Archives of Academic Emergency Medicine. 2022; 10(1): e41

OR I G I N A L RE S E A RC H

Safety and Adverse Events Related to COVID-19 mRNA
Vaccines; a Systematic Review
SeyedAhmad SeyedAlinaghi1, Amirali Karimi2, Zahra Pashaei1, Arian Afzalian2, Pegah Mirzapour1, Kobra
Ghorbanzadeh3, Afsaneh Ghasemzadeh4, Mohsen Dashti4, Newsha Nazarian5, Farzin Vahedi2, Marcarious M.
Tantuoyir2,6, Ahmadreza Shamsabadi7, Omid Dadras1,8, Esmaeil Mehraeen9∗

1. Iranian Research Center for HIV/AIDS, Iranian Institute for Reduction of High Risk Behaviors, Tehran University of Medical Sciences,
Tehran, Iran.

2. School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

3. Department of Nursing, Khalkhal University of Medical Sciences; Khalkhal, Iran.

4. Department of Radiology, Tabriz University of Medical Sciences, Tabriz, Iran.

5. School of Medicine, Islamic Azad University, Tehran, Iran.

6. Biomedical Engineering Unit, University of Ghana Medical Center (UGMC), Accra, Ghana.

7. Department of Health Information Technology, Esfarayen Faculty of Medical Sciences, Esfarayen, Iran.

8. School of Public Health, Walailak University, Nakhon Si Thammarat, Thailand.

9. Department of Health Information Technology, Khalkhal University of Medical Sciences, Khalkhal, Iran.

Received: March 2022; Accepted: April 2022; Published online: 28 May 2022

Abstract: Introduction: Knowledge of vaccine-related adverse events is crucial as they are among the most important fac-
tors that cause hesitation in receiving vaccines. Therefore, we aimed to systematically review the adverse events
related to the mRNA vaccines reported in the literature. Methods: A systematic literature search was carried out
in the databases of Scopus, PubMed, Cochrane, and Web of Science. We selected original studies that explored
the side effects of mRNA COVID-19 vaccines using a two-phase (title/abstract and full-text) screening process.
Results: Cardiac complications were the most commonly reported severe adverse events. It appeared that sys-
temic adverse reactions are more common after the second dose of vaccines. The number of adverse effects
reported after the Pfizer vaccine was higher than other vaccines, mostly due to its earlier approval and more
widespread use throughout the world. Cardiac adverse events had a higher prevalence but no significant associ-
ation has been found between COVID-19 mRNA vaccines and cardiac adverse events except for myopericarditis.
Conclusion: Vaccines play a crucial role in controlling the COVID-19 pandemic and decreasing mortalities and
the results of the present review acknowledge the fact that the benefits outweigh the adverse events of these
vaccines.

Keywords: Adverse effects; COVID-19 vaccines; 2019-nCoV Vaccine mRNA-1273; mRNA vaccines; BNT162 Vaccine

Cite this article as: SeyedAlinaghi S, Karimi A, Pashaei Z, Afzalian A, Mirzapour P, Ghorbanzadeh K, Ghasemzadeh A, Dashti M, Nazarian N,

Vahedi F, Tantuoyir MM, Shamsabadi A, Dadras O, Mehraeen E. Safety and Adverse Events Related to COVID-19 mRNA Vaccines; a Systematic

Review. Arch Acad Emerg Med. 2022; 10(1): e41. https://doi.org/10.22037/aaem.v10i1.1597.

∗Corresponding Author: Esmaeil Mehraeen; Department of Health Infor-
mation Technology, Khalkhal University of Medical Sciences, Khalkhal, Iran.
Postal Code: 5681761351, Tel: +98-45-32426801, Fax: +98-45-32422305, E-mail:
es.mehraeen@gmail.com , ORCID: http://orcid.org/0000-0003-4108-2973.

1. Introduction

The COVID-19 pandemic is a global health crisis that de-

mands enormous measures in order to be controlled. Mass

vaccination of the population is critical for containing it;

thus, countries all over the world are attempting to vaccinate

their people against this disease (1-4). Vaccines operate by

stimulating the body’s natural immunological response. Im-

mediately after the genetic sequence of the novel coronavirus

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S. SeyedAlinaghi et al. 2

was uncovered, vaccine manufacturers all around the world

jumped into action to develop a vaccine (5). Currently avail-

able SARS-CoV-2 vaccines are produced using one of the fol-

lowing technologies: mRNA-based vaccines, whole virus or

inactivated virus vaccines, protein subunit vaccines, and vi-

ral vector-based vaccines (6).

Pfizer-BioNTech BNT162b2 and Moderna mRNA1273 are the

first and only mRNA-based vaccines approved by the World

Health Organization so far and have been used in several

countries. These vaccines encode a stable full-length SARS-

CoV-2 spike ectodomain, derived from the Wuhan-Hu-1 ge-

netic sequence (7, 8). They are a novel-nucleic acid type

of vaccine that employs genomic information such as mes-

senger RNA (mRNA), a method that introduces a portion of

the genetic code into human cells (9, 10). Furthermore, the

high level of reactogenicity of the SARS-CoV-2 mRNA vac-

cines is one of their distinguishing features, provoking both

local and systemic reactions observed by the majority of pa-

tients in Phase 1-3 trials. Additionally, the levels of systemic

reactogenicity associated with SARS-CoV-2 mRNA vaccines

have generated concerns about a more serious adverse event

profile in patients with underlying immunological dysregula-

tion as these patients, who often consume immunosuppres-

sive and biologic medications for immune-mediated inflam-

matory illnesses such as inflammatory bowel disease (IBD),

were mostly exempted from the vaccine trials. Activation

of the innate immune system through pattern-recognition

receptor ligation, followed by the production of inflamma-

tory cytokines such as tumor necrosis factor, interleukin-6,

and interleukin-1 is often responsible for the vaccine’s reac-

togenicity (11, 12).

Adverse drug reactions (ADRs) and medication-related inci-

dents could be fatal, likewise, the side effect of vaccines could

be catastrophic. If clinical trials are not powered enough

to detect the very rare events, these rare but important ad-

verse events may go undetected. Due to variances in age,

race, and underlying conditions, the reported rates of ad-

verse effects have been inconsistent across different stud-

ies. Even though their safety has been established, concerns

of immune-mediated disease flare-ups or new-onset inflam-

matory diseases following their administration have recently

emerged (13-16). The Vaccine Adverse Event Reporting Sys-

tem (VAERS), co-developed and maintained by the Centers

for Disease Control and Prevention (CDC) and the United

States Food and Drug Administration (FDA), serves as a na-

tional passive surveillance system for continuous monitoring

of vaccine safety once it has been distributed in the market

(17). The data from VAERS show that the most commonly

reported side effects are injection site pain, fever, headache,

neck pain, nausea, vomiting, drowsiness, diarrhea, dizziness,

enlarged lymph nodes, decreased alcohol tolerance, dysp-

nea, cough, stuffy nose, fainting, thirst, excessive sweating,

sore throat, loss of appetite, insomnia, irritability, stupor,

photosensitivity, eye pain, numbness in the extremities, and

malaise (18-20).

Vaccine safety is important to the success of any vaccination

effort, particularly during a pandemic. Hence, with the in-

crease in vaccination rates, it is crucial to monitor their ad-

verse events post-vaccination. Raising awareness of asso-

ciated adverse events (AEs) is crucial for reducing vaccine

hesitancy as well as improving the safety of vaccines if nec-

essary (21). Therefore, in this study, we aimed to system-

atically review the adverse events related to the mRNA vac-

cines reported in the literature. The findings could present

and enhance scientific literacy across the many stakehold-

ers and provide concise and evidence-based soltutions to the

COVID-19 vaccine safety concerns.

2. Methods

This review was conducted according to the Preferred Re-

porting Items for Systematic Reviews and Meta-Analyses

(PRISMA) guidelines. A systematic search of relevant records

was carried out in the online databases using selected key-

words on September 15th, 2021.

2.1. Data sources

We carried out a systematic search using the keywords

and search queries in online databases including Scopus,

PubMed, Cochrane, and Web of Science.

2.2. Search strategy

Search strategies were constructed by two authors of the

research team. Search terms were connected in a highly-

sensitive syntax via the Boolean operator OR. The search

strategy that was used to retieve the records in each online

database is as follows:

((((((COVID-19[Title]) OR (SARS-CoV-2[Title])) OR (SARS-

CoV2[Title])) OR (2019-nCoV[Title])) OR (Novel Coro-

navirus[Title])) AND ((((Vaccine*[Title]) OR (Vaccina-

tion[Title])) OR (Vaccinated[Title])) OR (Immuniza-

tion[Title]))) AND (((((Safety[Title]) OR (Side effect*[Title]))

OR (Adverse event*[Title])) OR (Adverse effect*[Title])) OR

(Adverse reaction*[Title]))

2.3. Eligibility criteria

Original English articles that reported the adverse events of

mRNA COVID-19 vaccine were included, applying the fol-

lowing exclusion criteria:

1) Abstracts/conference abstracts or unavailability of full

texts

2) Ongoing clinical trials with unpublished results

3) Non-original studies, including review articles, meta-

analyses, protocols, and editorials

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3 Archives of Academic Emergency Medicine. 2022; 10(1): e41

Figure 1: PRISMA flow diagram of the systematic review.

4) Studies on other types of vaccines rather than mRNA vac-

cines, or those only reporting efficacy of mRNA vaccines

without reporting their adverse events

5) Protocols of randomized clinical trials (RCTs) and other

original studies

2.4. Selection of studies and Data Screening

The EndNote X9 software was used to organize the retrieved

articles. Search results from different databases were com-

bined in a single EndNote library and duplicates were re-

moved. Two authors independently screened the retrieved

articles in two steps. First, the title and abstract of the re-

trieved records were screened and the ineligible articles were

removed. The full texts of the remaining articles were re-

viewed based on the inclusion and exclusion criteria and the

eligible studies were included in the final qualitative analysis

of the results.

2.5. Data Extraction

The following data were independently extracted by four re-

searchers: first author, type of study, country of research,

manufacturer of the mRNA vaccine, sample population, age,

gender, severe adverse events, time from the injection to the

appearance of adverse events, and local and systemic ad-

verse events.These findings were organized into a table and

were used for qualitative synthesis. Another author reviewed

the extracted data and addressed any inconsistencies that ex-

isted between authors.

2.6. Quality assessment

The Newcastle-Ottawa scale (NOS) was used to assess the

quality of included studies. This criteria yields a maximum

score of nine for questions regarding selection, comparabil-

ity, and exposure (22). Studies with poor quality assessment

scores of four or less were excluded from this systematic re-

view.

3. Results

Our search yielded a total of 1062 studies, and two more

records were identified through manual searching. After re-

moving the 547 duplicates, 515 records remained. A total of

171 records were excluded in the title/abstract screenings,

and 346 full-text reports were assessed for eligibility (344

from database search, two via manual searching). Finally, 74

studies were found to be eligible for this systematic review

(Figure 1).

The mean NOS quality assessment score of the studies was

6.5. No study had a score of four or less and therefore, no

study was excluded from this systematic review due to low

quality score.

The purpose of this study was to review and describe the

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S. SeyedAlinaghi et al. 4

findings of articles that reported safety and adverse events re-

lated to COVID-19 mRNA vaccines. We included articles that

investigated the adverse effects of COVID-19 mRNA vaccines

(Pfizer-BioNTech, Moderna, BNT, and BNT162b1) in the 1st,

2nd, and 3rd-phase RCTs, cross-sectional, and cohort stud-

ies.

3.1. Adverse reactions

In both Pfizer and Moderna vaccines mild to moderate lo-

cal and systemic adverse reactions were reported. The find-

ings have shown that the incidence of systemic adverse re-

actions could increase following the second dose. Also, the

prevalence of systemic adverse reactions in younger adults

(age group of 18-55) was higher in comparison with older

adults. Injection site pain and muscle pain were the most

common local adverse reactions reported in studies. Also,

headache was the most prevalent systemic adverse reaction,

followed by fatigue, myalgia, chills, and fever. Other local ad-

verse reactions included tenderness, redness, urticaria, rash

and swelling, neck pain, hand numbness, erythema, indura-

tion, itching, local loss of hair, and edema. Some other less

common systemic adverse reactions were as follows: body

aches, gastrointestinal symptoms, arthralgia, nausea, vomit-

ing, diarrhea, dizziness, vertigo, weakness, and visual symp-

toms (Table 1). It should be noted that adverse reactions and

severe adverse events could affect all healthy, pregnant, and

immunocompromised vaccine recipients.

3.2. Severe adverse events (SAE)

In this review, severe adverse events were reported and clas-

sified into five categories including cardiac, allergic, neuro-

logic adverse events, and adverse events that may occur in

pregnant and immunocompromised patients who received

COVID-19 mRNA vaccines. The time interval between inoc-

ulation and onset of severe adverse events varied from one

hour to 84 days after the injection of the first or second dose.

Severe adverse events are reported as follows:

-Cardiac
Most of the reported severe adverse events were related to

cardiac events. A cross-sectional study among 700 partic-

ipants who received Pfizer-BioNTech reported severe chest

pain (0.4%) and acute hypertension (0.3%) after the first vac-

cine shot (6). A retrospective study among 113 allogeneic

hematopoietic stem cell transplant recipients, who received

Pfizer and Moderna vaccines, reported tachycardia and in-

creased blood pressure (0.8%) (23). In a 3rd phase RCT

among 14134 participants who received mRNA-1273 (Mod-

erna), the authors reported one case of cardiopulmonary ar-

rest (0.007%) (24). Another study on 884,828 participants

who received Pfizer vaccine reported myocarditis (risk ratio,

3.24 and risk difference 2.7 events per 100,000 persons) (25).

A cross-sectional study on 8275 participants reported one

case of acute myocardial infarction (26). Another cross-

sectional study on 432 participants who received the Mod-

erna vaccine reported chest pain (1.85%) and syncope

(0.93%) (27). Likewise, in another cross-sectional study on

803 participants who had received Pfizer vaccine, chest pain

(1.12%) and Syncope (0.12%) were reported as serious ad-

verse events (20). Another cross-sectional study on 190 pa-

tients who had received the Pfizer vaccine reported one case

of supraventricular tachycardia (1%) and one case of de-

compensated heart failure (1%) (28). In a 2nd phase RCT

on 43,448 participants, 21720 of whom received BNT162b2

vaccine, one case of paroxysmal ventricular tachycardia

(0.004%) was reported (29).

-Pregnancy
Among studies included in our review, two studies were con-

ducted on pregnant women who had received mRNA vaccine

during their pregnancy, and one study on 35691 pregnant

women reported possible serious adverse effects as follows:

spontaneous abortion (46 cases; 37 in the first trimester, 2

in the second trimester, and 7 in which the trimester was

unknown or not reported), stillbirth, premature rupture of

membrane, and vaginal bleeding with 3 reports for each, and

no congenital anomalies were documented (30). In another

study on pregnant women, the rates of adverse pregnancy

outcomes among 133 women who received at least 1 dose of

the COVID-19 vaccine in pregnancy were similar to that of

unvaccinated pregnant women regarding stillbirth (0.0% vs

0.2%), fetal abnormalities (2.2% vs 2.5%), postpartum hem-

orrhage (9.8% vs 9.0%), cesarean delivery (30.8% vs 34.1%),

small for gestational age (12.0% vs 12.8%), maternal high-

dependency unit or intensive care admission (6.0% vs 4.0%),

and neonatal intensive care unit admission (5.3% vs 5.0%).

In addition, three fetal abnormalities, including spina bifida,

ventriculomegaly, and hydronephrosis, were reported. The

spina bifida case was diagnosed before the pregnant woman

received the first dose of the vaccine. The ventriculomegaly

case was diagnosed at 37 weeks gestation and was isolated,

with no associated brain abnormalities, as confirmed by fetal

brain magnetic resonance imaging. The hydronephrosis was

mild, with no associated abnormality at birth (31).

-Allergic
Some studies reported rare allergic adverse events such as

swelling of eyelids, severe allergic reaction of eyelids, ana-

phylactoid reactions, and Angioedema (9, 24, 27, 32, 33). In

a cross-sectional study conducted on 700 participants who

received Pfizer vaccine, two cases with swelling and severe

allergic reaction of eyelids were reported (1). In a similar

cross-sectional study on 432 participants who received Mod-

erna vaccine, swelling in the mouth or throat (0.46), asthma

exacerbation (0.46%), swelling of lips (0.23%), and anaphy-

laxis (0.23%) were observed (27). Also, in the 3rd phase RCT

among 14,134 white and black USA residents who received

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5 Archives of Academic Emergency Medicine. 2022; 10(1): e41

Moderna, hypersensitivity reactions were reported in 1.5% of

participants (24, 27). Two cross-sectional studies reported al-

lergic reactions in 2.2% (15 out of 688) of participants and two

cases of Angioedema (0.4%) (2 out of 474) within 48 hours of

vaccine injection, respectively (34, 35).

Between December 14, 2020, and January 18, 2021, based

on CDC reports, after vaccination with 9,943,247 Pfizer-

BioNTech doses and 7,581,429 Moderna doses in the US

(CDC unpublished data, February 2021), the risk of ana-

phylaxis was 4.7 cases/per-million-dose for Pfizer-BioNTech,

and 2.5 cases/per-million-dose for Moderna vaccine. Over-

all, since late January 2021, CDC reported 66 cases of ana-

phylaxis, including 47 cases after the Pfizer-BioNTech vac-

cine and 19 cases after the Moderna vaccine. All these 66 per-

sons were treated in health care settings. The median time to

event was 6 minutes (range, <1-45 minutes). Almost all cases

recovered in the follow-up and no deaths from anaphylaxis

after vaccination with either product were reported (36).

In another cross-sectional study, the authors investigated the

adverse effects of 578,835 doses of the mRNA-based vac-

cines in the Japanese population, 733 Adverse Event Follow-

ing Immunizations or AEFIs (85 males [12%], 647 females

[88%], 1 unknown [< 1%]) were reported. Among these, there

were 181 (first dose: 177; second dose: 3; unknown: 1) sus-

pected anaphylaxis reports, resulting in a reporting rate of

31.3/100,000 doses. In 171 of 181 cases, women developed

suspected anaphylaxis and anaphylactoid symptoms within

≤5min or >30 min of injection (33).
- Neurologic
In total, 10 studies reported adverse neurologic events

among healthy patients and patients with prior neuro-

logic diseases. These adverse events were Bell’s palsy, her-

pes zoster, ischemic stroke, new or worsening neurologi-

cal symptoms (muscle weakness, walking difficulty, gait in-

stability, visual problems, pain, sensory disturbances, and

sphincteric problems) among patients with underlying neu-

rological diseases, Guillain-Barre syndrome, seizure, loss of

consciousness, fainting, syncope, leg paresthesia, functional

syndromes, acute transverse myelitis, and lumbar radicu-

lopathy exacerbation (20, 24-27, 29, 37-40).

A 3rd-phase RCT on 14134 who received Moderna reported

three cases of Bell’s palsy in both the vaccine group (<0.1%)

and placebo group (<0.1%) (24). In addition, one case of Bell’s

palsy was reported 11 days after the 1st dose of Pfizer vaccine

in a cross-sectional study. The unadjusted 15-day rate of ad-

verse events per 100,000 residents following the first dose of

vaccine was the same in both vaccinated and unvaccinated

groups for Bell’s palsy (26). Herpes zoster was observed at the

rate of 15.8 events per 100,000 persons among 884,828 who

received the Pfizer vaccine (25). Other neurological symp-

toms were as follows: 73 participants (16.7%) who had a his-

tory of rare neuro-immunological disorders reported new or

worsening neurological symptoms following Pfizer and Mod-

erna vaccination (37), 36 participants (15.1%) with Multi-

ple Sclerosis who received Pfizer COVID-19 vaccine reported

new or worsening neurological symptoms (muscle weakness,

walking difficulty, gait instability, visual problems, pain, sen-

sory disturbances and sphincteric problems) (41), Guillain-

Barre syndrome (GBS) was seen in a healthy male 4 days after

the second dose of Moderna (39), there was one case of the

seizure (0.23%) after receiving Moderna vaccine (27), food in-

tolerance (0.25%), loss of consciousness or fainting (0.25%),

seizures (0.12%), and syncope (0.12%) among 803 partici-

pants who had received Pfizer (20), and one case of leg pares-

thesia in a 2nd-phase RCT of Pfizer vaccine (29).

In addition, a cohort study on 704,003 participants who re-

ceived Pfizer vaccine reported 33 (0.005%) serious adverse

events, 17 of which (51.5%) were neurologic (2.4/100,000

doses) in the first 30 days after vaccination, however, no

death was reported due to the complications. Among those

17 patients, seven cases had seizures (0.99/100,000 doses);

four mentioned functional syndromes (0.56/100,000 doses);

three had GBS (0.43/100,000 doses); two were diagnosed

with acute transverse myelitis (0.28/100,000 doses); and one

case was consistent with lumbar radiculopathy exacerbation

(0.14/100,000 doses) (40).

- Immunocompromised patients
A retrospective study on 113 allogeneic hematopoietic stem

cell transplant recipients who received Pfizer-BioNTech

and Moderna vaccine reported one case of axillary lym-

phadenopathy, one case of increased blood pressure, and

tachycardia. In addition, neutropenia, thrombocytopenia,

lymphopenia, and eosinophilia were observed in 13.3%,

11.5%, 8.8%, 4.4% of vaccine recipients 20.5, 34, 19.5, and

28 days after vaccination. In addition, they reported new

chronic Graft-versus-host disease (GVHD) (9.7%) or wors-

ening chronic GVHD (3.5%) 3 to 48 days after vaccination.

Also, two patients experienced both new and worsening

GVHD symptoms. One patient with a previous history of

chronic GVHD was hospitalized (23). Another study on 80

allogeneic hematopoietic cell transplantation recipients or

CD19-based chimeric antigen receptor T-cell (CART) ther-

apy patients who received Pfizer vaccine reported cytope-

nia (12% of the patients after the 1st dose and 10% of the

patients after the 2nd dose), graft-versus-host disease exac-

erbation (4.5%), and a single case of impending graft rejec-

tion as possible vaccination adverse effects within 1st week

of injection (42). One cohort study on 741 solid organ trans-

plant recipients who received Pfizer or Moderna vaccines, re-

ported one case of acute rejection after the 2nd dose, and in-

fection (3% after 1st dose and <0.01% after 2nd dose) within

7 days post-vaccination. Lao, in a cohort study that was con-

ducted on 151 cancer patients and 54 healthy patients who

received Pfizer or Moderna vaccines, reported only one case

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S. SeyedAlinaghi et al. 6

of deranged liver function test 3 weeks after the 1st dose in

the control group (43). In a study of 373 cancer patients

who received Pfizer-BioNTech or Moderna vaccine, eight pa-

tients reported severe adverse events as follows: chest pain

(0.3%), dyspnea (1.1%), urosepsis(0.3%), febrile neutrope-

nia (0.3%), and lymphadenopathy (0.5%) within seven days

after injection, and venous thromboembolism (VTE) (0.3%)

within seven days after vaccination (44).

4. Discussion

In this review, we synthesized the safety data and side effects

of COVID-19 vaccines from 74 published articles. It appeared

that the adverse reactions were often mild to moderate with

few serious adverse events. At least one case of serious ad-

verse events was reported in 30 articles. Most studies had in-

vestigated the adverse events after the Pfizer-BioNTech vac-

cine, while few studies had studied Moderna (mRNA-1273) or

both mRNA vaccines’ adverse effects. The number of adverse

effects reported after the Pfizer vaccine was higher, but this

was mostly due to its earlier approval and more widespread

uptake across the world. The reported severe adverse events

associated with the COVID-19 vaccines were more frequently

related to allergic events, neurological events, and cardiovas-

cular implications including chest pain, myocardial infarc-

tion, acute hypertension, tachycardia, myocarditis, syncope,

supraventricular tachycardia, decompensated heart failure,

and paroxysmal ventricular tachycardia.

The majority of vaccine recipients reported at least one lo-

cal or systematic side effect after inoculation with the mRNA

COVID-19 vaccine. Albeit, all reported side effects were mi-

nor and had a short duration. Local and systemic adverse

reactions were found to be more prevalent after the sec-

ond dose. Common adverse reactions were injection site

pain, headache, muscle pain, myalgia, chills, and fever. The

systemic adverse reactions had moderate intensity in the

young age group in comparison with those who were 65 years

old or older. The majority of adverse reactions like fatigue,

joint pain, muscle pain, and headache were reported by the

younger age group (18-55 years) and obviously, less reported

by the older adults. These findings are in line with findings

of a similar study that assessed 11 clinical trials of COVID-19

vaccines (45).

Ten studies in this review reported possible cardiac adverse

effects. In those who received Pfizer vaccine, severe chest

pain, acute hypertension, tachycardia, myocarditis, syncope,

supraventricular tachycardia, decompensated heart failure,

and paroxysmal ventricular tachycardia were reported. On

the other hand, increased blood pressure, tachycardia, car-

diopulmonary arrest, chest pain, and syncope were reported

in Moderna receivers. In addition, acute myocardial in-

farction was documented after mRNA vaccine inoculation.

No significant association has been found between COVID-

19 mRNA vaccines and cardiac adverse events mentioned

above, except for myopericarditis. The findings of a system-

atic review conducted to investigate the safety and adverse

events of COVID-19 vaccines among children and adoles-

cents were in line with our findings; 27 cases of approved my-

ocarditis or pericarditis were found in 7 assessed studies (in-

cluding one RCT, two case series, and four case reports), all

of which occurred after the 2nd dose of Pfizer vaccine. This

systematic study’s findings show an incidence rate of 0.008%

for myopericarditis in adolescents aged 16 to 17 years old and

also 0.01% in adolescents aged 12 through 15 years following

the second dose (25, 46).

In another study, 16 cases of myocarditis, pericarditis, and

myopericarditis were reported after injection of both types

of mRNA vaccines. These severe cardiac adverse effects oc-

curred after the first vaccine dose in six cases (35%), after the

second dose in ten cases (59%), and after both doses in one

case (6%). The median time to event was 14 days (range 1–28)

after the first vaccination and 3 days (range 1–17) after the

second shot (47). Similar findings were reported in a system-

atic review that investigated the cardiac adverse outcomes af-

ter COVID-19 vaccine injection. In total, 42 acute myocardial

infarction (AMI) and 35 myocarditis cases were reported af-

ter COVID-19 vaccination and 41 (98%) and 31 (89%) of these

cases had been vaccinated by mRNA vaccines, respectively.

The majority were men, and myocarditis cases were younger

than AMI patients. Myocarditis was observed after an aver-

age of 3 days after vaccination, while AMI mostly occurred af-

ter an average of 1 day. Thirty-five (83%) myocarditis and six

(33%) AMI patients developed symptoms after their second

dose. The majority of the myocarditis (83%) and AMI patients

(86%) had received the Pfizer BioNTech vaccine. The remain-

ing patients with myocarditis received the Moderna (14%)

and Janssen vaccine (2%) vaccines, while AMI patients had

received the Oxford-AstraZeneca vaccine (11%) and Mod-

erna vaccine (3%) (48). These findings were consistent with

our study indicating a strong possibility of myocarditis (risk

ratio, 3.24; [CI95% 1.55-12.44]) after BNT162b vaccination;

however, this risk was significantly lower in comparison with

myocarditis after SARS-COV-2 infection, which is 18.28 (95%

confidence interval [CI95% 3.95-25.12]) (25). In addition,

some included studies in our review had reported cases of

severe chest pain and acute myocardial infarction.

It seems that the rate of adverse pregnancy outcomes is

no different between vaccinated and unvaccinated pregnant

women and no association between mRNA vaccines and

pregnancy outcomes was found. This finding was consis-

tent with the findings of other systematic reviews, which were

conducted on pregnant women who received either of the

mRNA vaccines. No increased risk of adverse obstetrical or

neonatal outcomes was reported and the proportion of in-

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7 Archives of Academic Emergency Medicine. 2022; 10(1): e41

fant outcomes reported, including spontaneous abortions,

stillbirth, induced abortion ectopic pregnancy, and sponta-

neous abortions, were similar to non-vaccinated pregnant

women. Also, safety data indicated that pregnant and lac-

tating populations experienced vaccine-related reactions at

similar rates to the general population (49, 50).

The findings of included studies showed that those who have

received the Pfizer vaccine are more likely to have aller-

gic reactions than those who received Moderna vaccine. A

systematic review including 26 articles, involving 26,337,421

mRNA SARS-CoV-2 vaccine recipients (14,505,399 doses of

Pfizer-BioNTech and 11,831,488 doses of Moderna) reported

similar results. This study reported that vaccination with

Pfizer-BioNTech vaccine resulted in higher rate of anaphy-

lactic reactions compared to Moderna vaccine (9.31/per-

million-dose and 3.42/per-million-dose). This study also re-

ports a lower incidence of non-anaphylactic reactions with

Pfizer compared to Moderna (75.27/per-million-doses, ver-

sus 99.01/per-million-doses administered) (51). In another

systematic review and meta-analysis, which investigated the

risk of allergic and severe adverse events, the incidence

rate of anaphylaxis was reported as 7.91/per-million-cases

(among 41,000,000 patients) (52).

The post-COVID-19 vaccination neurological adverse events

are relatively rare and the causal association between neuro-

logical symptoms and vaccination is uncertain. Bell’s palsy

was reported as one of the neurological adverse events in

two assessed studies (26, 53). However, no significant differ-

ences in Bell’s palsy incidence were reported between vacci-

nated and unvaccinated individuals. A review has also ac-

knowledged that most Bell’s palsy cases were associated with

mRNA vaccines. No difference was found between clinical

features of vaccine-associated Bell’s palsy and conventional

types and the pathogenesis remains unclear (54). In addition,

some neurological adverse events including Guillain-Barre

syndrome, herpes zoster, seizure, loss of consciousness or

fainting, syncope, leg paresthesia, and acute transverse were

reported; the causal association of adverse events and vacci-

nation or coincidence of them must be carefully assessed.

Most of the COVID-19 vaccine randomized trials have ex-

cluded those with immunocompromised conditions, so

there is limited data available about adverse events in in-

dividuals with autoimmune disease and cancer. However,

in transplant recipients, graft-versus-host disease exacerba-

tion, and impeding graft rejection were reported as possible

vaccination adverse events. No significant difference was re-

ported between severe complications in cancer patients and

healthy patients, as the control group, who received Pfizer or

Moderna vaccines (43, 44).

The adverse events of vaccination should continuously be

monitored to identify any new issues in the safety of vac-

cines, which require investigations. In other words, while

assessing the safety of vaccines, any unexpected or unusual

patterns in vaccinated individuals, which have a higher rate

than the general population should be considered. In this

study, the most commonly reported serious adverse events

were cardiac events, additional studies are recommended to

investigate the association between vaccination and cardiac

complications. Also, in order to collect data on the clinical,

cardiological, neurological, and immunological profile of the

COVID-19 vaccinated population, cohort studies could fur-

ther assess the frequency of adverse events in the general

population.

5. Conclusion

Some severe adverse events were observed among the recipi-

ents of mRNA vaccines, but a direct relationship between the

vaccines and adverse events has not been clearly established

for the adverse events, except for myopericarditis. The rate

of severe adverse effects is low and obviously, the benefits of

receiving vaccines in preventing severe COVID-19 and death

outweigh the possible rare adverse events of the COVID-19

vaccines. Therefore, healthcare officials should enlighten

people on the safety of the vaccines, in this case mRNA vac-

cines, to avoid further hesitations in COVID-19 vaccination,

which may endanger the lives of people and pose a huge bur-

den on the healthcare system.

6. Declarations

6.1. Acknowledgments

This systematic review was supported by Tehran University

of Medical Sciences with the grant no. 1400-3-119-55855 and

the ethics code: IR.TUMS.IKHC.REC.1400.510.

6.2. Data availability

The data is at the disposal of the corresponding author of the

article and it it can be made available to the researchers upon

request.

6.3. Authors’ contributions

(1) The conception and design of the study:Esmaeil

Mehraeen, SeyedAhmad SeyedAlinaghi

(2) Acquisition of data:Amirali Karimi, Zahra Pashaei

(3) Analysis and interpretation of data: Pegah Mirzapour,

Arian Afzalian

(4) Drafting the article: Kobra Ghorbanzadeh, Afsaneh

Ghasemzadeh, Mohsen Dashti, Newsha Nazarian, Farzin

Vahedi, Marcarious M. Tantuoyir, Ahmadreza Shamsabadi

(5) Revising it critically for important intellectual content:

SeyedAhmad SeyedAlinaghi, Omid Dadras

(6) Final approval of the version to be submitted: all authors

This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0).
Downloaded from: http://journals.sbmu.ac.ir/aaem



S. SeyedAlinaghi et al. 8

6.4. Funding and supports

This research received a grant from Tehran University of

Medical Sciences (Grant no. 1400-3-119-55855).

6.5. Competing interests

The authors declare that there is no conflict of interest re-

garding the publication of this manuscript.

6.6. Availability of data and material

The authors stated that all information provided in this arti-

cle could be shared.

6.7. Consent to publication

Not applicable

6.8. Ethics approval and consent to participate

The present study was approved by Tehran Uni-

versity of Medical Sciences with the ethics code:

IR.TUMS.IKHC.REC.1400.510.

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13 Archives of Academic Emergency Medicine. 2022; 10(1): e41

Table 1: Severe adverse events, local and systemic side effects of mRNA COVID-19 vaccination

First Author
Country

Study type Manuf-
acturer*

Sample Age Gender (%) Severe adverse event Time to
appearance

Side effects (%)

Local Systemic
Tom T.
Shimabukuro.
(55) USA/
White

Cross-
sectional

PB, M 35,691 16 to 54
years

Female (100) Spontaneous
abortion, Preterm

birth, small size for
gestational age

N/A Injection-site
pain

Headache,
Myalgia, Chills,

and fever

Abu-
Halaweh,
S. (56) USA

Observational
cohort

PB 491 >70
years

Male (67)
Female (33)

N/A N/A Injection site
pain, Muscle

pain

Fatigue,
Headache,

Arthralgia, Fever
Abu-
Hammad, O.
(57) USA

Cross-
sectional

PB 409 N/A N/A No severe adverse
reaction

1.39 ± 1.12
days

Injection site
pain or arm
numbness

Fatigue, Myalgia,
Headache

Al Ghafri, T.
S. (58) Oman

Cross-
sectional

PB 753 62 Males (54.1),
Female
(45.9)

No severe adverse
reaction

2 days Pain and
tenderness

Fever and body
aches

Al Khames
Aga, Q. A. (9)
USA

Cross-
sectional

PB 700 18 and
above

Male (51.6),
Female
(48.4)

Tenderness or
swollen lymph

nodes, severe allergic
reaction of eyelids,
severe chest pain,

acute hypertension,
acute hyperglycemia

1.903±2.128
days

Pain, Redness,
Urticarial, and
swelling at the

site of the
injection

Fatigue, body
Pain, Headache,

Muscle Pain,
Fever, and

gastrointestinal
effects

Alhazmi, A.
(10) Saudi
Arabia

Cross-
sectional

PB 533 18 to 70
years

Male (43),
Female (57)

Hospitalization due
to side effect

1-5 days Pain, and
redness at the

site of injection

Fatigue, Fever,
Chills, and
headache

Ali, H. (23)
USA

Retrospective
study

PB 113 66.5 Male (69),
Female (31)

Axillary
lymphadenopathy,

Increased blood
pressure, and
tachycardia

26 days Injection site
pain,

Injection-site
rash, and
swelling

Myalgia,
Arthralgia,

Fatigue, Nausea,
Vomiting,

Diarrhea, and
headache

Anderson, E.
J. (59) USA

RCT First
phase

M 40 56–70 Male (48),
Female (52)

Paronychia 2 days Injection-site
pain

Headache,
Fatigue, Fever,
Myalgia, and

chills,
Andrzejczak-
Grządko, S.
(18) Poland

Cross-
sectional

PB 196 20-84 Male (15),
Female (85)

Enlarged lymph
nodes, decreased
alcohol tolerance

N/A Injection site
pain, Shoulder
pain, Muscle
aches, Neck

pain, and hand
numbness

Headache, Fever,
Chills, Nausea,

Vomiting,
Drowsiness,

Diarrhea, and
dizziness

Baden,
L. R. (24)
USA/White
and black

RCT Third
phase

M 14134 51.4 Male (52.7),
Female
(47.3)

Cardiopulmonary
arrest, Bell’s palsy

N/A Injection site
pain, Erythema,
Induration, and

tenderness

N/A

Barda, N.
(25) USA

RCT PB 884828 36 Male (52),
Female (48)

Myocarditis,
Lymphadenopathy,

Appendicitis,
Arrhythmia,
Deep-vein

thrombosis,
Myocardial
infarction,
Myocardial
Infarction,

intracranial
hemorrhage,
pulmonary

embolism, herpes
zoster

N/A N/A Vertigo

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S. SeyedAlinaghi et al. 14

Table 1: Severe adverse events, local and systemic side effects of mRNA COVID-19 vaccination

First Author
Country

Study type Manuf-
acturer*

Sample Age Gender (%) Severe adverse event Time to
appearance

Side effects (%)

Local Systemic
Bardenheier,
B. H. (26)
USA/white,
black

Cross-
sectional

PB 8275 18 and
above

Male (38.1),
Female
(61.9)

Acute Myocardial
Infarction, Bell’s

Palsy, Stroke,
ischemic, Venous

thromboembolism,
and Pulmonary

Embolism

15-day N/A N/A

Benda, M.
(60) Austria

Cross-
sectional

PB 259 65.1 Male (57.5),
Female
(42.5)

No severe adverse
reaction

7-day Injection site
pain

Fatigue, Severe
headache,

Severe general
muscle pain,

and fever
Blakeway,
H. (31)
UK/ Afro-
Caribbean,
Asian eth-
nicity, and
White

Retrospective
cohort study

PB, M 1328 18-40 Female (100) Spina bifida,
Ventriculomegaly,

hydronephrosis, fetal
abnormalities,

postpartum
hemorrhage

N/A N/A N/A

Caminati,
M. (61) Italy

Cross-
sectional

N/A 253 N/A N/A No severe adverse
reaction

N/A N/A N/A

Levy I. (62)
Israel

Prospective
study

PB 143 49.8±11.5
years

Male and
female

N/A 21 days Local pain Fatigue,
headache, fever,

Li J. (63) UK RCT PB 463 57·8±4.7 Male (54)
Female (46)

N/A 28 days and
84 days

Mild to
moderate pain at

the injection
site,

injection-site
redness, or

swelling.

Fever, fatigue,
headache, and

muscle and joint
pain

Li J. (32)
China

Prospective
study

N/A N/A N/A N/A Anaphylactic
reaction (1/100000)

N/A Pain at the
injection site,
injection-site

redness or
swelling

Fever, fatigue,
headache, and

muscle and joint
pain

Li X. (64) UK Cohort
study

N/A 126661070 N/A Male (49.5)
Female
(50.5)

Hemorrhagic and
non-hemorrhagic
stroke, pulmonary

embolism, Bell’s
palsy, immune

thrombocytopenia,
Guillain-Barre
syndrome, and
disseminated
intravascular
coagulation

N/A N/A N/A

Ligumsky H.
(65) Israel

Retrospective
cohort study

PB 326 66 Male (37.7)
Female
(62.3)

N/A 40 days Local pain (n =
64, 19.6%)

Weakness (17.5)
Myalgia (12.6)
Headache (6.4)

Liu X. (66)
China

RCT First
phase

PB 296 51 Male (16.4) Female
(83.6)

N/A 7 days after the
1st or 2nd dose
Pain, Redness,

Swelling,
Induration

Headache,
Fatigue, Joint
pain, Muscle
pain, Chills,

Nausea,
Anorexia,
Diarrhea,
Vomiting

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15 Archives of Academic Emergency Medicine. 2022; 10(1): e41

Table 1: Severe adverse events, local and systemic side effects of mRNA COVID-19 vaccination

First Author
Country

Study type Manuf-
acturer*

Sample Age Gender (%) Severe adverse event Time to
appear-

ance

Side effects (%)

Local Systemic
Lotan I. (37)
USA

Cross-
sectional

PB, M 438 51 Male (16.4)
Female
(83.6)

New or worsening
neurological

symptoms

N/A Local reactions,
including pain,

redness, swelling
at the injection

site

Muscle
weakness, Visual
symptoms, Gait

instability,
Increased pain,

Sensory
disturbances,

Sphincteric
problems

Lotan I. (41)
Israel

Cross-
sectional

PB N/A 42 Male (24)
Female (76)

New or worsening
neurological

symptoms (Muscle
weakness, Walking

difficulty, Gait
instability, Visual
problems, Pain,

Sensory disturbances,
Sphincteric problems)

N/A Pain/redness/
swelling at the
injection site

Generalized
muscle pain,

headache,
dizziness, fever,
chills, fatigue,

Maeda K.
(67) Japan

Present
prospective

observa-
tional study

PB 225 41.8 Male (30.2)
Female
(69.8)

N/A 28 days Site pain Systemic fever,
headache, and

fatigue

Mascellino
MT. (68)
Brazil

N/A PB, M 9000 N/A Male (55)
Female (45)

N/A 28 days A small pinched
pain at the

injection site, a
little bit of

redness

Fatigue,
headache,

muscle, and
joint pain, and

fever
Massoud F.
(69) Kuwait

Cross-
sectional

N/A 111 N/A N/A N/A N/A Pain at the
injection site

(43.8)

Fatigue (46.9),
Headache (34.4),

Myalgia (50)
Matarneh
AS. (39)
Qatar

Cross-
sectional

PB, M N/A N/A N/A Guillain-Barre
syndrome

4 days N/A Upper extremity
weakness and

numbness four
days following

the vaccine.
Mathioudakis
AG. (70) UK

Cross-
sectional

PB, M 532 45 N/A N/A N/A Pain, swelling,
tenderness,

redness, itching,
or other

Fever, skin rash,
shortness of

breath, tingling
in the mouth,

face,
body/extremities,

swelling in the
face or mouth,

generalized
swelling,

anaphylaxis,
tiredness or

fatigue, flu-like
illness

McMurry R.
(71) USA

Cohort
study

PB, M 31029 N/A N/A N/A Within
7,14,21

days

Local pain and
swelling

Fatigue, fever,
chills, myalgia,

arthralgia,
headache, lym-
phadenopathy,

erythema,
diarrhea,

vomiting, Facial
paralysis,

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S. SeyedAlinaghi et al. 16

Table 1: Severe adverse events, local and systemic side effects of mRNA COVID-19 vaccination

First
Author
Country

Study type Manuf-
acturer*

Sample Age Gender
(%)

Severe adverse event Time to
appear-

ance

Side effects (%)

Local Systemic
Menni C.
(72) USA

Prospective
observa-

tional study

PB 1607620 50·6 Male
(38·4)

Females
(61·6)

N/A Within 8
days

Pain, Swelling,
Tenderness,
Itch, Swollen

armpit glands,
Redness,
Warmth,

Bruising, rash,
skin burning,

Headache, Fatigue, Chills and
shiver, Diarrhea, Fever,

Arthralgia, Myalgia, Nausea, red
welts on face and lips

Modenese
A. (73)
Italy

Observational
study

PB 76 48.4 Males
(19)

Females
(81)

N/A 4 weeks Pain sensation
at the injection

site 73.6%
redness in the
injection site

Asthenia and sleepiness, chills,
32%, myalgia and arthralgia, 31%
for headache/ migraine, and 18%

for fever, diarrhea, erythema,
abdominal pain, itch, and vertigo

Hall
VG (74)
Toronto,
Canada

Prospective
study

M 127 66.2 Male
(69.3)

Female
(30.7)

Varicella-Zoster
Virus reactivation
(0.78%), Fever and

pruritic rash (0.78%),
hospitalization

(0.78%)

Within 7
days

Pain,
erythema,

swelling

Fever, headache, fatigue,
myalgia, arthralgia, chills,

Hatmal
MM (75)
Jordan

Cross-
sectional

PB, M 612 18
and

above

N/A N/A Within
4h to
three
days

Pain, swelling Fatigue, headache, sleepiness,
laziness, chills, myalgia, joints

pain, fever, dizziness, decreased
sleep quality, numbness in limbs,

tingling in limbs, dry or sore
throat, nausea, sweating,
abdominal pain, irregular

heartbeats, clogged nose, runny
nose, haziness, chest pain,
dyspnea, cough, diarrhea,
abnormal blood pressure,

allergic reactions, itchy, swollen
ankles and feet, vomiting.

Kadali
RAK. (27)
USA

Cross-
sectional

M 432 18-
80

years
old

Male
(10.4)

Female
(89.6)

Seizures (0.23%),
chest pain (1.85%),

syncope (0.93%),
swelling in the
mouth/throat

(0.46%), asthma
exacerbation

(0.46%), swelling of
lips(0.23%),

anaphylaxis (0.23%)

N/A Pain, swelling,
itching, rash,

lym-
phadenopathy,

skin
discoloration,

bleeding,

Weakness, headache, chills, fever,
sweating, dizziness, flushing,

Myalgia, arthritis, muscle
stiffness/spasm, Nausea,

decreased appetite, diarrhea,
abdominal pain, heartburn,

vomiting, constipation,
swallowing, decreased sleep
quality, anxiety, decrease in
memory, depression, manic

mood changes, psychological
stress, brain fogging or

confusion, incoordination,
extremity weakness, fainting,

seizures, herpes or shingle-like
lesions, eye pain, runny nose,

ringing sensation in the ears, ear
pain, blurred vision, flashing

lights, changes in hearing,
double vision, nose bleed,

bleeding gums, hoarseness,
Palpitations heart, blood

pressure changes, chest pain,

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17 Archives of Academic Emergency Medicine. 2022; 10(1): e41

Table 1: Severe adverse events, local and systemic side effects of mRNA COVID-19 vaccination

First Author
Country

Study type Manuf-
acturer*

Sample Age Gender (%) Severe adverse event Time to
appearance

Side effects (%)

Local Systemic
syncope, Shortness

of breath, and cough,
hives, atopic eczema,
fever, swelling in the

mouth/throat,
asthma

exacerbation,
anaphylaxis, burning

with urination,
frequent urination,

blood in urine,
urinary incontinence

Renuka A.K.
Kadali. (20)
USA

Cross-
sectional

PB 803 18-90
years

old

Male (13.4)
Female
(86.6)

Food intolerance
(0.25%), Loss of
consciousness

/fainting (0.25%),
Seizures (0.12%),

Chest pain (1.12%),
Syncope (0.12%)

N/A Sore arm/pain,
swelling at the
injection site,
Itching, Lym-

phadenopathy
Rash, skin

discoloration,
Bleeding, Loss of

hair locally

Soreness, fatigue,
myalgia, headache,

chills, fever, joint
pain, nausea, muscle

spasm, sweating,
dizziness, flushing,

feelings of relief,
brain fogging,

anorexia, localized
swelling, decreased

sleep quality, itching,
tingling, diarrhea,
nasal stuffiness,

palpitations
Kim T. (76)
Republic of
Korea

Cross-
sectional

2574 20 to
≥60

Male (24.7)
Female
(75.2)

none <3 hour-≥48
hour

Local tender-
ness/erythema/

heating
sensation,

edema

General myalgia,
febrile sensations,

chills, fatigue, rash,
headache, Arthralgia,

Dizziness, Nausea,
vomit, pruritus,

dyspnea
MiloslavKluger.
(35) Czech
Republic

Cross-
sectional

PB, M 474 N/A Male (25.7)
Female
(73.6)

Unknown
(0.6)

Severe side effects
(0.4%), Angioedema

(0.4%)

N/A injection site
pain, injection
site swelling,
injection site

redness, ulcers,
vesicles, blisters,
angular cheilitis,

white/red
plaque, oral
paresthesia,

taste
disturbance,

halitosis,
bleeding gingiva,
swollen mucosa,
rash, Urticarial,

angioedema

Fever, chills,
headache/fatigue,
muscle pain, joint

pain, nausea,
lymphadenopathy

Iguchi, T.
(33) Japan

Cross-
sectional

PB 578,835
doses
and
733
ad-

verse
events

22-56
years

old

Male (12)
Female (88)

181 cases of
Anaphylaxis and

anaphylactoid
symptom

≤5min
->30,min

N/A Anaphylaxis and
anaphylactic

symptoms

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S. SeyedAlinaghi et al. 18

Table 1: Severe adverse events, local and systemic side effects of mRNA COVID-19 vaccination

First Author
Country

Study type Manuf-
acturer*

Sample Age Gender (%) Severe adverse event Time to
appearance

Side effects (%)

Local Systemic
A. Riad.
(77) Czech
Repub-
lic/South
Moravian

Cross-
sectional

PB 877 43 Male (11.6)
Female
(88.4)

N/A 1-3 days Injection site
pain and

redness, labial
blisters, plaque,

bleeding gingiva,
halitosis, lym-
phadenopathy

Fatigue,
headache,

muscle and joint
pain, chills, rash,

nausea, fever

A. Riad.
(78) Slo-
vakia/Slovak

Cross-
sectional

PB 522 37.77±11 Male (23)
Female (77)

N/A 1-3 Injection site
pain, swelling,

and redness, oral
side effects, lym-

phadenopathy

Fatigue, chills,
muscle, and
joint pain,
headache,

malaise, fever,
nausea, rash

Y. Rechavi.
(79) Is-
rael/Arabs

Cohort
study

PB 136 40.09 Male (34)
Female (66)

N/A N/A Injection site
pain, swelling,

and redness

About 23
patients in 1st
dose and 71 in

the 2nd one
R. Ram. (42)
Israel/Arabs

Cohort
study

PB 80 65 Male (55)
Female: (45)

GVHD exacerbation
(4.5%)

1st week Vasculitis rash
on the leg after
allogeneic HCT,

arthralgia,

Cytopenia,
fasciitis,

humoral or
cellular response

B. Quiroga.
(80)
Spain/European

Cohort
study

PB 708 44±11 Male (35)
Female (65)

N/A N/A A local reaction
followed by

Myalgia

Tiredness,
headache

K. Polewska.
(28)
Poland/Jewish

Cross-
sectional

PB 190 68 Male (64.7)
Female
(35.3)

Supraventricular
arrhythmia (n=2),

COVID after 1st dose
(n=2), COVID after

2nd dose (n=3),
Pneumonia (n=1),
dialysis peritonitis

(n=1), catheter
infection (n=1),
deterioration of
glycemic control

(n=2),
decompensated

heart failure (n=1)

7 days for
local 1-3

days
systemic

30days for
severe

adverse
effects

Local site
reaction, pain,
shoulder pain,

sinusitis

Fatigue, muscle
pain, joint pain,
headache, chills,

increased
sweating,

change in smell
and taste,

deterioration of
glycemic
control,

dizziness

F. Polack.
(29) 152 sites
worldwide/
White, Black
or African
American,
Hispanic or
Latinx

RCT Second
phase

PB 43,448 52 all
>16

Male (51)
Female (49)

Shoulder injury, right
axillary

lymphadenopathy,
paroxysmal
ventricular

arrhythmia, right leg
paresthesia

7days for
local

Injection site
pain (1 severe),

redness,
swelling, lym-
phadenopathy

Fatigue,
headache, fever,

chills

F. Pimpinelli.
(81)
Italy/European

Cohort
study

PB 92 N/A Male (53.3)
Female
(46.7)

N/A N/A Pain, tenderness Fever, headache,
malaise,

myalgia, chills
M. I.
Parvej. (34)
Bangladesh/
Indo-Aryan

Cross-
sectional

N/A 1529 18 and
above

Male (66)
Female (34)

Thrombosis (0.15%)
Allergy (2.2%)

2 days Pain in the
injection site

Fever, Muscle
Pain, headache,
allergy, itching,

diarrhea

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19 Archives of Academic Emergency Medicine. 2022; 10(1): e41

Table 1: Severe adverse events, local and systemic side effects of mRNA COVID-19 vaccination

First Author
Country

Study type Manuf-
acturer*

Sample Age Gender (%) Severe adverse event Time to
appear-

ance

Side effects (%)

Local Systemic
A. Park. (16)
Korea/Asian

Cross-
sectional

PB 27368 20 and
above

Male (10)
Female (90)

Dyspnea (0.025) 24 hrs Pfizer(first dose):
Local pain

Pfizer(second
dose): Local pain

Pfizer(first dose):
Fever, Chills,

Myalgia, Headache,
Nausea, Vomiting

Pfizer(second
dose): Fever, Chills,
Myalgia, Headache,
Nausea, Vomiting

D. S.
Panda. (82)
India/Indo-
Aryan

Cross-
sectional

N/A 29 18 and
above

Male (68.8)
Female
(31.2)

N/A N/A N/A Fever, Headache

M. T. Ou.
(83) USA

Prospective
cohort

M 741 60 Male (43)
Female (57)

acute rejection of
graft after 2nd dose

(0.1%) Infection
(after 1st dose (0.4%)

and after 2nd dose
(0.1%))

<7 days pain in injection
site

fatigue, headache

Oh HK. (84)
Korea/Asian

Retrospective
study

PB 3586814 N/A N/A N/A N/A N/A Myalgia, fever,
headache

J. Morales-
Nunez.
(85) Mex-
ico/Hispanic

Cohort
study

PB 303 45±12 Male (40.9)
Female
(59.1)

N/A N/A Rhinorrhea,
dysgeusia, chest

pain

Myalgia, shivers,
arthralgia, fever,

irritability,
odynophagia,

cough, headache,
diarrhea

L. Monin.
(43)
UK/White
and Black

Cohort
study

PB 205 73
cancer

40.5
healthy

Male (52)
Female (48)

Deranged liver
function test grade 4

(0.5%)

3 weeks
after 1st

dose

Injection site
pain, erythema,
swelling, lym-
phadenopathy

Flue like
symptoms, fatigue,

headache, chills,
arthralgia, nausea
or vomiting, fever,

diarrhea
NoémieTissot.
(86) France

Prospective
cohort

PB 311 55.4 ±
6.4

Male (40)
Female (60)

N/A Between
21 and 28

days

Injection site
symptoms pain
and erythema

Fever chills joint
pain Fatigue
muscle pain

headache
Emanuel
Zitt. (87)
Austria

Cohort
study

PB 50 67.6 ±
14

Male (68)
Female (32)

N/A 7 days Pain Fever chills joint
pain Fatigue
muscle pain

headache
XiaomoXiong.
(88) USA

Cohort
study

PB, M 8,976 18–64
years

Male (21.4)
Female
(78.6)

Death (2.7%),
Life-threatening

illness (2.7%),
Permanent Disability

(1%),
Hospitalizations

(7.1%)

7 days Injection site
pain

Pyrexia chills
Dizziness Fatigue
Nausea Headache

Pyrexia, pain in
extremity, Dyspnea

Wi YM. (89)
Korea

Cohort
study

PB 80 35.83 ±
10.99

Male (31)
Female (69)

N/A After the
first and
second

week

Pain,
redness/swelling
Lymphadenopa-

thy

Vomiting, nausea,
fatigue, chills, fever,
myalgia, arthralgia

Werbel WA.
(90) USA

Cohort
study

PB, M 12 57 Male (55)
Female: (45)

N/A 14 days Pain,
redness/swelling

Fatigue, chills,
fever, myalgia,

diarrhea, headache
Edward E.
Walsh. (91)
USA

RCT First
phase

PB 195 35 Male (42)
Female (58)

N/A 7 days Pain,
redness/swelling

Fever, fatigue, chills

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S. SeyedAlinaghi et al. 20

Table 1: Severe adverse events, local and systemic side effects of mRNA COVID-19 vaccination

First Author
Country

Study type Manuf-
acturer*

Sample Age Gender (%) Severe adverse event Time to
appearance

Side effects (%)

Local Systemic
Alfred
Chung
Pui So. (44)
UK

Retrospective
cohort

PB, M 373 56 Male (37.5)
Female
(62.5)

chest pain(0.3%),
Dyspnea(1.1%)„
Urosepsis(0.3%)„

VTE(0.3%)

7 days Pain at injection
site/Sore arm,

Erythema

Vomiting,
nausea, fatigue,

chills, fever,
myalgia,

arthralgia,
diarrhea,

dizziness, lym-
phadenopathy,

anorexia,
paresthesia,

abdominal pain
Novena
Skroza. (92)
USA

Cohort
study

PB 436 57.26 Male (60)
Female (40)

N/A 10 days N/A N/A

Tom T.
Shimabukuro.
(30) USA

Cohort
study

PB, M 35,691 27.43
Female

100

N/A 14 days After Pain, red-
ness/swelling

Vomiting,
Nausea, Fatigue,

Chills, Fever,
Myalgia,

Arthralgia,
Diarrhea, Rash

Cinzia Ro-
tondo, (93)
Italy

Cohort
study

PB, M 325 60.2 ±
14.2

Male (42)
Female (58)

N/A 4 days after
vaccination

Pain,
redness/swelling

Chills, Fever,
Myalgia,
diarrhea,

headache fever
Yu-Wei
Chen. (94)
USA

Cohort
study

PB, M 81 70 Male (60)
Female (40)

Respiratory distress,
acute hemolytic
anemia, Shock

requiring pressure
support, Myositis,

Cardiogenic shock,
Pancreatitis/rash

1, 5, 7 days N/A N/A

Patrice
Chevallier.
(95) France

Prospective
study

PB 112 57 Male (50.7)
Female
(62.2)

N/A 7 days Pain, redness,
Swelling

Fever, Chills,
Fatigue, Myalgia,

Headache,
Nausea

Laurence
Chu. (96)
USA White,
African
Ameri-
can, Asian,
American
Indian, Na-
tive Hawai-
ian

RCT Second
phase

M 600 18-87 Male (35)
Female (65)

N/A 7 days Pain, Erythema,
swelling, Lym-
phadenopathy

Headache,
fatigue, myalgia,
arthralgia, nau-
sea/vomiting,

chills

Coggins.
(11) USA
White,
Black, Asian,
Hawaiian

Cohort
study

PB 206 42.4 Male (30.6)
Female
(69.4)

N/A N/A Soreness, pain Fatigue,
headache,
myalgia,

arthralgia, fever,
chills, Lym-

phadenopathy

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21 Archives of Academic Emergency Medicine. 2022; 10(1): e41

Table 1: Severe adverse events, local and systemic side effects of mRNA COVID-19 vaccination

First Author
Country

Study type Manuf-
acturer*

Sample Age Gender (%) Severe adverse event Time to
appearance

Side effects (%)

Local Systemic
Efrati. (97)
Israel

Cohort
study

PB 333 46 Male (51)
Female (49)

N/A At least 7
days

Pain, redness,
and swelling

Fever, chills,
Fatigue,

Headache,
Nausea,

Vomiting,
Diarrhea,

Muscle aches,
joint aches,

Allergic reaction
Nagla A El-
Shitany. (98)
Saudi Arabia
Retrospec-
tive

Cross-
sectional

PB 455 N/A Male (35.8)
Female
(64.2)

N/A N/A Arm pain,
injection site

pain, swelling,
and redness

Whole-body
pain, muscle

ache, joint ache,
hypersensitivity,

burning
sensation in the

eye
Robert W.
French.
(99) Multi-
national
African
American,
American
Indian or
Alaska,
Asian, Latin

RCT Third
phase

PB 2260 12-25 Male (51)
Female (49)

N/A 7 days Pain at the
injection site,

Swelling,
Redness

Fatigue,
Headache,

Chills, Muscle
pain, joint pain,
fever, diarrhea,

vomiting

Miguel
García-
Grimshaw.
(40) Mexico

Prospective
observa-

tional
cohort

PB 704,003 36 Male (74.2)
Female
(26.8)

0.005 with no
observed deaths

3 to 5 hours Injection site
pain

Headache,
Fatigue, Muscle
pain, joint pain,
chills, Nausea,

Fever,
Tachycardia,
Rhinorrhea,

Diarrhea,
vomiting,
irritability

Yarden
Golan. (100)
USA African
American,
white, Asian

Cohort
study

PB, M 50 35 Female (100) none 80 days Pain, redness,
swelling, itching,
rash around the

injection site

Fever, Chills,
Headache, Joint

pain,
Muscle/body
aches, fatigue,

Nausea,
Diarrhea

Time to appearance: Time from injection to the appearance of adverse events; *PB, Pfizer BioNTech; M, Moderna.
RCT: randomized controlled trial

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	Introduction
	Methods
	Results
	Discussion
	Conclusion 
	Declarations
	References