Vaccines | Free Full-Text | Incidence and Nature of Short-Term Adverse Events following COVID-19 Second Boosters: Insights from Taiwan’s Universal Vaccination Strategy

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Vaccines | Free Full-Text | Incidence and Nature of Short-Term Adverse Events following COVID-19 Second Boosters: Insights from Taiwan’s Universal Vaccination Strategy


1. Introduction

Adverse events (AEs) resulting from repeated COVID-19 vaccine booster doses have become a significant area of research [1,2,3,4]. While vaccines remain one of the most effective means to prevent diseases, vaccine-related adverse events have always been a concern for the public [5,6,7]. Recent studies from large pharmacovigilance databases indicate substantial variability in adverse event incidence rates, emphasizing the need for context-specific analysis in vaccine safety surveillance to maintain public trust and inform future vaccination strategies [8,9,10,11,12]. There are numerous reports of adverse events following COVID-19 vaccination, with particular emphasis on specific groups such as the elderly [13], pregnant women [2,14,15], and those with pre-existing medical conditions. Furthermore, retrospective reports have highlighted vaccine-related neurological adverse events [1,7,16] and cardiovascular complications [3,17,18]. These reports significantly impact public willingness to receive vaccinations, consequently affecting vaccination rates [7,19,20]. Of particular concern are the severe adverse events associated with booster vaccines, such as vaccine-induced myocarditis and pericarditis, multisystem inflammatory syndrome in children (MIS-C), and multisystem inflammatory syndrome in adults (MIS-A) [21,22,23,24,25,26,27]. The question of whether the incidence and severity of side effects increase with additional doses is of utmost importance and urgently requires detailed clinical reports to understand the current situation [28].
Repeated administration of booster doses is crucial for enhancing protective immunity against COVID-19. However, there is a growing need for large-scale studies to support public concerns about the adverse events of these repeated doses. The risk of AEs can be repeated upon subsequent administrations of the same vaccine. Given the variety of COVID-19 vaccines available, each based on different technological platforms such as mRNA and non-replicating viral vectors, potential mechanisms for this can involve immunological responses such as hypersensitivity or immune sensitization, especially relevant in the context of repeated exposures to vaccine antigens [3,13,29]. Moreover, the risk of AEs can be cumulative, potentially due to cumulative immunological effects or other underlying biological factors. This cumulative aspect is paramount in assessing the long-term safety and sustainability of ongoing COVID-19 vaccination strategies, particularly in the context of administering booster doses [30]. A comprehensive analysis of these mechanisms, in terms of pharmacovigilance, is vital for enhancing the efficacy and safety of current and future vaccination strategies against COVID-19 and other diseases.
The primary objective of this study is to investigate the incidence rates of adverse events (AEs) following the administration of the second booster dose (fourth dose) of the COVID-19 vaccine. Taiwan boasts high vaccination rates globally (first dose coverage at 93.8%, second at 89.06%, third at 76.9%, and fourth at 25%) and encourages booster vaccinations for the entire population in contrast to the strategies of other countries that focus primarily on high-risk groups [31,32]. This research utilizes data from the Vaccine Adverse Event Reporting System (VAERS) at Taipei Veterans General Hospital to analyze the types and incidence rates of AEs, and the correlation between the occurrence of AEs after the first and second boosters. Additionally, we evaluate whether the occurrence of AEs is a repeated phenomenon or indicative of a cumulative risk of AEs. Furthermore, we explore the relationship between the choice of vaccine brand and the booster–booster combination in relation to the occurrence of AEs. This comprehensive investigation aims to provide critical insights into the safety profile of repeated booster doses, enhancing the decision-making process for vaccine administration and public health policy.

2. Materials and Methods

2.1. Taiwan’s Vaccination Program for Booster Vaccines

Taiwan’s booster vaccine program, distinguished by its high vaccination rates (first dose coverage at 93.8%, second at 89.06%, third at 76.9%, and fourth at 25% on 25 December 2023), adopts a comprehensive and inclusive approach. The government’s policy encourages staggered booster vaccinations for the entire population, a contrast to the strategies of other countries that focus primarily on high-risk groups. Integral to this program is a mix-and-match strategy, especially for booster doses, recommending mRNA or subunit vaccines following initial viral vector vaccines to enhance immune response. This strategy adapts to the availability of vaccines, exemplified by the predominant use of the Moderna BA.1 variant vaccine during the fourth dose rollout, due to its availability and the depletion of other brands. The decision for administering the second booster is informed by immunological evidence, allowing for its administration three months after the first booster. A significant focus of the research is the prevalent use of the mRNA1273 (Moderna COVID-19 vaccine, Spikevax (Cambridge, MA, USA)) vaccine in the booster program, particularly notable during the administration of the second booster that included the bivalent version of the Moderna COVID-19 vaccine (vaccine against original strain and BA.4/5 variant, mRNA-1273.214 in Taiwan). This scenario offers a unique opportunity providing insights into the occurrence of adverse events in a real-world context.

2.2. Vaccine Adverse Event Reporting System (VAERS) in Taipei Veterans General Hospital

In addition to a centralized Taiwan’s Vaccine Adverse Event Reporting System (VAERS) maintained by Taiwan Centers for Disease Control, Taipei Veterans General Hospital (TVGH) was requested to operate its own VAERS. Individuals who receive their vaccination at TVGH are sent a reminder message seven days post-vaccination, directing them to an online, anonymous questionnaire since most events are reported within a week [33]. They are encouraged to fill out this survey regardless of whether they experienced symptoms or not. This digital survey collects data on the vaccine brand, the dates of both the first and second booster shots, and any post-vaccination symptoms. It includes a section for recipients to describe in their own words the nature of the symptoms (such as fever, fatigue, pain at the injection site, headache, severe allergies, etc.), the timing of their onset after the vaccination, and any follow-up actions they undertook, whether it was self-care at home or seeking outpatient or emergency medical treatment.

A key aspect of this approach is the mandatory reporting of any symptoms by all vaccine recipients, regardless of whether they experience any. This inclusive reporting system guarantees a detailed accumulation of data regarding post-vaccination effects, thereby enhancing the precision and dependability of the study.

2.3. Study Design

This cross-sectional study investigated the vaccination status and associated adverse events reported over a three-month period at the end of 2022 at the vaccination site of Taipei Veterans General Hospital. The adverse events were categorized as severe and non-severe by the researchers. The study data included basic demographic information of the participants, vaccination details, and descriptions of any adverse event. The analysis aimed to explore the correlation between vaccine recipients who experienced adverse events and those who did not, examining potential influencing factors.

2.4. Data Sources

Data collection spanned from the announcement of the second booster (fourth dose)’s availability to citizens and foreign residents over 18 years old on 27 October 2022 until 19 January 2023. Patients receiving vaccines underwent thorough medical examinations, including checks for allergic reactions, acute infection symptoms, and major vaccine-related adverse events. Post-vaccination, patients were provided with a Chinese-language Google Form questionnaire, accessible via a QR code, to report any adverse events within seven days of vaccination. The questionnaire included demographics, vaccine brand choice for the second booster, and any adverse event experienced. To ensure privacy, gender was not included in the questionnaire. The information was anonymized upon submission, with each respondent limited to one submission. This study, approved by the IRB of Taipei Veterans General Hospital (IRB 2022-12-005AC#1), ensured comprehensive data collection while maintaining participant confidentiality.

2.5. Study Population

The study population comprised individuals who sent their response after receiving vaccinations at the vaccination site of Taipei Veterans General Hospital between 27 October 2022 and 19 January 2023. Responders with duplicate submissions, incomplete responses, and incorrect responses were excluded (Figure 1).

2.6. Basic Demographic Information and Vaccination History

Basic information, including respondents’ age and vaccination history, including the brand and time of each dose of vaccine, were extracted from the VAERS. First boosters and second boosters with the same brand of boosters were considered as homologous, and were otherwise classified as heterologous. Vaccines were further divided into two groups of “mRNA1273 (Moderna)” and “others” because of the high share of mRNA1273 vaccines.

2.7. Classification of AEs, Serious Adverse Events (SAEs), and Non-Serious Adverse Events (NSAEs)

Adverse event reports were self-submitted by participants with settled options in the questionnaire and also their own descriptions. Regardless of primary doses, only AEs after the first booster were considered. The responses were categorized by Lin, C.H. and Chen, Y.C. based on the questionnaire’s design. Symptoms potentially related to the cardiovascular system (like chest tightness or difficulty breathing) were classified as Serious Adverse Events (SAEs). Other symptoms, including localized reactions at the injection site, flu-like symptoms, rapid heartbeat, gastrointestinal issues, and muscle aches, were categorized as Non-Serious Adverse Events (NSAEs). This classification was utilized to analyze the correlations and potential influencing factors between vaccine recipients who experienced adverse events (both SAEs and NSAEs) and those who did not report any adverse events.

The first author (Lin, C.H.) classified the multiple descriptions into 6 domains: “cardiac symptoms”, “local reactions”, “flu-like symptoms”, “gastrointestinal symptoms”, “muscle/joint pain”, and “others” as described in another previous study [34]. AEs reported after the first and second boosters were referred to as first and second AEs, respectively.

2.8. Definition of Repeated Adverse Events

Repeated adverse events (repeated AEs) refers to the occurrence of adverse events following each subsequent dose of the COVID-19 vaccine. This category is particularly focused on analyzing whether individuals who experienced AEs after one dose are more likely to experience similar events following subsequent doses. Cumulative risk of AEs (cumulative AEs) assesses whether the likelihood or severity of adverse events increases with each subsequent dose of the vaccine. This concept is crucial for evaluating the long-term safety of the vaccination, especially in a regime involving multiple booster doses. In the current study, we investigated incidence-dependent cumulative risk by evaluating whether the incidence of AEs increases with additional doses.

2.9. Statistical Analysis

To estimate the incidence rates of AEs, we employed point estimation using a binomial distribution to calculate the incidence rates (IRs) and 95% confidence interval (95% CI) of AEs for each category. We used the Fisher exact test to compare the effects of various factors and identify the factors associated with the occurrence of AEs after the second booster. Furthermore, Poisson regression analysis was used to identify factors associated with AEs following the second booster. Incidence rate ratios (IRRs) were used to evaluate the effect of association. To test repeated occurrences of AEs, the McNemar test was used to explore the association between first AEs and second AEs. We examined the IRs of first AEs and second AEs to evaluate the cumulative risk of AEs. All statistics were analyzed using R (R-4.3.2 for Windows); a p-value < 0.05 was considered statistically significant.

4. Discussion

To address widespread public concerns about adverse events (AEs) due to repeated vaccinations, this study analyzed VAERS data from Taipei Veterans General Hospital to explore the AEs following the administration of the second COVID-19 booster dose. The incidence rates of adverse events (AEs) were relatively high, at 25.6% after the first booster and 24.9% after the second. Most notably, these AEs were predominantly non-serious, with symptoms such as injection site pain and fatigue being the most common. We observed the pattern of adverse events (AEs) following COVID-19 booster vaccinations to be repetitive rather than cumulative, where individuals who experienced an AE following the first booster were more likely to report AEs after the second booster. This finding underscores the importance of considering previous AEs, the brand of the second booster, and the booster combination in devising personalized vaccination strategies. These results are vital for health providers and enhancing the understanding of vaccine safety, particularly in the context of administering booster doses.

This study offers crucial insights into the occurrence of adverse events (AEs) following COVID-19 booster vaccinations, particularly in a real-world setting in Taiwan where vaccinations are not limited to priority groups. In our study, we observed a considerable incidence rate of adverse events (AEs) post COVID-19 booster vaccinations. It is essential to recognize that the majority of these AEs were minor, frequently manifesting as injection site pain, fatigue, or low-grade fever. The finding is compatible with a recent systematic review of 22 randomized controlled trials involving over 3.4 million older adults reporting an overall incidence rate of adverse events at 36.6% [4]. The temporal association of these AEs following vaccination does not necessarily imply causation, and it is important to consider the possibility of temporal bias. Additionally, the reliance on self-reported data may lead to an inflated incidence rate due to the underreporting of non-events. There is notable variability in AE incidence rates across large pharmacovigilance databases, as seen in recent studies [8,9,10,11,12]. Our findings contribute further insights into common but non-fatal AEs, consistent with the general profile of vaccine-related side effects that are typically transient and resolve without serious consequences [2,8,9,10,11,35,36]. Therefore, the high incidence rate observed should be interpreted within the larger framework of vaccine safety, emphasizing that the benefits of protection against COVID-19 far outweigh the minor discomforts associated with these non-serious AEs, a fact that should be clearly communicated to address public concerns.
Our observations indicate that individuals who experienced side effects after their first COVID-19 booster often faced similar issues with subsequent doses. Conversely, those who did not encounter side effects initially tended to remain symptom-free after additional doses. This finding is compatible with findings in a study focusing on AEs after primary series in Japan [37]. This trend may be linked to the body developing a heightened sensitivity or allergic response, particularly in those already predisposed to such reactions. Ingredients in the vaccines, such as polyethylene glycol (PEG) and lipid nanoparticles (LNPs), can be responsible for triggering these responses in sensitive individuals [30]. The presence of vaccine adjuvants, which boost the body’s response to the vaccine, can also play a role. Understanding why these reactions happen is important for finding ways to prevent side effects in people who are more likely to have them, especially when considering their past experiences with allergies and sensitivities during booster vaccinations. Additionally, it is important to consider the possibility of reporting bias, where individuals more conscious of their adverse events (AEs) might be more likely to report them, potentially influencing our findings.
Our study found no evidence indicating that adverse events (AEs) increase in frequency with successive COVID-19 booster doses within the same demographic group. This suggests that although an effective immune response is crucial for vaccine effectiveness, and repeated vaccinations may activate the immune system, this does not necessarily lead to a higher frequency of adverse events (AEs) with each subsequent booster dose. This insight is particularly relevant considering the World Health Organization’s (WHO) updated guidelines in 2023, which now recommend booster vaccinations mainly for priority groups, following a comprehensive assessment of the risks and benefits associated with additional doses. [38,39]. Our results provide reassuring evidence regarding the safety of administering second booster doses in public COVID-19 vaccination programs. This information is essential for public health communication, offering reassurance about the safety of receiving multiple booster doses during ongoing efforts to combat COVID-19.

Cautions are needed for interpretation the current result. The reliance on self-reported data in our research might have led to an overestimation of the incidence rates of adverse events. This is particularly relevant as self-reported data can vary in accuracy and completeness, which may skew the true incidence of these events. It is important to note that our findings predominantly apply to common and minor adverse events, given that the number of cases reported was relatively small. Therefore, these results may not be generalizable to rare and severe adverse events. This limitation underscores the need for further studies with more robust data collection methods to accurately assess the incidence of both common and rare adverse events following COVID-19 booster vaccinations.

The association between comorbidities and occurrence of adverse events remained unanswered, while some observational studies noting a higher percentage of adverse events among individuals with comorbidities [12]. Contrarily, some study found no significant increase in risk or severity of vaccine-related side effects in participants with comorbidities [40]. However, our study did not include data on participants’ comorbidities or prior COVID-19 infections, limiting our ability to analyze these factors’ impact on vaccine response and adverse events. This highlights the need for further research on a larger scale specifically focused on individuals with multiple comorbidities to better understand the risks associated with COVID-19 vaccination in this population.
In our study, we limited the reporting of adverse events to within 7 days post-vaccination to increase response rate and minimize recall bias. This approach, however, may have introduced bias by potentially overlooking adverse events that occur weeks later and generally capturing only common and minor reactions. It is noteworthy that a study revealed the median time to embolic event onset was 6 days for mRNA vaccines and 11 days for viral vector vaccines (those were not used as a booster), partially aligning with our study’s reporting period [33]. Therefore, the interpretation of our study’s results should be warranted, considering these limitations and the generally captured common and minor reactions in the short term.

Moreover, there are still some limitations to the current study. First, a significant limitation of this study is reporting bias. The reliance on self-reported data means patients without adverse events may be less inclined to report their status, potentially leading to an overestimation of the incidence of adverse events. This bias can skew the results towards those who experienced more noticeable or bothersome symptoms. Moreover, a significant limitation of this study is the absence of gender data in the questionnaire. The lack of gender-specific information precludes analysis of gender differences in vaccine responses, this gap in data may impact the study’s relevance to diverse populations. Secondly, the study’s methodology is susceptible to recall bias. Since data collection is based on participants’ recollections of their symptoms and the timeline of these symptoms post-vaccination, participants may forget minor symptoms or misremember the severity and timing of their symptoms. Third, the intensity of discomfort or severity of adverse events in this study was subjectively evaluated by the participants themselves, rather than through objective assessment by medical experts. This subjective evaluation can lead to a variation in the reported intensity of symptoms. Fourth, the study’s findings may not be generalizable to the broader population due to the limited sample size and the specific demographic characteristics of the study participants. Larger and more diverse sample sizes are needed to validate these findings across different populations. Fifth, the study does not account for all possible confounding factors, such as underlying health conditions, concurrent medication use, or previous exposure to COVID-19, which can influence the occurrence and reporting of adverse events. Sixth, the reliance on online questionnaires for data collection may introduce a selection bias, as it excludes individuals without internet access or those who are less technologically inclined. Seventh, the study establishes a temporal association between vaccination and the occurrence of adverse events but does not prove causality. Further investigation is needed to establish a direct causal relationship. Furthermore, our study did not include data on participants’ prior infections with COVID-19, nor did it encompass information regarding their comorbidities, limiting our ability to analyze the impact of previous COVID-19 infections and existing health conditions on vaccine response and adverse events.


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