Introduction

In the Republic of Korea (hereinafter, Korea), 70% of the total population received the first round of coronavirus disease 2019 (COVID-19) vaccination by September 2021 [1]. Growing expectations arose for returning to normal activities and easing quarantine measures; however, in November 2022, the Omicron variant of the COVID-19 virus emerged [2]. Due to its infectiousness and vaccine-evasiveness, Omicron became the dominant strain in Korea and worldwide. Pfizer and Moderna developed and distributed bivalent COVID-19 vaccines worldwide, and emergency authorization and vaccination began in major developed countries [3–6].

In Korea, the administration of bivalent COVID-19 mRNA vaccines started with the emergency approval of Moderna BA.1 (October 11, 2022), Pfizer BA.1 (November 7, 2022), Pfizer BA.4/5 (November 14, 2022), and Moderna BA.4/5 (December 26, 2022) [3,7–10]. These vaccines received approval for both primary vaccination and booster doses. Currently, booster doses can be administered 3 months after completing the primary vaccination or being released from isolation due to COVID-19 infection. Individuals at risk from mRNA vaccines can opt for a recombinant spike protein nanoparticle vaccine (e.g., Novavax) as a booster [3].

Monitoring and investigating adverse events (AEs) or health conditions during the early stages after the administration of Moderna's and Pfizer's bivalent mRNA vaccines are crucial for vaccine safety [11–14]. The Korea Disease Control and Prevention Agency (KDCA) conducted a text-message survey (TMS) to monitor and investigate AEs and health conditions after bivalent COVID-19 mRNA booster vaccination, including Pfizer BA.1, Pfizer BA.4/5, Moderna BA.1, and Moderna BA.4/5 vaccines, among adults aged 18 years or older according to the vaccination plan [3]. In previous studies conducted in Korea, AEs of AstraZeneca, Pfizer, Moderna, and Janssen COVID-19 vaccines were investigated across all age groups, providing important safety information [12–14]. However, these studies focused on AEs following 2 doses of primary series monovalent vaccinations. Due to the limited information available regarding the safety of bivalent mRNA booster vaccines, this study aimed to assess and disseminate safety information on 4 bivalent mRNA vaccines used in Korea in comparison with that of the existing monovalent vaccines. This study analyzed the data for AEs reported to the COVID-19 vaccination management system (CVMS; a web-based passive vaccine safety surveillance system), as well as from the TMS.

Materials and Methods

COVID-19 Vaccination Management System

The CVMS is used to monitor AEs following immunization and identify potential safety signals for further evaluation [12,13,15]. In accordance with the Infectious Disease Control and Prevention Act, from October 11, 2022 to March 30, 2023, 6,576,729 bivalent mRNA vaccines (including Moderna BA.1, Pfizer BA.1, Pfizer BA.4/5, Moderna BA.4/5) were administered in Korea, and 2,553 AEs after vaccination were reported to the CVMS. Among these, 6,547,057 doses were administered to adults, with 2,527 AEs reported. Data on booster vaccinations and vaccines other than Pfizer/Moderna vaccines (e.g., Novavax) were excluded, as they were reported in previous studies [16]. AEs reported to the CVMS were classified as non-serious or serious according to the KDCA’s guidelines. The characteristics of AEs reported to the CVMS were stratified by sex, age, and vaccine type, and the types of symptoms reported as AEs were described in descending order of frequency. The AEs reported to the CVMS are suspected cases and do not necessarily indicate a medically confirmed diagnosis.

Text-Message Survey

The KDCA’s TMS investigated AEs and health conditions following COVID-19 vaccination in specific population groups such as pregnant women and adolescents, as well as when new vaccines were introduced [7,12–14]. To monitor AEs and health conditions after vaccination, text messages were sent for 8 days from the day of vaccination (day 0) to the seventh day. From October 11, 2022 to January 27, 2023, 40,022 adults who received Pfizer BA.1, Pfizer BA.4/5, Moderna BA.1, and Moderna BA.4/5 vaccines responded to the survey, which included questions about health problems experienced after vaccination. AEs and health conditions were evaluated according to age and vaccine type.

The SAS ver. 9.4 program (SAS Institute) was used to perform all analyses in this study. Passive surveillance activities were conducted by the KDCA; this study was not approved by an institutional review board in accordance with government regulations. The TMS was exempted from review by the Korean Public Institution Review Committee, designated by the Ministry of Health and Welfare (No: P01-202306-01-011).

Results

AEs Reported to the CVMS

From October 11, 2022 to March 30, 2023, 2,527 AEs were reported to the CVMS among adults who received the bivalent mRNA vaccines. Among them, 2,369 were non-serious, and 158 were serious. Serious AEs included 33 deaths (0.5%), 4 cases of anaphylaxis (0.1%), and 121 AEs of special interest (AESIs). During the study period, 6,547,057 doses were administered to adults, resulting in an overall reporting rate of 38.6 per 100,000 doses (34.4 per 100,000 for Pfizer and 46.8 per 100,000 doses for Moderna) (Table 1).

AESIs included admission to an intensive care unit, life-threatening conditions, and permanent disability/sequelae. Of the total AEs reported, 2,369 cases were non-serious (reporting rate, 36.2 per 100,000 doses), and 158 were serious including death and major AEs (reporting rate, 2.4 per 100,000 doses). The reporting rates of non-serious AEs per 100,000 doses for Pfizer BA.1, Pfizer BA.4/5, Moderna BA.1, and Moderna BA.4/5 were 31.9, 32.6, 43.7, and 42.5, respectively. The reporting rates of serious AEs were 1.5, 2.1, 3.2, and 3.4, respectively. The reporting rates of AEs per 100,000 doses were 38.1 for men and 39.1 for women. Non-serious AEs were reported at rates of 35.6 for men and 36.7 for women, while serious AEs were observed at rates of 2.5 for men and 2.3 for women per 100,000 doses, respectively. Teenagers had the highest rate at 97.2 per 100,000 doses, followed by individuals in their 20s (50.3); while those in their 60s and those aged 70 and older showed the lowest rates at 37.0 and 36.1 per 100,000 doses, respectively (Table 1).

Thirty-three deaths were reported (incidence rate, 0.5 per 100,000 doses; 0.5 for Pfizer and 0.6 for Moderna). The rate was 0.5 for both sexes. Individuals aged 70 and older had the highest rate at 0.9, followed by those in their 60s at 0.4 and those in their 50s at 0.1. No deaths were reported among individuals in their 40s or younger (Table 1).

Among the AESIs, acute cardiovascular injuries such as myocarditis, pericarditis, strokes, and myocardial infractions were observed in 17 individuals (9 men and 8 women). Three cases of myocarditis were reported, with 2 men (in their 20s and 60s, respectively) and 1 woman in her 50s. Two cases of pericarditis were reported, both in women (1 in her 20s and 1 in her 80s). In addition, 2 cases of strokes were reported (1 man in his 60s and 1 woman in her 70s). Furthermore, 3 cases of myocardial infarctions were reported, all in women (1 in her 60s and 2 in her 70s). The remaining cases were confirmed to have experienced chest pain and other symptoms (Table 2).

Among the non-serious AEs reported in the CVMS for both Moderna and Pfizer vaccines, myalgia was the most common at 13.7 and 9.6 per 100,000 doses, respectively, followed by headache, dizziness, and allergic reactions. The most common serious AEs were acute cardiovascular injuries and vaccine-associated enhanced diseases, followed by acute respiratory distress and Guillain-Barré syndrome. Most of these events were reported in fewer than 20 cases (Table 2).

Self-Reported AEs Collected through the TMS

Between October 11, 2022 and January 27, 2023, 40,022 adults responded to the TMS. For the Moderna BA.1 vaccine, the survey was conducted from October 11, 2022 to October 20, 2022 with 10,009 respondents (2.1%) out of 486,246 people vaccinated. For the Moderna BA.4/5 vaccine, the survey was conducted from December 26, 2022 to January 27, 2023 with 9,999 respondents (6.7%) out of 149,919 people vaccinated. For the Pfizer BA.1 vaccine, the survey period was from November 7, 2022 to November 25, 2022 with 10,001 respondents (2.6%) out of 388,132 people vaccinated. Finally, the survey on the Pfizer BA.4/5 vaccine was conducted from November 14 to November 24, 2022, with 10,013 respondents (1.7%) out of 572,418 vaccinated people (Table 3).

Pain at the injection site was the most common local AE for both the Moderna and Pfizer vaccines, followed by swelling and itching. Myalgia was the most common systemic AE, followed by fatigue, fever, headaches, and chills. Approximately 10.0% to 13.1% of the respondents reported limits to normal daily activities, and 1.4% to 1.9% visited a medical institution (Figure 1). After receiving the bivalent vaccines, 27.4% to 33.2% of the respondents reported experiencing health problems, primarily on the day after vaccination (day 1). AEs started decreasing on the second day after vaccination (day 3) (Figure 2).

Discussion

This study evaluated AEs following bivalent mRNA vaccination in Korea, since providing safety information based on real-world data is crucial to aid decision-making regarding vaccination strategies. In Korea, 6,547,057 doses of the bivalent vaccines were administered as boosters to adults as of March 30, 2023. According to the CVMS, the reporting rate of AEs after bivalent vaccination among adults was 38.6 per 100,000 doses, which is lower than the AE rates observed with previously administered vaccines in Korea [12,14]. Similar to existing mRNA vaccines, most cases were mild and moderate. The most common AEs were myalgia and headache, with AESIs occurring less frequently than with the original vaccines [12,14]. A woman in her 70s vaccinated with Pfizer BA.1 and a man in his 20s vaccinated with Moderna BA.4/5 had a causal relationship, and the causality for the remaining cases was either not established or was under investigation [17]. In total, 33 deaths were reported, mostly in people over 60 (32 cases), and none reported in those under 40, except for 1 person in their 50s. In addition, no specific symptoms were identified beyond the previously known AEs, and there was no significant difference in the incidence rate [18,19]. Analyzing the relationship between vaccines and deaths requires considerable time and effort; therefore, a comparative analysis with existing death statistics should be conducted before interpreting these findings.

The results of the TMS were consistent with those previously reported from the Pfizer and Moderna vaccine clinical trials [18–22]. Most cases were mild or moderate and temporary, with pain at the injection site being the most common local AE. Fatigue and myalgia were the most commonly reported systemic AEs, and no serious events were documented. According to both the TMS in Korea and V-Safe data from the United States, most events affecting daily life occurred on the day following vaccination (Figure 2) [18,19,22,23]. According to the Australian Active Surveillance data, the most frequently reported local AEs after vaccination with both Pfizer and Moderna BA.1 and BA.4/5 were pain at the injection site. Additionally, myalgia and headache were commonly reported systemic AEs. The Moderna bivalent vaccine exhibited a higher incidence of health problems than the Pfizer bivalent vaccine, similar to reported data from Korea (Figure 1) [24].

One limitation is that data from the TMS reflect self-reported events, not diagnoses by medical doctors, potentially affecting the accuracy of establishing causal relationships between vaccines and events. The results concerning individuals who visited medical institutions might have been underestimated or overestimated, as hospital visits could have varied based on individual characteristics. Furthermore, data from the TMS are derived from only approximately 40,000 individuals who agreed to participate due to time and budget constraints. Thus, these findings’ generalizability to the entire population in Korea is limited.

In conclusion, no major safety issues were identified beyond the previously known AEs. Additionally, the findings confirmed minimal AEs, as reported in clinical trial data [3,8–10,18,19,22]. Although most countries including Korea have ceased administering bivalent vaccines and have started distributing new vaccines against the XBB 1.5 variant since October 2023 [25,26], ongoing vaccine development and safety monitoring are crucial as new variants of COVID-19 continue to emerge. Therefore, we expect that the results of this study will contribute to the development of vaccines against new variants of COVID-19 and to addressing AEs in the future.

HIGHLIGHTS

• This study examined the safety profile of Pfizer and Moderna bivalent mRNA booster vaccines for individuals aged 18 and above in the Republic of Korea

• Bivalent vaccines were associated with fewer AEs than the original vaccines, with common post-vaccination events being injection site pain, headache, fatigue, and myalgia.

Article information

Ethics Approval

The surveillance activity based on the CVMS was conducted by the KDCA in accordance with the Infectious Disease Control and Prevention Act in Korea; the study was not subject to institutional review board approval. The studies based on the TMS were exempted from review by the Public Institutional Review Board designated by the Ministry of Health and Welfare (No: P01-202306-01-011).

Conflicts of Interest

The authors have no conflicts of interest to declare.

Funding

None.

Availability of Data

The data used in this study are protected under the Personal Information Protection Act.

Authors’ Contributions

Conceptualization: SKC, SK; Data curation: SKC, SK, MK; Formal analysis: SKC, MK, YH; Investigation: SKC, TEK, YL, JJ; Methodology: SKC, SK, MK; Supervision: EB; Validation: SK, EB; Visualization: SKC, SK; Writing–original draft: SKC, SK; Writing–review & editing: all authors. All authors read and approved the final manuscript.

Figure 1.

Comparison of adverse events and health conditions reported through the text-message survey by persons aged 18 years and older after Pfizer or Moderna bivalent mRNA vaccination. Values represent the percentage of respondents who reported adverse events and health conditions at least once during days 0 to 7 post-vaccination.

Figure 2.

Adverse events and health conditions reported through the text-message survey by persons aged 18 years and older on each day after Pfizer or Moderna bivalent mRNA vaccination. Values represent the percentage of respondents who reported adverse events and health conditions at least once from days 0 to 7 post-vaccination.

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Figure & Data

References

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