Heterogeneous Adverse Events Associated with mRNA-Based COVID-19 Vaccines: Comparison
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Serious and severe adverse events following mRNA COVID-19 vaccinations are rare. While a definitive causal relationship was not established in most cases, important adverse events associated with post-vaccination included rare and non-fatal myocarditis and pericarditis in younger vaccine recipients, thrombocytopenia, neurological effects such as seizures and orofacial events, skin reactions, and allergic hypersensitivities.

  • COVID-19 vaccines
  • mRNA vaccines
  • adverse events
  • myocarditis
  • pericarditis
  • thrombocytopenia

1. Introduction

The development of safe and effective vaccines represents a critical public health measure for the control and mitigation of the ongoing novel Coronavirus Disease 2019 (COVID-19), which is caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Three vaccines for COVID-19 prophylaxis were initially made available to the U.S. public under Emergency Use Authorization (EUA) by the U.S. Food and Drug Administration (FDA): two mRNA-based vaccines (the Pfizer-BioNTech BNT162b2 and Moderna mRNA-1273 vaccines) and Johnson & Johnson’s Janssen adenoviral vector-based vaccine. The Pfizer-BioNTech and Moderna vaccines both utilize a lipid nanoparticle-encapsulated mRNA platform that encodes the prefusion stabilized spike (S) protein of SARS-CoV-2 [1,2][1][2]. The surface-exposed S protein is a fusion glycoprotein that mediates host cell recognition and entry by binding to the host cell receptor angiotensin-converting enzyme 2 (ACE2) [3,4][3][4]. Both mRNA-based COVID-19 vaccines are administered intramuscularly as a two-dose primary series, and booster doses are available. On 23 August 2021, the BNT162b2 vaccine, now marketed under the brand name Comirnaty®, received full U.S. FDA approval for individuals aged 16 years and older [5]. The U.S. FDA approved the second mRNA-based COVID-19 vaccine, known as the Moderna vaccine (now Spikevax®), on 31 January 2022, for individuals aged 18 years of age and older [6]. Recently, the U.S. FDA expanded EUA for the primary two-dose regimen of both the Pfizer-BioNTech and Moderna vaccines for use in recipients as young as 6 months of age [5,6][5][6].
Clinical trials and nationwide vaccination campaigns have demonstrated the effectiveness of the Pfizer-BioNTech and Moderna vaccines in preventing or mitigating symptomatic disease among vaccinated adults [1,2,7][1][2][7]. While the public health benefits of vaccination are clear, COVID-19 vaccines have been associated with rare adverse events in susceptible individuals. Since the rollout of the mRNA vaccines in December 2020, a number of common, but mild, side effects have been reported for both the Pfizer-BioNTech and Moderna vaccines, including fatigue, headache, muscle pain at the injection site, and fever [8]. However, more severe adverse events, like myocarditis and pericarditis, have been infrequently documented following COVID-19 vaccination, especially in younger patients. The U.S. FDA announced its intention to delay a decision on authorizing the Moderna vaccine for adolescents (ages 12–17) so that the agency could rcheviewck the risk of developing a rare inflammatory heart condition following Moderna vaccination in the pediatric population [9].

2.1. Myocarditis and Pericarditis

2. Heterogeneous Adverse Events Associated with mRNA-Based COVID-19 Vaccines

2.1. Myocarditis and Pericarditis

Myocarditis refers to the inflammation of the myocardium, and its etiology can be autoimmune, infectious, or idiopathic in nature [11,12][10][11]. Similarly, pericarditis is an inflammatory condition affecting the pericardium, the outer lining surrounding the heart. Acute myocarditis is characterized by an infiltration of immune cells and inflammatory cytokines into the heart, which results in non-ischemic damage to cardiomyocytes [12][11]. The apical proinflammatory cytokine interleukin (IL)-1 plays a pivotal role in myocardial inflammation [13][12]. In particular, IL-1α profoundly influences the immune response that leads to myocarditis as it is released from dying myocardium cells [13][12]. Furthermore, dysregulated autoreactive CD4+ T cells and their cytokines are critical for the autoimmune-related induction of myocarditis in genetically predisposed individuals [14,15,16][13][14][15]. Acute myocarditis can present with nonspecific symptoms such as chest pain or discomfort, dyspnea, dizziness, and arrhythmias. While most cases of myocarditis tend to resolve spontaneously [17][16], inflammation may progress to a chronic stage in susceptible individuals and eventually result in pathological cardiac remodeling, fibrosis, contractile dysfunction, and life-threatening dilated cardiomyopathy [18][17].

Collectively, there are 90 patients who were diagnosed with myocarditis or pericarditis following vaccination with either the BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine. Frequencies and percentages were used to describe the study population characteristics in terms of the following variables: age category, gender, prior health status, vaccine type, number of doses received, and time to presentation after mRNA vaccination. Common cardiac-specific symptoms included chest pressure and pain (substernal, mid-sternal, or retrosternal), intermittent palpitations, and dyspnea. Patients typically showed biomarker evidence of myocardial injury (elevated troponin levels) and cardiac magnetic resonance (CMR) imaging abnormalities consistent with Lake Louise criteria [50][18] for confirming suspected cases of myocarditis. Among the case reports/series reviewed, a higher frequency of post-vaccination myocarditis/pericarditis patients were 20 years of age or younger (n = 43, 47.8%), and 91% (n = 82) were male. The median age was 21 years (range was from 14 to 70 years of age). Time from COVID-19 vaccination to symptom onset was collected for 81 of the total 90 patients. Thirty-six patients, which included 33 males and 3 females, experienced symptoms of acute myocarditis 48 h or earlier from the time of vaccination, whereas 45 patients (42 males and 3 females) manifested symptoms of CMR-confirmed acute myocarditis after 48 h from the time of vaccination. Of note, 75 patients (83%) described in the case reports/series were previously healthy prior to developing myocarditis and had no medical history of cardiac issues. Fifteen patients (16.7%) who developed post-vaccination myocarditis/pericarditis had prior medical conditions that included obesity, hyperlipidemia, obstructive sleep apnea, liver function test (LFT) elevation, asthma, insulin resistance, vitiligo, a prior history of pericarditis, and an episode of atrial fibrillation. A substantially greater proportion of the 90 patients described in the case report/series [22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] developed myocarditis/pericarditis after receiving the second dose (n = 79, 87.8%) of either the Pfizer-BioNTech or Moderna vaccine. 

Mevorach et al. [51][47] rcheviewecked data collected from active surveillance initiated by the Israeli Ministry of Health during a nationwide COVID-19 vaccination campaign implemented from December 2020 to the end of May 2021. The authorscholars of this study found that out of the approximately 5.1 million individuals who received the two-dose regimen of the Pfizer-BioNTech vaccine, 136 cases of definite or probable myocarditis had occurred following receipt of the second dose of the vaccine [51][47]. Consistent witTh our findings in this review, thee susceptible individuals were predominantly male (91%) and under the age of 30 (76%). Myocarditis after the second Pfizer-BioNTech vaccine dose had the highest standardized incidence ratio for male recipients between the ages of 16 and 19 years (13.60 per 100,000 people; 95% CI, 9.30–19.20) [51][47]. These results were comparable to another study in which post-vaccination myocarditis incidence was estimated using the Israeli Clalit Health Services database. 

2.2. Thrombocytopenia

Immune thrombocytopenia (ITP) is defined as a decrease in platelet count, typically below 100 × 109/L (reference range, 150–400 × 109/L) that manifests as variable bleeding symptoms (e.g., petechiae or purpuric skin rashes, gingival bleeding, epistaxis, and easy bruising). The pathophysiology of primary ITP, an acquired immune disorder, is attributed to immune-mediated destruction of platelets, involving antiplatelet antibodies and T cells, and impaired megakaryocytopoiesis [69][48]. Secondary ITP is associated with other underlying disorders, such as autoimmune disease, immune dysregulation, and certain infections, including COVID-19 [69,70][48][49]. The reported annual incidence estimates for acute ITP are approximately 3.3 per 100,000 adults and between 1.9 and 6.4 per 100,000 children [71][50]. Previously, ITP has been reported to the VAERS passive surveillance system as a rare adverse event following such routine vaccinations as measles-mumps-rubella (MMR), Haemophilus influenzae type B, hepatitis B virus (HBV), pneumococcus, human papilloma virus (HPV), varicella-zoster virus, diphtheria-tetanus-acellular pertussis, and polio [72][51]. It is unclear whether a causal relationship exists between these vaccines and the development of ITP. The cause of vaccine-related thrombocytopenia is thought to be immune-related because antibodies are detected on platelets in the majority of cases [73][52].

Cases of new-onset ITP occurring post-immunization with the Pfizer-BioNTech and Moderna mRNA vaccines have been reported, attracting public attention. In one published case report, a 22-year-old, otherwise healthy, male patient developed purpuric lesions (petechiae) and gum bleeding on day three post-vaccination with the Pfizer-BioNTech BNT162b2 vaccine [54][53]. Upon presentation, laboratory tests revealed that the patient was in severe thrombocytopenia with a platelet count of 2 × 109/L. Two months prior to the COVID-19 mRNA vaccination, the patient’s routine lab work indicated a platelet count of 145 × 109/L. The patient tested negative for COVID-19, HIV, hepatitis B and C viruses, and Epstein-Barr virus (EBV). By day six, the patient’s platelet count increased to 28 × 109/L and, due to the exclusion of any alternative etiologies, the patient was diagnosed with immune thrombocytopenia [54][53]. The patient’s platelet count recovered to reference levels by day eleven post-vaccination, and a follow-up assessment indicated that the patient remained healthy without evidence of autoimmune disease.

2.3. Allergic Hypersensitivities

The majority of common adverse reactions attributed to vaccinations are not immunologically mediated and occur as a result of the pharmacology of the vaccine, its excipients, or inactive ingredients in the formulation [74][54]. Non-immunologically mediated reactions typically include toxic effects and medication interactions. By contrast, anaphylactic allergic reactions to vaccinations, although extremely rare, are typically triggered by an IgE-mediated mechanism that involves prior exposure to an allergen in a genetically predisposed individual and the production of allergen-specific IgE antibodies [75,76][55][56]. Immunologically mediated reactions can also include T cells and other immunologic mechanisms. An anaphylactic reaction (or immediate-type hypersensitivity) to a vaccine generally occurs within minutes to an hour or more after allergen exposure and constitutes a multisystem, potentially life-threatening event due to the widespread release of histamine and other vasoactive mediators. In cases of diagnosed anaphylaxis, common presentation symptoms included pruritic hives, throat closure, angioedema, wheezing, nausea and vomiting, tachycardia, hypotension, dyspnea, and tongue swelling. Nonanaphylactic adverse events following mRNA COVID-19 vaccination predominantly manifested as cutaneous reactions and delayed large local reactions such as injection site swelling/pain, erythema, rash, and urticaria. Female gender and a previous history of atopy were the most frequently identified risk factors for anaphylactic and nonanaphylactic reactions to the SARS-CoV-2 mRNA vaccines. Patients with a known history of anaphylaxis, dermatologic comorbidities (such as atopic or contact dermatitis), asthma, or allergic rhinitis were more susceptible to allergies associated with these vaccines [58,59][57][58]. It has been hypothesized that the polyethylene glycol (PEG)-conjugated lipid derivative in the formulation of the SARS-CoV-2 mRNA vaccines may be an antigen for anaphylaxis and nonanaphylactic reactions [78][59]. The female predominance in reported cases of vaccine-associated anaphylactic and nonanaphylactic reactions may be the result of a higher frequency of sensitization to PEG through the use of such PEG-containing products as cosmetics [79][60]. Despite the higher risk to females, Alhumaid et al. [77][61] concluded that the results of their systematic review and meta-analysis shshould not dissuade individuals from receiving the mRNA COVID-19 vaccines. The prevalence of mRNA vaccine-associated anaphylaxis is very low, and although nonanapylactic reactions occur at a higher rate, the cutaneous manifestations are largely self-limiting [77][61].

2.4. CNS and Orofacial Events

CNS and orofacial adverse reactions following mRNA COVID-19 vaccination have been reported in observational cohort studies, case reports, and case series. Documented neurological adverse events include CNS syndromes, cerebrovascular disorders, and peripheral nervous system disorders. Bell’s palsy, a rare idiopathic peripheral facial paralysis, has been reported as an adverse reaction to the novel anti-SARS-CoV-2 mRNA vaccines, as well as cerebral venous thrombosis, and acute transverse myelitis [80][62]. 

The most common post-vaccination CNS syndrome was seizures, with 33 patients (median age of 63 years) experiencing this adverse event [60][63]. Seventeen (51.5%) of these patients were males. Thirty-one patients received the Pfizer-BioNTech vaccine, while two received the Moderna vaccine. Only 17 seizures constituted first-onset seizures, with four being characterized as first-onset unprovoked. The remaining patients reported a pre-existing history of epilepsy. Other CNS syndromes included encephalopathy (n = 4) and demyelinating diseases (n = 4). Acute ischemic stroke (AIS) was the most common cerebrovascular disorder seen in this observational cohort study [60][63]. 

An immunization stress-related response was observed in 39 patients who received the Pfizer-BioNTech vaccine [60][63]. The median age for these patients was 51 years, and 16 were males. Immunization stress-related responses included sensory complaints, dizziness, headaches, focal twitching, unsteadiness, abnormal movement/twitching, and visual blurring. The authorscholars stated that their observational study does not establish a causal relationship between the reported neurological complications and recent mRNA vaccination [60][63]. Furthermore, no neurological morbidity was found. The authorscholars therefore concluded that the benefits of mRNA COVID-19 vaccination exceed any concerns about neurological adverse effects.

2.5. Dermatological Reactions

Adverse dermatological events, such as rashes, injection-site reactions, and even alopecia areata, have been documented as possible side effects of mRNA COVID-19 vaccination. A registry-based study was conducted to characterize the morphology and timing of cutaneous manifestations following administration of the novel mRNA vaccines ([66] (see Table 1))[64]. The international registry represented a collaborative endeavor between the American Academy of Dermatology and the International League of Dermatological Societies; case entry was restricted to healthcare workers only. The vaccine arm of the registry collects information about the timing of the vaccine doses, morphology, duration of the dermatological reaction, and treatment. From 24 December 2020, to February 14, 2021, this registry recorded 414 unique patient cases of cutaneous reactions to the Moderna (83%) and Pfizer-BioNTech (17%) vaccines [66][64]. A wide spectrum of post-vaccination dermatological events was reported, from common injection-site reactions to urticaria, morbilliform eruptions, and more atypical manifestations such as erythromelalgia and pityriasis-rosea-like eruptions. Reported cases were predominantly female (90%), white (78%), and from the U.S. (98%), with a median age of 44 years. Of the 414 patient cases evaluated, data on both mRNA vaccine doses was available for only 180 patients. Of those 180, 21% of the cutaneous reactions occurred after the first vaccine dose, 63% after the second dose only, and 16% of the reactions were reported with both doses [66][64]. The median time from first vaccination to symptom onset was 7 days, while the median time from second vaccination to symptom onset was 1 day. In addition, a delayed large local arm reaction (DLLR)—characterized by a patch of erythema, induration, and tenderness at the injection site—occurred more frequently after receipt of the Moderna vaccine (94%), with a median time to presentation onset of 7 days after the first dose. DLLRs developed more rapidly following the second Moderna vaccine dose (median time of 2 days). The etiology of DLLRs is unknown, but the pathology is consistent with delayed-type hypersensitivity [66][64]. ResCults from this study demonstrated that cutataneous side effects of COVID-19 vaccination are usually self-limited without any therapeutic intervention, and the risk of such adverse events does not outweigh the health benefits of immunization against SARS-CoV-2 [66][64].

3. Conclusions

The novel Pfizer-BioNTech and Moderna mRNA vaccines continue to serve as effective and critical tools in the healthcare industry’s anti-COVID-19 arsenal for reducing the morbidity and mortality of SARS-CoV-2 infection. Common local and systemic adverse reactions to mRNA COVID-19 vaccination include injection-site pain and tenderness, fatigue, and headache. However, clinicians need to be aware of rare, more serious adverse events that have occurred in close temporal proximity to mRNA vaccine administration—namely, myocarditis, immune thrombocytopenia (ITP), anaphylaxis and other allergic hypersensitivities, CNS and orofacial effects, and dermatological reactions. In tThis review, aere is a  robust male predominance in vaccine-associated myocarditis was observed among reported cases, particularly after the second-dose mRNA vaccine. Patients were predominantly young (≤25 years), male, and previously healthy with no prior history of cardiac disease. Cases indicate a female predominance in anaphylactic reactions and cutaneous adverse events following exposure to both mRNA vaccines. Females with a previous history of allergic reactions also had an elevated risk of mRNA vaccine allergy (both anaphylactic and nonanaphylactic). Neurological adverse events included CNS demyelinating disorders, such as acute transverse myelitis (ATM), and peripheral nervous system disorders (e.g., Bell’s palsy). Most patients presenting with ITP developed severe thrombocytopenia after the first mRNA vaccine dose and had various bleeding symptoms (e.g., gingival bleeding, epistaxis, petechiae, or diffuse bruising). The post-vaccination incidence of these heterogenous adverse events was rare in light of the billions of individuals worldwide who have received at least one dose of a mRNA vaccine, although the reports largely reflect occurrences in the U.S. and other developed countries. Moreover, the adverse conditions were generally self-limiting, and patients responded well to treatment options. Further research and long-term population-level surveillance are needed to assess the possibility of causality and the pathological mechanisms underlying these adverse reactions. As vaccination rates continue to increase in populations, clinicians should be able to rapidly recognize symptoms of more serious vaccine-associated adverse events for prompt assessment and initiation of warranted therapeutic intervention.

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