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Published On: August 17th, 2021By Categories: Fundamental Science

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In the earliest days of the COVID-19 pandemic, reports of cardiovascular injury in those infected with SARS-CoV2 emerged as a significant concern. The volume of people with cardiovascular damage presented the very real possibility that after the viral pandemic had subsided, the world may be faced with a second wave of illness and death from people with post-COVID-19 complications. The risk of long-term consequences made the need to develop a successful vaccine even more pressing.

By April of 2021, the global vaccination plan was in action and cases began to fall. Early on Israel was among the world leaders in vaccine up-take (https://ijhpr.biomedcentral.com/articles/10.1186/s13584-021-00440-6). Using the Pfizer-BNT mRNA vaccine, they rapidly moved through their highest risk groups and quickly provided vaccines to lower risk individuals, including adolescents. But as more young people were vaccinated, health officials noticed reports of myocarditis in young people shortly after vaccination.

Was it possible that mRNA vaccines whose benefits included protecting against the heart damage associated with COVID-19 could themselves cause cardiac injury?

What is Myocarditis?

Myocarditis is an inflammation of the heart muscle. In most cases it is caused when a virus or bacteria infects a person, and travels to the heart. The immune system attacks the foreign invader to protect against damage. But in myocarditis either the infectious agent or the immune response (or both) causes damage to the heart muscle. Myocarditis can also be caused by autoimmune diseases like rheumatoid arthritis and some medications (https://www.nhlbi.nih.gov/health-topics/heart-inflammation).

The precise rate of myocarditis is hard to measure as many cases are asymptomatic (https://www.myocarditisfoundation.org/about-myocarditis/). Some estimates suggest a rate of 1 in 5-10,000 people (https://www.ncbi.nlm.nih.gov/books/NBK459259/), but even the higher end of that range might be an underestimate the true risk, given the lack of symptoms in many people. Myocarditis is most common in young, otherwise healthy individuals, with males being twice as likely to develop the condition than females (https://www.myocarditisfoundation.org/about-myocarditis/).

While most cases are resolved without long term consequences, myocarditis is not always benign. By some estimates, up to 40% of cases of a type of heart failure called Dilated Cardiomyopathy are linked to myocarditis (https://rarediseases.org/rare-diseases/myocarditis/).

The Root of the Problem

The Israeli vaccination program started to vaccinate youth 16 years of age and older with the Pfizer-BNT mRNA vaccine in late January, 2021, and by early April there were reports of increased rates of myocarditis in vaccinated people. The Israeli Ministry of Health noted 110 cases of myocarditis in a population of 5 million vaccinated individuals, which is in line with the normal rate myocarditis. However, the rate in males under 30 years of age was unexpectedly high (https://www.ema.europa.eu/en/news/covid-19-vaccines-update-ongoing-evaluation-myocarditis-pericarditis).

More recently, countries like the United States and Canada, which did not include people under 18 years of age until May, also reported cases of myocarditis in the younger cohort associated with the mRNA vaccines. Like Israel, most cases occurred in younger people.

The most comprehensive and publicly accessible data on COVID-19 vaccines and myocarditis come from the United States Centers for Disease Control (CDC) which presented its findings in two online seminars, most recently on June 26 (https://www.idsociety.org/multimedia/clinician-calls/cdcidsa-covid-19-clinician-call-myocarditis-after-covid-19-mrna-vaccine-plus-vaccine-qa/). According to the Vaccine Adverse Events Reporting System (VAERS) – an open system in the United States that is used to track adverse events following any type of vaccination – the United States administered 300 million doses of mRNA vaccines and received 1,226 reports of myocarditis following vaccination. These numbers were in line with what would be expected in the general population and are not cause for concern. However, in that same dataset, a disproportionate number of cases occurred in young males, specifically after the second dose of an mRNA vaccine. These numbers range from ~1 in 15,000 males between 12-17 years of age to ~1 in 50,000 males aged 25-29 years old. In the relatively short period of time mRNA vaccines had been administered to young people, coupled with the close association with the timing of vaccines, these numbers are concerning.

A Balanced Argument

Any medical treatment comes with risk. The decision to take a treatment or not is made after weighing the risks of the therapy versus the risks associated with the condition and the benefits of treatment. While the overall numbers of young people developing myocarditis after vaccination are a significant risk and a real reason for concern, what does the risk-benefit calculation tell us?

COVID-19: The Original Risk

Young people are generally less likely to develop severe illness from SARS-CoV2 infection or die from COVID-19. Although the risk is lower, it is not insignificant. In the United States, approximately 2 million pediatric cases of COVID-19 have been reported, with 12% requiring hospitalization and one-third of hospitalized patients were admitted to the Intensive Care Unit (ICU) (https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2778347). As of July 3, 2021, 477 COVID-19 deaths have been reported in children under 18, and an additional 2,666 in the 18-29 age group (https://covid.cdc.gov/covid-data-tracker/#demographics). Approximately 60% of the deaths in people under 30 are male. Using the raw numbers, the health risks associated with COVID-19 in young people far exceed those associated with vaccination.

Comparing Apples to Apples

The simplest assessment of the risks and benefits of COVID-19 vaccination in young people is to compare the rates of myocarditis following vaccination with those following infection. As of June 20, 2021, approximately 29 million Americans under 30 had been fully vaccinated (https://covid.cdc.gov/covid-data-tracker/#vaccination-demographic), with 518 confirmed reports of myocarditis submitted for review to VAERS (https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/adverse-events.html). This translates to 0.002% of vaccinated people under the age of 30. No deaths from post-vaccination myocarditis have been reported to date.

In a study of NCAA athletes with a previous COVID-19 infection, 2.3% were discovered to have myocarditis related to the infection (https://jamanetwork.com/journals/jamacardiology/fullarticle/2780548). Interestingly, only 0.3% of athletes experienced overt signs of myocarditis, suggesting that many cases of COVID-19 myocarditis are likely to be missed because of the lack of clear symptoms. Additionally, there have been over 4,000 cases of multisystem inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection (https://www.aappublications.org/news/2021/06/23/acip-covid-vaccination-myocarditis-062321). Like myocarditis, MIS-C can cause inflammation of the heart. To date, 36 deaths of post-COVID-19 MIS-C have been reported in the United States. The risk of cardiac inflammation associated with COVID-19 in children is significantly higher than the risk associated with vaccination.

Myocarditis has a wide range of severity, from asymptomatic to fatal. Most cases of post-COVID-19 vaccination myocarditis reported to VAERS involved hospitalization, suggesting a higher degree of severity. But, Dr. Judith Guzman-Cottrill, a Professor of Pediatrics at the Oregon Health and Science University School of Medicine, noted that in a case study of 7 patients she co-authored for the journal Pediatrics, none of the patients were critically ill, even though the study indicated ICU status for all patients (https://www.idsociety.org/multimedia/clinician-calls/cdcidsa-covid-19-clinician-call-myocarditis-after-covid-19-mrna-vaccine-plus-vaccine-qa/). In these cases, the ICU was used because it was the only place that could provide close cardiac monitoring of pediatric cases, and not because the patients were critically ill. Data collected by the United States Vaccine Safety Datalink (VSD) finds that the average hospital stay for post-vaccine myocarditis was 1 day, compared to an average of 6.1 days for non-vaccine related myocarditis. Furthermore, the mortality rate for myocarditis in children is 4-7% (https://www.idsociety.org/multimedia/clinician-calls/cdcidsa-covid-19-clinician-call-myocarditis-after-covid-19-mrna-vaccine-plus-vaccine-qa/) but there are no reports of post-vaccination deaths in children who developed myocarditis.

Myocarditis is not a trivial condition, but the data collected to date indicate that the short-term outcomes in cases following COVID-19 vaccination are positive and that most cases are mild.

In the Long Run

While the vast majority of post-vaccine myocarditis cases have fully resolved and there does not appear to be any lingering effects, myocarditis is still a serious issue. Because the heart has a limited ability to repair itself, some minor injuries can expand over time and develop into more serious issues, including heart failure. The clinical evaluations of patients who developed myocarditis post-COVID-19 vaccination suggest that risk of long-term effects is small, but the full picture will not be known for some time.

On the other hand, lingering health issues following COVID-19 is a known risk, including for younger individuals. A study of 312 people diagnosed with COVID-19 between February 28 and April 4, 2020 found that 61% of patients reported persistent symptoms 6 months later (https://www.nature.com/articles/s41591-021-01433-3). Although only 13% of people under 15 years of age reported lingering health issues, 52% of people between 16 and 30 years old had symptoms 6 months post-diagnosis. Interestingly, the persistent effects of COVID-19 did not depend on severity of illness, nor did co-morbidities correlate with long-term effects. Just as the long-term effects of myocarditis following vaccination should be considered, so too should the impact of COVID-19 on the long-term health of people.

Limiting the Reach of SARS-CoV2

The Pfizer-BNT vaccine is 96% effective at preventing COVID-19 in people 16 years of age and older (https://www.nejm.org/doi/full/10.1056/nejmoa2034577). A study involving 2,260 adolescents 12 to 15 years old found vaccination with the Pfizer-BNT mRNA vaccine was 100% effective against symptomatic disease (https://www.nejm.org/doi/full/10.1056/NEJMoa2107456). The astonishingly effective nature of the COVID-19 vaccines underscores the very strong benefits of vaccination in both adolescents and adults.

People who are vaccinated against disease are less likely to develop the condition and individually reap the benefits of vaccination. But the benefits of vaccination are most effective when large segments of the population are vaccinated, as this provides a shared immunity, often called ‘herd immunity’. Vaccines can prevent the spread of infections and protect those who can not or choose not to be vaccinated.

The ability of COVID-19 vaccines to prevent the spread of SARS-CoV2 is not yet determined, but early studies are promising. Those who are vaccinated have lower amounts of the virus in their body when they do become infected (https://www.nature.com/articles/s41591-021-01316-7), which is likely to be linked to a lower ability to transmit SARS-CoV2. Two studies – one a preprint (https://www.medrxiv.org/content/10.1101/2021.03.11.21253275v1) and the other recently published (https://www.nejm.org/doi/full/10.1056/NEJMc2107717) – present findings that show vaccinated people are, in fact, less likely to transmit the virus to others. Together these studies suggest that vaccination of young and other low risk individuals may provide protection for others who are at high risk of severe illness or death, by decreasing the spread of the virus.

One unanswered question concerning the benefits of vaccination is the ability of children and adolescents to transmit SARS-CoV2. If children are not effective spreaders of SARS-CoV2, their vaccination would have less impact in controlling its spread. In a study of household transmission in Israel, researchers estimated that people under 20 years of age had a risk of infection that was 43% of adults, and their ability to infect others was 63% of the adult risk (https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1008559). The study noted that the relatively mild or asymptomatic nature of COVID-19 in children could lead to an underestimation of the numbers, but under-reporting is unlikely to account for the lower rates of infection and transmission in children. An analysis of 32 studies confirmed the idea that children and adolescents are less susceptible to SARS-CoV2 infection compared to adults, but found that the evidence for a lesser role in transmission was “weak” (https://jamanetwork.com/journals/jamapediatrics/fullarticle/2771181). At this point it Is not clear how beneficial COVID-19 vaccination would be on reducing transmission involving young people.

Rise of the Mutants

The continuing rise of new variants – which is facilitated by unvaccinated individuals who act as a reservoir for evolution – creates an ever-changing risk profile. The emergence of the SARS-CoV2 delta variant in the United Kingdom offers some insight into the risks associated with not vaccinating young people.

In a pre-print study led by researchers at Imperial College London in the United Kingdom, it was reported that the delta variant was 2.5-times more likely to be found in people under 50 years of age, and between 2 and 5-times higher in people between 5 and 24 years of age (https://spiral.imperial.ac.uk/bitstream/10044/1/89629/10/react1_r12_preprint_final.pdf). Together, the data show that the more infectious delta variant is using a combination of unvaccinated youth and the easing of social distancing restriction to spread and become the dominant variant in the United Kingdom. In the United States a similar trend is emerging where cases in young people infected with the delta variant are rising, while vaccinated segments of the population continue to show much lower rates of COVID-19 morbidity and mortality (https://www.yalemedicine.org/news/5-things-to-know-delta-variant-covid).

While currently available COVID-19 vaccines have been reported to have reduced effectiveness against the delta variant, mRNA vaccines remain highly effective. A Public Health England study showed that two doses of the Pfizer-BNT mRNA vaccine were 88% effective in reducing symptomatic infection with the delta variant, as compared to 93% against the earlier alpha form of SARS-CoV2 (https://www.medrxiv.org/content/10.1101/2021.05.22.21257658v1). The highly effective nature of approved COVID-19 vaccines against the delta variant offers significant protection for young people who are at increased risk for infection and negative outcomes.

Narrowing the Focus

The decision to vaccinate or not is the end result of weighing all the relevant risk factors against the proven benefits of the vaccine. But not all risks and benefits are equally applicable to all people. These variations may lead to more specific recommendations where higher risks or greater benefits tips the balance for or against vaccination within certain cohorts.

The low risk of severe illness of death for youth who develop COVID-19 is not universal. Like adults, those with pre-existing conditions like asthma and diabetes have much higher risk of critical illness and death. Furthermore, as has been seen since almost the beginning of the pandemic, children of lower income families and those who are part of racialized and ethnic minority communities have higher rates of hospitalization and death. These elevated risks in certain populations of youth favour vaccination, even with the risk of myocarditis.

One option that is under consideration is restricting COVID-19 vaccines to a single dose in people under 18. In Canada, the National Advisory Committee on Immunization has recommended that any person who experiences myocarditis after a first dose of an mRNA vaccine should not seek a second dose until more information is gathered to provide guidance (https://www.canada.ca/content/dam/phac-aspc/documents/services/immunization/national-advisory-committee-on-immunization-naci/recommendations-use-covid-19-vaccines/summary-updates-july-2-2021-en.pdf). If the issue with myocarditis is essentially an overdose of the vaccine, this may be a viable solution to provide some protection while decreasing risk. However, the emergence of the SARS-CoV2 delta variant creates a significant obstacle. While vaccines tested against the delta variant show strong protection, this protection is significantly weakened if only one dose is given. A single dose of the Pfizer-BNT mRNA vaccine offers 33% protection against symptomatic infection, versus 88% with two doses (https://www.medrxiv.org/content/10.1101/2021.05.22.21257658v1.full.pdf). Without a second dose booster, the lower effectiveness of the vaccine could represent a permanently diminished level of protection.

Another option under consideration is increasing the time between doses. The immune response to vaccination is particularly strong in young people and a second dose within weeks of the first could create an over-stimulation of the immune system for some. Myocarditis can be caused by viral infection, but it could also be the result of a hyperactive immune response: this is a possible mechanism to explain the increased risk of myocarditis in some young people. Increasing the time between the first and second dose would increase the risk of infection between doses, but that risk would be limited in time, unlike the option of giving only one dose to young people. In Canada, the Canadian Paediatric Society recommends a window for a second dose ranging from 21 days to 4 months (https://www.cps.ca/en/documents/position/covid-19-vaccine-for-children). Continuing other protective measures like wearing masks and physical distancing until the full compliment of doses is administered would lower the risk of infection. At present there are no studies to support the effectiveness of a vaccine strategy in which the interval is extended in young people, but the sustained immune response seen in adults when the interval is prolonged offers some encouraging data.

What Do the Professionals Say

For many, the ability to access and understand the diversity of research studies and reports on COVID-19 vaccination can be challenging. Add in the influence of social and mainstream media reports and it quickly becomes overwhelming. In cases like this, professional medical and scientific societies can offer valuable guidance about what the research says.

Organizations including the American Academy of Pediatrics, Infectious Disease Society of America(https://www.hhs.gov/about/news/2021/06/23/statement-following-cdc-acip-meeting-nations-leading-doctors-nurses-public-health-leaders-benefits-vaccination.html), and Canadian Paediatric Society (https://www.cps.ca/en/documents/position/covid-19-vaccine-for-children) support the vaccination of children 12 years of age and older against COVID-19. In fact, the American Heart Association, whose mission is to make the “world free of cardiovascular diseases and stroke” (https://www.heart.org/en/about-us), continues to recommend COVID-19 vaccinated for all individuals over 12 years of age. Specifically, these medical and healthcare societies note that the risk for myocarditis is much higher and likely to be more severe with COVID-19 than the vaccine, and that the growing risk from the delta variant is of particular concern for young people (https://newsroom.heart.org/news/statement-following-cdc-acip-meeting-from-nations-leading-doctors-nurses-and-public-health-leaders-on-benefits-of-vaccination).

The Final Word

Details about the mechanisms by which COVID-19 vaccines might cause myocarditis in young people, along with the clinical considerations that should be included in making a determination about vaccination, are topics that scientists and healthcare professionals will debate, discuss, and consider for some time. What is important for most people is what the research means for themselves or their children. So, what are the take-home messages from what we know and don’t know about myocarditis and COVID-19 vaccines?

Is there a link? Data from Israel and the United States seem to show that some people – primarily males under 30 years old – have an increased risk of developing myocarditis after a COVID-19 vaccination. This risk is associated with mRNA vaccines and occurs most commonly after the second dose.

What is the risk? The risk for developing myocarditis after a COVID-19 vaccination is not increased for most people, but in young males the risk is several times higher than normal. Although the risk of post-vaccination myocarditis is increased in this group, the absolute risk of developing myocarditis is still very low. In fact, the risk of developing myocarditis following COVID-19 is much higher than the post-vaccination risk.

What should I do? All the risks discussed in this article and in research studies apply to large groups of people. This information is suitable for making recommendations and creating guidelines that can be broadly applied, but some individuals may have conditions or circumstances that necessitate choices that are different from what is generally recommended. Most medical professionals agree that children and adolescents at high risk for developing severe COVID-19 would strongly benefit from vaccination, and that the risk of myocarditis is much lower and less severe than those associated with COVID-19. For children who are at low risk of contracting COVID-19 and developing complications, the decision is more complicated. Consulting with healthcare professionals would allow for a careful weighing of all the factors that are specific to each person, and permits an informed decision that is based on the best available data.

About the Author: Glen Pyle

Glen Pyle, PhD is a Professor of Molecular Cardiology at the University of Guelph and an Associate Member of the IMPART Team Canada Investigator Network at Dalhousie Medicine.