4.1. Safety Profile across Vaccines
Large differences in observed rates of adverse events of special interest (AESIs) across age groups and genders indicate the need for stratification or standardization before using background rates for safety monitoring. There is considerable population-level heterogeneity in AESI rates between databases [
16]. A prospective observational study from northern India has indicated that AESIs associated with the ChAdOx1-nCoV-19 vaccine are more common among females, individuals with hypothyroidism, diabetics, or those who had a history of COVID-19 prior to vaccination. Females and individuals with hypothyroidism also face a higher risk of persistent adverse events. Particular attention needs to be paid to AESIs such as arthropathy, recurrent viral infections, and severe dengue fever. Future studies should explore the role of gender-related and hormonal differences in the occurrence of COVID-19-vaccine-related adverse events. Considering that a significant proportion of COVID-19 infections and non-trivial rates of AESIs occur post-vaccination, there needs to be a strategic reconsideration of blanket recommendations for mass vaccination. Women, individuals with comorbidities such as hypothyroidism, and those with a history of COVID-19 should be informed about the protective benefits of vaccines as well as the risks of adverse events post-vaccination. Compared to further large-scale promotion, an individualized vaccination strategy may be a better choice for public health safety [
17].
In addition, clinical trials may not observe participants for enough time to detect all possible side effects. Knowledge about vaccine-related adverse reactions is incomplete, and risk assessment may vary from person to person, particularly for those with genetic immune issues that could increase risk. Such instances are uncommon and typically found only in post-market analysis [
18,
19]. Also, the lack of definitive proof linking COVID-19 vaccinations to the majority of cases is a critical issue necessitating further research to determine any causative connections [
20]. In Victoria, Australia, a clinical surveillance study on the long-term follow-up and outcomes of COVID-19-vaccine-associated myocarditis revealed that symptoms persist for many patients for up to 180 days after the onset of the AESI. Notably, male patients frequently exhibit quicker symptom resolution, even with initially higher troponin levels, underscoring a gender-specific disparity in recovery. This observation underscores the critical need for further research and prolonged follow-up to understand the implications fully [
21]. In Taiwan, it has been observed that certain AESIs can manifest over an extended period, sometimes spanning several hundred days, highlighting the necessity for ongoing monitoring.
Following the Emergency Use Authorization (EUA), significant overlap between injuries from mRNA vaccine products and both Post-Acute Sequelae of SARS-CoV-2 Infection (PACS) and severe acute COVID-19 illnesses has been observed, often concealing the vaccine’s role in causing these conditions. Moreover, frequent mRNA booster injections may paradoxically impair immune function, increasing the likelihood of COVID-19 infection. Alongside this, a number of serious AESIs like deaths, cancers, cardiac issues, and various other health disorders have been reported, raising substantial concerns. These concerns are particularly acute for the elderly and point to an urgent need to investigate the link between vaccines and AESIs, as well as the issues related to DNA contamination and abnormal protein production associated with the mRNA vaccines [
22].
Moreover, when considering regional differences, the incidence rates of adverse events of special interest such as deep vein thrombosis and pulmonary embolism in Scotland were notably higher during the pandemic period [
23]. These regional data underscore the variability in vaccine response and the importance of contextual analysis. On the other hand, the ChAdOx1 vaccine has been associated with a higher number of adverse reaction events, specifically drawing attention to an immune-mediated mechanism termed vaccine-induced thrombocytopenic thrombosis (VITT) [
24,
25]. This condition has manifested with a particularly higher risk profile for cerebral venous thrombosis (CVT) in women following ChAdOx1 vaccination [
24], which emphasizes the need for gender-specific risk assessment and communication.
Given these diverse findings, the imperative to communicate risks and corresponding mitigation measures with greater detail, clarity, and care becomes evident. This approach is essential for ensuring the public understands the current risks associated with vaccination and can make informed decisions regarding their health.
4.2. Risk Management in Vaccination
In patients with Post-Acute Sequelae of SARS-CoV-2 Infection (PACS), the presence of SARS-CoV-2 proteins and mRNA has been detected in tissue samples. Studies have reported the detection of the SARS-CoV-2 nucleocapsid and spike proteins in the appendix of an individual with PACS and lymphoid hyperplasia of the appendix as long as 426 days after the onset of symptoms. Furthermore, the nucleocapsid protein of SARS-CoV-2 was also found in skin tissue [
26,
27]. These findings emphasize the critical need for advanced surveillance of adverse reactions, especially those that may have a delayed onset. The possibility that reactions could manifest several hundred days after vaccination necessitates vigilant and long-term monitoring. Effective risk communication is essential in fostering public confidence in vaccine safety. Openly sharing risk management data and measures for post-vaccination adverse events enables the public to make informed health decisions [
28].
In Singapore, increased rates of myocarditis/pericarditis, appendicitis, and CVT linked to COVID-19 mRNA vaccines have been observed [
29]. It is imperative to educate patients on the expected reactions to a homologous COVID-19 mRNA vaccine booster, which are generally less frequent and severe than those following the second vaccine dose [
30]. An individualized approach to vaccination may enhance public health safety, particularly for specific demographics, including women, individuals with certain comorbidities, and those with previous COVID-19 infections [
17].
4.3. Policy Implications
The adverse event information provided by the TFDA can only reflect the ‘reported’ cases of death but cannot be conclusive on the reasons for the higher excess deaths observed after 31 March 2022. Whether the mutation of the virus and/or the policy implementation is causative should be further explored. To mitigate the risk from the perspective of the vaccine program, development of evidence-based recommendations is key to enhancing the safety and efficacy of vaccines. Such recommendations could extend to improving surveillance systems to better capture adverse events, which is crucial for the timely detection and response to potential vaccine-related issues [
28]. Enhanced surveillance not only aids in immediate risk management, but also contributes to the long-term goal of strengthening vaccine safety systems [
31]. Transparency in reporting and the tailoring of public health communications are also fundamental to maintaining and building vaccine confidence [
28].
It should be noted that providing the public with a clear understanding of vaccination risks and the measures in place to mitigate them is essential [
32]. This understanding becomes the foundation upon which individuals can make informed decisions regarding their health and vaccination choices. Furthermore, it is critical to recognize and address demographic-specific responses to vaccines. The young and elderly populations may react differently to vaccines, necessitating adjustments in vaccination strategies and post-vaccination monitoring for these groups [
33]. Policy frameworks could be refined to ensure rigorous post-vaccination monitoring, especially in age groups or populations that have reported higher incidences of adverse reactions [
33].
In light of the dynamic landscape of COVID-19 and the occurrence of breakthrough infections, there is a call for strategic reconsideration of blanket mass vaccination policies. An in-depth analysis of the rates of adverse events of special interest within the vaccinated population should inform such policy revisions, ensuring that recommendations are nuanced and tailored to the evolving epidemiological context [
17]. The integration of these insights into policy-making will ensure that vaccination programs are not only reactive to current trends but also proactively designed for resilience and public trust in the face of future challenges.
This study highlights the importance of enhanced surveillance systems capable of detecting and analyzing subtle changes in adverse events promptly. Regular updates on vaccine efficacy and emerging variants are recommended. Surveillance systems must be dynamic and responsive, capable of adapting monitoring strategies to the evolving nature of vaccines and pathogens. Particular attention should be paid to highlighted conditions like myocarditis/pericarditis and stroke, with a focus on vulnerable demographics to tailor public health responses [
24].
4.4. Further Research Needs
The identification of research gaps highlights a significant need for future investigations into the long-term safety and efficacy of different COVID-19 vaccine brands and types [
34]. There is a particular necessity to understand the vaccine response among diverse ethnic groups, which is crucial for tailoring vaccination strategies appropriately [
35,
36]. Future studies should prioritize assessing the durability of immunity conferred by vaccines over extended periods [
37,
38]. This includes investigating how long immunity lasts following the full initial vaccination series and subsequent booster doses. Moreover, it is essential to understand the robustness of vaccine-induced protection against the continuously evolving virus variants, which may differ in virulence and transmissibility [
39,
40,
41].
Additionally, research should not only encompass broad population-wide analyses but also focus on specific populations that may present unique responses or higher risks of adverse events [
42]. This could involve individuals with underlying health conditions, different age brackets, or varying exposure risks. Precision medicine research could be a strategy to disclose the individual vaccine-related adverse effects via tools like single-nucleotide polymorphism. The polymorphism of major histocompatibility complex (MHC) should be analyzed to find out the association between specific MHC haplotypes and vaccine-related adverse effects. Through this approach, immune pathogenesis after vaccine inoculation can be explored, and then we can predict possible specific adverse effects for certain individuals before vaccine injection. Thus, we can choose which kind of vaccine, like DNA vaccine, RNA vaccine, or protein vaccine, is most suitable for each individual. Therefore, possible severe adverse effects after vaccination can be avoided.
By addressing these research needs, future studies can contribute to the development of vaccines that are both effective and safe for all segments of the population [
43]. Such work will be instrumental in guiding public health decisions and maintaining confidence in vaccination programs as an essential component of global health initiatives.
4.5. Significance and Limitations
We wanted to tell a story by comparing vaccination rates locally in Taiwan with those in other world regions to give the overall conclusion that Taiwan has a relatively higher vaccination rate (at least one vaccine dose) compared with Asia or the rest of the world. Based on this context, we provided reported cases stratified by different age groups. Among all age groups, we found that the 18–50 years age group had the highest number of reported cases under the same classification of adverse events compared to other age groups. However, a higher number of death notifications could be observed in groups with higher age ranges. Adverse events with the highest number of reported cases were found to be, in the following order, cerebrovascular stroke, myocarditis/pericarditis, and acute myocardial infarction, of which one is in accordance with previous studies that stated that myocarditis is the most reported adverse event [
44,
45]. Therefore, the higher vaccination coverage in Taiwan was presented as a context to link with the reported adverse events in Taiwan to further explore whether there are any underlying factors that may affect the different profiles of adverse events in local regions, which could include demographic composition or policy implementations.
One of the critical points we wanted to address is the exploration of the underlying reasons that could be potentially related to reported adverse events from vaccination from a local perspective. Amer et al. [
46] supports our point that more attention should be directed toward countries with political conditions that hinder the vaccination process while cautiously interpreting current vaccination results. In addition, at this point, the COVID-19 pandemic is not a major issue and concern because of better implementations of control measures in the past few years. However, it is at this point that we need to raise much more concern for the side effects or adverse events based on the VAERS. Seneff and Nigh [
47] suggested that re-evaluation of COVID-19 vaccines is required based on the fact that it is an unprecedented vaccine; a vaccine normally takes 12.5 years to develop, yet it took a relatively short period of time to develop COVID-19 vaccines with reported high efficacy (90–95%).
On the other hand, we also compared the reported adverse events between vaccinations for COVID-19 and influenza. For the COVID-19 vaccine, 31.2 adverse events were reported per 100,000 doses administered. For the influenza vaccine, 3.99 adverse events were observed per 100,000 doses administered [
48]. It was also mentioned that the influenza vaccine (RIV4) generally is safe among the Taiwan population when compared to the overall safety profiles for the influenza vaccine in this population [
48]. Since the adverse event datasets were both adopted from the VAERS and both have limitations in determining the causality from the vaccines, it would be comparable and reasonable to state that the COVID-19 vaccine has potentially higher reported adverse events than other types of vaccine.
In Taiwan, there has been a significant variation in the cumulative observation time for different brands of COVID-19 vaccines, and there are also substantial differences in the basic characteristics (such as age) of the populations vaccinated with each brand. Data on adverse events related to COVID-19 vaccines are solely derived from the reports received by the Vaccine Adverse Event Reporting System (VAERS) of the Centers for Disease Control. One of the limitations of the VAERS is that it recorded reported adverse events without elucidating the number of doses or different brands of vaccine under the stratifications of various adverse events of special concern, age ranges, or time of onset. An adverse event report refers to any incident reported voluntarily by the notifier at any time post-COVID-19 vaccination due to suspicion of or an inability to rule out a connection with the vaccine administration. Although these reported incidents occur after the administration of the vaccine, they do not imply causation by the vaccine itself. In addition, the adverse event data are not categorized by employing the GRADE system. The current VAERS also lacks a control vaccine (e.g., influenza vaccine), which would have been required to identify the higher risks of SARS-CoV-2 vaccines in this study. All of these limitations implicate the potential impacts of policy implementations with different timeframes of vaccinations and different vaccine brands, leading to the complexity of elucidating the causations of adverse events including different brands of vaccine, doses, demographics, or other contributing factors.
Taken together, despite the limitations in investigations of causation between the vaccine and reported adverse events, and the lack of GRADE system and control vaccine in the VAERS, the purpose of the passive safety surveillance conducted through the spontaneous adverse event reporting system is to statistically assess and analyze factors affecting vaccine safety, such as the demographics, vaccine manufacturer, batch number, and symptoms of adverse events, to identify potential safety concerns at the earliest opportunity. We thus provide an insight from global to local perspectives on how to best utilize local adverse event reporting systems to address the importance of paying more attention to characterizing the causation between these adverse events and vaccination and implementing better surveillance systems and refinement of policies by tailoring personal requests for different types of vaccines.