ABSTRACT
Introduction
Current safety data from Phase 3 clinical trials have concluded that apart from transient local and systemic reactions, no safety concerns were identified for the Moderna COVID-19 vaccine (mRNA-1273). However, Phase 3 studies are insufficient to detect rare adverse events (AEs). A literature search of the two major electronic databases, Embase and PubMed, was performed to enable the identification and characterization of all relevant articles from December 2020 to November 2022.
Areas Covered
This narrative review summarizes the key safety outcomes associated with the mRNA-1273 vaccine to inform healthcare decisions and increase public awareness of mRNA-1273 vaccine safety. The primary adverse events (AEs) reported within a diverse population, receiving the mRNA-1273 vaccine, were; localized injection site pain, fatigue, headache, myalgia, and chills. In addition, the mRNA-1273 vaccine was also associated with; less than a 1-day change in the menstrual cycle, a 10-fold higher risk of myocarditis and pericarditis within young males aged 18–29 years and increased levels of anti-polyethylene glycol (PEG) antibodies.
Expert Opinion
The transient nature of commonly observed AEs and the rare occurrence of severe events within mRNA-1273 recipients show no significant safety concerns which should prevent vaccination. However, large-scale epidemiological studies with longer follow-up periods are required to surveillance rare safety outcomes.
KEYWORDS:
1. Introduction
The Coronavirus Disease 2019 (COVID-19) is an ongoing global pandemic that has resulted in 2,125,577 confirmed deaths within the European Union (EU) and continues to pose a significant threat to public health worldwide [Citation1,Citation2]. COVID-19 is a communicable disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection arises through the SARS-CoV-2 ‘S’ protein binding to its cell surface receptor on angiotensin-converting enzyme 2 (ACE2), enabling viral entry into type II pneumocytes within the human lung [Citation1]. The World Health Organization (WHO) has made it a priority to ensure ‘everyone, everywhere’ has access to COVID-19 vaccines to protect against serious illness, hospitalization and death from COVID-19 [Citation3].
1.1. COVID-19
The most prevalent symptoms of COVID-19 are; fever (chills), new continuous dry cough, fatigue, and upper respiratory tract symptoms such as pharyngitis, headaches, and myalgia [Citation1,Citation4]. Similarities in the presentation of COVID-19 with other seasonal illnesses, such as colds and flu, have made it challenging for individuals to initially differentiate the symptoms of the disease and isolate themselves leading to the spread of the disease. However, over time PCR testing and antigen tests made it easier to diagnose COVID than to diagnose flu. COVID-19 is predominantly spread from person to person through respiratory droplets and contact transmission, where the disease can be propagated through close contact with an infected individual or by touching surfaces covered in droplets [Citation1,Citation4]. The high transmissibility rates of SARS-CoV-2 have made it imperative to implement preventative measures such as vaccines to reduce the spread of the disease, particularly within susceptible populations at risk of severe outcomes. Of known COVID-19 deaths in England and Wales from January to May 2021, older adults (over 60 years) accounted for more than 90% of reported deaths. In contrast, children (<10 years old) accounted for less than 0.1% [Citation5].
Individuals with underlying co-morbidities such as hypertension, diabetes, preexisting respiratory infection, cardiovascular disease, immunocompromised and cancer are predisposed to develop severe symptoms of COVID-19. Presently the National Institute of Health and Care Excellence (NICE)recommends preventive measures, self-care, and close monitoring for the management of COVID-19 [Citation1,Citation6]. In addition, up-to-date COVID-19 vaccines are recommended by the National Health Service (NHS) to; significantly lower the risk of COVID-19-associated hospitalization and morbidity, reduce transmission and provide protection against COVID-19 variants, further illustrating the need for vaccines [Citation7].
1.2. Moderna COVID-19 vaccine
The Moderna COVID-19 vaccine (mRNA-1273) obtained Emergency Use Listing (EUL) by WHO on 30 April 2021, and around 161 million doses have been administered within the European Union/European Economic Area (EU/EEA) as of November 2022 [Citation8,Citation9]. mRNA-1273 is a messenger RNA (mRNA) vaccine comprised of strands of mRNA encapsulated within liquid nanoparticles (LNPs). The strands of mRNA provide the genetic template for encoding the viral Spike (S) glycoprotein of SARS-CoV-2, which performs a crucial function in transmission and infection [Citation10]. The LNP system allows uptake of the mRNA complex into host cells upon intramuscular administration enabling the delivery of mRNA to the cytosol. Subsequently, the mRNA sequence is translated into S proteins within the ribosomes allowing the body to generate an immune response to the foreign S protein and retain memory immune cells [Citation10]. The mRNA-1273 vaccine has shown 94.1% efficacy in preventing COVID-19 within phase 3 trials and is effective across different populations. However, safety data regarding the vaccine’s adverse effects (AEs) are limited from clinical trials due to their short follow-up periods and strict inclusion and exclusion criteria [Citation11].
1.3. Safety
As of November 2022, 68.2% of the world population has received a minimum of one dose of a COVID-19 vaccine which leaves 31.8% still unvaccinated and susceptible to COVID-19 and its severe outcomes [Citation12]. Furthermore, the US Census Bureau’s experimental Household Pulse Survey (HPS) on why adults over 18 years do not get the COVID-19 vaccine determined that around half claimed they were concerned about possible AEs, signifying a gap in public knowledge regarding the safety profiles of COVID-19 vaccines [Citation13]. Current safety data from phase 3 clinical trials have concluded that apart from transient local and systemic reactions, no safety outcomes were identified for the mRNA-1273 vaccine. However, phase 3 studies are inadequate to detect rare AEs, including anaphylactic reactions or myocarditis among adolescents and young adults [Citation11]. Therefore, continued evaluation of the safety profile of the mRNA-1273 vaccine is warranted. This review aims to summarize the key safety outcomes associated with the mRNA-1273 vaccine from the latest evidence available to inform healthcare decisions and increase public awareness of mRNA-1273 vaccine safety.
2. Method
2.1. Data sources and search strategy
A literature search of the two major electronic databases, Embase and PubMed, was performed to enable the identification and characterization of all relevant articles. Search terms considered different abbreviations for the Moderna vaccine (Moderna vaccine OR mRNA-1273) and safety (Safety OR Adverse effects) to achieve a comprehensive search. Boolean search terms such as ‘(“Moderna vaccine” OR mRNA-1273) AND safety*’ and Medical Subject Headings (MeSH) terminology restricted the search results to provide more relevant articles. Citation analysis was also utilized to retrieve relevant studies from articles’ reference lists. The search period for this review was from December 2020 to November 2022. An overview of the preliminary search strategy can be viewed in of the Appendix.
2.2. Study screening and selection
A single reviewer was assigned to eliminate duplicates identified within the two databases before the screening. Single screening of titles and abstracts of articles was conducted to exclude articles assessing different outcomes to the subject being studied. A flow chart summarizing the screening and selection process is depicted in . Full-text English articles which evaluated the reactogenicity or different safety outcomes of the mRNA-1273 vaccine as a primary or secondary outcome were eligible for inclusion. The study designs permitted within the review were randomized control trials (RCTs), including phase 1 and 2 trials, cross-sectional studies, cohort studies, post-authorization surveillance, observational studies, and qualitative studies. Full-text analysis of identified articles was performed to enable the exclusion of studies which did not satisfy the predetermined eligibility criteria. Full inclusion and exclusion criteria can be viewed in in the Appendix. All eligible studies were exported to EndNote software.
Figure 1. PRISMA flow chart depicting study screening and selection process.
2.3. Data selection and synthesis
Information regarding the intervention, study design, sample size and characteristics, relevant AEs and limitations were extracted from each eligible study. Data collected was summarized within a standardized Microsoft Word data collection table ( (qualitative summary of included RCTs) and (qualitative summary of included observational studies)). The primary outcome of interest was the safety and reactogenicity profile associated with the mRNA-1273 vaccine. In addition, data comparing AEs in vaccine recipients and controls were reported from RCTs and rates of specific AEs within populations were reported from observational studies.
Table 1. Qualitative summary of included RCTs (randomized control trial studies).
Table 2. Qualitative summary of included observational studies.
3. Results
Twenty full-text studies applicable to the review topic have been included. Analysis of the studies included have been summarized within (qualitative summary of included RCTs) and (qualitative summary of included observation studies). A primary search of the two electronic databases, Embase and PubMed, generated 1,365 articles, of which 1,335 were selected for screening following the removal of duplicate studies. In addition, a single screening of titles and abstracts excluded 1,298 studies irrelevant to the subject of interest. Twenty studies which did not satisfy the set inclusion and exclusion criteria were also eliminated following full-text eligibility analysis. Therefore a total of twenty articles were identified for inclusion following the addition of three studies discovered through citation analysis. This information has been summarized within a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart depicting the study selection process (). Six studies are RCTs conducted within different population groups assessing vaccine safety as a primary or secondary outcome. Of the fourteen observational studies included, four were cohort studies, three post-authorization surveillance studies, two retrospective studies, two cross-sectional studies, one prospective, non-inferiority trial, one longitudinal study and one registry-based study. Overall, this review analyzed a wide range of study designs assessing various safety outcomes of the mRNA-1273 vaccine as their primary or secondary outcomes.
4. Discussion
4.1. Common adverse effects
Recent studies investigating the safety outcomes of the mRNA-1273 vaccine have concluded that aside from transient local and systemic reactions, no serious adverse effects (AEs) have been identified [Citation14–16]. The most prevalent symptoms reported within mRNA-1273 recipients were localized symptoms (96.06%), generalized symptoms (67.59%), musculoskeletal symptoms (62.5%) and gastrointestinal symptoms (35.4%) [Citation14]. Of these, a sore arm or localized pain, generalized weakness or fatigue, headache, myalgia or muscle pain, chills, fever, and nausea were the most commonly reported, usually occurring within a day after vaccine administration and resolving after 2 days [Citation14–16]. The AEs observed indicate COVID-19 symptoms and are initiated by the body’s immune response to the foreign ‘S’ protein produced from the mRNA introduced by the vaccine [Citation4,Citation10]. This response is comparable to the reaction the body has to SARS-CoV-2, thereby resembling certain symptoms of the disease. Irrespective of the AEs experienced, 97.02% of mRNA-1273 recipients intended to receive the second dose indicating the mild and transient nature of the adverse effects experienced. Moreover, 81.71% of participants had already received the second dose of the vaccine by the completion of this study [Citation14]. This further suggests that vaccine hesitancy regarding the safety of the mRNA-1273 vaccine was not a concern among this group. However, the severity of these common AEs can differ between individuals.
A larger, retrospective study investigating the clinical characteristics of COVID-19 vaccination AEs found that within individuals receiving mRNA-1273, 0.34% experienced a mild AE, 0.005% experienced major severe AEs, and a very small proportion experienced an anaphylactic event [Citation15]. Common major AEs were severe skin reactions, acute paralysis, anaphylaxis, acute respiratory distress syndrome and lymphadenitis. The large population (n = 2,343,396) examined within this research paper and the long study period of 25 weeks allowed the ability to detect rarer adverse effects such as Guillain-Barré syndrome, thrombocytopenia, and acute cardiac injury [Citation15]. However, the small fraction of major severe AEs within this study is reassuring and further confirmed by phase 3 trials which determined the frequency of grade 3 AEs among the placebo group (1.3%) was similar to that observed within the vaccine group (1.5%) [Citation15,Citation16]. Medically attended AEs (9.7% vs 9% respectively) and serious AEs (0.6% in both groups) were also comparable within the placebo and mRNA-1273 vaccine groups [Citation16]. The inclusion of racial and ethnic minorities within the trial population of this randomized control trial further improves the generalizability and validity of these findings [Citation16]. Additionally, the severity and frequency of AEs increased following the second dose of mRNA-1273, demonstrating the need for more caution after administering this dose [Citation15,Citation16]. The increase in the intensity of AEs following the second dose can be attributed to the substantially increased anti-SARS-CoV-2-spike bAb (binding antibody) levels after the second vaccination exceeding levels found in convalescent COVID-19 sera leading to a more robust immune response [Citation17].
4.2. Safety outcomes by population demographics
4.2.1. Children
The European Medicines Agency (EMA) has authorized the mRNA-1273 vaccine for primary vaccination courses for children from 6 months of age. However, the safety and immunogenicity of the vaccine within children are largely unknown [Citation18]. Recent safety data has shown a higher incidence of local and systemic AEs within children receiving the mRNA-1273 vaccine than within placebo groups after both doses; however, AEs reported were mainly low-grade, with the most common being pain at the injection site (93% after 1st dose and 95% after 2nd dose), headache (31% after 1st dose and 54% after 2nd dose), and fatigue (43% after 1st dose and 65% after 2nd dose) [Citation19,Citation20]. Irritability or crying, sleeplessness and loss of appetite were also frequently observed in children aged 6 to 36 months. However, the incidence was similar within the placebo and mRNA-1273 groups.
These symptoms suggest a fever caused by the immune response when a pyrogenic such as the SARS-CoV-2-spike protein enters the body and is typically resolved within 1–3 days [Citation19]. Grade 3 AEs such as erythema, swelling and lymphadenopathy were uncommon and more frequent after the second dose, similar to what is observed within adult populations [Citation16,Citation19,Citation20]. Vaccine-related serious adverse effects, a multisystem inflammatory syndrome in children, myocarditis, or pericarditis were also not observed in children aged 6 months to 11 years. Overall, Phase 3 trials have concluded that the incidence of AEs occurring within 28 days of the injection was similar within the mRNA-1273 vaccine group and placebo group [Citation19,Citation20], proving the relative safety of the mRNA-1273 vaccine within children aged 6 months to 11 years.
Including healthy children alone and the overrepresentation of White participants within these trials provides room for potential selection bias reducing the generalizability and reliability of these results. However, the studies have acknowledged the underrepresentation of Black populations and have adjusted accordingly [Citation19]. Furthermore, the limited follow-up periods increase the risk of type 2 errors for more serious AEs, even though a large sample size has been utilized to account for type 1 errors. This shows a demand for more widescale investigations in children receiving mRNA-1273 to detect rare adverse reactions [Citation19].
4.2.2. Adolescents
Between July 2021 and December 2021, 66032 adolescents aged 12–17 years were reported to have received both doses of the mRNA-1273 vaccine within the United States (US); however, similar to children, data on the safety profile of the vaccine within adolescents is limited [Citation21,Citation22]. A recent phase 3 trial conducted with 3,732 participants aged 12–17 years which compared the AEs related to the mRNA-1273 vaccine against a placebo, found the most common adverse reactions after the first or second dose were; injection-site pain, headache and fatigue with a higher incidence observed after the last dose [Citation22]. These results are analogous to clinical trials conducted in adults [Citation15,Citation16], showing no particular patterns of concern within this population. No grade 3 local reactions were reported within the placebo group compared to 6.8% after the first dose and 8.9% after the second dose within those receiving mRNA-1273; however, local and systemic reactions generally resolved after four days. Incidences of local reactions sustained for more than 7 days, primarily axillary swelling or tenderness, were also higher among the mRNA-1273 group after the first and second dose compared to the placebo, indicating the possible requirement for longer follow-up within this population after vaccination [Citation22]. Generally, the incidence of local and systemic AEs among adolescents after the mRNA-1273 vaccine was similar to those observed among adults, and the overall benefit-risk profile of the vaccine was encouraging [Citation22].
Randomized controlled trials such as this study are the most efficient method for analyzing the safety of new treatments since it eliminates the risk of bias within results, particularly confounding, improving the validity of inferences made regarding a causal relationship [Citation23]. However, the safety data presented from this trial was based on a median follow-up of 83 days, which may be inadequate to detect rare AEs [Citation22].
4.2.3. Older adults
Ageing has been associated with a decline in different immune cells leading to poorer immune responses to infection [Citation24]. The decline in immune function in older adults may also contribute to different reactogenicity profiles to mRNA-1273 compared to children and adolescents. Occurrence of both injection-site and systemic AEs was shown to be more frequent among younger participants (18 to <65 years of age) than among older participants (≥65 years of age) [Citation16]. This is presumably due to a decrease in lymphocytes involved in the adaptive immune response within older populations resulting in a less robust immune response to the foreign antigen [Citation24]. Furthermore, erythema, induration and swelling were commonly reported within the older populations (26.5%, 24.5% and 28.6%, respectively) compared to younger populations (13.3%, 7.1% and 10.2%, respectively) [Citation25]. A possible explanation for this is the immune system’s reduced ability to distinguish self-antigens from nonself which occurs within older adults resulting in delayed hypersensitivity reactions such as these [Citation26,Citation27]. However, local and systemic AEs were largely mild or moderate in severity and resolved within 1–3 days [Citation25]. The overall prevalence of local and systemic AEs was similar within younger and older participants, with the most common being headache, fatigue, myalgia, chills, and injection-site pain, showing no particular safety concerns within this population demographic [Citation25,Citation28].
4.2.4. Pregnant persons
The exclusion of pregnant persons from clinical trials has resulted in a gap in understanding the safety profile of the mRNA-1273 vaccine within pregnant individuals and its effect, if any, on the unborn fetus [Citation16]. Post-authorization surveillance of AEs within pregnant women following COVID-19 vaccination found that the most common pregnancy-specific outcomes were spontaneous abortion(SAB), vaginal bleeding, and preterm delivery within individuals who received mRNA-1273 [Citation29]. A quarter of these reports accounted for SAB. However, most participants who had experienced SAB were 35 years or older [Citation29]. Increased maternal age has been linked with an increased risk of miscarriage, and it was determined that women aged≥35 years have a higher likelihood of experiencing early termination of pregnancy [Citation30]. Furthermore, an observational cohort study also confirmed that the frequency of miscarriage or stillbirth was reported at similar rates between pregnant controls and vaccinated groups within 7 days after the first dose (2.1% vs 1.5%) [Citation31]. Conversely, a multivariable analysis adjusting for age group, previous SARS-CoV-2 infection, and trimester established an increase in the risk of significant health events within 7 days after the second dose of mRNA-1273 within pregnant individuals compared to unvaccinated controls (aOR 4·4 [2.4–8.3]) [Citation31]. However, the slightly wider confidence interval (CI) observed here makes this result less reliable and potentially suggests the need for a larger sample size to confirm this outcome. Additionally, when the outcome variable was restricted to events requiring medical consultation, this increased risk was no longer detected [Citation31]. Generally, when comparing vaccinated pregnant and vaccinated non-pregnant groups, the incidence of significant AEs was consistently lower among pregnant individuals across all mRNA vaccine types and doses [Citation31]. This is potentially due to the unique immunological state observed within the pregnancy, leading to different immunological responses and reactogenicity [Citation32]. During pregnancy, the immune system is modulated to protect the mother from the environment and prevent fetal harm. The developing active immune system of the fetus also modifies the mother’s immune response, leading to differences in how pregnant women respond to the presence of microorganisms [Citation32]. This may also explain why pregnant women are more susceptible to COVID-19 and its severe outcomes showing the need for preventative measures such as vaccination.
4.2.5. Cancer patients
Cancer patients are highly susceptible to COVID-19 and its complications due to the mechanism by which the disease and its treatments weaken the immune system. Particular types of cancer, such as leukemia and lymphoma, can specifically target the immune system to reduce its function [Citation33]. This significantly lessens the ability of cancer patients to fight infections such as COVID-19, leaving them vulnerable to its severe outcomes, including death [Citation33]. Therefore, prevention through vaccination is key within this group and is recommended by oncological societies such as Cancer Research [Citation34]. The variations in immune function observed within cancer patients may have pronounced differences in their immune response and reactogenicity to the mRNA-1273 vaccine compared to individuals without the disease. However, excluding cancer patients, particularly patients with ongoing therapy from clinical trials, means safety data is scarce. Observational studies conducted with cancer patients have identified similar adverse effects of the mRNA-1273 vaccine to ones studied within non-oncologic populations [Citation35,Citation36]. The most common systemic reactions reported were fever followed by malaise and myalgia, with prevalent local AEs being pain at the injection site after both doses of the vaccine [Citation35,Citation36]. Increasing age was associated with a decreased likelihood of exhibiting adverse effects (p = 0.016). These results reinforce similar findings from RCTs conducted on older adults [Citation28].
Incidence of grade 3 or worse events within cancer patients was 1.8%; however, 5 cases of thromboembolism were reported alongside immune-related AEs, which occurred in 4% of patients treated with immunotherapy and 4% of patients treated with chemoimmunotherapy. Although of significant concern, these adverse effects are all probability due to disease-related and treatment-related complications (36). Cancer has been recognized by NICE guidance and the Department of Health as a risk factor for venous thromboembolism (VTE) [Citation37]. Recent studies have calculated a 2.3% cumulative incidence ([CI], 2.2% to 2.3%) of VTE 12 months after the cancer diagnosis compared to 0.35% (95% CI, 0.34% to 0.36%) in the comparison cohort [Citation37,Citation38]. Therefore, an increased risk of thromboembolism or immune-related AEs instigated concerning the vaccine cannot be established from the data presented.
Interestingly a cohort study found a correlation between higher Eastern Cooperative Oncology Group (ECOG) scores and a lower proportion of patients suffering from systemic AEs [Citation35]. ECOG scores are utilized within clinical trials to measure how cancer impacts a patient’s daily living, with low scores indicating a slight decline in function [Citation39]. The reduced incidence of systemic AEs within cancer patients with higher ECOG scores may result from the reduced immune function observed in the later stages of cancer characterized by higher ECOG scores generating less robust immune responses hence, lower systemic effects. This further establishes the need for vaccines which boost the immune system and equip it to fight infections. However, this relationship between ECOG scores and AE incidence did not show a statistically significant association (p = 0.012) and requires further investigation within larger study populations [Citation35].
4.3. Safety outcomes of interest
The EMA and Centers for Disease Control and Prevention (CDC) identified the following safety outcomes associated with the mRNA-1273 vaccine as a cause for concern; however, the underlying mechanism of these AEs is not fully understood [Citation40]. In addition, due to their short study periods, restrictive inclusion criteria and small sample sizes, clinical trials are not powered to detect infrequent and serious AEs, including myocarditis/pericarditis. This can lead to increasing hesitancy and mistrust among the general public resulting in reduced vaccine uptake.
4.3.1. Menstrual irregularities
The recent EMA COVID-19 vaccine safety update has recognized the possible association of menstrual irregularities, such as heavy menstrual bleeding, to the mRNA-1273 vaccine; however menstrual symptoms were not generally included within the solicited AEs studied in clinical trials [Citation16,Citation28,Citation40]. A cohort study examining reports made to v-safe found that from 63,815 respondents who reported irregularities or vaginal bleeding, 41.9% received the mRNA-1273 vaccine demonstrating a plausible link between mRNA-1273 and menstruation [Citation41]. Menstrual symptoms included; irregularities in menstrual timing (42%), an increase in severity of menstruation (41.9%), menopausal bleeding (44.7%) and resumption of menses in persons whose menstrual cycles were suppressed by medication, conception, or breastfeeding (42.5%). These responses commonly occurred within 7 days following each dose of the vaccine and at 3-month and 6-month surveys after the second dose [Citation41]. Therefore, many of these reports could be a case of positive rechallenging where the menstrual change has occurred after the first dose and has resumed following the second dose indicating the possibility that the vaccine has triggered the irregularities [Citation40]. Unfortunately, this study could not directly compare responses among individuals to confirm this hypothesis, making this area require continued monitoring. Menstruation is the process of endometrium shedding, which occurs monthly as the body discards the buildup of the uterus lining and is regulated by levels of estrogen and progesterone hormones [Citation42,Citation43]. The immune response following the mRNA-1273 vaccine may cause the endometrium (a component of the immune system) to adapt its immune environment to protect the uterus leading to abnormal menstrual changes such as those observed [Citation44]. However, menstrual irregularities are common amongst women and have also been observed in the absence of COVID-19; therefore, a true correlation between the mRNA-1273 vaccine and these irregularities cannot be established, particularly since this study was not able to compare incidence with baseline rates [Citation41].
Conversely, a study analyzing menstrual cycle data between vaccinated and unvaccinated individuals determined a less than 1-day change in cycle length in association with both COVID-19 vaccine doses (0.64 day-increase (98.75% CI 0.27–1.01). Of this population, 35% had received the mRNA-1273 vaccine. The increase in cycle length was predominantly driven by individuals who had received their vaccine doses within a single cycle period [Citation45]. ACE2 receptors involved in SARS-CoV-2 infection (also targeted by mRNA-1273 vaccines) are also present within the endometrium and ovaries, where they modulate estradiol and progesterone production to increase or decrease cells on the endometrium concerning cycle stage [Citation44]. An explanation for the changes in cycle length is the robust immune response produced by mRNA vaccines which may disrupt this modulation when timed correctly [Citation44,Citation45]. However, the study determined these changes were not clinically significant and generally returned to baseline cycle lengths quickly [Citation45]. Further follow-up on subsequent cycles is necessary to confirm this.
4.3.2. Myocarditis and pericarditis
The relatively small sample sizes associated with clinical trials are inadequate to detect the incidence of rare AEs such as myocarditis [Citation22]. Active post marketing surveillance of the mRNA-1273 vaccine has shown increased relative incidences (RI) of myocarditis/pericarditis following the first and second doses of mRNA-1273 over a 7-day risk period [Citation46,Citation47]. Individuals vaccinated with mRNA-1273 had a significantly increased rate of myocarditis or myopericarditis compared with unvaccinated follow-up within males and females (adjusted hazard ratio 3.92 (2.30 to 6.68)) [Citation48]. Furthermore, the risk of reporting myocarditis/pericarditis was 10-fold higher among young males aged 18–29 years compared to females [Citation46–48]. The study’s large sample size and demographic variability make these results more generalizable and present a true concern regarding the risk of myocarditis/pericarditis within young males following mRNA-1273 vaccination. Myocarditis, defined as inflammation of the myocardium, can occur in response to infections or damage to the heart through autoimmune diseases [Citation49]. The robust immune response associated with the mRNA-1273 vaccine (bAb levels exceeding those found in convalescent COVID-19 sera) triggers inflammation which can rarely affect the heart leading to cases of myocarditis/pericarditis [Citation17,Citation50]. However, the mechanism of mRNA-1273-related myocarditis/pericarditis within young males is not yet understood, although generally, a higher incidence of myocarditis unrelated to COVID-19 has been apparent within males [Citation51]. As of April 2021, the CDC has recognized the increase in cases of myocarditis and pericarditis associated with mRNA vaccines. However, the CDC recommends vaccination since the benefits outweigh the risks associated with COVID-19 (including myocarditis) [Citation52]. Additionally, the severity of cases of myocarditis/pericarditis has not been assessed concerning the mRNA-1273 vaccine. It is an area that requires further research to determine the risks associated with mRNA-1273-related myocarditis/pericarditis.
4.3.3. Anti-PEG antibodies
The inclusion of (polyethylene glycol) PEG within drug formulations have been accompanied by the production of anti-PEG antibodies, which can reduce the therapeutic efficacy and safety of PEGylated drugs such as the mRNA-1273 vaccine [Citation53], which incorporates PEG within the liquid nanoparticle (LNP) formulation to improve stability of the vaccine [Citation10]. Recent studies have found a significant increase in the titers of anti-PEG IgG and IgM antibodies following 2 doses of mRNA-1273 compared to no changes in anti-PEG IgG and IgM levels within unvaccinated individuals [Citation54,Citation55]. The antibodies have been shown to specifically recognize PEG within the PEG−lipid component of the mRNA-1273 vaccine suggesting an increased association of an immune response against these components, which can reduce the therapeutic effect of the vaccine and elicit a greater incidence of AEs [Citation53,Citation55]. Furthermore, the increase in levels of anti-PEG IgG and IgM was concurrent with a higher rate of systemic (and total) reactogenicity following the second dose of mRNA-1273; however, the exact mechanism of this relationship has not been studied. Research suggests the association of anti-PEG antibodies with hypersensitivity reactions [Citation53,Citation55]. In addition, the incidence of delayed large local reactions has been reported among recipients of the mRNA-1273 vaccine, although mild may be of concern to recipients [Citation56]. A registry-based analysis of 414 cutaneous reactions revealed 83% of reactions occurred within mRNA-1273 recipients. More than 50% of these reactions accounted for delayed large local reactions, which occurred after a median of 7 days from the first dose and lasted around 4 days [Citation56]. The etiology of these reactions may be linked to hypersensitivity reactions in response to PEG within mRNA-1273 induced by C activation [Citation53]. However, such delayed injection-site reactions were only reported within 0.8% of participants after the first dose and 0.2% after the second dose within a phase 3 clinical trial [Citation16]. Although the concerns related to the occurrence of hypersensitivity are low, the effect of increased levels of anti-PEG associated with the mRNA-1273 vaccine alone requires further investigation with larger cohorts to confirm this relationship between reactogenicity and change in anti-PEG antibodies [Citation55].
4.3.4. Thromboembolic outcomes
This review did not identify any studies that reported thromboembolic outcomes with thrombocytopenia associated with the Moderna vaccine, which has been reported as a potential concern with ChAdOx1 nCoV-19 (AstraZeneca)22,23 and Ad26.COV.2.S (Janssen) vaccines [Citation57].
4.3.5. 4.4.Limitations
This review has several limitations which must be considered when interpreting the data presented. First, due to the limited median follow-up periods (ranging from 7 to 82 days) within included studies, a complete evaluation of the long-term safety profile of the mRNA-1273 vaccine was not possible; however, since the vaccine is relatively new, long-term safety data is limited. Second, the evidence presented within this review cannot be used to deduce a causal relationship between AEs and the vaccine due to factors such as the availability of the vaccine, individual comorbidities, and different health behaviors, which this review has not been able to adjust for, findings, therefore, must be interpreted with caution. Third, the inclusion of only two databases, exclusion of gray literature, unpublished work and pre-print servers has greatly reduced the breadth of research and limited the search’s comprehensiveness. Fourth, the confidence intervals for some rare side effects (for example, anti-PEG antibodies) were wide. Fifth, we did not critically appraise the quality of the studies. Sixth, the exclusion of the other mRNA vaccine Pfizer (BNT162B2) reduces the completeness of this review. Finally, ongoing safety evaluation regarding the long-term and rare and serious adverse effects of the mRNA-1273 vaccine is warranted as CIs for some of the serious AEs are wide.
5. Conclusion
The review summarized safety data from spontaneous reports and real-world studies across a broad population, including children, adolescents, older adults, pregnant women, and cancer patients. The main AEs reported within the population range were localized injection site pain, fatigue, headache, myalgia, and chills which generally resolved within two days following administration. An increase in severity was reported following the second dose of mRNA-1273 which can be accounted for by the heightened immune response achieved by this dose. In contrast, the mRNA-1273 vaccine has been associated with a less than 1-day change in menstrual cycle length, particularly within individuals receiving two doses within the same cycle. This change was not clinically significant; however, further follow-up on subsequent cycles is warranted to determine any long-term effects.
Furthermore, a 10-fold higher risk of myocarditis and pericarditis has been found in young males aged 18–29 years within a 7-day risk period; however, the incidence has been low. Additionally, increased levels of anti-PEG IgG and IgM antibodies following 2 doses of the mRNA-1273 vaccination were identified. This increase in anti-PEG antibodies was associated with increased systemic events and delayed hypersensitivity reactions.
6. Expert opinion
The high transmissibility rates of COVID-19 infection have made it essential to implement prevention methods to target the spread of the disease, particularly within susceptible populations at risk of severe COVID-19 outcomes. However, the mounting rates of public concern regarding the safety of COVID-19 vaccines, such as the mRNA-1273 vaccine, have contributed to the increasing vaccine hesitancy. The review determined that the transient nature of commonly observed AEs and the rare occurrence of severe events within mRNA-1273 recipients show no significant safety concerns which should prevent vaccination. On the contrary, the overall risk-benefit profile of vaccination is favorable and should be encouraged within all populations to prevent COVID-19 and its severe outcomes. For example, a study by Patone et. al found that there was an increased risk of myocarditis within 28 days after a SARS-CoV-2–positive test before vaccination (Incidence Rate Ratio (IRR), 11.14 [95% CI, 8.64–14.36]) than in vaccinated individuals (IRR, 5.97 [95% CI, 4.54–7.87]) showing that the benefits of vaccination outweigh the rare AEs associated with the mRNA-1273 vaccine [Citation58]. This research informs the general public of the relative safety outcomes of the mRNA-1273 vaccine to enable an informed decision-making process which considers the known risks alongside benefits and reduces the uncertainty observed among the public to promote vaccination. Additionally, knowledge of the potential risks associated with the mRNA-1273 vaccine, such as myocarditis, enables healthcare providers to make patient-centered care decisions. Limited safety data are available on minority ethnic groups such as Black persons and high-risk groups, for instance, pregnant and breastfeeding women or immunocompromised patients, particularly within RCTs, showing a knowledge gap which requires targeted study. Although a statistically significant relationship between mRNA-1273 vaccination during pregnancy and SAB was not established, large-scale observational studies are warranted to assess further the risks associated with mRNA vaccine-related SAB. Safety data regarding pregnant and immunocompromised populations is essential since they are at an increased risk of COVID-19 complications and, therefore, may have different reactogenicity profiles to that observed within adults. Consequently, the inclusion of minor ethnic groups and risk groups within RCTs will significantly increase the diversity of the study population, making results more generalizable and allowing the detection of AEs not commonly observed within healthy populations.
There is also a lack of data regarding the rare AEs associated with the mRNA-1273 vaccine. Although observational studies have found an increased risk of myocarditis and pericarditis among young males aged 18–29, the physiological mechanism of increased mRNA-1273-related myocarditis/pericarditis incidence within young males remains undetermined and long-term evaluation within this group is necessary to validate this relationship further. Furthermore, recent data have identified increased levels of anti-PEG antibodies following mRNA-1273 vaccination associated with increased systemic events and delayed hypersensitivity reactions. Incidence of such hypersensitivity reactions is uncommon; however, the effect of increased anti-PEG antibodies on the frequency of systemic AEs observed following vaccination and on other PEGylated drugs needs to be established through controlled studies with larger study populations.
On-going safety research for the mRNA-1273 vaccine is essential since it is relatively new and long-term safety data is limited. The continued large-scale epidemiological study will allow monitoring of the known AEs, identification of emerging/rare AEs, detection of variations in AEs experienced among different populations and identification of potential risk factors for specific AEs. Additionally, large-scale epidemiological studies with longer follow-up periods are required to surveillance rare safety outcomes of this vaccine. Utilization and awareness of spontaneous reporting systems such as VAERs should be encouraged for the continued capture and surveillance of adverse events following vaccination. The accessibility of such platforms enables early detection of rare AEs, which many RCTs are not powered to detect. However, a major limitation of spontaneous reporting systems is the absence of a control group. Therefore, large-scale observational studies, such as registry-based studies, are warranted to determine a causal relationship between the mRNA-1273 vaccine and the AE of interest. This will allow the public and healthcare professionals to make informed and patient-centered decisions regarding vaccine uptake.
Article highlights
Twenty full-text studies applicable to the review topic have been included.
The primary adverse events (AEs) reported were; localized injection site pain, fatigue, headache, myalgia, and chills.
The mRNA-1273 vaccine was associated with; less than a 1-day change in the menstrual cycle, a 10-fold higher risk of myocarditis/pericarditis within young males and increased levels of anti-polyethylene glycol (PEG) antibodies.
The mRNA-1273 vaccine showed no significant safety concerns.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or mending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Additional information
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References
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Appendix
Table A1. Summary of the set inclusion and exclusion criteria for study selection.
Table A2. Overview of the preliminary search strategy. A broad literature search of the 2 major electronic databases, Embase and PubMed, was performed. Search terms considered different abbreviations for the exposure (Moderna Vaccine) and the outcome (adverse effects) within each database. The search period was set from 2020 till 2022 within both databases.