Safety of COVID-19 mRNA-1273 booster doses in Asian populations: A literature review of post-marketing observational studies

ABSTRACT

Real-world data on the safety of COVID-19 booster doses in Asian populations are needed to inform national immunization programs. The safety profile of mRNA-1273 (Moderna, Inc.) was evaluated using post-marketing observational data. PubMed and EMBASE were searched on June 30, 2025, for studies meeting the following predefined criteria: observational design, adverse events (AEs), mRNA-1273 boosters (dose 3+), and population data from the South-East Asia and Western-Pacific regions. Data on study characteristics, and AE incidence and severity, were extracted. Of 886 records screened, 27 studies from eight countries (Japan, the Republic of Korea, Australia, Taiwan, Indonesia, Thailand, the Philippines, and Singapore) met the inclusion criteria. Across studies, mRNA-1273 boosters were well tolerated, with severe AEs occurring at low frequency. Based on the included observational studies, these findings support the favorable safety profile of mRNA-1273 boosters in Asian populations. Long-term safety monitoring is needed to guide public-health responses to evolving SARS-CoV-2 variants.

Introduction

The COVID-19 pandemic triggered a global effort to develop, authorize, and deploy safe and effective vaccines to prevent severe disease and death. As of July 2025, more than 13 billion doses of COVID-19 vaccines were estimated to have been administered worldwide.¹ Informed by decades of research, the mRNA platform advanced to clinical use, enabling the development of mRNA COVID-19 vaccines that were among the first to be authorized and distributed globally.² The first mRNA vaccine for protection against COVID-19 to receive Emergency Use Authorization in the United Kingdom (December 2, 2020) was BNT162b2 (Comirnaty®, Pfizer-BioNTech).³ mRNA-1273 (SPIKEVAX®, Moderna, Inc.) was introduced shortly thereafter and was rapidly adopted internationally, receiving Emergency Use Authorization in the United States (US) on December 18, 2020, and World Health Organization (WHO) Emergency Use Listing on April 30, 2021. Regulators in Asia began authorization and rollout from February 2021, including in Singapore (February 3, 2021), Taiwan, the Philippines (both May 5, 2021), Japan, and the Republic of Korea (both May 21, 2021). It was estimated that by December 2023, over 1 billion doses of mRNA-1273 had been administered globally.^4–8

During the initial rollout of COVID-19 vaccines, people were offered a primary series (usually two doses) based on the original SARS-CoV-2 strain, depending on the vaccine type offered and the immune status of the individual.⁹ Although the clinical profile of mRNA COVID-19 vaccines was well defined in large clinical trials,^10,11 it was of primary importance to demonstrate their favorable benefit–risk profiles when used at a large population level. Real-world vaccine effectiveness (VE) studies demonstrated that mRNA vaccines were highly effective for preventing severe disease and death,^12,13 with global estimates showing that 2.5–14.5 million deaths were prevented by COVID-19 vaccines during the early phases of the pandemic.^14,15 In addition to assessment of VE, national health authorities implemented enhanced safety surveillance programs, building on existing reporting systems and innovative use of near-real time digital data-collection technologies.¹⁶ For example, in Japan, a joint council in the Ministry of Health, Labour and Welfare (MHLW) met every 2–3 weeks to assess individual safety reports and compare adverse event (AE) rates with expected background incidence.¹⁷ During the initial rollout of COVID-19 mRNA vaccines, safety concerns identified in the Asia-Pacific (APAC) region included anaphylaxis and myo- or pericarditis.^18–21

Although most AEs following immunization (AEFIs) reported during the initial rollout of the mRNA primary series of COVID-19 vaccines in the US reflected nonserious reactogenicity events such as injection-site pain, fatigue, and headache,²² rare cases of myocarditis and pericarditis have been observed (occurring in 0.01% to <0.1% of the vaccinated population), including with mRNA-1273.^23–26 Most of these cases occurred within 7 days following vaccination, were more frequent after the second dose of the primary series and in younger men, and were described as mild and self-limiting.⁴ The most common etiology of myocarditis is viral infection,⁴ and SARS-CoV-2 infection has been associated with an increased risk of myocarditis in both the acute and post-acute phases of COVID-19.^27,28 The risk of myocarditis is reportedly seven-fold higher after SARS-CoV-2 infection (risk ratio [95% CI], 14.82 [11.09–19.81]) than after COVID-19 vaccination (1.95 [1.44–2.65]).²⁹ In addition, myocarditis following COVID-19 vaccination has a milder clinical course compared with post-viral myocarditis in patients aged ≤30 years.³⁰ Overall, the available evidence strongly supports a positive benefit–risk ratio for the continued use of COVID-19 mRNA vaccines.³¹

Booster doses of updated vaccines are recommended to address the challenges of waning immunity after the primary series and immune escape of newly emerging SARS-CoV-2 variants.²⁶ In adults, the initial two-dose primary series of mRNA-1273 was administered as two 50-µg doses (total dose, 100 µg),⁴ whereas Moderna’s mRNA COVID-19 vaccine boosters were developed with a reduced dosing regimen of 50-µg, reflecting adjustments to optimize immunogenicity while minimizing reactogenicity.²⁶ The variant-containing boosters included bivalent formulations targeting both the original strain and Omicron BA.1 or BA.4/5 variants, and subsequently, monovalent formulations targeting newer variants, including XBB.1.5, JN.1, or KP.2, and most recently, LP.8.1.³² Although the WHO has declared the end of the emergency phase of the pandemic, COVID-19 continues to contribute to healthcare burden, particularly among older adults and medically vulnerable populations.³³ In response, many national health authorities recommend at least annual or more frequent revaccination with COVID-19 vaccines for groups considered at high risk of severe illness.³⁴ Considering the ongoing use of COVID-19 vaccine boosters, with an estimated 33% of global population having received a booster dose by the end of 2023,³⁵ continued assessment of the real-world safety of COVID-19 mRNA vaccine booster doses is important. These data can inform national immunization programs and support vaccine safety communication to the public from governments, medical societies, immunizers, and other trusted information providers. Data generated in this setting are valuable because a wide range of factors can influence vaccine responses, including host genetics, environmental exposure, health status, and nutritional and microbiome differences.³⁶

While global efforts to characterize the benefit–risk profile of the mRNA-1273 primary series have shown a consistent safety profile,^37,38 there is a pressing need to evaluate the safety of mRNA-1273 booster doses, particularly in the APAC region. Given the region’s diverse demographics, comorbidity profiles, and vaccine-deployment strategies,^39,40 it is important to explore whether regional differences exist and ensure that local recommendations remain appropriate. To our knowledge, no prior systematic review or meta-analysis has synthesized real-world safety data on this specific topic. To address this, the present targeted literature review synthesized published data on AEs following mRNA-1273 booster doses across APAC countries. By drawing on post-marketing surveillance and observational studies, this review addresses an evidence gap to inform national immunization strategies and reinforce public confidence in ongoing COVID-19 booster programs.

Methods

A targeted literature review was conducted to identify post-marketing observational studies evaluating the safety of mRNA-1273 booster doses administered in APAC countries. The aim of this review was to capture evidence reflecting real-world experience following administration of third or subsequent doses of the vaccine, including both monovalent and bivalent formulations.

A comprehensive literature search was conducted in PubMed and EMBASE (Ovid) databases to identify studies describing AEs occurring after mRNA-1273 booster doses that were published from database inception to June 30, 2025. The predefined search strategy included a combination of subheadings and text words to represent COVID AND vaccination AND Moderna vaccine names (mRNA-1273, elasomeran, Spikevax, davesomeran, and andusomeran) AND Asian country or territory names, including Australia (see Supplementary Table S1 for the full search strategy). Additional relevant studies were identified using PubMed’s Similar Articles function.

Eligibility criteria

Studies were included in the analysis if they met the following criteria: observational or post-marketing design (prospective, retrospective, or surveillance-based) irrespective of the data-collection method (e.g., spontaneous, solicited, self-reporting, health-professional reported, and/or a variety of digital collection methods); evaluated AEs or adverse reactions (ARs) following mRNA-1273 booster doses (third or subsequent doses); reported population-level data from at least one country within the APAC region; published in English; and based on human data. Review articles, editorials, commentaries, letters, case reports, case series, and studies evaluating only the primary vaccination series or restricted to special populations (e.g., immunocompromised individuals, children, or pregnant women) were excluded.

Screening and data extraction

A total of 886 unique records were identified. After duplicate removal and title/abstract screening, 346 records remained; 142 full-text articles were assessed for eligibility, and 27 met all inclusion criteria (Figure 1(A)). Data extracted from each study included country, study design, sample size, population characteristics, vaccine type and formulation, AE definitions, reporting mechanisms, and incidence or frequency of AEs. Frequency categories were described using Council for International Organizations of Medical Sciences (CIOMS) terminology (“very common,” “common,” “uncommon,” “rare,” “very rare”).²⁴ AEs were categorized as either nonserious AEs or serious AEs (SAEs), adverse events of special interest (AESIs, events designated for enhanced monitoring due to regulatory or public health relevance), or ARs when causality was at least a reasonable possibility. Events classified as “serious” were generally defined as those that resulted in death, were life threatening, required hospitalization or prolonged existing hospitalization, or resulted in persistent or significant disability/incapacity or congenital anomaly/birth defect⁴¹; however, definitions varied between reporting systems and studies.

Figure 1.

Study selection process.

(A) Study selection flow diagram. (B) Distribution of countries contributing studies.

Assessment of immediate post-vaccination AEs, often referred to as individual AEFIs (I-AEFIs) reports, was critically important at the time of initial introduction of COVID-19 vaccines to understand the risk of anaphylaxis and other acute reactions. Policies requiring people to remain at the vaccination site under observation for at least 15 min⁴² were often adopted, and studies including I-AEFI reports are described.

Synthesis approach

Findings were summarized descriptively across countries and AE types. Where possible, reported rates were standardized as incidence per 100,000 doses administered to facilitate cross-study comparisons. Data were grouped into four predefined AE categories: immediate AEs (e.g., anaphylaxis, syncope), reactogenicity (local/systemic ARs), national AE surveillance reports, and cardiac-related AEs (e.g., myocarditis, pericarditis).

Results

The 27 studies that met the inclusion criteria were conducted in eight APAC countries: Japan (n = 6), the Republic of Korea (n = 5), Australia (n = 4), Taiwan (n = 4), Indonesia (n = 3), Thailand (n = 3), Singapore (n = 1), and the Philippines (n = 1) (Supplementary Table S2; Figure 1(B)). The most common class of AE reported was ARs (16 studies), followed by AESIs (7 studies), cardiovascular events (6 studies), and AEFIs (2 studies). Study designs included prospective observational studies, digital or Web-based surveys, and analyses of national vaccine safety surveillance databases. Across all studies, mRNA-1273 boosters were administered either as homologous or heterologous doses, encompassing both monovalent and variant-containing formulations.

Immediate adverse events following immunization (I-AEFI)

Monitoring for I-AEFIs was an early priority of post-marketing safety surveillance, particularly to detect events such as anaphylaxis and syncope. Two key publications identified in the literature review evaluated I-AEFIs, typically defined as events occurring within 15–30 min after administration of mRNA-1273,^43,44 in Australia and Japan. In Australia, a retrospective review assessed I-AEFI reports recorded via surveys completed in pharmacy prescribing software at the time of vaccination across 314 Australian pharmacies.⁴³ A total of 513,974 doses of mRNA-1273 were administered in the study period (July 2021–June 2022), of which 300,547 were booster doses.⁴³ The total number of I-AEFIs after booster doses was 35, and all the predefined events (syncope, nausea/vomiting, and anaphylactic reactions) were reported at rates of <5 per 100,000 doses.⁴³ Rates were lower after booster doses than after the primary series. The most common events reported as ‘other’ (across all vaccines) included hyperhidrosis, injection-site bleeding, and paresthesia.⁴³

A study of I-AEFIs that included all individuals vaccinated at a large mass-vaccination site in Sendai City, Japan, reported prevalences of any acute AEs of 180 and 70 per 100,000 doses following the third (n = 221,716) and fourth mRNA-1273 (n = 32,934) doses, respectively.⁴⁴ In that study, serious cases of acute allergic reaction (27.51 and 6.07 per 100,000 doses after the third and fourth doses, respectively) and anaphylaxis (1.35 and 3.04 per 100,000 doses, respectively) were rarely reported.⁴⁴ No significant differences were observed between age strata, sex, or vaccine brand.⁴⁴ Additionally, a large study from the Republic of Korea reported an overall incidence rate of anaphylaxis (although not specifically I-AEFIs) after booster doses of mRNA-1273 of 0.13 per 100,000 doses, which appeared to decline with increasing age and was lower than the incidence rate observed with the primary course.⁴⁵

Adverse reactions

ARs are a subset of AEs for which a causal relationship to the vaccine is considered at least a reasonable possibility; symptoms were predefined in the clinical and prospective observational studies ARs. Sixteen studies contained information on AR incidence (Table 1). Data were generally collected using digital surveys (Short Message Service [SMS] or Web-based) that registered participants at the time of vaccination.^46–61

Table 1.

Studies reporting adverse reactions in APAC countries.

Author	Country	Study population	Vaccine	N	Most frequent symptoms
Chen et al.46	Taiwan	Adults ≥18 y who received dose 3 at TVGH	mRNA-1273	5374	Local reaction (54%), tiredness (38%), headache (23%)
Choi et al.47	Korea	Adults ≥18 y completing survey after mRNA vaccine	mRNA-1273 BA.1 mRNA-1273 BA.4/5	20,008	Pain (22–27%), myalgia (14–19%), fatigue (13–18%)
Lin et al.48	Taiwan	Adults ≥18 y who received dose 4 at TVGH	mRNA-1273	384	Local reaction (23%), tiredness (16%), headache (14.8%)
Mazarakis et al.49	Australia	Adults aged ≥18 y who had 3 doses of COVID-19 vaccine	mRNA-1273 XBB.1.5	177	Tenderness (81%), pain (71%), fatigue/malaise (57%)
McLeod et al.50	Australia	18–50 y	mRNA-1273 BA.1 mRNA-1273 BA.4/5	42	Pain (98%), fatigue (79%), headache (71%)
		50–70 y		33	Pain (94%), fatigue (67%), headache (58%)
Naito et al.51	Japan	Healthcare workers primed with BNT162b2	mRNA-1273	870	Pain (94%), fatigue (80%), headache (68%)
Okumura et al.52	Japan	Workplace vaccination program	mRNA-1273	301	Pain (95%), fever (82%), malaise (79%)
Omae et al.53	Japan	Japanese corporate workers	mRNA-1273	1492	Pain (84%), fatigue (59%), fever (57%)
Pakki et al.54	Indonesia	Adults ≥18 y primed with CoronaVac	mRNA-1273	101	Sore arm (100%), chills (72%), fatigue (57%)
Salter et al.55	Australia	People ≥5 y vaccinated in pharmacy	mRNA-1273	67,637	Local reactions (47%), systemic aches (44%), fatigue (44%)
Soegiarto et al.56	Indonesia	Healthcare workers primed with 2 doses of CoronaVac	mRNA-1273	75	Pain (25%), fever (13%), fatigue (6%)
Suryadinata et al.57	Indonesia	Healthcare workers	mRNA-1273	23	Pain (74%), tenderness (65%)
Tan-Lim et al.61	Philippines	Healthcare workers non-infected with COVID-19	mRNA-1273	80	Fever (NR), pain (NR), myalgia (NR)
Tetsuka et al.59	Japan	COVID-19 exposed adults ≥ 18 y	mRNA-1273	456	Pain (90%), fatigue (72%), headache (65%)
Tsangthapornpong et al.58	Thailand	University students primed with mRNA-1273 vaccine	mRNA-1273	100	Pain (99%), myalgia (68%), fatigue (60%)
Tseng et al.60	Taiwan	Healthy adults primed with COVID-19 vaccine (ChAdOx1 × 2; ChadOx1/mRNA1273; mRNA-1273 × 2)	mRNA-1273	N = 123 (Ch/Ch) N = 179 (Ch/1273) N = 212(1273 × 2)	Injection site tenderness (66–80%), fatigue (39–47%), myalgia (36–41%)

APAC, Asia-Pacific; NA, not applicable; NR, not reported; TVGH, Taiwan Veterans General Hospital; y, years.

N, number of mRNA-1273 booster recipients; n, number of events; IR, incident rate per 100,000 doses.

A randomized adaptive trial from Australia in adults who had received a primary series of BNT162b2 found that solicited ARs were very common in those who received a booster dose of mRNA-1273,⁵⁰ with pain reported by more than 90% of participants and systemic reactions by 60–80%. Similar AR frequencies were reported in prospective observational studies conducted in Japan, Indonesia, and Thailand.^51,52,54,58 In contrast, in a survey conducted by the Korean Disease Control and Prevention Agency (KDCA), ARs were lower but still very common in the 8-day period following vaccination with bivalent mRNA-1273.⁴⁷ Among ~20,000 survey respondents, local and systemic ARs were reported at rates of 25.3–30.8%, although hospital visits or admissions were rare (<0.1%).⁴⁷ The most common reported symptoms were pain (21.9–26.5%), myalgia (13.6–19.3%), and fatigue (3.2–17.7%).⁴⁷

The Taiwanese survey-based study investigated solicited ARs occurring within 7 days after vaccination with either a first⁴⁶ or second⁴⁸ booster dose. The overall rate of ARs was 58.6% after the first booster and 26.0% after the second booster dose,^46,48 suggesting fewer and milder reactions with subsequent doses. The most commonly reported events after first and second boosters were local reactions (54.3% and 23.2%, respectively), tiredness (37.6% and 15.9%), and headache (23.2% and 14.8%).^46,48

Across the studies, the most commonly reported symptoms were pain, fatigue, headache, and myalgia, which are consistent and similar to those observed during prelicensure studies of mRNA-1273 booster doses.^62,63 In addition, four studies identified fever as one of the three most common symptoms.^52,53,56,61 Variations in the absolute reporting frequencies between studies likely reflect the differences in study design and population (Table 1).

National population-based AE reporting systems

Five studies reported rates and types of AEs after mRNA-1273 or variant booster doses, based on data from three national health authority surveillance networks established to monitor the safety of vaccination programs during specific time periods after vaccine introduction.^{17,45,47,64,65} These systems include the COVID-19 Vaccination Management System (CVMS; the Republic of Korea), the Vaccine Adverse Event Reporting System (Taiwan), and the Adverse Event Following Immunization surveillance system under the Department of Disease Control (AEFI-DDC; Thailand) (Table 2).^{17,45,47,64,65}

Table 2.

Studies reporting unsolicited adverse events in APAC countries.

Author	Country	Study population	Vaccine	N	AEs, n (IR)	Nonserious AEs, n (IR)	SAEs, n (IR)	Deaths, n (IR)
Choi et al.47	Korea	Adults ≥18 y completing survey after mRNA vaccine	mRNA-1273 BA.1	1,987,609	937 (47.1)	869 (43.7)	68 (3.4)	12 (0.6)
			mRNA-1273 BA.4/5	218,983	96 (43.8)	93 (42.5)	3 (1.4)	1 (0.5)
Hu et al.65	Taiwan	Individuals ≥6 months who received COVID-19 vaccinations	mRNA-1273 BA.1	NR	109 (NR)	43 (NR)	66 (NR)	13 (NR)
			mRNA-1273 BA.4/5	NR	97 (NR)	44 (NR)	53 (NR)	0 (NR)
			mRNA-1273 XBB.1.5	861,743	24 (2.8)	11 (NR)	13 (1.5)	2 (NR)
Janekrongtham, et al.64	Thailand	Those aged ≥12 y who received a booster vaccine	mRNA-1273	5,692,599	NR	NR	All ages M (11.7) F (8.2) 12–17 y M (0) F (0) 18–20 y M (0.7) F (0) 21–40 y M (5.4) F (7.6) 41–60 y M (11.7) F (5.9) 61–80 y M (28.5) F (9.6) >80 y M (39.9) F (104.3)	NR
Lee et al.45	Korea	Individuals ≥5 y who received COVID-19 vaccinations	mRNA-1273	10,849,608	17,703 (163.2)	16,968 (156.4)	735 (6.8)	125 (NR)
Yamaguchi et al.72	Japan	Individuals ≥12 y who received COVID-19 vaccinations	3rd dose	33,183,096	1005 (NR)	NR	NR	107 (0.32)
			4th dose	15,589,490	231 (NR)	NR	NR	27 (0.17)
			5th dose	1,297,862	20	NR	NR	3 (0.23)
Yamaguchi et al.17	Japan	Individuals 5–11 y who received a third COVID-19 booster vaccination	mRNA-1273	30,597,546	712 (HCP) 420 (MAH)	NR	NR	78

AE, adverse event; APAC, Asia-Pacific; F, female; HCP, healthcare provider; M, male; MAH, marketing authorization holder; NA, not applicable; NR, not reported; SAE, serious adverse event.

N, number of mRNA-1273 booster recipients; n, number of events; IR, incident rate per 100,000 doses; y, years.

Two studies from the Republic of Korea analyzed vaccine safety data from the National COVID-19 Vaccination Task Force Adverse Event Investigation Team and the CVMS. The first study, covering the period from February 2021 to June 2022 recorded 16,968 nonserious AEs at a rate of 156.4 per 100,000 doses administered, and 735 SAEs at a rate of 6.8 per 100,000 doses after receipt of the third dose (first booster) of monovalent mRNA-1273.⁴⁵ The second study covered the period from October 11, 2022, to January 27, 2023,⁴⁷ when Omicron (BA.1 and BA.4/5)-containing bivalent booster doses were implemented. The rates of AEs for BA.1- and BA.4/5-containing formulations were lower than those observed with the initial mRNA-1273 booster reported in the first study. Nonserious AEs were reported at rates of 43.7 and 42.5 per 100,000 doses for BA.1- and BA.4/5-containing formulations, respectively, and 3.4 and 1.4 per 100,000 doses, respectively, for SAEs.⁴⁷ These rates align with those published in the KDCA COVID-19 Vaccination Adverse Events Report, which also indicates further declines in AE reporting rates in the Republic of Korea for subsequent booster doses (XBB.1.5: 21 per 100,000 doses; JN.1: 5 per 100,000 doses).⁶⁶

AEs in Japan are reported through the MHLW. Up to March 12, 2023, the overall rates of AE reported after booster doses of mRNA-1273 monovalent (>33 million doses) and Omicron (BA.1 and BA.4/5)-containing bivalent vaccines (>15 million doses) were <0.01% for all ages.¹⁷ The MHLW has published additional data suggesting AEs were reported at similar low rates after the administration of XBB.1.5- and JN.1-containing monovalent formulations.^67,68

A review of AEs reported to the Taiwanese Vaccine Adverse Event Reporting System⁶⁵ included information on booster doses that was stratified by the brand. Overall, for monovalent boosters, there was a total of 1817 cases, including 840 nonserious AEs and 977 SAEs.⁶⁵ Specifically for the XBB.1.5 formulation (861,743 doses administered between September 26, 2023, and December 31, 2023), reports of AEs and SAEs were very rare, with incidence rates of 2.8 and 1.5 per 100,000, respectively, across the whole population.⁶⁵ Rates of individual AEs were not listed by brand; however, across all brands of XBB.1.5-containing vaccine combined, the number of AESIs reported was low.⁶⁵ There were two cases of cardiovascular stroke and one case each of vasculitis, acute pancreatitis, Guillain–Barré syndrome, facial palsy, myocarditis, pericarditis, and acute myocardial infarction.⁶⁵ This study also reported a total of 206 AEs (87 nonserious AEs and 119 SAEs) for mRNA-1273 bivalent boosters (BA.1 September 24, 2022, to February 8, 2023; and BA.4/5 November 18, 2022, to February 8, 2023), but no information on the incidence and nature of these events was provided.⁶⁵

Deaths reported after mRNA-1273 booster doses

Reported mortality following vaccination must be interpreted in the context of background mortality rates in vaccinated populations, particularly as older adults and individuals with underlying conditions – who have higher expected mortality – were prioritized during the pandemic. In addition, deaths are typically reported based on temporal association rather than confirmed causality, and only a small proportion are ultimately determined to be vaccine-related following standardized pharmacovigilance assessment.^69–71

The only datasets identified in this literature review that included incidence data for fatalities were a study from the Republic of Korea evaluating Omicron-containing (BA.1 and BA.4/5) bivalent vaccines⁴⁷ and a study from Japan that included mortality rates across doses three to five⁷² (Table 2). In the study from the Republic of Korea, which assessed data collected through the National COVID-19 Vaccination Task Force Adverse Event Investigation Team and the CVMS, mortality events were very rare, occurring at rates of 0.6 and 0.5 per 100,000 doses for BA.1- and BA.4/5-containing formulations, respectively,⁴⁷ and with just one death assessed as causally related to vaccination. In the study from Japan reporting data from the MHLW, the mortality rates for all mRNA-1273 monovalent and Omicron-containing BA.1 and BA.4/5 bivalent vaccines were 0.32, 0.17, and 0.23 per 100,000 doses for doses 3, 4, and 5, respectively; no causal relationship with vaccination was identified in any of these cases.⁷²

Cardiac-related AEs

The identification of myocarditis and pericarditis as rare AEs occurring shortly after vaccination during the global rollout of COVID-19 vaccines has contributed to ongoing monitoring and investigation, including in the APAC region. Six studies reported cardiac-related AEs in APAC countries, including the incidence of myocarditis and/or pericarditis (three studies from the Republic of Korea and one study each from Japan, Thailand, and Singapore) (Table 3).^{17,45,73–76} Methods for classifying myocarditis and/or pericarditis varied across studies and included use of the Brighton Collaboration criteria (BCC) in Japan¹⁷; adjudication by a KDCA Expert Committee using the BCC^45,73 or the European Society of Cardiology guideline for the diagnosis and management of pericardial diseases⁷⁴ in the Republic of Korea; application of the US-CDC case definitions in the Thailand study⁷⁵; and case identification through national claims data (ICD-10 codes) in the Singapore study.⁷⁶

Table 3.

Studies reporting serious cardiac events in APAC countries.

Author	Country	Study population	Vaccine	N	Myocarditis, n (IR)	Pericarditis, n (IR)	Any cerebrovascular cardiac, or thrombotic event, n (IR)
Cho et al.73	Republic of Korea	Individuals ≥12 y who received ≥1 dose of mRNA-1273	mRNA-1273 (dose 3)	6,930,450	All ages 11 (0.19)	NA	NA
Lee et al.45	Republic of Korea	Individuals ≥5 y who received COVID-19 vaccinations	mRNA-1273 (doses 3 + 4)	All age groups 10,849,608	All ages 23 (0.2) ≤19 y 1 (1.92) 20–29 y 2 (0.29) 30–39 y 4 (0.31) 40–49 y 2 (0.16) 50–59 y 5 (0.24) ≥60 y 9 (0.15)	All ages 5 (0.04) ≤19 y 0 (0.0) 20–29 y 1 (0.15) 30–39 y 0 (0.0) 40–49 y 1 (0.08) 50–59 y 2 (0.09) ≥60 y 1 (0.02)	NA
Lee et al.74	Republic of Korea	Individuals ≥12 y who received COVID-19 vaccinations	mRNA-1273	All age groups 6,944,931	NA	All ages NR (0.04) 18–29 y NR (1.02) 30–39 y NR (0.0) 40–49 y NR (0.0) 50–59 y NR (0.09) 60–69 y NR (0.03) 70–79 y NR (0.0) 80–89 y NR (0.0)	NA
Mahasing et al.75	Thailand	Recipients of COVID-19 vaccinations	mRNA-1273	NR	All ages 4 (NR)	NA	NA
Wee et al.76	Singapore	Adults ≥ 18 y who received mRNA vaccine	mRNA-1273	NR	NA	NA	0–30 d 396 (1.98) 31–60 d 545 (2.6) 61–90 d 584 (2.71) 91–120 d 614 (2.82) 121–180 d 1287 (2.92) Reference 2560 (2.67)
Yamaguchi et al.72	Japan	Individuals ≥12 y who received COVID-19 vaccinations	mRNA-1273 mRNA-1273 BA.1 mRNA-1273 BA.4/5	All age groups 3,518,419 (dose 3)	15–19 y M 4 (3.1) F 0 (0) 20–24 y M 8 (1.1) F 0 (0) 25–29 y M 3 (0.4) F 2 (2.5) 35–39 y M 2 (3.1) F 0 (0) 40–44 y M 1 (0.1) F 0 (0) 55–59 y M 1 (0.1) F 0 (0) 60–64 y M 1 (0.1) F 0 (0) >65 y M 0 (0) F 0 (0)	NA	NA

APAC, Asia-Pacific; d, days; F, female; IR, incident rate per 100,000 doses; n, number of events; N, number of mRNA-1273 booster recipients; NA, not applicable; NR, not reported; M, male; y, years.

Three studies from the Republic of Korea reported myocarditis/pericarditis cases included in the same national dataset that was collected through a reporting system coordinated by the KDCA.^45,74 Incidence rates of myocarditis and pericarditis in the Republic of Korea after a third dose of mRNA-1273 were 0.19 per 100,000 doses and 0.04 per 100,000 doses, respectively.^45,73,77 The incidence of myocarditis and pericarditis was higher in males and those aged 18–39 years, with estimates being lower after dose 3 than after doses 1 and 2 (0.9–1.26 per 100,000 doses and 0.32–0.44 per 100,000 doses, respectively).^45,74

Clinical findings associated with cases of myocarditis and pericarditis were not presented stratified by brand. However, 9.1% of vaccine-associated cases of myocarditis reported after dose 3 were classified as “severe” (required intensive care unit [ICU] admission, fulminant myocarditis, or death)⁷³ compared with 19.8% of all cases, suggesting that both the severity and incidence of myocarditis were lower after booster doses compared with the primary series. In addition, 42.5% of pericarditis cases required hospitalization and six patients were treated in the ICU; all hospitalized cases were discharged after a median 1.5 days.⁷⁴

In Japan, the MHLW reported the highest rates of myocarditis (BCC levels 1–3 according to expert review panels) after mRNA-1273 in young males aged 15–24 years (1.05–3.10 cases per 100,000 doses) after the third dose; only two cases were reported after the fourth dose, and none after the fifth dose.¹⁷

Severe cardiac clinical outcomes were assessed in a study from Singapore,⁷⁶ which evaluated mortality and cardiac, cerebrovascular, or thrombotic events after infection or booster doses of mRNA-1273 (n = 648,214) administered between January 2022 and December 2022, and found no elevated risk of either all-cause mortality or cardiovascular events following booster vaccination.⁷⁶ The adjusted hazard ratio for time windows up to 180 days after mRNA-1273 vaccination (compared with >180 days after vaccination) ranged from 0.26 to 0.65 for all-cause death, and from 0.52 to 0.86 for any cardiac, cerebrovascular, or thrombotic event, thus reinforcing the vaccine’s favorable safety profile during the Omicron transmission period.⁷⁶

Discussion

This review of post-marketing studies across APAC nations provides support for the favorable safety profile of the mRNA-1273 COVID-19 booster vaccine. Across diverse populations (including Japan, the Republic of Korea, Australia, Taiwan, Indonesia, Thailand, the Philippines, and Singapore), ARs, and particularly local and systemic symptoms such as pain, fatigue, and headaches, were common but predominantly mild and transient, with the majority resolving within 3 days. In addition, the reviewed data consistently show that AEs, including SAEs, occurred at rates considered rare (0.01% to <0.1%) or very rare (<0.01%), as defined by CIOMS classification.²⁴ As observed in global safety reviews of mRNA COVID-19 vaccines, the majority of AE reports were classified as nonserious, and, where symptoms were described, the most commonly reported events resembled those generally classified as ARs; therefore, these findings are not unexpected.^22,25,78 These results are consistent with clinical studies for licensure of ancestral-strain booster doses and updated variant vaccines,^26,62 showing that most ARs were mild to moderate, and transient. Across included studies, no new safety signals emerged beyond known, previously characterized AEs. Overall, ARs tended to occur less frequently after more recent booster doses of mRNA-1273 compared with earlier doses. The observation in Taiwan that the primary series of vaccination was associated with more ARs than were additional doses^46,48 has been observed elsewhere in the world.⁷⁸ SMS-based surveys conducted in the 7-day period after vaccination in the US (V-safe) and Australia (AusVaxSafety) identified a similar trend for mRNA COVID-19 vaccines.^78,79

The reported rates of anaphylaxis and syncope are consistent with the rates reported for other licensed vaccines (0.1–1 episodes per 100,000 doses depending on the vaccine⁸⁰; adolescents: 2.99 per 10,000 vaccination events⁸¹). Low rates of anaphylaxis and syncope are important for maintaining public confidence during rapid, large-scale deployment of vaccines as occurred during the pandemic. Although it is inevitable that coincidental deaths of recently vaccinated individuals occur during population-wide vaccination programs, the mortality rates reported in these studies from APAC countries were very low (0.5–0.6 deaths per 100,000 doses across the monovalent and bivalent formulations in the Republic of Korea⁴⁷; 0.17–0.32 deaths per 100,000 doses across dose numbers 3–5 in Japan⁷²), and only a small fraction of reported deaths were assessed as potentially related to vaccination (1 per 100,000 doses in the Republic of Korea study; none in the Japan study^47,72). This is consistent with studies conducted in other regions and a self-controlled case series conducted in the US that specifically assessed the risk of deaths associated with COVID-19 vaccines and did not find any increased risk of non-COVID mortality, all-cause mortality, or cardiac mortality in 14- and 28-day risk windows after vaccination with mRNA-1273.⁷⁷ These findings provide reassurance for the ongoing use of the vaccine and for the potential use of mRNA vaccines in similar future contexts.

Importantly, the data also address safety concerns surrounding myocarditis and pericarditis. Incidence rates were lower after booster doses than after primary series vaccinations, a pattern consistent with global incidence data after booster doses.⁸² Several factors have been proposed to explain these observations, including the longer intervals between booster doses as compared with the primary series.

In studies where severity was assessed, the majority of patients had a mild clinical course and recovered quickly. Furthermore, real-world surveillance from Japan, the Republic of Korea, and Singapore found no increase in mortality or cardiovascular event risk following mRNA-1273 booster doses. These studies did not provide insights into potential long-term consequences of acute cardiac episodes after COVID-19 vaccination; however, mid- to long-term follow-up of myocarditis cases in the US (~6 months) and Australia (12–18 months) found that the majority of patients did not experience ongoing symptoms and/or showed improvements across the study period.^83,84 Of note, cardiac imaging indicated that 82% of US patients aged ≤30 years with a clinical diagnosis of acute myocarditis after COVID-19 mRNA vaccination showed imaging findings of cardiac injury at ~3 weeks after vaccination, suggesting ongoing surveillance of these patients is warranted.⁸³

A key strength of the large population-based surveillance systems included in this review is their capacity to detect rare SAEs. The findings of this review should be considered in the context of several limitations. Although the search strategy was designed to collect a comprehensive list of manuscripts reporting on mRNA-1273 booster doses, methodologies of systematic reviews, such as formal assessments of study quality and bias, were not performed. Most studies were observational in nature, with some relying on passive reporting to accrue cases, meaning there is a possibility of bias and likely underreporting, and in some cases, a lack of detailed reporting. Moreover, the observational nature of the data means that causality cannot be inferred. While the scope of this review focused on countries in a specific geographic region, there are likely differences between countries with respect to important factors such as AE-reporting behaviors; therefore, there may be limited value in extrapolating findings from one country to others in the same region. Furthermore, reported incidence rates of myocarditis and pericarditis should be interpreted with caution, as differing classification methods can produce discordant case assessments, thus restricting the comparability of studies.⁸⁵ In addition, this review excluded studies restricted to specific vulnerable or special populations (e.g., immunocompromised individuals, pregnant persons, pediatric populations, or individuals with specific chronic conditions) in order to provide a broad population-level safety overview. While this approach improves comparability across heterogeneous national datasets, it limits the ability to draw conclusions regarding the safety profile of mRNA-1273 booster doses in these clinically important subgroups. Lastly, this review only included manuscripts that were reported in English, which may have omitted additional relevant literature presented in other languages, thereby limiting extrapolation of the findings from various countries in the APAC region.

This manuscript provides a comprehensive overview of the findings of independent studies from the APAC region that assessed the safety of mRNA-1273 when given as a booster dose. In the context of the region’s diverse demographics, healthcare systems, and vaccine deployment strategies, these data, combined with local epidemiological data and real-world evidence of VE of booster doses, can inform country-specific assessments of the benefit–risk profile of mRNA-1273 and guide national immunization policies. Transparent communication of these data may also support evidence-based communication strategies for healthcare providers and the public, and improve vaccine confidence in ongoing and future booster campaigns across APAC. This is important because vaccination remains one of the most effective measures to help reduce the continued burden of morbidity and mortality from COVID-19 in several APAC settings, which continues to disproportionately affect older adults and those with chronic conditions.

Biography

Veronica V. Urdaneta, MD, MPH, is a distinguished physician and public health expert with more than 30 years of experience across clinical medicine, epidemiology, pharmacovigilance, and regulatory affairs. She is the Global Clinical Safety Lead for Moderna’s COVID-19 Franchise, directing global safety and risk management and leading safety physicians responsible for pharmacovigilance strategy, regulatory submissions, and safety communications for Moderna’s COVID-19 vaccines worldwide.

Born in Venezuela, Dr. Urdaneta earned her medical degree from Zulia University (1989) and completed MPH degrees in Epidemiology at Zulia University and Johns Hopkins University. She also completed a fellowship in Malariology and Tropical Diseases.

Before joining Moderna, she held senior safety leadership roles at Merck, Endo Pharmaceuticals, and Janssen, contributing to the safety assessment of vaccines and therapeutic products. Earlier, she served as State Epidemiologist for the Pennsylvania Department of Health, directing statewide infectious disease surveillance and pandemic preparedness efforts. Her work has supported regulatory approvals and peer-reviewed publications. Dr. Urdaneta is a frequent speaker at international conferences and has served as a public health spokesperson and advisor at both state and national levels in the U.S. She is a member of IDSA, ISPE, and ASTMH.

Funding Statement

This research was funded by Moderna, Inc. Writing support was provided by Epidemiological Research and Methods LLC. Medical writing and editorial support were provided by MEDiSTRAVA in accordance with Good Publication Practice (GPP 2022) guidelines, funded by Moderna, Inc., and under the direction of the authors.

Disclosure statement

All authors are employees of Moderna and may hold stock/stock options in the company: CC, AKB (Moderna, Australia); DE, VU (Moderna, Inc., USA); and PM (Moderna, Singapore).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21645515.2026.2662118