1. Insights from Israel (Pfizer’s mRNA vaccine)

A population-based observational study featured in the New England Journal of Medicine on August 25, 2021, titled “Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting,” utilized the Clalit Health Services database, which includes medical records for over half of Israel's population (more than 4.7 million individuals).

Researchers matched 884,828 vaccinated individuals (who received Pfizer's mRNA vaccine) with 884,828 unvaccinated controls. The two groups were nearly identical regarding age, gender, residence, socioeconomic status, and pre-existing chronic conditions.

This meticulous matching aimed to ensure that any differences noted between the groups were likely attributable to the vaccine. The study examined 25 adverse events reported to systems like the Vaccine Adverse Event Reporting System (VAERS), which may arise within 21 days following either the first or second vaccine dose.

The 25 adverse events analyzed include:

1. Acute kidney injury
2. Anemia
3. Appendicitis
4. Arrhythmia
5. Arthritis
6. Bell’s palsy
7. Stroke
8. Deep vein thrombosis
9. Herpes simplex infection
10. Herpes zoster infection
11. Intracranial hemorrhage
12. Enlarged lymph nodes
13. Lymphopenia
14. Myocardial infarction
15. Myocarditis
16. Neutropenia
17. Other thromboses
18. Paresthesia
19. Pericarditis
20. Pulmonary embolism
21. Seizures
22. Syncope
23. Thrombocytopenia
24. Uveitis
25. Vertigo

Notably, this study did not consider common side effects such as fever or injection site pain as vaccine-related adverse events.

The researchers analyzed their findings using risk ratios (RR) and risk differences (RD). While RR provides a relative measure, RD offers an absolute perspective, making it a more reliable metric for evaluating rare events.

The results indicated that the vaccinated group faced increased risks compared to the unvaccinated group for several conditions, including:

• Myocarditis: RR = 3.24, RD = 2.7 excess cases per 100,000 individuals, predominantly among males aged 20-34.
• Lymphadenopathy: RR = 2.43, RD = 78.4 excess cases per 100,000 individuals.
• Appendicitis: RR = 1.4, RD = 5 excess cases per 100,000 individuals.
• Herpes zoster infection: RR = 1.43, RD = 15.8 excess cases per 100,000 individuals.

Interestingly, the vaccinated group exhibited decreased risks for anemia, acute kidney injury, intracranial hemorrhage, and lymphopenia in comparison to the unvaccinated group.

The reasons behind the mRNA vaccine's protective effect against certain adverse events remain unclear, but they may be linked to general immune responses rather than the vaccine itself. Conversely, the vaccine's potential contribution to the four adverse events mentioned is also under investigation.

For the remaining 17 adverse events, no significant differences were found between the vaccinated and unvaccinated groups, suggesting these occurrences may have happened regardless of vaccination status.

The authors summarized their findings in the following table:

Additionally, this study made a comparable analysis involving 173,106 individuals infected with SARS-CoV-2 and 173,106 uninfected individuals, discovering increased risks of various adverse events among those infected.

2. Findings from the U.S. (Pfizer’s and Moderna’s mRNA vaccines)

A paper published in the Journal of American Medical Association (JAMA) on September 3, 2021, titled “Surveillance for Adverse Events After COVID-19 mRNA Vaccination,” presented a similar population-based observational study conducted in the U.S.

Utilizing the Vaccine Safety Datalink (VSD), which contains health data for approximately 12.5 million Americans, the researchers matched vaccinated individuals (within 21 days of receiving a dose of Pfizer’s or Moderna’s vaccine) with unvaccinated and vaccinated individuals who received their vaccine 22-42 days prior.

The study aimed to identify 23 potential adverse events linked to mRNA vaccination, including:

1. Acute disseminated encephalomyelitis
2. Anaphylaxis
3. Encephalitis/myelitis
4. Guillain-Barré syndrome
5. Immune thrombocytopenia
6. Kawasaki disease
7. Narcolepsy
8. Seizures
9. Transverse myelitis
10. Appendicitis
11. Bell’s palsy
12. Myocardial infarction
13. Acute respiratory distress syndrome
14. Disseminated intravascular coagulation
15. Multisystem inflammatory syndrome
16. Myocarditis/pericarditis
17. Pulmonary embolism
18. Hemorrhagic and ischemic stroke
19. Thrombotic thrombocytopenic purpura
20. Venous thromboembolism
21. Cerebral venous sinus thrombosis
22. Thrombosis with thrombocytopenia syndrome
23. Younger subgroup of myocarditis/pericarditis

Among the 23 events studied, only two were statistically significant. Anaphylaxis showed an excess of about 5 cases per million doses, primarily occurring within 30 minutes post-vaccination, with most cases affecting females with a history of allergies.

The younger subgroup of myocarditis/pericarditis demonstrated a 9.8-fold increased risk for individuals aged 12-39 within the first 21 days after vaccination, translating to an excess of 6.3 cases per million doses.

The majority of affected individuals were male, with most experiencing symptoms within a week of vaccination, and while many were hospitalized, none resulted in fatalities.

The reasons why younger individuals, particularly males, are more susceptible to vaccine-related myocarditis or pericarditis remain uncertain. Some experts speculate that a heightened immune response may be a contributing factor, potentially exacerbated by younger individuals’ faster metabolism, leading to increased production of inflammatory spike proteins.

3. Findings from the U.K. (AstraZeneca’s DNA and Pfizer’s mRNA vaccines)

A study published in the British Medical Journal (BMJ) on August 27, 2021, titled “Risk of Thrombocytopenia and Thromboembolism after COVID-19 Vaccination and SARS-CoV-2 Positive Testing: Self-Controlled Case Series Study,” employed a slightly different design from those conducted in Israel and the U.S.

This self-controlled case series design involved the same individuals being studied at different time points—pre- and post-vaccination and pre- and post-infection. This method effectively controlled for many variables that might differ between individuals.

The study investigated the association between vaccination and several disorders related to blood clotting, including:

1. Thrombocytopenia
2. Venous thromboembolism
3. Arterial thromboembolism
4. Cerebral venous sinus thrombosis
5. Ischemic stroke
6. Myocardial infarction
7. Other rare blood clotting diseases

Using data from the National Immunization Management System, which includes records from 29.1 million individuals in England, the study compared incidence rates of the aforementioned conditions following vaccination against pre-vaccination and pre-infection rates.

Findings indicated that individuals vaccinated with either the Pfizer’s mRNA or AstraZeneca’s DNA vaccine faced a slight increase in risk for several conditions, although these relative risks were generally considered low.

The study highlighted that the relative risk of cerebral venous sinus thrombosis (CVST) was around four times higher, but given the rarity of this event, it does not significantly alter the overall risk profile.

Fortunately, the study also calculated the risk difference for certain adverse events, demonstrating that the risk of these events among the SARS-CoV-2 infected group was significantly higher than that among vaccinated individuals.

What these studies reveal

The three observational studies from Israel, the U.S., and the U.K. collectively underscore that while mRNA and DNA vaccines are associated with certain risks, these risks are notably lower than those posed by SARS-CoV-2 infection itself.

Overall, it appears that Pfizer’s mRNA vaccine is likely responsible for a moderate increase in cases of myocarditis, pericarditis, lymphadenopathy, appendicitis, herpes zoster infection, anaphylaxis, and ischemic stroke. However, it is essential to note that observational studies cannot definitively establish causation, a role reserved for randomized controlled trials (RCTs).

The unique challenges in understanding the risks associated with these vaccines stem from the lack of long-term data. The studies conducted thus far have primarily focused on short- to medium-term risks, as they followed individuals for a limited duration post-vaccination.

Despite these limitations, the studies are invaluable due to their controlled design, which allows for a clearer understanding of the safety profile of these vaccines compared to earlier studies lacking control groups.

As we reflect on nearly a year since the commencement of mass vaccinations, a clearer picture of the safety profile of mRNA and DNA vaccines has emerged. Although there are associated risks, they must be carefully weighed against the risk of infection and the benefits of vaccination. Ultimately, for the majority of individuals, the decision to vaccinate remains a prudent choice.

For more insights on heart inflammation related to mRNA vaccines, refer to: Heart Inflammation From mRNA Vaccine: Probable Causes and Precautions.

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