The coronavirus (COVID-19) pandemic, which began in 2019, has resulted in numerous infections and deaths. A vaccine against COVID-19 was developed and made available within just 1 year of the declaration of the pandemic in March 2020, mostly owing to the extraordinary efforts of pharmaceutical companies. In Japan, vaccination began in February 2021 [1]. Initially, infections among children were rare, and even if they did occur, their symptoms were mild. Therefore, the vaccination was initially targeted at individuals aged 12 years. However, owing to an increase in infections among children caused by virus mutations, in Japan, the eligibility for vaccination was expanded to include children aged 5 years and older starting from February 21, 2022, and infants aged 6 months and older starting from October 24, 2022 [2,3]. The vaccination rate for children in Japan is 9.8% for one or more doses in children and 2.8% in infants [4]. One of the reasons for the low vaccination rate is concerns among parents regarding adverse events following vaccination. It can be inferred that parents do not want their children to experience the same symptoms of fever and strong fatigue that they have experienced. Therefore, the Ministry of Health, Labor and Welfare and Japanese Pediatric Association have announced that adverse events associated with pediatric vaccines are extremely minor and occur less frequently than those in adults [2,3,5]. Another reason is the lack of disclosure regarding effectiveness. The Ministry of Health, Labour and Welfare has refrained from publicly disclosing vaccine effectiveness in its advisory board meetings since September 2022, which may have caused distrust among the parents [6]. Because the effectiveness of pediatric vaccines has not been made public in Japan, this study was conducted to evaluate the effectiveness of vaccination among children aged ≥6 months in a pediatric clinic in Japan during the eighth and ninth waves of the pandemic to provide information regarding the effectiveness of pediatric vaccines to parents who are hesitant about getting their children vaccinated. In the case of influenza vaccines, immunization was made mandatory for elementary and junior high school students by the Vaccination Act of 1977. However, an increasing number of lawsuits seeking compensation from the government for high fever and subsequent sequelae after vaccination led to the relaxation of the requirement to obtain parental consent for those who wished to receive the vaccine, starting in 1987. In 1994, mass vaccination was abolished and voluntary vaccination was implemented.

According to reports from the Ministry of Health, Labor, and Welfare, vaccination rates for influenza have fluctuated at approximately 30% in 2001 and have fluctuated at approximately 50% since 2004 [7]. Diseases such as measles and rubella, which are part of routine immunizations, have vaccination rates of approximately 95% [8]. Vaccines that are perceived as effective by recipients and their guardians may have higher vaccination rates, while those whose effectiveness is questioned may have lower rates. In this study, I provide a reference on the COVID-19 vaccination status of all cases tested during the study period and compare the effectiveness of vaccines in the two most recent epidemic seasons. This study, although based on a limited number of cases from a single clinic, examines whether the continued use of an outdated vaccine remains effective against a mutating virus.

Participants

From November 2022 to the end of October 2023, patients who visited the Mukainada Child Clinic with fever (37.5°C or higher) and those whose parents requested severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing were included in this study. Patients with a temperature below 37.5°C, those who were of high school-going age or older, or those aged under 6 months who were not eligible for vaccination were excluded. The total number of patients tested was 1,616: 840 boys and 776 girls. Their ages ranged from 0 years and 7 months to 15 years and 8 months (median age: 5 years and 8 months). As the study targeted all patients who visited the clinic during the infection outbreak period, the required sample size was not calculated or justified.

Data Collection

Clinical data of the study participants were obtained from electronic medical records between November 1, 2022 and October 31, 2023. Specimens were collected from all individuals via nasal pharyngeal mucous sampling, and the SARS-CoV-2 antigen rapid qualitative test (SARS-CoV-2, or influenza simultaneously, Denka Company Limited, Tokyo, Japan) was performed. Because of the availability of the antigen rapid qualitative test kit at my facility, I prioritized speed and did not conduct polymerase chain reaction tests. During the examination, the guardians were asked about the child’s COVID-19 vaccination status. Data on vaccine manufacturer, number of doses, and vaccination timing were not collected. Details on the history of COVID-19 are presented in Table S1.

Statistical Analysis

The current gold standard for vaccine effectiveness is the test-negative case-control (TNCC) design [9]. Vaccine effectiveness was determined using a TNCC design and Fisher’s exact test. Vaccine effectiveness was determined using the following equation: (morbidity rate of unvaccinated–morbidity rate of vaccinated)/morbidity rate of unvaccinated × 100 (%).

The Kolmogorov–Smirnov test was used to assess whether the data were normally distributed. The threshold for statistical significance was a two-tailed p-value <0.05. Owing to the difficulty of determining severity at the clinical level, the highest body temperature at the time of the visit was recorded. The most severe cases in children were caused by acute encephalopathy induced by high cytokine levels. High body temperature is a risk factor for influenza encephalopathy [10]. Therefore, the highest body temperature recorded until medical examination was considered as an indicator in this study.

Ethical Statement

The purpose of the research was explained to the patient’s parents, who verbally confirmed their willingness to participate. In addition, the parents were given the opportunity to opt out if they later changed their mind. Within the hospital premises, a poster was displayed with the following information: “Participation in this study is voluntary and not mandatory. If you do not wish your information to be used in this research, please notify us within 1 month of the examination using the contact details below. This will not result in any adverse effects on your medical treatment. If we do not receive any communication from you, we will assume that you consent to participate in the study.” An explanatory document was prepared and handed to the parents before the medical examination; its content was explained, and it was documented in the medical record that consent was obtained. The study was approved by the Hiroshima Prefecture Medical Association Review Committee (Approval Number: 0019).

Status of the 8^th and 9^th Waves in My Area and Clinic

The first cases of COVID-19 were reported on January 16, 2020 in Japan, March 7, 2020 in Hiroshima, and April 24, 2021 at my clinic. Figure 1 shows the trends of positive cases in Hiroshima Prefecture and my clinic. The number of new infections in Hiroshima Prefecture was based on the data published in the Hiroshima Prefecture Novel Coronavirus Infection Data Site [11]. Although there is no explicit definition, the periods of surges in new infection cases are commonly referred to as “waves.” Until the end of October 2023, reports from the Ministry of Health, Labour and Welfare and local governments classified these waves from the first to the ninth (Figure 1) [12,14]. Since May 8, 2023, a comprehensive investigation of all cases in Japan has been discontinued; as a result, the official total number for the ninth wave has not been surveyed. The COVID-19 morbidity rates among individuals eligible for vaccination from 6 months to junior high school third grade were compared between the unvaccinated and vaccinated groups (Table 1). The morbidity rate among unvaccinated and vaccinated patients was 23.8%, whereas that for vaccinated patients was 30.4%. The calculated vaccine effectiveness was –27.5% (p = 0.137). However, the vaccinated patients were notably older (9 years and 6 months vs. 5 years and 4 months), making the comparison inappropriate. Therefore, the comparison was conducted by dividing the eligible age groups into three categories: 6 months to <5 years, 5 years to <12 years, and 12-15 years. The morbidity rate increased with age, and the vaccine effectiveness for each group was 0.7% (p >0.999), –6.2% (p = 0.785), and 16.7% (p = 0.643), respectively. Owing to the limited number of cases in a single clinic, statistical significance was not achieved. However, there did not appear to be a preventive effect, particularly in the younger age group. Considering the entire 1-year study period, the infection prevention effectiveness of the vaccine appeared to be limited. Considering the rapid mutation and changes in COVID-19 strains, it was thought that this might contribute to the observed trends. Therefore, the periods were divided into the eighth wave (November 2022 to May 7, 2023) and the ninth wave (May 8, 2023 to the end of October 2023).

Figure 1: Transition of New COVID-19 Cases.

The first case in Hiroshima was reported on March 7, 2020, and the first case at my clinic occurred on April 24, 2021.

a: Although there is no explicit definition, the periods of surges in new infection cases are commonly referred to as “waves.” Until the end of October 2023, reports from the Ministry of Health, Labor, and Welfare and local governments classified these waves from the first to the ninth. There are three blanks in the trend of positive cases at my clinic.

b: The first blank corresponds to the period when the clinic was closed owing to my own infection.

c: This represents a blank caused by the difficulty in obtaining testing reagents.

d: This study corresponds to the dotted lines encompassing the eighth and ninth waves.

Table 1: Infection and Vaccine Effectiveness Rates between Vaccinated and Unvaccinated Individuals during the Eighth and Ninth Waves.

COVID-19: Coronavirus disease.

Status of the 8^th Wave at My Clinic

The COVID-19 morbidity rate and vaccine effectiveness during the eighth wave are presented in Table 2. For unvaccinated patients of all ages, the morbidity rate was 33.6%, whereas that for vaccinated patients was 31.3%. The vaccine effectiveness was 7.1% (p = 0.874). Vaccine effectiveness was 14.8% (p > 0.999) in the 6-month to <5-year group, 31.3% (p = 0.132) in the 5- to <12-year group, and 35.1% (p = 0.471) in the 12- to 15-year group.

Table 2: Infection and Vaccine Effectiveness Rates between Vaccinated and Unvaccinated Individuals during the Eighth Wave.

COVID-19: Coronavirus disease.

Status of the 9^th Wave at My Clinic

The COVID-19 morbidity rate and vaccine effectiveness during the ninth wave are presented in Table 3. The morbidity rate among unvaccinated patients of all ages was 16.4%, whereas that among vaccinated patients was 29.7%. The vaccine effectiveness was calculated to be –80.9% (p = 0.010). The vaccine effectiveness was –15.2% (p >0.999) for the 6-month to <5-year group, –75.6% (p = 0.053) for the 5- to <12-year group, and –10.0% (p > 0.999) for the 12- to 15-year group.

Table 3: Infection and Vaccine Effectiveness Rates between Vaccinated and Unvaccinated Individuals during the Ninth Wave.

COVID-19: Coronavirus disease.

The body temperatures of patients with COVID-19 at the time of their clinic visits were compared between the unvaccinated and vaccinated groups. The average temperature was 38.83 ± 0.72°C for unvaccinated individuals and 38.71 ± 0.66°C for vaccinated individuals (p = 0.154). No significant difference was observed, even when age differences were considered in the analysis.

Initially, in a study conducted in April 2021 involving 50 children aged 5–11 years, the effectiveness evaluation cut-off date was October 8, 2021 (approximately 177 days or roughly 6 months), and the reported preventive effectiveness rate against infection was 90.7% [15]. Subsequently, in a study conducted in June 2021 involving 1776 children aged 6 months to less than 2 years and 2750 children aged 2 to 4 years, the data collection cut-off date was June 17, 2022 (approximately 361 days or roughly 12 months). The reported preventive effectiveness against infection was 73.2% [16]. According to a previous study of more than 1 million children aged ≤11 years from October 29, 2021 to January 6, 2023, the effectiveness against infection reached 59.9% 1 month after the first dose but decreased to 33.7% at 4 months and 14.9% at 10 months [17]. In a review of papers published from 2019 to 2021 that demonstrated the effectiveness of pediatric COVID-19 vaccines, the overall effectiveness of COVID-19 vaccination was found to be 96.09% [18]. The effectiveness of pediatric COVID-19 vaccines from Japan during the earlier phases of this study (sixth and seventh waves) has been reported to be 72% [19]. A review of papers published before 2022 found that vaccination remained effective even during the predominance of the Omicron variant. However, these studies reported a decrease in the protective effectiveness of Omicron vaccines compared with the Delta subvariant [20]. The current study suggests that the effectiveness is significantly lower, possibly because it occurred more than a period of approximately 1.5 years after these previous studies, and the circulating strains of the virus might have changed.

In Japan, vaccination for individuals aged ≥5 years became available from February 21, 2022, and for those aged ≥6 months, vaccination became available from October 24, 2022 [2,3]. Assuming immediate vaccination, individuals aged ≥5 years would be in the postvaccination period for 253 days during the eighth wave and 441 days during the ninth wave. Similarly, those aged ≥6 months would be in the post-vaccination period for 8 days during the eighth wave and 196 days during the ninth wave. In addition, vaccination for individuals aged ≥12 years has been available since June 2021 [21]. The reason for the lower vaccine effectiveness during the ninth wave than during the eighth wave appears to be the elapsed time since vaccination. In Japan, until August 2023, vaccination for children under 12 years of age until August 2023 involved the use of the conventional vaccine, and until September 2023, a bivalent vaccine targeting the Omicron variant (original strain/BA.1) was used [22]. Although the predominant strain was replaced, vaccine effectiveness during the ninth wave was low because of the continuous administration of the outdated vaccine. During the ninth wave, not only was vaccine effectiveness low but the vaccinated group also had a higher incidence rate. In the case of influenza vaccines, early childhood vaccination is associated with the hypothesis of “original antigenic sin,” leading to an increase in subsequent infection rates [23]. The COVID-19 vaccine, like the influenza vaccine, primarily induces immunity to the spike protein. To address viruses that undergo repeated mutations in the spike protein, it is recommended that the old strain vaccine be transitioned promptly to one that targets emerging variant strains.

Regarding the prevention of severe cases, assessment is limited to the consideration of body temperature in clinics without hospitalization facilities. In severe cases such as influenza encephalopathy, increased cerebrospinal fluid and serum levels of interleukin (IL)-6, soluble tumor necrosis factor receptor 1, and IL-10 have been reported [24]. Compared with those during febrile seizures, serum IL-6 levels are significantly elevated in influenza encephalopathy [25]. Elevated IL-6 levels can be considered an indicator of a cytokine storm, with progressive high fever [26,27]. The highest body temperature at the time of medical consultation for patients with COVID-19 in this study did not show a significant difference between vaccinated and unvaccinated individuals. In other words, it was impossible to obtain results indicating that vaccination prevented severe illness.

This study had some limitations. First, the study focused on all patients who visited a single clinic during the investigation period, which limits the sample size. Therefore, the sample size was not calculated or justified. The limited number of cases and absence of data on the number of vaccine doses and time since vaccination reduce the reliability and validity of my results. Second, as patients and their parents had a vague recollection of the exact date of vaccination, accurately determining the vaccination dates during the brief clinic visits was impossible. Therefore, the question was simply whether they had been vaccinated, and the period between vaccination and infection could not be verified. Third, the TNCC study design could include diseases other than COVID-19, potentially overlapping outbreaks. Fourth, this study focused on children who visited a single clinic during its open hours. Patients who experienced seizures or loss of consciousness at night, or those who were critically ill from the beginning and transported to the ICU by ambulance even during the day, were not included. Thus, selection bias may exist as severely ill patients did not visit the clinic. Fifth, as this study did not include all patients in the region, generalizing the findings to other populations is not possible. Sixth, stringent COVID-19 measures might have led some parents to avoid testing for mild symptoms in their children, making the results less conclusive. Seventh, as this study did not assess the participants’ living conditions, the possibility of individuals becoming complacent with infection prevention measures simply because they received the vaccine cannot be ruled out, and the reliability may be lower than that of a double-blind method. However, there seemed to be no discernible effect of living conditions, at least in comparison to mild side effects such as fever or pain caused by vaccination. Finally, the effectiveness of vaccines during the early stages of the epidemic could not be estimated because data were not available. In the future, it is hoped that data collection on vaccine effectiveness will evolve beyond individual clinics, with organizations such as pediatric associations taking the lead.

When addressing viruses with frequent mutations in the spike protein, it is recommended to promptly transition from an old strain vaccine to one targeting emerging variant strains. Therefore, it is imperative for the government to work toward establishing a system capable of responding to new mutations without the necessity of inoculating previously purchased vaccines through inventory disposal.

Acknowledgments: The author greatly appreciates the patients and their guardians for their invaluable cooperation and contribution in the survey. Their support was instrumental to the success of the research. The author acknowledges Dr. Natsuko Masuda, who continued the investigation in the author’s absence. The author also acknowledges all the staff at the medical clinic who assisted in the examination and testing.

Funding Information: This research received no external funding.

Author Contributions: Conceptualization, Methodology, Formal Analysis, Investigation, Writing – Original Draft Preparation, Writing – Review & Editing, and Project Administration, T.K. (sole author). The author has read and approved the final version of the manuscript.

Data Availability Statement: All data generated or analyzed during this study are included in this published article and its supplementary information file.

Conflicts of Interest: The author declares no conflict of interest.

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