exposure-crossover study. Canadian Medical Association Journal 2021, 193, E10-E18, doi:10.1503/cmaj.201686.
Fishman, B.; Goitein, O.; Berkovitch, A.; Rahav, G.; Matetzky, S. First report of myocarditis in two patients with COVID-19 Omicron variant: case report. European Heart Journal - Case Reports 2022, 6, doi:10.1093/ehjcr/ytac407.
Wolter, N.; Jassat, W.; Walaza, S.; Welch, R.; Moultrie, H.; Groome, M.; Amoako, D.G.; Everatt, J.; Bhiman, J.N.; Scheepers, C.; et al. Early assessment of the clinical severity of the SARS-CoV-2 omicron variant in South Africa: a data linkage study. The Lancet 2022, 399, 437-446, doi:https://doi.org/10.1016/S0140-6736(22)00017-4.
Mahase, E. Covid-19: Hospital admission 50-70% less likely with omicron than delta, but transmission a major concern. BMJ 2021, 375, n3151, doi:10.1136/bmj.n3151.
Roy, R.; McDonaugh, B.; O’Gallagher, K. COVID-19 and the heart. British Medical Bulletin 2022, 144, 4-11, doi:10.1093/bmb/ldac022.
Gao, J.; Feng, L.; Li, Y.; Lowe, S.; Guo, Z.; Bentley, R.; Xie, C.; Wu, B.; Xie, P.; Xia, W.; et al. A Systematic Review and Meta-analysis of the Association Between SARS-CoV-2 Vaccination and Myocarditis or Pericarditis. American Journal of Preventive Medicine 2022, doi:https://doi.org/10.1016/j.amepre.2022.09.002.
Lee, B.Y. Florida Surgeon General Warns Against Young Men Getting Covid-19 mRNA Vaccines, What’s His Justification? Available online: https://www.forbes.com/sites/brucelee/2022/10/09/florida-surgeon-general-warns-against-young-men-getting-covid-19-mrna-vaccines-whats-his-justification/?sh=54bc95d64105 (accessed on January 11).
State Surgeon General Dr. Joseph A. Ladapo Issues New Mrna COVID-19 Vaccine Guidance. Available online: https://www.floridahealth.gov/newsroom/2022/10/20220512-guidance-mrna-covid19-vaccine.pr.html (accessed on January 11).
WHO Coronavirus (COVID-19) Dashboard. Available online: (accessed on November 22).
Dong, E.; Du, H.; Gardner, L. COVID-19 Dashboard. Available online: (accessed on January 10).
Msemburi, W.; Karlinsky, A.; Knutson, V.; Aleshin-Guendel, S.; Chatterji, S.; Wakefield, J. The WHO estimates of excess mortality associated with the COVID-19 pandemic. Nature 2023, 613, 130-137, doi:10.1038/s41586-022-05522-2.
Wang, H.; Paulson, K.R.; Pease, S.A.; Watson, S.; Comfort, H.; Zheng, P.; Aravkin, A.Y.; Bisignano, C.; Barber, R.M.; Alam, T.; et al. Estimating excess mortality due to the COVID-19 pandemic: a systematic analysis of COVID-19-related mortality, 2020–21. The Lancet 2022, 399, 1513-1536, doi:10.1016/S0140-6736(21)02796-3.