The first case of coronavirus disease (COVID-19) was reported in late December 2019 in Wuhan, China [1]. This infectious disease started to spread rapidly across China and then to many countries. The World Health Organization declared COVID-19 as a pandemic in March 2020. Because of the devastating effect of this disease, the development of a vaccine against severe acute respiratory syndrome coronavirus (SARS-CoV)-2, which is the causative virus of COVID-19, has progressed rapidly and extensively [2,3].

SARS-CoV-2 has a spike protein that induces a host response by binding to the angiotensin converting enzyme 2 receptor, the same receptor used by the SARS-CoV.4 Vaccines have been developed, with the spike protein as the main target, and several vaccines have been administered in various countries.

Currently, several studies on the efficacy and safety of COVID-19 vaccines have been reported. We would like to review the safety of the COVID-19 vaccines reported in those studies and make some suggestions for emergency physicians to help prepare for patients presenting with adverse vaccine reactions.

COVID-19 vaccines are categorized according to the manufacturing technique: mRNA vaccines, adenovirus vector vaccines, and inactivated virus vaccines [5]. mRNA vaccines, which are developed by Pfizer-BioNtech, New York, NY, USA (BNT162b2) and Moderna, Cambridge, MA, USA (mRNA-1273), are lipid nanoparticle-encapsulated, nucleoside-modified RNA-based vaccines that encode the receptor-binding domain of the SARS-CoV-2 spike protein [6-9]. This lipid nanoparticle carrier system prevents the rapid enzymatic degradation of mRNA and facilitates in vivo delivery [6]. Because lipid nanoparticles are sensitive to temperature, this type of vaccine should be transported and stored under extremely low temperatures [7].

ChAdOx1 nCoV-19, which is developed by AstraZeneca, London, UK, is a replication-defective chimpanzee adenovirus vector vaccine. This vaccine contains the SARS-CoV-2 structural surface glycoprotein antigen (spike protein) gene [10,11]. Recombinant adenoviruses were initially developed as vehicles for gene therapy. However, they are currently being used as vaccine vectors because of their attractive characteristics. The adenovirus genome can be rendered replication-defective by deleting certain regions, and it can induce transgene-specific immune responses. Additionally, because of its relative thermostability, it is easier to store and transport ChAdOx1 nCoV-19 vaccines than mRNA vaccines [12,13]. However, preexisting immunity due to natural infections of adenovirus may reduce the immunogenicity of vector vaccines [12]. Therefore, adenoviruses isolated from chimpanzees, not human adenoviruses, are being used as vaccine carriers [13]. Previously, replication-defective chimpanzee adenovirus vectors have been used as novel vaccines, such as Ebola vaccines [14,15]. The Ad26.COV2.S vaccine (Bridgewater Township, NJ, USA) and the Gam-COVID-Vac (Sputnik V; Gamaleya Research Institute, Moscow, Russia) are also recombinant, replication-defective adenovirus vector vaccines that contain the SARS-CoV-2 spike protein [16,17].

The CoronaVac (Sinovac Biotech, Beijing, China) and Sinopharm COVID-19 vaccines have the inactivated form of SARS-CoV-2 [18,19]. Inactivated virus vaccines have been widely used for vaccine development, including polio, hepatitis A, and influenza vaccines [20-22]. In an inactivated virus vaccine, the pathogen is killed or modified so that it cannot cause the disease. CoronaVac is a vaccine that inactivates SARS-CoV-2 by injecting beta-propiolactone after harvesting the virus using African green monkey kidney cells (Vero cells) [18]. The inactivated form of SARS-CoV-2 can no longer replicate, but the spike protein remains intact and can induce immunogenicity.

Both humoral and cellular immune responses are critical in verifying the immunity induced by vaccines [5]. Several previous studies demonstrated the efficacy of BNT162b2 and ChAdOx1 nCoV-19 vaccines in inducing both responses. Sahin et al. [23], in one of the studies, demonstrated that two doses of BNT162b2 elicited high SARS-CoV-2 neutralizing antibody titers. Additionally, robust receptor-binding domain–specific CD8+ and T helper type 1 CD4+ T cell responses were elicited by two doses of BNT162b2, and interferon-γ was produced by a large fraction of cells. A previous study demonstrated that BNT162b2 vaccination was 95% effective in preventing the occurrence of COVID-19 [7].

Vaccination with ChAdOx1 nCoV-19 showed anti-spike protein antibody responses and the induction of antigen-specific T cells against the SARS-CoV-2 spike protein [24,25]. According to Voysey et al. [11], the overall efficacy of ChAdOx1 nCoV-19 was 70.4%. Interestingly, the efficacy was higher in participants who received a low dose followed by a standard dose (90.0%) than in those who received two standard doses (62.1%).

Several adverse reactions due to vaccination have been reported, including hypersensitivity responses and excessive cytokine release [26]. Hypersensitivity is classified into four types according to the mechanism triggered by vaccines. Both the active component (antigen) and the other components of the vaccine can cause hypersensitivity [27]. Anaphylaxis is an acute onset systemic reaction that requires urgent management, and it is considered the most serious hypersensitivity reaction. The incidence rate of anaphylaxis after vaccination is estimated to be approximately 1.31 per million vaccine doses [27]. Proinflammatory cytokines such as interleukin 1, interleukin 6, and tumor necrosis factor α are released in response to vaccination [26]. These cytokines can cause pain at the local site by inducing inflammation [28]. Additionally, they may cause systemic symptoms such as headache, fatigue, malaise, nausea, and fever [28,29]. Unfortunately, these systemic symptoms are similar to the symptoms of infectious diseases including COVID-19 [7]. Safety reports of COVID-19 vaccines demonstrated in previous studies are summarized in Table 1 [7,10,11,30-33].

COVID-19 vaccination is a key issue and challenge in global health. The reported efficacy of various COVID-19 vaccines is excellent regardless of the type of vaccine, and the majority of studies have shown similar results for safety. Most of the local and systemic adverse reactions after vaccination have been of mild or moderate grade, and severe reactions have been reported in a very small proportion of patients. In general, these adverse reactions tended to be more common and more severe in younger age groups than in older age groups. In the study of BNT162b2 vaccines, more systemic reactions were reported after the second dose than after the first dose. The most common local adverse reaction was tenderness and pain at the injection site, and most patients improved within a few days. As a systemic adverse reaction, fatigue was most commonly reported, with headache and myalgia also commonly reported. Although fever (body temperature ≥38°C) was reported in approximately 10% to 20%, most of the systemic adverse reactions resolved within a few days. In addition, except for cases of hospitalization due to anaphylaxis, no patients required hospitalization due to adverse reactions with a proven relationship to vaccine administration.

Since the emergence of the COVID-19 pandemic, there have been many changes in medical institutions including the ED [36]. In particular, all types of medical personnel are making intense efforts to prevent the spread of COVID-19 in medical institutions. In the ED, patients with suspected COVID-19 are isolated, and medical personnel are required to wear personal protective equipment (PPE) when being in close contact with the patient [37,38]. The need for patient isolation and the additional amount of time required to wear PPE have caused many difficulties not only for medical personnel but also for patients [38,39]. Moreover, the inadequate bed capacity for isolation has also been an important issue, which increases the burden on the emergency medical system [40]. As mentioned earlier, the systemic adverse reactions that occur after COVID-19 vaccination are similar to those of infectious diseases including COVID-19. Therefore, with the current guidelines for determining the need for isolation based on symptoms, it is inevitable that patients who visit the ED with complaints of a systemic adverse reaction will also be isolated. Although there is no risk of transmission among these patients and they do not require special measures such as isolation and wearing PPE, it cannot be easily determined that it is a systemic reaction caused only by vaccination. In particular, the Republic of Korea experienced the spread of Middle East respiratory syndrome in medical institutions in 2015, and the EDs were considered a high-risk place for disease transmission [41]. Based on these past experiences and the nature of EDs visited by various people, all types of emergency medical personnel are bound to be more sensitive to the prevention of disease transmission. In the near future, nationwide vaccinations will be carried out to the general population. If more patients visit the ED with complaints of adverse reactions, then the aforementioned problems, including patient isolation and treatment time will increase. Moreover, these reactions may contribute to ED crowding, which is known to have a negative impact on patients, such as a high mortality rate [42,43]. This can further lead to significant obstacles to providing necessary treatment for patient with life-threatening conditions.

It is difficult to manage these patients because urgent treatment may be required, such as for anaphylaxis, or symptoms may be caused by other diseases not related to the vaccine administration. However, it is clear that the number of patients with adverse reactions will increase after nationwide vaccination. Therefore, we would like to make some suggestions for the prevention of predictable problems such as increasing treatment time and ED crowding. First, it will be necessary to increase isolation bed capacity. Given that adverse reactions will occur after nationwide vaccination, each medical institution and ED will require more isolation beds than that available currently. If there are inadequate isolation beds, then the patient’s treatment may be delayed, which will lead to ED crowding and may negatively affect patient outcomes. Second, a dedicated treatment center for adverse reactions due to vaccine administration that is open 24/7 is required. This can help prevent ED crowding and aid clinicians in systematically managing adverse reactions due to vaccine administration. Third, it is possible to consider home observation for a few days or outpatient treatment rather than visiting the ED for most of the adverse reactions after vaccination. According to previous studies on COVID-19 vaccination, most of the local and systemic reactions after vaccination were mild to moderate in severity and improved within a few days. In addition, the use of prophylactic paracetamol may help relieve symptoms [33]. Therefore, we can consider prescribing an analgesic such as paracetamol to relieve or prevent adverse reactions.

In health care, proper operation is as crucial as knowledge and technology. Therefore, with advances in knowledge and technology, the operation of the health care system must also develop. As there are many studies on the impact of COVID-19 on the social, economic, and public health, studies on vaccination adverse effects, and the resulting changes in health care will also be needed. These studies will provide a blueprint for the proper operation of the ED and medical institutions when new infectious disease outbreaks occur.