Abstract

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This paper examines critical safety issues of mRNA lipid nanoparticle formulations (hereinafter referred to as genetic vaccines and mRNA vaccines) for coronavirus disease 2019 (COVID-19)— including Comirnaty (development code BNT162b2), Spikevax (development code mRNA-1273), and Kostaive (development code ARCT-154) for intramuscular injection—and discusses the necessity for revocation of approval and market withdrawal. The genetic vaccines that received special approval for emergency were widely recommended for administration as a public health measure during the COVID-19 pandemic, with approximately 103.46 million people in Japan (79.5% of the population) receiving the genetic vaccine. Despite numerous reports of health injuries both domestically and internationally as of June 2025, the Japanese government has not conducted a nationwide health injury survey into these adverse health effects. These vaccines were approved without adequate non-clinical testing and long-term safety evaluation, and administration continued without sufficient disclosure of adverse events. This paper discusses in detail the scientific deficiencies in the regulatory review of genetic vaccines, inadequacies in post-marketing risk management, and issues concerning significant adverse drug reactions and potential DNA contamination in genetic vaccines. It is evident that genetic vaccines that received special approval for emergency by the Japanese government lack sufficient evidence of efficacy, and their potential risks to public health cannot be overlooked. A comparison with previous cases of pharmaceutical approval revocations indicates that revoking the approval and withdrawing genetic vaccines from the market is not only reasonable but also necessary. Therefore, we call upon the Japanese government and relevant regulatory agencies to implement prompt measures and conduct a thorough reassessment.

Introduction

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This paper addresses the mRNA lipid nanoparticle formulations (hereinafter referred to as genetic vaccines and mRNA vaccines) that received special approval for emergency in May 2021 during the COVID-19 pandemic under Article 14-3, paragraph 1 of the Order for Enforcement of the Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices (hereinafter referred to as the “Pharmaceuticals and Medical Devices Act. [PMD Act]”) (Table 1). It describes the significant public health event  that occurred in Japan related to these formulations and discusses the grounds for revocation of approval (Article 74-2 and Article 75-3 of the PMD Act) (Table 1) and the necessity to withdraw these products from the market. All legislation mentioned in this paper refers to Japanese law unless otherwise specified.

The genetic vaccines that received special approval for emergency as a public health measure during the COVID-19 pandemic [1] were promoted for widespread administration to the Japanese population  [2-4]. However, despite numerous reports of adverse reactions following administration both domestically and internationally (Figure 1), as of June 2025, the Japanese government (hereinafter referred to as “the government”) has not conducted a nationwide investigation of adverse health effects caused by genetic vaccine administration. Following the report of multiple fatalities, the government should have immediately suspended administration or implemented appropriate measures (Article 69-3 of the PMD Act) (Table 1), conducted nationwide post-marketing surveillance, and scientifically evaluated the results, as were done previously with the diphtheria-pertussis-tetanus (DPT) vaccine, measles-mumps-rubella (MMR) vaccine, and mouse brain-derived Japanese encephalitis vaccine. When a large number of deaths have been reported following the administration of a pharmaceutical product, review of approval or product recall measures should be considered in accordance with relevant laws and regulations. Furthermore, an “Opinion on the Safety Evaluation of the COVID-19 Vaccine” had already been issued by the Pharmaceutical Administrative Evaluation and Surveillance Commission [5]. Although this opinion urged a careful assessment of the risks associated with administration, the government did not respond with sufficient seriousness. Instead, it continued to promote administration, during which time the number of reported health-related adverse events continued to rise [6].

The Japanese regulatory authorities have emphasized the need for rapid vaccine deployment during a national crisis [7, 8]; however, this approach does not exempt oversight bodies from their ongoing responsibilities to ensure transparency, update safety assessments, and disclose relevant risks to the public. The failure of Japanese administrative agencies to adhere to fundamental principles of public health policy, such as “evidence-based decision-making,” and “prioritizing public health and safety above all else,” and their failure to implement appropriate risk management, have resulted in adverse drug reactions of unprecedented scale in both number and medical severity among the Japanese population. This paper provides a critical analysis of structural deficiencies in Japan’s regulatory response to genetic vaccines during the COVID-19 pandemic and presents scientific grounds for the revocation of approval and market withdrawal of mRNA vaccines.

Defects in Review Report and Package Insert

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One contributing factor to the large-scale adverse drug reactions caused by genetic vaccines is that the Pharmaceuticals and Medical Devices Agency (PMDA) directly applied the “Guideline for Non-clinical Studies on Vaccines for the Prevention of Infectious Diseases,” which had been used for reviewing conventional vaccines, to these first-in-human genetic vaccines (Tables 2 and 3). This guideline mandates a narrower scope of testing and less rigorous standards compared to requirements for general pharmaceutical products [9-23]. Genetic vaccines should properly be classified as gene therapy products based on their mechanism of action [24, 25] (Table 4), yet they were reviewed under the same regulatory framework as conventional vaccines despite not being pharmacologically or structurally equivalent [26].

Consequently, several key elements typically evaluated in non-clinical safety studies—such as biodistribution, pharmacokinetics, organ-specific toxicity, placental transfer, fetal toxicity, and immunogenicity—were not assessed. Studies on carcinogenicity and genotoxicity were also omitted. Given the extremely short follow-up period in clinical trials (only several weeks to several months), approval was granted without sufficient evaluation of long-term safety in either non-clinical or clinical settings. Additionally, sufficient information on adverse events observed in clinical trials—particularly the potential for a broad spectrum of adverse reactions—was not adequately communicated to Japanese healthcare professionals or the general public. The monovalent mRNA vaccine corresponding to the Omicron strain XBB.1.5 spike protein was approved based solely on non-clinical data without conducting sufficient clinical trials, on the grounds that antibody titer increases and safety profiles were similar to those of previously approved genetic vaccines [27].

According to the Ministry of Health, Labour and Welfare (MHLW)’s initial explanation, mRNA-LNP formulations remain at the injection site and the modified mRNA is rapidly degraded. Modified mRNA refers to mRNA that has been modified with methyl pseudouridine (m1Ψ), resulting in enhanced RNA stability and reduced immunogenicity. This was used in genetic vaccines (Pfizer, Moderna) to enhance spike protein production efficiency. (This explanation was previously available on the MHLW website but has since been removed.)  However, subsequently published studies using rats and mice revealed that lipid nanoparticles (LNPs) accumulate in numerous organs including bone marrow and ovaries (in descending order of accumulation: liver, spleen, adrenal glands, ovaries, bone marrow, small intestine, lymph nodes, large intestine, lungs, thyroid, etc.) [28, 29], reach the fetus via the placenta and umbilical cord in pregnant mice [30], and remain in the bloodstream for at least two weeks following administration [31]. Although the PMDA had access to pharmacokinetic data in rats—submitted by pharmaceutical companies around February 2021 [28, 32]—it did not provide this information to medical institutions or the public. The failure to disclose that LNPs distribute systemically, cross the blood-brain barrier, and accumulate in organs such as the ovaries and adrenal glands represents a serious lapse in responsibility and may constitute regulatory oversight failure.

Furthermore, LNPs themselves have been reported to be highly inflammatory substances [33], and the production of anti-polyethylene glycol (PEG) antibodies has been confirmed [34]. Research demonstrating that LNPs remain in the bloodstream for at least two weeks post-administration clearly indicates that the two-day deferral period for blood donation—adopted by the Japanese Red Cross Society and similar organizations [35]—lacked a sufficient scientific basis. Since genetic vaccines were approved as pharmaceutical products, information regarding their pharmacokinetics should have been clearly documented in the package insert and thoroughly communicated to healthcare professionals. However, the package inserts for mRNA vaccines provide only minimal pharmacokinetic information, and dissemination of relevant data to healthcare institutions was significantly insufficient. Such circumstances may be evaluated as a failure by marketing authorization holders (MAHs) to fulfill their “duty to warn.” When both the MAH and regulatory authorities failed to provide accurate and necessary information in a timely manner, such omissions may have presented a potential violation of Article 68-10 of the PMD Act (Table 1), which requires the disclosure of safety-related information. Notwithstanding these concerns and the emergence of multiple safety issues, the Japanese government proceeded to grant full marketing approval for Pfizer’s genetic vaccine in 2024.

Despite being aware of numerous adverse events during clinical trials of its mRNA vaccine (Comirnaty; development code BNT162b2), Pfizer did not disclose this important safety information to regulatory authorities, including Japan’s MHLW. This fact was revealed through a freedom of information lawsuit filed by a U.S. citizen group. In 2021, the court ordered the FDA (U.S. Food and Drug Administration) to disclose materials that Pfizer had submitted, revealing that an unprecedentedly wide spectrum of adverse events had been reported from the outset. These adverse events span an extremely broad range, from common diseases to rare and intractable conditions [36]. A wide variety of adverse events, including thrombocytopenia and myocarditis, have been reported worldwide following genetic vaccine administration [37-42].

For adverse events that were originally of concern regarding genetic vaccines, these possibilities should have been clearly documented in the pharmaceutical package insert from the initial stages, with appropriate warnings provided to healthcare professionals, as part of the “duty to warn.” However, actual package inserts contained almost no explicit documentation of the numerous adverse events (e.g., myocarditis, thrombosis, autoimmune reactions, etc.) being reported following genetic vaccine administration. Consequently, it became difficult for physicians to provide recipients with adequate explanations, including risks, creating a situation where the principle of informed consent could not function effectively. Information necessary for citizens to make informed decisions regarding genetic vaccine administration was not appropriately provided, compromising the foundation of medical ethics—the guarantee of the right to self-determination.

Particular attention should be drawn to PFSB/SD (Safety Division, Pharmaceutical and Food Safety Bureau) Notification No. 0328007 (March 28, 2005), titled “Post-approval Safety Data Management: Definitions and Standards for Expedited Reporting [43].” Section 2.2, “Adverse Drug Reaction (ADR),” clearly states that “For regulatory reporting purposes, if an event is spontaneously reported, even if the relationship is unknown or unstated, it meets the definition of an adverse drug reaction.” This explicitly indicates that adverse events should be treated as adverse drug reactions at the time they are reported.

All adverse event reports published on the MHLW website [6]—including those documenting adverse reactions, deaths (Figure 1), and serious health injuries following COVID-19 vaccination—as well as adverse events presented at academic conferences, should be regarded as “adverse drug reactions” irrespective of proven causality. Consequently, the inclusion of such adverse event information in pharmaceutical package inserts is a regulatory and ethical imperative. A failure to reflect this data appropriately constitutes a serious breach of the duty of MAHs and regulatory authorities to ensure adequate safety communication.

An administrative document disclosure request to MHLW (Disclosure No. 3333; Administrative Document Disclosure Decision Notice, MHLW PSEHB Notification No. 0403-37) revealed that MHLW and PMDA had obtained similar data prior to this information being disclosed. Since the initiation of genetic vaccine administration, MHLW has received diverse spontaneous adverse event reports from medical institutions nationwide. However, MHLW has not adequately established systems to disseminate this information to medical institutions and the general public in a timely and appropriate manner. Furthermore, there appears to be a significant problem with the approach of positioning these formulations equivalently with conventional “vaccines,” not treating spontaneously reported adverse events as “side effects” or “adverse drug reactions”  and promoting administration without adequate causal relationship assessment or safety verification. When administrative bodies tasked with safeguarding public health and safety fail to respond transparently to scientifically recognized risks, their institutional and ethical accountability becomes a matter of utmost concern. In this context, MHLW bears institutional accountability for its failure to ensure transparency regarding adverse event data, for promoting genetic vaccines under the label of “vaccines,” and for neglecting to appropriately categorize spontaneously reported adverse events as “adverse drug reactions.” The dereliction of duty by an agency entrusted with protecting citizens’ lives—particularly its failure to disclose critical safety information and to conduct proper verification— should be subject to thorough and independent review processes, with appropriate public accountability mechanisms.

Had it been disclosed during the regulatory review process that an unprecedentedly wide spectrum of distinct types of disorders had been reported as adverse events, it is questionable whether Pfizer’s genetic vaccine would have received special approval. The transparency and integrity of the approval process for genetic vaccines must be subject to renewed and rigorous scrutiny. To prevent recurrence, it is imperative to promptly initiate a comprehensive investigation by independent third-party bodies and to ensure full accountability.

Despite receiving information from pharmaceutical companies and adverse event reports from physicians, the government took no specific countermeasures and instead openly ignored these concerns, reviewing and approving genetic vaccines with novel mechanisms of action, including self-amplifying mRNA (saRNA)-LNP formulations (commonly called replicon vaccines), as infectious disease prevention vaccines, and announced a policy to initiate routine administration for high-risk groups (elderly individuals, etc.) beginning in October 2024 (details will be discussed in Section 5). Such responses are inappropriate for public health policy that requires careful judgment based on scientific evidence and represent serious problems from the perspective of ensuring public safety.

As demonstrated above, both during the approval review process and in the post-marketing surveillance of adverse reactions to genetic vaccines, the PMDA and MHLW appear to have withheld critical safety information. Given their institutional responsibility to safeguard public health, such actions raise serious concerns regarding the potential infringement of the public’s right to know and right to self-determination. The result was the occurrence of serious and extensive health injuries. Given the protections enshrined in Article 13 and Article 25 of the Constitution of Japan—respectively safeguarding individual dignity and the right to maintain a standard of wholesome and cultured living—the government’s inaction may constitute a violation of constitutionally protected human rights. From a legal standpoint, such conduct may reasonably be characterized as regulatory oversight failure  and a breach of statutory obligations.

In addition to these legal and ethical concerns, the absence of any reference to this serious structural risk in the PMDA’s review report suggests a significant limitation in the current evaluation framework, raising concerns regarding the robustness of scientific assessment and compliance with established pharmaceutical regulatory standards. Therefore, a violation of the obligation to conduct a proper safety evaluation, as stipulated in Article 14 of the PMD Act, is strongly suspected. A rigorous and comprehensive reassessment by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the MHLW, as well as independent third-party institutions, is urgently warranted to determine whether the scientific and ethical standards essential for ensuring safety have been properly fulfilled.

Suppression of Contradictory Real-World Data in Vaccine Policy-Making

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When genetic vaccines for SARS-CoV-2 first received special approval [1], these products were widely promoted as being effective in preventing infection. In Japan, approximately 103.46 million people (79.5% of the population) received their second dose of genetic vaccines within a short period (Figure 2) [4]. Although Japan lagged behind other countries in initiating administration, it eventually became the country with the highest genetic vaccine administration rate worldwide (Figure 2) [44].

However, since 2023, it has been claimed that “there is no protective effect against the infection, but there is protection against severe disease [45].” Documents prepared by the MHLW and submitted to its own Advisory Board clearly illustrate the unsubstantiated and arbitrary nature of this statement.

One of the documents prepared by MHLW and submitted to the 50^th COVID-19 Advisory Board presents comparative data on the COVID-19 case fatality rates among unvaccinated individuals and those who received one or two doses of genetic vaccines. The case fatality rates across all age groups were 0.12% (unvaccinated), 0.41% (single dose), and 0.58% (two doses), respectively, showing a trend of increasing case fatality rates with increasing doses of genetic vaccines (Table 5) [46]. This trend is more pronounced in specific age groups. Nevertheless, the document emphasizes only the data for the 65 years and older age group in red text, presenting figures that appear to show reduced case fatality rates following genetic vaccine administration in that age group. This exploits a phenomenon statistically known as “Simpson’s Paradox” [47], which is a typical method for creating misleading impressions.

Subsequently, no nationwide case fatality rate data disaggregated by number of genetic vaccine doses has been published. At the 92^nd Advisory Board meeting held on July 27, 2022, Document 2-5 presented data on the number of new positive cases instead of case fatality rates (Table 6) [48]. According to this data, in most age groups, the number of new positive cases (per 100,000 population) among unvaccinated individuals was lower than among those who had received genetic vaccines. For example, in the 65-69 age group, unvaccinated individuals had 66.5 new positive cases, compared to 265.5 cases among those who received two doses and 169.5 cases among those who received three doses. These figures make it difficult to conclude that genetic vaccine administration was effective in preventing the infection; rather, it is evident that individuals who received the administration had higher infection rates. Perhaps due to confronting these inconvenient real-world data findings (Figure 3), no similar administration history-stratified data have been published since.

MHLW did not disclose data in response to freedom of information requests concerning infection and case fatality rates stratified by genetic vaccine administration history. In ongoing litigation (Case Nos. 44 and 297 of 2023 [Gyo-U]), the Ministry explained that it had not repeated such tabulations because members of the Advisory Board had raised concerns regarding the tabulation methodology.

As a result of this litigation, both the Tokyo District Court and Tokyo High Court rendered decisions to “dismiss the plaintiff’s claims.” The following extraordinary reasons were presented: “no relevant documents exist,” and “at the 90^th COVID-19 Advisory Board meeting, the view was expressed that ‘it is inappropriate to simply compare severity rates and case fatality rates of infected individuals by vaccination history when conducting post-hoc evaluation and verification of the epidemiological effects of vaccination.’ Therefore, it was decided not to create documents comparing severity rates and case fatality rates thereafter.”

In fact, within six months of the rollout of genetic vaccines, data had already begun to reveal elevated case fatality rates in specific age cohorts. Accordingly, the claim that “vaccines prevent severe disease” was no longer tenable based on the available evidence at that time. Citing public epidemiological data from New South Wales, Australia, Parry et al. point to the possibility of a dose-dependent relationship between the number of COVID-19 genetic vaccine doses and severity indicators (number of hospitalizations and ICU admissions) [28]. According to the state’s official report, COVID-19-related hospitalization and ICU admission rates progressively increased as the number of genetic vaccine doses increased from one to two, three, and four doses. This observation is noteworthy as it suggests the accumulation of immune abnormalities or spike protein-related toxicity in some individuals receiving genetic vaccines.

Similarly, given that data on new positive cases published in July 2022 demonstrated that vaccinated individuals tended to have higher infection rates than unvaccinated personals, claims that “vaccine benefits outweigh the risks” and that “approved vaccines have benefits that far outweigh possible risks” [49, 50] lack objective foundation and cannot be justified to the public.

Therefore, although real-world data collected and acknowledged by MHLW itself contained evidence unfavorable to vaccine effectiveness, the Ministry consistently failed to disclose this information to the public and continued to conceal it. These actions appear inconsistent with the principles of governmental accountability and the public’s right to know, potentially undermining the Ministry’s obligations to maintain transparency and uphold evidence-based policymaking.

Structural Bias and Immune Mechanisms Undermining Vaccine Efficacy

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One critical concern in evaluating the efficacy of genetic vaccines arises from the definition of the case counting window in pivotal trials [51]. As Doshi pointed out, excluding cases that occur within the first 7–14 days after the initial dose may introduce a systematic bias that inflates the apparent efficacy [52]. In an observational study by Kitano et al., case counting was initiated 14 days after the second dose [53], suggesting that a similar bias structure may also be present in those data. These early cases likely occurred during a period of maximal susceptibility, when the immune response remained incomplete [51]. While such cases are often omitted from the efficacy denominator, they are typically included in safety assessments. This methodological choice may result in an overestimation of efficacy, particularly if early post-vaccination reactogenicity correlates with transient immunosuppression. Acknowledging this limitation is essential when interpreting headline efficacy results, especially in the context of emergency use authorizations.

Importantly, a disproportionately high number of deaths have been reported within the first few days following mRNA vaccine administration (Figure 4) [54-57]. This temporal clustering follows a pattern consistent with a discrete Erlang distribution, suggesting a non-random concentration of events shortly after exposure [58]. Notably, both 2021 and 2024 datasets display a consistent temporal profile, with a peak on Day 2 post-vaccination followed by a gradual monotonic decline. By June 2021, the reported post-vaccination mortality rate had reached approximately 0.002% [59], remaining relatively stable through 2024 [54]. The reproducibility of this pattern across independent datasets underscores the need for timely signal detection, robust causal inference, and transparent risk communication. Failure to incorporate such early adverse event patterns into safety and efficacy evaluations may introduce bias, particularly under emergency authorization frameworks.

Another potential source of bias in the interpretation of early trial and observational data relates to the diagnostic criteria used to confirm SARS-CoV-2 infection. As emphasized in the World Health Organization (WHO) Information Notice for IVD (In Vitro Diagnostic Medical Device) Users issued in January 2021 [60], RT-PCR–based diagnosis should be interpreted in conjunction with clinical presentation and cycle threshold (Ct) values. High Ct values (e.g., >35) are known to correlate poorly with viral infectivity and are more likely to reflect residual, non-viable viral RNA fragments rather than active infection [61, 62]. However, during the initial phases of mass testing, many clinical studies and public health surveillance systems did not report cycle threshold (Ct) values or applied high Ct cutoffs without adequate clinical contextualization. In Japan, available evidence indicates that no nationally standardized Ct threshold was established for RT-PCR diagnostics during the COVID-19 pandemic. Instead, Ct cutoffs varied considerably across laboratories and testing platforms, with some institutions reportedly considering values as high as <40 as positive [63, 64]. This diagnostic heterogeneity critically undermined the reliability and comparability of SARS-CoV-2 case definitions. As a result, there is a credible possibility that early baseline cases, particularly among asymptomatic individuals, were likely inflated due to the inclusion of PCR-positive results that lacked clinical significance. Such diagnostic inflation could have distorted estimations of baseline infection and mortality risk, thereby affecting the perceived effectiveness of vaccination, especially if pre-vaccine risk levels were overstated. Accordingly, future revisions to diagnostic protocols must address this structural vulnerability to ensure consistency, reliability, and scientific integrity in pandemic response policy.

In parallel, mortality attribution practices also present serious concerns. Substantial institutional and procedural challenges remain in the causal assessment of deaths following COVID-19 vaccination. According to the WHO guidelines for causality assessment of adverse events following immunization (AEFI) [65, 66], a robust determination requires systematic evaluation of temporal relationships, biological plausibility, exclusion of alternative causes, and integration of supportive evidence such as autopsy findings. While PMDA has developed causality assessment guidelines in line with international standards, questions remain regarding the uniform application of these criteria and the transparency of their implementation, particularly in cases involving post-vaccination fatalities.

The absence of a standardized and rigorously applied evaluation framework undermines the scientific credibility of vaccine safety surveillance. In practice, although over 2,000 post-vaccination deaths have been reported by physicians in Japan, autopsies have been performed in only approximately 10% of cases. Consequently, nearly 99% of these reports have been classified as “causality indeterminable.” This systematic lack of post-mortem investigation has prompted strong concern among forensic and clinical experts, highlighting the urgent need for a nationally coordinated system of cause-of-death determination [67-69].

In the early phase of the COVID-19 pandemic, Japan faced considerable administrative disruptions and infection control priorities that severely limited the capacity to conduct autopsies [70]. These constraints likely impaired accurate cause-of-death assessments for both COVID-19–related and post-vaccination deaths, thereby compromising the validity of subsequent causal evaluations.

Moreover, in Japan and many other countries, it became common practice to classify deaths as “COVID-19–related” based solely on positive PCR test results, even in the absence of corroborating clinical or pathological evidence. Such a failure to distinguish between deaths from COVID-19 and deaths with COVID-19 risks a substantial overestimation of mortality statistics and poses a threat to the integrity of epidemiological indicators [71, 72].

For accurate assessment of vaccine risk–benefit profiles, mortality data should be stratified based on standardized causality determination criteria, including autopsy findings, comorbid conditions, and temporal proximity between symptom onset and death [55]. When vaccine efficacy is evaluated in the absence of such diagnostic and attributional rigor, doubts regarding the validity of such efficacy estimates are not only understandable, but arguably unavoidable.

Despite these limitations, expert advisory panel members entrusted with shaping national health policies failed to sufficiently disclose the underlying scientific uncertainties to the public [73]. Given their significant involvement in policymaking, any failure by such entities to uphold accountability standards merits serious scrutiny, potentially to a degree comparable to or exceeding that applied to governmental bodies.

Meanwhile, at the European Parliament in October 2022, Pfizer’s vaccine development director testified under oath that “infection prevention efficacy was not investigated during the clinical trial stage” [74]. Subsequently, real-world data analysis revealed that the more genetic vaccines individuals received, the more likely they were to contract SARS-CoV-2 [50, 75, 76]. This may be attributable to genetic vaccines causing original antigenic sin due to prolonged antigen persistence in the body compared to conventional vaccines, as well as IgG4 class switching of anti-spike protein antibodies [77-81].

Original antigenic sin refers to a phenomenon whereby the immune system responds strongly to antigens from an initially encountered pathogen (virus or bacteria), and subsequent immune responses to similar pathogens become suboptimal.

Indeed, spike proteins derived from mRNA vaccines have been reported to persist in the human body for an extended duration following vaccination, particularly within lymphoid tissues,  the bloodstream, and various organs [82-86]. Repeated administration of mRNA vaccines has been associated with elevated IgG4 responses, which may modulate immune reactivity [87]. This raises concerns regarding the potential for immune tolerance, although the extent to which this contributes to recurrent SARS-CoV-2 infections remains to be clarified.

In Japan, COVID-19 cases have continued to occur at substantial levels since the introduction of genetic vaccines (Figure 3). Time-series analysis of epidemiological indicators based on publicly available MHLW data from 2020 to 2023 revealed no sustained downward trend in positive cases, severe cases, or deaths following widespread vaccine administration. The recurrence of infection waves, particularly from 2021 onward, suggests that the infection suppression effect of genetic vaccines at the population level may have been limited, warranting further investigation.

This observation is consistent with the potential immunosuppressive mechanisms discussed above and the capacity of formulations to induce original antigenic sin. Specifically, increased IgG4 possesses anti-inflammatory properties that may, under certain circumstances, impact infection defense, potentially leading to reduced immune responses against certain pathogens [88]. Normal antiviral immune responses are predominantly mediated by IgG1 and IgG3 subclasses, which are associated with strong pro-inflammatory and neutralizing activity [89]. However, chronic or repeated antigenic stimulation—such as sustained exposure to the SARS-CoV-2 spike protein—has been shown to induce a relative increase in IgG4 subclass antibodies specific to the spike protein. Several studies have reported that the frequency of anti–spike protein IgG4 antibodies rises in a dose-dependent manner with successive administrations of genetic vaccines [77-79, 81]. This finding is consistent with results showing that higher numbers of genetic vaccine doses are associated with repeated SARS-CoV-2 infections [50]. Furthermore, it is theoretically conceivable that excessive antigen production by the formulation could enhance Treg (regulatory T cell) function, resulting in diminished immune responses [90]. Particularly, it has been suggested that an increase in IgG4 and the induction of immune tolerance observed after genetic vaccine administration may lead to reduced protection against infection [87], warranting further investigation.

Supporting these concerns, mortality rates for specific cancers—including ovarian cancer, leukemia, lip/oral cavity/pharyngeal cancer, and pancreatic cancer— have shown a notable increase in Japan since the initiation of genetic vaccine administration [91]. In line with this concern, Abue et al. recently reported an association between repeated mRNA vaccination and reduced overall survival in patients with pancreatic cancer. This observation was accompanied by elevated IgG4 levels and increased infiltration of Foxp3-positive immunoregulatory cells in tumor tissues, suggesting a possible immunomodulatory effect [92]. While these findings raise important questions, further studies are warranted to determine causality and underlying mechanisms. Furthermore, recent statistics show that Japan’s life expectancy, which had increased consistently over previous decades, peaked in 2020—the onset year of the COVID-19 pandemic—and has shown a declining trend since the introduction of genetic vaccines in 2021 [93, 94]. This decline corresponds with a rise in overall mortality observed during the same period. Age-adjusted mortality rates, which reached their lowest point in 2020, began increasing in 2021 and accelerated further in 2022 [93, 95]. These temporal patterns may indicate a shift in public health dynamics around 2020, warranting further investigation into potential contributing factors.

Currently, direct causal relationships with genetic vaccines remain unknown, but the characteristics of repeatedly administered genetic vaccines strongly suggest the likelihood of long-term immunosuppression or immune dysfunction in recipients. These findings highlight the urgent need for independent re-evaluation of genetic vaccine safety, efficacy, and long-term public health impact based on transparent and stratified data.

Biosafety Risks Associated with Self-Amplifying mRNA Vaccine Platforms

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Among next-generation genetic vaccine technologies, saRNA platforms have attracted attention for their enhanced antigen expression efficiency (Figure 5) [96, 97]; however, concerns have been raised regarding their safety, regulatory classification, and insufficient clinical evaluation [98].

According to clinical trials and the review report [99, 100], the adverse reaction profile of the saRNA vaccine (trade name Kostaive for intramuscular injection, development code ARCT-154), developed by Arcturus Therapeutics and marketed by Meiji Seika Pharma, was similar to Pfizer’s mRNA vaccine; thus the formulation was evaluated as “non-inferior” to existing formulations.

Non-inferiority refers to the concept that a new pharmaceutical product is “not statistically inferior in efficacy or safety” compared to existing standard treatments.

In other words, this means it could reasonably have been anticipated that adverse events similar to those observed with Pfizer and Moderna (trade name Spikevax, development code mRNA-1273) mRNA vaccines might occur. Therefore, it was sufficiently predictable that adverse events like those of conventional mRNA vaccines would occur with saRNA vaccines. Indeed, according to a document published by Meiji Seika Pharma Co., Ltd. in May 2025, multiple adverse events were reported within just a few months after initiating the administration of this formulation, including four fatalities [101, 102]. These facts indicate the necessity for rigorous investigation of whether appropriate preliminary risk assessments were conducted and whether adequate warnings and countermeasures were implemented in anticipation of these adverse events.

Moreover, Arcturus Therapeutics and Meiji Seika Pharma conducted a non-inferiority trial comparing a saRNA vaccine with a conventional mRNA vaccine (Pfizer) as a fourth-dose booster to evaluate the efficacy of the replicon-based formulation [103]. However, the trial cohort consisted exclusively of individuals who had previously received multiple doses of genetic vaccines, raising concerns that preexisting immune modulation or waning immunity may have confounded the evaluation of vaccine efficacy. This design limitation potentially undermines the appropriateness of the trial for assessing the standalone performance of the saRNA platform.

Amidst this situation, the vaccine formulation introduced for routine clinical use in October 2024 contains the spike protein of the JN.1 variant—an antigen for which comprehensive non-clinical and clinical safety evaluations had not yet been completed at the time of approval [99, 104]. These updated formulations were approved via the “partial change approval” pathway as stipulated under Article 14, paragraph (15) of the PMD Act (Table 1) [99, 105]. However, the JN.1 spike protein differs from the ancestral strain by approximately 3.5% at the amino acid level, resulting in alterations to structural and immunological properties [106]. If evaluated under the regulatory framework applicable to gene therapy or nucleic acid-based pharmaceuticals, such a degree of antigenic divergence would likely warrant independent non-clinical and clinical studies to reassess safety and efficacy.

The reliance on regulatory categorization as an “infectious disease vaccine,” rather than as a gene therapy or nucleic acid pharmaceutical, may have permitted streamlined approval without rigorous reassessment. This regulatory classification discrepancy raises important questions regarding the sufficiency of existing approval pathways for next-generation genetic vaccines with evolving antigenic profiles. Given that saRNA vaccines arguably fall within the conceptual and mechanistic domain of gene therapy products [107], their evaluation without genotoxicity or carcinogenicity studies [9], and with shortened follow-up durations [102], may represent a gap in regulatory oversight. A reappraisal of regulatory categorization criteria is warranted to ensure alignment between product mechanism, safety requirements, and public health protections.

On the other hand, genetic recombination experiments conducted at research institutions such as universities and companies require strict risk management from a biosafety perspective to avoid infection risks and unexpected recombination risks. As part of this approach, measures are implemented to minimize risks, such as dividing genes within viral vectors across multiple plasmids [108]. In contrast, the saRNA vaccine approved in Japan incorporates both the mRNA replication enzyme (replicase) and the antigen gene on a single vector (Figure 5), suggesting that biosafety safeguards may be insufficient for pharmaceutical products intended for human use. This co-localization raises concerns about sustained replicase activity [109], which may result in prolonged antigen expression and potential dysregulation of the immune system. Such effects could increase the risk of adverse immune responses, including hyperinflammation and autoimmunity, especially in vulnerable individuals. Furthermore, the single-vector design introduces structural risks that may elevate the likelihood of unintended recombination or horizontal gene transfer, posing substantial biosafety and infection control concerns.

From a pharmacokinetic and pharmacodynamic perspective, the immature design of current genetic vaccine formulations (both mRNA- and saRNA-LNPs) raises three fundamental concerns—referred as the “three Os”: Off-target expression, Overproduction of antigenic proteins, and Out-of-control in bioreactivity and the host reaction [24]. These risks are particularly salient in mRNA–LNP platforms, where cellular uptake and translation are not confined to targeted tissues, antigen production may far exceed physiological levels, and systemic dissemination, unintended action, host responses in any place remains poorly characterized. Without rigorous evaluation of these dimensions in nonclinical studies, the overall safety profile remains inadequately defined.

In May 2025, President Donald Trump signed an Executive Order titled “Improving the Safety and Security of Biological Research,” which drew considerable attention by instituting a moratorium on high-risk gain-of-function (GOF) research involving infectious pathogens and toxic agents, as well as by mandating a complete suspension of federal funding for such research conducted in foreign countries [110]. This Executive Order aims to rebuild risk management for life science research triggered by the COVID-19 pandemic and indicates a progressing trend toward strengthened international regulation of high-risk GOF research and experiments lacking biosafety measures [111, 112]. Given that saRNA vaccines, including conventional mRNA vaccines, have similar high-risk characteristics [113], comparable regulatory reassessments are strongly warranted in countries beyond the United States.

Safety Issues (Defects in Adverse Event Reporting, Recognition of Health Injuries, and Risk Assessment)

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The SARS-CoV-2 spike protein used as an antigen in genetic vaccines has been reported to contribute to vascular endothelial cell injury, thrombosis, inflammatory response induction, and mitochondrial dysfunction, with multiple studies documenting spike protein-related toxicity across various organ systems [28, 114, 115]. Structural analyses have further suggested that the original Wuhan strain spike protein contains motifs homologous to gp120 and prion-like domains [116], may be capable of crossing the blood-brain barrier [117], and exhibits amyloidogenic properties in vitro [118]. The continued use of mRNA platforms encoding such biologically active and potentially pathogenic proteins as pharmaceutical agents raises important safety considerations, particularly regarding their long-term effects.

In parallel, suggestions have emerged that SARS-CoV-2 may be of artificial origin [119-121], further underscoring the necessity of rigorous oversight regarding the handling and dissemination of related genetic materials.

Shortly after the initiation of genetic vaccine administration, myocarditis and pericarditis were identified as adverse drug reactions [40] and added to the package insert for genetic vaccines [122]. In December 2021, the Minister in Charge of Promoting Vaccinations stated, “Some people develop myocarditis from vaccines, but the probability is low, and the condition is mild. Most people recover” [123]. This statement minimized these inherently serious conditions. Subsequent analysis by Japanese research groups reported a significantly increased incidence of myocarditis and pericarditis in individuals under 30 years of age who received genetic vaccines [124]. Adverse events have been reported successively not only in Japan but also in countries where genetic vaccines have been administered [38-42], and the number of cases with health injuries recognized by MHLW is overwhelmingly higher than for conventional vaccines such as influenza vaccines (Figure 1) [56, 125]. The number of recognized cases continues to increase, and the ultimate extent of health injuries in Japan remains unclear.

Until the end of 2021, the MHLW routinely published cumulative data on post-vaccination deaths officially certified under the government relief program. Starting in 2022, these cumulative updates ceased, compelling researchers to reconstruct the data manually from individual review committee minutes and annual reports (Figure 1). This interruption in transparent data dissemination appears to reflect a broader institutional tendency where information potentially deemed politically or administratively sensitive is selectively disclosed or withheld.

Furthermore, in May 2022, MHLW classified vaccinated individuals without recorded vaccination dates as unvaccinated, and following accusations of data misuse [126], discontinued public release of HER-SYS (Health Center Real-time Information-sharing System on COVID-19) data [127]. Such practices hinder independent verification and weaken the foundations of scientific discourse in public health. Ensuring transparency in the disclosure of public health data is essential to safeguard scientific integrity, uphold public trust, and support evidence-based policy decisions.

Additionally, it has been disclosed that members of the Study Group on Adverse Reactions under the Health Sciences Council of the Subcommittee on Immunization and Vaccination received funding from pharmaceutical companies [128]. Although this clearly constitutes a conflict of interest (COI), MHLW failed to undertake remedial reconstruction of a neutral committee by disinterested third parties. This inaction may constitute violations of multiple Japanese statutes, including the National Public Service Ethics Act, the Administrative Procedure Act, and the State Redress Act. Moreover, these actions may amount to breaches of official duties under the Penal Code, potentially involving bribery and breach of trust, thereby raising the possibility of criminal liability under Japanese law.

This case also raises serious concerns under international regulatory and ethical norms, potentially violating conflict of interest management guidelines established by the Council for International Organizations of Medical Sciences (CIOMS) in collaboration with the World Health Organization (WHO) [129]. In public health policy, transparency, accountability, and appropriate management of conflicts of interest in decision-making processes are essential [130, 131]. The lack of transparency in institutional operations and inadequate information disclosure observed in this case represent significant issues from an international perspective.

The available evidence indicates that substantial safety concerns remain regarding these pharmaceutical products.

Inadequate Real-World Evidence and Pharmacovigilance

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Immediately following the initiation of genetic vaccine administration in February 2021, numerous deaths were reported by physicians on a voluntary basis [6]. Post-marketing surveillance results also documented numerous adverse events. Nevertheless, the continued non-disclosure of these facts by the government may be regarded as a significant omission inconsistent with its institutional duty to ensure public health transparency. This constituted a violation of the duty to warn, which is a fundamental principle of medical care (Medical Care Act), resulting in persistent impediments to physicians’ fulfillment of their duty to provide adequate explanations to patients. This can be evaluated as substantial state interference with physicians’ professional judgment and obstruction of medical practice autonomy.

Countries that promoted genetic vaccine administration have experienced alarming increases in excess mortality [95, 132-134] (Figure 6), and Japan has experienced a marked decline in life expectancy and a concerning upward trend in cancer incidence [91]. Despite multiple warnings concerning the potential risks associated with genetic vaccines, the Japanese government has continued their routine administration [104].

Japan failed to operationalize a robust, adaptive pharmacovigilance system capable of near real-time detection and evaluation of vaccine-related adverse events, despite possessing a universal healthcare framework and advanced digitized infrastructure such as HER-SYS. In contrast, countries such as Israel rapidly leveraged national health insurance databases and hospital networks to facilitate real-time safety monitoring and outcome tracking [135, 136]. Japan’s inadequate response reflects a missed opportunity for early signal detection and suggests structural inertia within regulatory and public health institutions. Integrating existing medical information systems could have enabled more responsive safety assessments, thereby enhancing transparency and facilitating evidence-based policy decisions.

In evaluating the safety of genetic vaccines, it is essential to contextualize reported adverse events by comparing them with established baseline incidence rates in the unvaccinated population. Without such reference points, temporal associations alone may lead to misinterpretation of vaccine-attributable risks. Cases of myocarditis, thrombosis, and sudden cardiac death must be assessed against background rates stratified by age and sex to determine whether observed frequencies exceed expected norms [137, 138]. In Japan, publicly available pharmacovigilance reports have seldom provided stratified baseline rates [139], limiting the capacity for risk quantification and hindering transparent risk–benefit assessments. Future evaluations should incorporate rigorous epidemiological frameworks that include background incidence rates to more accurately characterize the safety profile of genetic vaccine products.

The ongoing administration of pharmaceutical products without established long-term safety profiles raises substantial ethical concerns, potentially conflicting with established principles of medical ethics established in the Declaration of Geneva and Declaration of Helsinki: “The health and well-being of my patient will be my first consideration” (Declaration of Geneva); “In medical research involving human subjects, the well-being of the individual research subject must take precedence over all other interests” (Declaration of Helsinki, Paragraph 6); and “Medical practitioners are to contribute to the improvement and promotion of public health through the administration of medical care and health guidance, and thereby ensure the healthy lives of the citizens” (Medical Practitioners’ Act, Article 1) [140, 141].

In view of accumulating safety signals and the continued lack of transparent, long-term post-marketing data, urgent regulatory reassessment is warranted. Consideration should be given to the immediate suspension of current authorizations and potential market withdrawal of genetic vaccines. Such regulatory measures must be accompanied by rigorous, independent epidemiological investigations to comprehensively assess the scope, magnitude, and temporal dynamics of potential adverse health outcomes associated with their administration.

Public Health Risks of Potential Residual DNA in mRNA-LNP Vaccines: Necessity for Regulatory Oversight and Corporate Transparency

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Emerging evidence from multiple countries, including Germany and the United States that vials of Pfizer/BioNTech and Moderna mRNA vaccines contained DNA fragments (plasmid DNA used in mRNA production) exceeding European Medicines Agency (EMA) regulatory limits (Table 7) [56, 142-149]. Notably, current regulatory thresholds for residual DNA were originally established prior to the introduction of advanced delivery systems such as liposomes and LNPs and have since been progressively relaxed [150]. However, these legacy standards are no longer appropriate for LNP-based formulations, which exhibit markedly enhanced transfection efficiency [151]. As a result, the existing regulatory framework is inadequate to accurately assess the residual DNA risk posed by these novel delivery systems. Therefore, discussions over whether LNP vaccines merely exceed or remain within outdated thresholds may be scientifically uninformative and risk obscuring the more pressing issue of actual biological hazard.

There has been considerable discussion among researchers regarding DNA contamination levels, with some criticism that accurate DNA measurement is difficult using Qubit fluorometry and quantitative PCR methods [152]. Nevertheless, MAHs have a responsibility under the Product Liability Act for providing scientific evidence to resolve these concerns. Additionally, the PMDA bears supervisory responsibility for requiring pharmaceutical companies to submit sufficient verification data to demonstrate that such issues are not present in their products. When DNA contamination exceeds regulatory limits, genetic vaccines fail to meet pharmaceutical product standards. This factor alone necessitates immediate discontinuation of genetic vaccine administration and product recall. Furthermore, if the PMDA failed to require pharmaceutical companies to submit data on potential DNA contamination during the regulatory review process, such an omission would reflect a critical deficiency in the new drug approval framework and a failure on the part of the regulatory authority to uphold its pharmacovigilance obligations.

While Pfizer and Moderna used degradation-resistant mRNA modified with methylpseudouridine to stabilize mRNA [153], it has been noted that methylpseudouridine causes translational frameshifting [154, 155]. This suggests that proteins other than the intended targets may be produced from methylpseudouridine-modified mRNA, which is extremely of concern [156]. Since there is no evidence that this possibility was investigated during the pharmaceutical review process, pharmaceutical companies have an obligation to provide data addressing both this issue and the DNA contamination concerns discussed above.

Requirements for Revocation of Approval and Market Withdrawal, and Past Cases

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Past cases of pharmaceutical approval revocation and market withdrawal have involved serious deficiencies in efficacy or safety, as well as the detection of carcinogenic substances exceeding regulatory limits. Following approval, pharmaceutical products undergo continuous evaluation of efficacy and safety through post-marketing surveillance (PMS) and reexamination. When serious problems are identified through this evaluation process, approval may be revoked by MHLW [157, 158]. Market withdrawal (recall) may also be implemented when quality issues are identified.

Genetic vaccines have already caused extensive harm worldwide following administration [56, 125]. Furthermore, given the absence of scientific evidence demonstrating efficacy in preventing the infection or severe disease, these formulations should be recognized as “not found to have the efficacy or effects indicated in the application” (PMD Act, Article 14, paragraph (2), item (iii), (a)) or “found to have no value as a pharmaceutical or quasi-pharmaceutical product as they have harmful effects which outweigh their efficacy or effects” (PMD Act, Article 14, paragraph (2), item (iii), (b)). Accordingly, the approval of these formulations should be revoked pursuant to Article 74-2, paragraph (1) of the PMD Act, on the grounds that they have come to fall under one or more of the conditions specified in Article 14, paragraph (2), item (iii), subitems (a) through (c) of the same Act (Table 1).

In Japan, although the pharmaceutical approval process should be based on scientific standards, decisions regarding revocation of approval may, in practice, be subject to administrative discretion. For example, gefitinib (Iressa), which had over 700 reported deaths, maintained its approval [159], while polysaccharide K (Krestin) was withdrawn from the market due to insufficient scientific evidence of efficacy rather than mortality risk [160]. Therefore, the criteria for revocation of approval lack consistency, and it is an undeniable fact that administrative judgments sometimes take precedence over scientific evidence. The case of sorivudine, which preceded the gefitinib (Iressa) incident, provides a critical precedent in Japan’s pharmaceutical regulatory history [161]. Although sorivudine was initially approved, it was rapidly withdrawn from the market following reports of serious adverse reactions [162]. This incident should have served as a foundational lesson for establishing more robust and fail-safe regulatory practices. Yet over time, with personnel turnover and a lack of institutional memory, the lessons learned were not embedded into the system, and the opportunity to strengthen regulatory governance was ultimately lost. This reflects a persistent challenge within Japanese administrative culture: it remains difficult to ensure that lessons from past failures are consistently carried forward within regulatory institutions.

Information on pharmaceutical products with revoked approval is partially published on MHLW and PMDA websites. However, this information is scattered across websites and, unlike unified databases such as those of the FDA and EMA, is not easily accessible to the public. To improve this situation, it is necessary to enhance transparency in Japan’s pharmaceutical review and approval processes, clarify the review criteria, and establish systems based on scientific evidence. It would be desirable to establish more transparent mechanisms by referencing the review data disclosure policies adopted by the FDA and EMA.

Despite strong scientific and legal grounds for revoking the approval of certain pharmaceutical products, regulatory action has been hindered by structural obstacles, including institutional conflicts of interest between the MHLW and industry, rapid personnel turnover, and judicial deference to administrative discretion. The discretionary nature of revocation under Article 74 of the PMD Act further contributes to regulatory inaction. To address these issues, we propose the establishment of an independent investigatory commission, strengthened parliamentary oversight, and international collaboration to ensure transparent, evidence-based governance and restore scientific integrity in regulatory decision-making.

Conclusion

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Given regulatory precedents for the revocation of drug approvals and product withdrawals from the market [56, 125], there is a compelling basis to assert that the SARS-CoV-2 genetic vaccines developed by Pfizer and Moderna, as well as Meiji Seika Pharma’s saRNA vaccine approved on a non-inferiority basis, fulfill the conditions warranting such regulatory actions. Accordingly, it is necessary that the MHLW and other relevant authorities promptly consider revoking the approval and initiating the market withdrawal of these pharmaceutical products.

In the United States, over 81,000 physicians, scientists, researchers, and citizens, along with 240 government officials, 17 public health and medical organizations, 2 state Republican organizations, 17 Republican county committees, and 6 scientific studies, have issued statements calling for market withdrawal of genetic vaccines [56, 163]. Furthermore, legislative efforts to prohibit SARS-CoV-2 genetic vaccines are underway in multiple U.S. states, including Florida, South Carolina, Tennessee, Iowa, Texas, Montana, Idaho, Washington, Kentucky, North Dakota, and Minnesota, with bill consideration and drafting beginning at various levels of government. For example, in Montana, legislation prohibiting genetic vaccine administration to humans was introduced in the state legislature in January 2025 [164, 165]. Given these developments, the movement for market withdrawal and revocation of approval of genetic vaccines is no longer confined to a single country but is becoming an international trend. Considering the lack of transparency and inadequate information disclosure identified in the approval review process and post-marketing surveillance of genetic vaccines, continuing administration of genetic vaccines with serious safety concerns poses profound problems from scientific and ethical perspectives and constitutes an infringement upon individual autonomy and human rights.

The risks and adverse events associated with SARS-CoV-2 genetic vaccines far exceed initially anticipated efficacy and adverse drug reactions, warranting immediate market withdrawal. Latest analyses based on real-world data demonstrate serious safety concerns regarding genetic vaccines (notable excess mortality, decreased efficacy and negative effects, increased autoimmune disease risk, DNA contamination and potential carcinogenic risk, risks substantially exceeding FDA recall criteria) [166, 167], making reassessment of vaccination policy and implementation of independent investigations essential. Based on the accumulated evidence to date, the continued administration of SARS-CoV-2 genetic vaccines poses significant public health concerns. Therefore, the revocation of their regulatory approval and immediate market withdrawal should be seriously considered by relevant authorities.

Acknowledgments

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We would like to express our sincere gratitude to Drs. Akinori Fujisawa, Masayasu Inoue, Masato Yoshino, and Yasufumi Murakami for their invaluable guidance and support. We are also grateful to Mr. Masamitsu Fujie for sharing data on the number of individuals certified under the Japan’s Vaccine Adverse Reaction Relief System, and to Dr. Kenji Fujikawa for providing data on DNA contamination in vaccine vials.

Author Contributions: Conceptualization, J.U. and M.F.; investigation, J.U., M.G., T.K., M.M., A.K., I.S., and M.F.; resources, T.K., Y.H., and M.F.; data curation, J.U., M.G., T.K., and M.F.; writing—original draft preparation, J.U.; writing—review and editing, J.U., M.G., T.K., Y.H., M.M., A.K., I.S., S.K., and M.F.; visualization, J.U., M.G., T.K. M.M., and A.K.; supervision, J.U. and M.F.; project administration, J.U. and M.F. All authors have read and agreed to the published version of the manuscript.

Conflict of Interest: The authors declare no potential conflicts of interest.

Funding Statement: This study did not receive any funding.

Ethics: Since only published data were used, it was determined that  ethics committee approval was not required in Japan.

Data Availability: This study utilizes only officially published data available from websites.

References

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