Duration of effectiveness of the COVID-19 vaccine in Japan: A retrospective cohort study using large- scale population-based registry data

Duration of effectiveness of the COVID-19 vaccine in Japan: A retrospective cohort study using large- scale population-based registry data | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Duration of effectiveness of the COVID-19 vaccine in Japan: A retrospective cohort study using large- scale population-based registry data Kohei Uemura, Sachiko Ono, Nobuaki Michihata, Hayato Yamana, Hideo Yasunaga This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4023571/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background Most evidence of the waning of vaccine effectiveness is limited to a relatively short period after vaccination. Methods Data obtained from a linked database of healthcare administrative claims and vaccination records maintained by the municipality of a city in the Kanto region of Japan were used in this study. The study period extended from April 1, 2020, to December 31, 2022. The duration of the effectiveness of the COVID-19 vaccine was analyzed using a time-dependent piecewise Cox proportional hazard model using the age, sex and history of cancer, diabetes, chronic obstructive pulmonary disease, asthma, chronic kidney disease, and cardiovascular disease as covariates. Results Among the 174,757 eligible individuals, 14,416 (8.3%) were diagnosed with COVID-19 and 936 (0.54%) were hospitalized for COVID-19. Multivariate analysis based on the time-dependent Cox regression model revealed a lower incidence of COVID-19 in the one-dose group (hazard ratio, 0.76 [95% confidence interval, 0.63–0.91]), two-dose (0.89 [0.85–0.93]), three-dose (0.80 [0.76–0.85]), four-dose (0.93 [0.88–1.00]), and five-dose (0.72 [0.62–0.84]) groups. A lower incidence of COVID-19-related hospitalization was observed in the one-dose group (0.42 [0.21–0.81]), two-dose (0.44 [0.35–0.56]), three-dose (0.38 [0.30–0.47]), four-dose (0.20 [0.14–0.28]), and five-dose (0.11 [0.014–0.86]) groups. Multivariable analyses based on the time-dependent piecewise Cox proportional hazard model revealed significant preventive effects of the vaccine at 0–1, 1–2, 2–3, 3–4, 7–8, ≥ 12 months for the incidence of COVID-19 and 0–1, 1–2, 2–3, 3–4, 4–5, 5–6, 7–8, and 9–10 months for hospitalization. Conclusions Vaccine effectiveness showed gradual attenuation with time after vaccination; however, protective effects against the incidence of COVID-19 and hospitalization were maintained for 4 months and ≥ 6 months, respectively. These results may aid in formulating routine vaccination plans after the COVID-19 pandemic. administrative claims data cohort study COVID-19 vaccination time-dependent effectiveness Figures Figure 1 Figure 2 Figure 3 Figure 4 Background High vaccination coverage against coronavirus disease 2019 (COVID-19) has contributed to the end of the pandemic. However, continuous measures must be taken against the outbreak of epidemics, including the emergence of new mutant strains. The “Omicron JN.1” strain, a descendant of the Omicron BA.2.86 strain, has spread globally. The duration and frequency of the administration of booster vaccinations need to be established. A better understanding of the waning of vaccine-induced protection plays an important role in formulating post-pandemic vaccination plans. Several COVID-19 types of vaccines have been manufactured worldwide since December 2020; however, clinical and laboratory evidence accumulated over a short period has shown that the effectiveness of the COVID-19 vaccine wanes over time [ 1 – 5 ]. Longitudinal dynamics of the immune response following the administration of the second dose of the BNT162b2 vaccine revealed a substantial decrease at 6 months, regardless of the sex and age of the patients [ 6 ]. A systematic review and meta-regression [ 7 ] reported that the effectiveness of vaccines against COVID-19 has decreased by 2–30%. However, other studies have reported that the effectiveness of the vaccines in preventing severe disease shows a minimal decrease (9–10%) for up to 6 months [ 7 – 10 ]. The effectiveness of the vaccine against COVID-19-related hospitalization and death at ≥ 20 weeks after receiving two doses of the ChAdOx1-S or BNT162b2 vaccine has shown limited waning [ 11 ]. The effectiveness of the vaccine in preventing the incidence of COVID-19 must be considered while formulating a post-pandemic dosing plan; however, it is even more important to consider strategies for the prevention of severe disease [ 12 ]. Maintaining healthcare resources and preventing the overstraining of the healthcare system are critical for the mitigation of future pandemics. The third (booster) dose is highly effective in preventing the incidence of severe disease [ 13 – 16 ]. The requirement for repeated booster vaccinations has been discussed widely. Nevertheless, it is unclear whether further doses should be administered to individuals who have received the fourth or fifth dose during the pandemic or who have stopped after the second or third booster dose. The administration of booster doses to younger and low-risk populations has commenced; thus, the period during which the vaccine can maintain its effectiveness in terms of both the incidence and severity of COVID-19 needs to be established. Identifying the ideal timing for the administration of booster doses plays a crucial role in the formulation of public health policies and resource optimization. Data regarding the waning of effectiveness of the vaccine is limited to a relatively short post-vaccination period or to age groups that do not include older adults or children or has been tracked to a limited extent following the emergence of the Omicron strain [ 14 ]. Therefore, this study investigated the duration of the effectiveness of the COVID-19 vaccine regarding the co-primary outcomes of the incidence of COVID-19 and COVID-19-related hospitalization. Real-world data for the population of a city in Japan comprising individuals of all ages were used in this study. Up to five doses of vaccinations had been administered during the Omicron wave in this population, and all individuals had been followed up for > 1 year after the administration of the third dose. Methods Data source and study design Data were obtained from a linked database of healthcare administrative claims and vaccination records maintained by the municipality of a city in the Kanto region of Japan. The vaccine records were linked to health insurance claims data via unique identification numbers. All personal information was excluded, and de-identified data were sent to the researchers for secondary use. The duration between April 1, 2020, and December 31, 2022, was set as the study period for this retrospective cohort study. The participants were already enrolled in the National Health Insurance system at the beginning of the study; therefore, their outcome data were considered to have been followed up from the beginning of the study to the point when they stopped receiving insurance coverage owing to death or relocation. The healthcare administrative claims database comprises data regarding age and sex, as well as information regarding medical examinations and treatments that the individuals underwent on the dates of diagnosis for any disease during outpatient visits and hospital admissions. The International Classification of Diseases 10th revision (ICD-10) codes were used to identify the disease. The vaccination records included information on the types and dates of vaccination. This study was approved by the institutional review board of the University of Tokyo. The requirement for obtaining informed consent was waived owing to the anonymized nature of the data. Study population All individuals who were enrolled in the database during the study and baseline periods, which was defined as 1 year before the start date of the study period (April 1, 2020), were included in this study. Vaccination status The vaccination status of the participants was defined as a time-dependent variable that distinguished the number of vaccinations. Individuals were included in the no-vaccination group from the commencement of the study until 14 days after receiving the first dose. Individuals who did not receive any doses of the vaccine during the study period were included in the no-vaccine group throughout the study period. The time point for the one-dose vaccine group was from 14 days after the first dose to 14 days after the second dose. The time points for the two-, three-, four-, or five-dose vaccine groups were also set similarly. The groups based on the total number of vaccinations were included in the descriptive analysis. Outcomes and covariates The time to the first incidence of COVID-19 determined from the beginning of the study period, which was confirmed using the ICD-10 code U071 without a suspected disease flag, was defined as the first co-primary outcome. The time to the first COVID-19 hospitalization determined from the beginning of the study period, which was confirmed using the ICD-10 code U071 without a suspected disease flag, was defined as the second co-primary outcome. Age (continuous variable) at the beginning of the study period, sex, and comorbidities (including cancer [C0-97], diabetes [E10-14], chronic obstructive pulmonary disease [J440-441, J448-449], asthma [J45], chronic kidney disease [N18], and cardiovascular disease [I1, I5-13, I20-25, I27, I30-51, I60-69] confirmed at the baseline period and without suspected disease flag) were used as covariates in the adjusted analysis of the effectiveness of the vaccine. Statistical analyses The characteristics of the participants were stratified according to the total number of vaccinations. A time-dependent Cox proportional hazard model with time-dependent vaccine status only (univariable analysis) and covariates confirmed in the baseline period (multivariable analysis) was used to estimate the effectiveness of one, two, three, four, and five doses of the COVID-19 vaccine on the two co-primary outcomes. The probability of the incidence of COVID-19 and COVID-19-related hospitalization, estimated via univariable analysis using the Breslow estimator, was plotted. Subgroup analyses were conducted based on age categories (0–9, 10–19, 20–29, 30–39, 40–49, 50–59, 60–69, 70–79, 80–89, and ≥ 90 years) for overall effectiveness of the COVID-19 vaccine comparing the non-vaccine group vs. the overall vaccine group including the groups with all doses. A time-dependent piecewise Cox proportional hazard model with the time-dependent vaccine status and time (14 days–1 month, 1–2 months, 2–3 months, 3–4 months, 4–5 months, 5–6 months, 6–7 months, 7–8 months, 8–9 months, 9–10 months, 10–11 months, 11–12 months, and ≥ 12 months after the COVID-19 vaccination) serving as interaction terms and covariates confirmed in the baseline period was used to investigate the time-dependent effectiveness of the COVID-19 vaccination against the co-primary outcomes. All participants were included in the at-risk population based on the calendar time according to their follow-up period to account for the confounding effect of the differences in COVID-19 epidemics and strains. All statistical analyses were performed using SAS ver. 9.4. Results Among the 199,488 individuals who were insured at the beginning of the study period from April 1, 2020, to December 31, 2022 (Fig. 1 ), 3,406 individuals without a continuous history of health insurance coverage and 21,325 participants who were not insured during the baseline period of 1.0 year were excluded. Thus, 174,757 individuals were included in the analysis population. A total of 14,416 individuals (8.3%) were diagnosed with COVID-19 and 936 (0.54%) were hospitalized for COVID-19 during the study period. Table 1 presents the baseline characteristics of the participants stratified according to the total number of vaccinations received. The mean age and proportion of women increased as the total number of vaccine doses increased. Table 2 presents the results of the univariable and multivariable analyses using the time-dependent Cox regression model. Multivariable analysis revealed a lower incidence of COVID-19 in the one-dose group (hazard ratio, 0.76 [95% confidence interval, 0.63–0.91]), two-dose (0.89 [0.85–0.93]), three-dose (0.80 [0.76–0.85]), four-dose (0.93 [0.88–1.00]), and five-dose (0.72 [0.62–0.84]) groups compared with that in the no-vaccine group. Similarly, a lower incidence of COVID-19-related hospitalization was observed in the one-dose (0.42 [0.21–0.81]), two-dose (0.44 [0.35–0.56]), three-dose (0.38 [0.30–0.47]), four-dose (0.20 [0.14–0.28]), and five-dose (0.11 [0.014–0.86]) groups compared with that in the no-vaccine group. Table 1 Baseline characteristics of the study population Characteristics All individuals (n = 174,757) No vaccine (n = 37,637) One dose of vaccine (n = 953) Two doses of vaccine (n = 17,340) Three doses of vaccine (n = 22,146) Four doses of vaccine (n = 28,172) Five doses of vaccine (n = 68,509) P-value * Age (years)ーmean ± standard deviation 62.8 ± 21.9 51.8 ± 28.3 58.9 ± 26.2 49.1 ± 24.3 54.5 ± 22.0 63.9 ± 17.7 74.6 ± 7.9 < 0.001 Age category (years)ーno. (%) < 0.001 0–9 4,643 (2.7) 4,110 (10.9) 34 (3.6) 329 (1.9) 166 (0.7) 4 (0.0) 0 (0) 10–19 5,910 (3.4) 1,731 (4.6) 62 (6.5) 1,877 (10.8) 1,634 (7.4) 599 (2.1) 7 (0.0) 20–29 8,500 (4.9) 4,085 (10.9) 88 (9.2) 2,090 (12.1) 1,573 (7.1) 619 (2.2) 45 (0.1) 30–39 10,190 (5.8) 3,831 (10.2) 71 (7.5) 2,574 (14.8) 2,289 (10.3) 1,329 (4.7) 96 (0.1) 40–49 13,884 (7.9) 3,828 (10.2) 94 (9.9) 2,713 (15.6) 3,545 (16.0) 3,418 (12.1) 286 (0.4) 50–59 14,957 (8.6) 3,377 (9.0) 73 (7.7) 1,787 (10.3) 3,465 (15.6) 4,820 (17.1) 1,435 (2.1) 60–69 25,895 (14.8) 3,157 (8.4) 83 (8.7) 1,266 (7.3) 2,613 (11.8) 4,488 (15.9) 14,288 (20.9) 70–79 52,355 (30.0) 5,158 (13.7) 170 (17.8) 1,972 (11.4) 3,461 (15.6) 7,124 (25.3) 34,470 (50.3) 80–89 32,295 (18.5) 5,852 (15.5) 210 (22.0) 2,148 (12.4) 2,828 (12.8) 4,960 (17.6) 16,297 (23.8) ≥ 90 6,128 (3.5) 2,508 (6.7) 68 (7.1) 584 (3.4) 572 (2.6) 811 (2.9) 1,585 (2.3) Male sexーno. (%) 82,279 (47.1) 20,174 (53.6) 497 (52.2) 9,289 (53.6) 10,624 (48.0) 12,549 (44.5) 29,146 (42.5) < 0.001 Clinical risk factorsーno. (%) Cancer 781 (0.4) 147 (0.4) 3 (0.3) 42 (0.2) 62 (0.3) 120 (0.4) 407 (0.6) < 0.001 Diabetes 2,909 (1.7) 436 (1.2) 17 (1.8) 220 (1.3) 322 (1.5) 493 (1.7) 1,421 (2.1) < 0.001 Chronic obstructive pulmonary disease 516 (0.3) 81 (0.2) 9 (0.9) 33 (0.2) 57 (0.3) 69 (0.2) 267 (0.4) < 0.001 Asthma 4,531 (2.6) 1,166 (3.1) 32 (3.4) 473 (2.7) 587 (2.7) 650 (2.3) 1,623 (2.4) < 0.001 Chronic kidney disease 906 (0.5) 175 (0.5) 7 (0.7) 57 (0.3) 93 (0.4) 142 (0.5) 432 (0.6) < 0.001 Cardiovascular disease 1,540 (0.9) 268 (0.7) 13 (1.4) 90 (0.5) 135 (0.6) 249 (0.9) 785 (1.1) < 0.001 *F-test for continuous age, chi-squared test for binomial or ordinal categorical variables. COVID-19: Coronavirus disease 2019 Table 2 Time-dependent Cox regression analysis for the incidence of COVID-19 and COVID-19-related hospitalization Incidence of COVID-19 Hospitalization of COVID-19 Hazard ratio (95% confidence interval) P-value Hazard ratio (95% confidence interval) P-value Univariable analysis One-dose COVID-19 vaccine group 0.68 (0.57, 0.81) < 0.001 0.51 (0.26, 0.98) 0.045 Two-dose COVID-19 vaccine group 0.78 (0.74, 0.82) < 0.001 0.54 (0.43, 0.68) < 0.001 Three-dose COVID-19 vaccine group 0.57 (0.54, 0.59) < 0.001 0.58 (0.46, 0.73) < 0.001 Four-dose COVID-19 vaccine group 0.55 (0.52, 0.58) < 0.001 0.37 (0.26, 0.53) < 0.001 Five-dose COVID-19 vaccine group 0.41 (0.35, 0.47) < 0.001 0.21 (0.027, 1.66) 0.14 Multivariable analysis One-dose COVID-19 vaccine group 0.76 (0.63, 0.91) 0.003 0.42 (0.21, 0.81) 0.01 Two-dose COVID-19 vaccine group 0.89 (0.85, 0.93) < 0.001 0.44 (0.35, 0.56) < 0.001 Three-dose COVID-19 vaccine group 0.80 (0.76, 0.85) < 0.001 0.38 (0.30, 0.47) < 0.001 Four-dose COVID-19 vaccine group 0.93 (0.88, 1.00) 0.033 0.20 (0.14, 0.28) < 0.001 Five-dose COVID-19 vaccine group 0.72 (0.62, 0.84) < 0.001 0.11 (0.014, 0.86) 0.036 Age (years) 0.98 (0.98, 0.98) < 0.001 1.04 (1.03, 1.04) < 0.001 Female sex 1.04 (1.01, 1.08) 0.019 0.66 (0.58, 0.75) < 0.001 Clinical risk factors Cancer 1.18 (0.91, 1.52) 0.21 1.19 (0.53, 2.66) 0.67 Diabetes 0.94 (0.82, 1.08) 0.4 0.92 (0.56, 1.52) 0.76 Chronic obstructive pulmonary disease 1.24 (0.91, 1.68) 0.17 0.86 (0.28, 2.68) 0.8 Asthma 1.30 (1.19, 1.42) < 0.001 1.16 (0.76, 1.78) 0.49 Chronic kidney disease 1.41 (1.12, 1.78) 0.003 1.44 (0.74, 2.77) 0.28 Cardiovascular disease 1.32 (1.11, 1.57) 0.001 1.04 (0.56, 1.93) 0.91 COVID-19: Coronavirus disease 2019 Table 3 presents the results of the subgroup analyses performed according to the age categories (0–9, 19–19, 20–29, 30–39, 40–49, 50–59, 60–69, 70–79, 80–89, and ≥ 90 years) for the overall effectiveness of the COVID-19 vaccine based on time-dependent univariable Cox regression analysis. Subgroup analyses revealed that the incidence of COVID-19 was inconsistent. The effectiveness against COVID-19-related hospitalization was significant among older individuals except among those aged ≥ 90 years. Table 3 Subgroup analysis according to the age categories for overall effectiveness of the COVID-19 vaccine in the no-vaccine group vs. vaccine group including all dose groups based on time-dependent univariable Cox regression analysis for the incidence of COVID-19 and COVID-19-related hospitalization Incidence of COVID-19 COVID-19-related hospitalization Hazard ratio (95% confidence interval) P-value Hazard ratio (95% confidence interval) P-value Overall effectiveness of the COVID-19 vaccine in non-vaccine group vs. vaccine group including all dose groups 0.62 (0.60, 0.65) < 0.001 0.52 (0.44, 0.63) < 0.001 Subgroup analysis based on age (years) 0–9 0.63 (0.45, 0.89) 0.008 - (-, -) - 10–19 0.77 (0.67, 0.87) < 0.001 - (-, -) - 20–29 0.80 (0.68, 0.93) 0.005 0.23 (0.022, 2.42) 0.22 30–39 1.03 (0.90, 1.18) 0.64 0.57 (0.11, 2.91) 0.50 40–49 1.08 (0.95, 1.23) 0.24 0.18 (0.056, 0.59) 0.004 50–59 1.16 (1.00, 1.34) 0.050 0.20 (0.096, 0.42) < 0.001 60–69 0.85 (0.73, 0.99) 0.038 0.19 (0.11, 0.32) < 0.001 70–79 0.94 (0.82, 1.08) 0.41 0.27 (0.18, 0.38) < 0.001 80–89 1.29 (1.11, 1.50) < 0.001 0.56 (0.40, 0.79) < 0.001 ≥ 90 3.07 (2.29, 4.12) < 0.001 1.59 (0.82, 3.10) 0.17 COVID-19: Coronavirus disease 2019 Figures 2 a and 2 b present the probability of the outcomes estimated using the univariable analyses. The estimated probability of the incidence of COVID-19 was lower in the vaccinated groups. The incidence of COVID-19 decreased as the frequency of vaccination increased. The estimated probability of COVID-19-related hospitalization was lower in the vaccinated groups. The incidence of COVID-19-related hospitalization decreased as the frequency of vaccination increased (four- and five-dose vs. one-, two-, and three-dose groups). Figure 3 presents the effectiveness of the vaccine against the incidence of COVID-19 according to the multivariable analysis based on the time-dependent piecewise Cox proportional hazard model. The effectiveness of two and three doses waned by approximately 4 months. The point estimate of the hazard ratio ranged from 0.29–0.83 by 4 months and from 0.86–1.21 thereafter. The preventive effects were statistically significant at 0–1, 1–2, 2–3, 3–4, 7–8, and ≥ 12 months. Supplemental Table 1 presents the time dependency of the effectiveness of the vaccine for all dose groups in the univariable analysis. Figure 4 presents the effectiveness of the vaccine in preventing COVID-19-related hospitalization according to multivariable analysis based on the time-dependent piecewise Cox proportional hazard model. The point estimates of the hazard ratio for two or three doses gradually increased in later months; however, they were < 1 throughout the observation period. The preventive effects were significant at 0–1, 1–2, 2–3, 3–4, 4–5, 5–6, 7–8, and 9–10 months. Supplemental Table 2 presents the time dependency of the effectiveness of the vaccine for all dose groups in the univariable analysis. Discussion A population-based retrospective cohort study was conducted using a linked database of healthcare administrative claims data and vaccination records of a city in Japan for a period extending from April 1, 2020, to December 31, 2022. Assessment of the effectiveness of one, two, three, four, and five doses of the COVID-19 vaccine on the two co-primary outcomes revealed the more definitive effectiveness against COVID-19-related hospitalization than against the incidence of COVID-19 in each dose group. The effectiveness of the vaccine against severe disease became more evident as the number of booster doses administered increased, which may be attributed to the recovery of effectiveness owing to the increase in antibody titers. Consistent with the findings of previous studies, the findings of the present study underscore the critical role of continuous and periodic booster vaccinations, especially in reducing the severity of COVID-19, even amidst the emergence of new variants, such as Omicron JN.1. The duration of effectiveness of the COVID-19 vaccine in preventing the incidence of COVID-19 and COVID-19-related hospitalization was investigated in this study. The effectiveness of the vaccine showed gradual attenuation with time after vaccination and the protective effectiveness was maintained for 4 months for the incidence of COVID-19 and ≥ 6 months for COVID-19-related hospitalization. The waning of the protective effectiveness against COVID-19-related hospitalization was milder than that against incidence. These findings are consistent with the trends reported by existing studies on the attenuation of the effectiveness of the first vaccine without booster vaccination and the second or third booster vaccination over time [ 7 – 16 ]. Furthermore, the present study indicated that the effectiveness against severe disease after the second or third booster vaccination persisted for > 6 months. The trends shown in Fig. 3 suggest that the effectiveness persisted for up to 1 year. Vaccinating younger individuals and individuals at low risk of severe disease every year, instead of every 6 months, may be sufficient. The findings of the present study may be useful for formulating routine vaccination plans after a pandemic. The present study has a few limitations. First, although the primary outcome was the incidence of COVID-19, the data did not include information on the results of COVID-19 antigen or polymerase chain reaction tests. Second, there may have been unmeasured confounding factors. Individuals who received a greater number of booster doses may have been biased toward individuals who were more likely to be infected or hospitalized. Third, the duration of the study was until December 31, 2022; thus, the follow-up period after the fourth and fifth doses was insufficient. Conclusion The present study identified a more definite effectiveness of the vaccine against COVID-19-related hospitalization, regardless of the number of booster doses administered; the effectiveness against the incidence of COVID-19 was not as strong. Vaccine effectiveness showed a gradual attenuation with time after vaccination and maintained effectiveness against the incidence of COVID-19 for 4 months and ≥ 6 months for COVID-19-related hospitalization. These findings will aid in identifying the optimal timing for the formulation of a routine vaccination plan after a pandemic. Abbreviations CI, Confidence Interval; COVID-19, Coronavirus Disease 2019; Hazard Ratio, HR; ICD-10, International Classification of Diseases, 10th revision Declarations Ethics approval and consent to participate: This study was approved by the Research Ethics Committee of the Graduate School of Medicine and Faculty of Medicine, The University of Tokyo (approval no. 2021187NI-(3)). Because our analyses involved the secondary use of anonymized data that had been routinely collected by the local government in Japan, the need for individual informed consent was waived in accordance with the current ethical guidelines for medical and health research involving human participants in Japan. Consent for publication: Not applicable. Availability of data and materials: The database used in this study is maintained by a city in the Kanto region of Japan. Restrictions applied to the availability of data were applied with permission for this study. Accordingly, these data are not publicly available. Competing interests: The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. Funding: This study was supported by the Grants-in-Aid for Innovative Drug Discovery and Development Project from the Japan Agency for Medical Research and Development (grant number: 21nf0101636h0001). The funding source played no role in the analysis, interpretation, or writing of this manuscript. Authors’ contributions: UK, OS, MN and Yasunaga H: Study concDeption and design. UK: Analysis of data. All authors: Interpretation of data. KU drafted the manuscript. OS, MN, Yamana H and Yasunaga H: Revising the manuscript critically for important intellectual content. All authors approved the final version of the manuscript. Acknowledgments: We would like to thank Editage (www.editage.com) for English language editing. References Goldberg Y, Mandel M, Bar-On YM, Bodenheimer O, Freedman L, Haas EJ, et al. Waning Immunity after the BNT162b2 Vaccine in Israel. N Engl J Med. 2021;385:e85. https://doi.org/10.1056/NEJMoa2114228 . Kobashi Y, Takebayashi Y, Yoshida M, Kawamura T, Shimazu Y, Kaneko Y, et al. Waning of Humoral Immunity and the Influencing Factors after BNT162b2 Vaccination: A Cohort Study with a Latent Growth Curve Model in Fukushima. 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Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months. N Engl J Med. 2021;385:e84. https://doi.org/10.1056/NEJMoa2114583 . Feikin DR, Higdon MM, Abu-Raddad LJ, Andrews N, Araos R, Goldberg Y et al. Duration of effectiveness of vaccines against SARS-CoV-2 infection and COVID-19 disease: results of a systematic review and meta-regression [published correction appears in Lancet. 2022;:] [published correction appears in Lancet. 2023;401(10377):644]. Lancet 2022;399:924–44. https://doi.org/10.1016/S0140-6736(22)00152-0 . Tang P, Hasan MR, Chemaitelly H, Yassine HM, Benslimane FM, Al Khatib HA, et al. BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the SARS-CoV-2 Delta variant in Qatar. Nat Med. 2021;27:2136–43. https://doi.org/10.1038/s41591-021-01583-4 . Chemaitelly H, Yassine HM, Benslimane FM, Al Khatib HA, Tang P, Hasan MR, et al. mRNA-1273 COVID-19 vaccine effectiveness against the B.1.1.7 and B.1.351 variants and severe COVID-19 disease in Qatar. Nat Med. 2021;27:1614–21. https://doi.org/10.1038/s41591-021-01446-y . Chemaitelly H, Tang P, Hasan MR, AlMukdad S, Yassine HM, Benslimane FM, et al. Waning of BNT162b2 Vaccine Protection against SARS-CoV-2 Infection in Qatar. N Engl J Med. 2021;385:e83. https://doi.org/10.1056/NEJMoa2114114 . Andrews N, Tessier E, Stowe J, Gower C, Kirsebom F, Simmons R, et al. Duration of Protection against Mild and Severe Disease by Covid-19 Vaccines. N Engl J Med. 2022;386:340–50. https://doi.org/10.1056/NEJMoa2115481 . Silva SJRD, Pena L. Collapse of the public health system and the emergence of new variants during the second wave of the COVID-19 pandemic in Brazil. One Health. 2021;13:100287. https://doi.org/10.1016/j.onehlt.2021.100287 . Thompson MG, Natarajan K, Irving SA, Rowley EA, Griggs EP, Gaglani M, et al. MMWR Morb Mortal Wkly Rep. 2022;71:139–45. https://doi.org/10.15585/mmwr.mm7104e3 . Effectiveness of a Third Dose of mRNA Vaccines Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance - VISION Network, 10 States, August 2021-January 2022. Ferdinands JM, Rao S, Dixon BE, Mitchell PK, DeSilva MB, Irving SA, et al. Waning of vaccine effectiveness against moderate and severe covid-19 among adults in the US from the VISION network: test negative, case-control study. BMJ. 2022;379:e072141. https://doi.org/10.1136/bmj-2022-072141 . Bar-On YM, Goldberg Y, Mandel M, Bodenheimer O, Freedman L, Kalkstein N, et al. Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel. N Engl J Med. 2021;385:1393–400. https://doi.org/10.1056/NEJMoa2114255 . Barda N, Dagan N, Cohen C, Hernán MA, Lipsitch M, Kohane IS, et al. Effectiveness of a third dose of the BNT162b2 mRNA COVID-19 vaccine for preventing severe outcomes in Israel: an observational study. Lancet. 2021;398:2093–100. https://doi.org/10.1016/S0140-6736(21)02249-2 . Additional Declarations No competing interests reported. Supplementary Files SupplementalTable1.docx SupplementalTable2.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 03 Apr, 2024 Reviews received at journal 26 Mar, 2024 Reviewers agreed at journal 20 Mar, 2024 Reviewers invited by journal 19 Mar, 2024 Editor assigned by journal 15 Mar, 2024 Submission checks completed at journal 15 Mar, 2024 First submitted to journal 07 Mar, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4023571","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":279939684,"identity":"4dc463b4-5e0a-473b-b718-ee176ca9e591","order_by":0,"name":"Kohei Uemura","email":"data:image/png;base64,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","orcid":"","institution":"The University of Tokyo","correspondingAuthor":true,"prefix":"","firstName":"Kohei","middleName":"","lastName":"Uemura","suffix":""},{"id":279939685,"identity":"f9f00485-58a9-4b31-a4ac-590151897408","order_by":1,"name":"Sachiko Ono","email":"","orcid":"","institution":"The University of Tokyo","correspondingAuthor":false,"prefix":"","firstName":"Sachiko","middleName":"","lastName":"Ono","suffix":""},{"id":279939686,"identity":"99620565-2af5-4227-ac6e-cc864b154b37","order_by":2,"name":"Nobuaki Michihata","email":"","orcid":"","institution":"Chiba Cancer Center Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Nobuaki","middleName":"","lastName":"Michihata","suffix":""},{"id":279939687,"identity":"5e9aed92-e440-40dd-91f8-c796fceca7d3","order_by":3,"name":"Hayato Yamana","email":"","orcid":"","institution":"Jichi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hayato","middleName":"","lastName":"Yamana","suffix":""},{"id":279939688,"identity":"16da01e4-dc76-4ca0-a620-d8a532279546","order_by":4,"name":"Hideo Yasunaga","email":"","orcid":"","institution":"The University of Tokyo","correspondingAuthor":false,"prefix":"","firstName":"Hideo","middleName":"","lastName":"Yasunaga","suffix":""}],"badges":[],"createdAt":"2024-03-07 08:29:54","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4023571/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4023571/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53018675,"identity":"4e1887f6-d7dc-4e6c-a6ef-0262b3c4200c","added_by":"auto","created_at":"2024-03-19 16:17:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":84133,"visible":true,"origin":"","legend":"\u003cp\u003eSelection of participants to analyze the effectiveness of the COVID-19 vaccine in preventing the incidence of COVID-19 or hospitalization.\u003c/p\u003e\n\u003cp\u003eCOVID-19: Coronavirus disease 2019\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4023571/v1/18d0e5c3b7007f206ec1c16a.png"},{"id":53018677,"identity":"40375768-dd8b-4695-8a50-785faa928603","added_by":"auto","created_at":"2024-03-19 16:17:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":46769,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e2a.\u003c/strong\u003eProbability of the incidence of COVID-19 estimated by the Breslow estimator in univariate analysis using a time-dependent Cox proportional hazard model with time-dependent vaccine status only.\u003c/p\u003e\n\u003cp\u003eCOVID-19: Coronavirus disease 2019\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2b.\u003c/strong\u003e Incidence probability of the requirement for hospitalization for COVID-19 estimated by the Breslow estimator in univariate analysis using a time-dependent Cox proportional hazard model with time-dependent vaccine status only.\u003c/p\u003e\n\u003cp\u003eCOVID-19: Coronavirus disease 2019\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4023571/v1/be0dbf1c050e5682b1a6546a.png"},{"id":53018679,"identity":"f53770fb-a258-4caf-9e10-05369d1c9f35","added_by":"auto","created_at":"2024-03-19 16:17:57","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":276364,"visible":true,"origin":"","legend":"\u003cp\u003eDuration of the effectiveness of the COVID-19 vaccine in preventing the incidence of COVID-19 after vaccination. \u003cbr\u003e\n Time-dependent piecewise Cox proportional hazard model with the time-dependent vaccine status and time (14 days–1 month, 1–2 months, 2–3 months, 3–4 months, 4–5 months, 5–6 months, 6–7 months, 7–8 months, 8–9 months, 9–10 months, 10–11 months, 11–12 months, and ≥12 months after the COVID-19 vaccination) serving as interaction terms, and covariates confirmed in the baseline period, namely, age, sex, and history of cancer, diabetes, chronic obstructive pulmonary disease, asthma, chronic kidney disease, and cardiovascular disease.\u003c/p\u003e\n\u003cp\u003eCOVID-19: Coronavirus disease 2019\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4023571/v1/60abe7cdb385f371831a3ebc.png"},{"id":53018680,"identity":"c9fc92bd-f42e-4957-89a7-d875006b1cbb","added_by":"auto","created_at":"2024-03-19 16:17:57","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":269907,"visible":true,"origin":"","legend":"\u003cp\u003eDuration of the effectiveness of the COVID-19 vaccine in preventing COVID-19-related hospitalization after vaccination. \u003cbr\u003e\n Time-dependent piecewise Cox proportional hazard model with the time-dependent vaccine status and time (14 days–1 month, 1–2 months, 2–3 months, 3–4 months, 4–5 months, 5–6 months, 6–7 months, 7–8 months, 8–9 months, 9–10 months, 10–11 months, 11–12 months, and ≥12 months after the COVID-19 vaccination) serving as interaction terms, and covariates confirmed in the baseline period, namely, age, sex, and history of cancer, diabetes, chronic obstructive pulmonary disease, asthma, chronic kidney disease, and cardiovascular disease.\u003c/p\u003e\n\u003cp\u003eCOVID-19: Coronavirus disease 2019\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4023571/v1/35697e71579aba19bea23fd8.png"},{"id":53019797,"identity":"77243751-fd05-4cec-9e65-ee841ce0c2c9","added_by":"auto","created_at":"2024-03-19 16:25:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":964044,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4023571/v1/8951d285-e67f-4a6d-8fc2-9a839e9330e4.pdf"},{"id":53018678,"identity":"55ef1be1-b3ea-4162-b8c8-ddf672fb4f0d","added_by":"auto","created_at":"2024-03-19 16:17:56","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":29014,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4023571/v1/55465e59cec59f8dc01ff7cc.docx"},{"id":53018676,"identity":"27717620-2126-4464-bd25-954c492a3804","added_by":"auto","created_at":"2024-03-19 16:17:56","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":30575,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable2.docx","url":"https://assets-eu.researchsquare.com/files/rs-4023571/v1/eb6bc5819e4d8ef066a055f9.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Duration of effectiveness of the COVID-19 vaccine in Japan: A retrospective cohort study using large- scale population-based registry data","fulltext":[{"header":"Background","content":"\u003cp\u003eHigh vaccination coverage against coronavirus disease 2019 (COVID-19) has contributed to the end of the pandemic. However, continuous measures must be taken against the outbreak of epidemics, including the emergence of new mutant strains. The \u0026ldquo;Omicron JN.1\u0026rdquo; strain, a descendant of the Omicron BA.2.86 strain, has spread globally. The duration and frequency of the administration of booster vaccinations need to be established. A better understanding of the waning of vaccine-induced protection plays an important role in formulating post-pandemic vaccination plans.\u003c/p\u003e \u003cp\u003eSeveral COVID-19 types of vaccines have been manufactured worldwide since December 2020; however, clinical and laboratory evidence accumulated over a short period has shown that the effectiveness of the COVID-19 vaccine wanes over time [\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Longitudinal dynamics of the immune response following the administration of the second dose of the BNT162b2 vaccine revealed a substantial decrease at 6 months, regardless of the sex and age of the patients [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. A systematic review and meta-regression [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] reported that the effectiveness of vaccines against COVID-19 has decreased by 2\u0026ndash;30%. However, other studies have reported that the effectiveness of the vaccines in preventing severe disease shows a minimal decrease (9\u0026ndash;10%) for up to 6 months [\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The effectiveness of the vaccine against COVID-19-related hospitalization and death at \u0026ge;\u0026thinsp;20 weeks after receiving two doses of the ChAdOx1-S or BNT162b2 vaccine has shown limited waning [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The effectiveness of the vaccine in preventing the incidence of COVID-19 must be considered while formulating a post-pandemic dosing plan; however, it is even more important to consider strategies for the prevention of severe disease [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Maintaining healthcare resources and preventing the overstraining of the healthcare system are critical for the mitigation of future pandemics.\u003c/p\u003e \u003cp\u003eThe third (booster) dose is highly effective in preventing the incidence of severe disease [\u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The requirement for repeated booster vaccinations has been discussed widely. Nevertheless, it is unclear whether further doses should be administered to individuals who have received the fourth or fifth dose during the pandemic or who have stopped after the second or third booster dose. The administration of booster doses to younger and low-risk populations has commenced; thus, the period during which the vaccine can maintain its effectiveness in terms of both the incidence and severity of COVID-19 needs to be established. Identifying the ideal timing for the administration of booster doses plays a crucial role in the formulation of public health policies and resource optimization.\u003c/p\u003e \u003cp\u003eData regarding the waning of effectiveness of the vaccine is limited to a relatively short post-vaccination period or to age groups that do not include older adults or children or has been tracked to a limited extent following the emergence of the Omicron strain [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Therefore, this study investigated the duration of the effectiveness of the COVID-19 vaccine regarding the co-primary outcomes of the incidence of COVID-19 and COVID-19-related hospitalization. Real-world data for the population of a city in Japan comprising individuals of all ages were used in this study. Up to five doses of vaccinations had been administered during the Omicron wave in this population, and all individuals had been followed up for \u0026gt;\u0026thinsp;1 year after the administration of the third dose.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData source and study design\u003c/h2\u003e \u003cp\u003eData were obtained from a linked database of healthcare administrative claims and vaccination records maintained by the municipality of a city in the Kanto region of Japan. The vaccine records were linked to health insurance claims data via unique identification numbers. All personal information was excluded, and de-identified data were sent to the researchers for secondary use.\u003c/p\u003e \u003cp\u003eThe duration between April 1, 2020, and December 31, 2022, was set as the study period for this retrospective cohort study. The participants were already enrolled in the National Health Insurance system at the beginning of the study; therefore, their outcome data were considered to have been followed up from the beginning of the study to the point when they stopped receiving insurance coverage owing to death or relocation.\u003c/p\u003e \u003cp\u003eThe healthcare administrative claims database comprises data regarding age and sex, as well as information regarding medical examinations and treatments that the individuals underwent on the dates of diagnosis for any disease during outpatient visits and hospital admissions. The International Classification of Diseases 10th revision (ICD-10) codes were used to identify the disease. The vaccination records included information on the types and dates of vaccination.\u003c/p\u003e \u003cp\u003e This study was approved by the institutional review board of the University of Tokyo. The requirement for obtaining informed consent was waived owing to the anonymized nature of the data.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eAll individuals who were enrolled in the database during the study and baseline periods, which was defined as 1 year before the start date of the study period (April 1, 2020), were included in this study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eVaccination status\u003c/h2\u003e \u003cp\u003eThe vaccination status of the participants was defined as a time-dependent variable that distinguished the number of vaccinations. Individuals were included in the no-vaccination group from the commencement of the study until 14 days after receiving the first dose. Individuals who did not receive any doses of the vaccine during the study period were included in the no-vaccine group throughout the study period. The time point for the one-dose vaccine group was from 14 days after the first dose to 14 days after the second dose. The time points for the two-, three-, four-, or five-dose vaccine groups were also set similarly. The groups based on the total number of vaccinations were included in the descriptive analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes and covariates\u003c/h2\u003e \u003cp\u003eThe time to the first incidence of COVID-19 determined from the beginning of the study period, which was confirmed using the ICD-10 code U071 without a suspected disease flag, was defined as the first co-primary outcome. The time to the first COVID-19 hospitalization determined from the beginning of the study period, which was confirmed using the ICD-10 code U071 without a suspected disease flag, was defined as the second co-primary outcome.\u003c/p\u003e \u003cp\u003eAge (continuous variable) at the beginning of the study period, sex, and comorbidities (including cancer [C0-97], diabetes [E10-14], chronic obstructive pulmonary disease [J440-441, J448-449], asthma [J45], chronic kidney disease [N18], and cardiovascular disease [I1, I5-13, I20-25, I27, I30-51, I60-69] confirmed at the baseline period and without suspected disease flag) were used as covariates in the adjusted analysis of the effectiveness of the vaccine.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eThe characteristics of the participants were stratified according to the total number of vaccinations. A time-dependent Cox proportional hazard model with time-dependent vaccine status only (univariable analysis) and covariates confirmed in the baseline period (multivariable analysis) was used to estimate the effectiveness of one, two, three, four, and five doses of the COVID-19 vaccine on the two co-primary outcomes. The probability of the incidence of COVID-19 and COVID-19-related hospitalization, estimated via univariable analysis using the Breslow estimator, was plotted. Subgroup analyses were conducted based on age categories (0\u0026ndash;9, 10\u0026ndash;19, 20\u0026ndash;29, 30\u0026ndash;39, 40\u0026ndash;49, 50\u0026ndash;59, 60\u0026ndash;69, 70\u0026ndash;79, 80\u0026ndash;89, and \u0026ge;\u0026thinsp;90 years) for overall effectiveness of the COVID-19 vaccine comparing the non-vaccine group vs. the overall vaccine group including the groups with all doses. A time-dependent piecewise Cox proportional hazard model with the time-dependent vaccine status and time (14 days\u0026ndash;1 month, 1\u0026ndash;2 months, 2\u0026ndash;3 months, 3\u0026ndash;4 months, 4\u0026ndash;5 months, 5\u0026ndash;6 months, 6\u0026ndash;7 months, 7\u0026ndash;8 months, 8\u0026ndash;9 months, 9\u0026ndash;10 months, 10\u0026ndash;11 months, 11\u0026ndash;12 months, and \u0026ge;\u0026thinsp;12 months after the COVID-19 vaccination) serving as interaction terms and covariates confirmed in the baseline period was used to investigate the time-dependent effectiveness of the COVID-19 vaccination against the co-primary outcomes. All participants were included in the at-risk population based on the calendar time according to their follow-up period to account for the confounding effect of the differences in COVID-19 epidemics and strains. All statistical analyses were performed using SAS ver. 9.4.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAmong the 199,488 individuals who were insured at the beginning of the study period from April 1, 2020, to December 31, 2022 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), 3,406 individuals without a continuous history of health insurance coverage and 21,325 participants who were not insured during the baseline period of 1.0 year were excluded. Thus, 174,757 individuals were included in the analysis population. A total of 14,416 individuals (8.3%) were diagnosed with COVID-19 and 936 (0.54%) were hospitalized for COVID-19 during the study period.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the baseline characteristics of the participants stratified according to the total number of vaccinations received. The mean age and proportion of women increased as the total number of vaccine doses increased. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e presents the results of the univariable and multivariable analyses using the time-dependent Cox regression model. Multivariable analysis revealed a lower incidence of COVID-19 in the one-dose group (hazard ratio, 0.76 [95% confidence interval, 0.63\u0026ndash;0.91]), two-dose (0.89 [0.85\u0026ndash;0.93]), three-dose (0.80 [0.76\u0026ndash;0.85]), four-dose (0.93 [0.88\u0026ndash;1.00]), and five-dose (0.72 [0.62\u0026ndash;0.84]) groups compared with that in the no-vaccine group. Similarly, a lower incidence of COVID-19-related hospitalization was observed in the one-dose (0.42 [0.21\u0026ndash;0.81]), two-dose (0.44 [0.35\u0026ndash;0.56]), three-dose (0.38 [0.30\u0026ndash;0.47]), four-dose (0.20 [0.14\u0026ndash;0.28]), and five-dose (0.11 [0.014\u0026ndash;0.86]) groups compared with that in the no-vaccine group.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of the study population\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll individuals\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;174,757)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo vaccine \u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;37,637)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOne dose of vaccine\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;953)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTwo doses of vaccine\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;17,340)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eThree doses of vaccine\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;22,146)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFour doses of vaccine\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;28,172)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFive doses of vaccine\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;68,509)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eP-value\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)ーmean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62.8\u0026thinsp;\u0026plusmn;\u0026thinsp;21.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51.8\u0026thinsp;\u0026plusmn;\u0026thinsp;28.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58.9\u0026thinsp;\u0026plusmn;\u0026thinsp;26.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49.1\u0026thinsp;\u0026plusmn;\u0026thinsp;24.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e54.5\u0026thinsp;\u0026plusmn;\u0026thinsp;22.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e63.9\u0026thinsp;\u0026plusmn;\u0026thinsp;17.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e74.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge category (years)ーno. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4,643 (2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4,110 (10.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e329 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e166 (0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u0026ndash;19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5,910 (3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,731 (4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62 (6.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1,877 (10.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1,634 (7.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e599 (2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u0026ndash;29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8,500 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4,085 (10.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e88 (9.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2,090 (12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1,573 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e619 (2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e45 (0.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30\u0026ndash;39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10,190 (5.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3,831 (10.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e71 (7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2,574 (14.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2,289 (10.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1,329 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e96 (0.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e40\u0026ndash;49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13,884 (7.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3,828 (10.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e94 (9.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2,713 (15.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3,545 (16.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3,418 (12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e286 (0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50\u0026ndash;59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14,957 (8.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3,377 (9.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1,787 (10.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3,465 (15.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4,820 (17.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1,435 (2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e60\u0026ndash;69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25,895 (14.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3,157 (8.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83 (8.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1,266 (7.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2,613 (11.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4,488 (15.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e14,288 (20.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e70\u0026ndash;79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52,355 (30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5,158 (13.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e170 (17.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1,972 (11.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3,461 (15.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7,124 (25.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e34,470 (50.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e80\u0026ndash;89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32,295 (18.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5,852 (15.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e210 (22.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2,148 (12.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2,828 (12.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4,960 (17.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e16,297 (23.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6,128 (3.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2,508 (6.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e584 (3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e572 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e811 (2.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1,585 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale sexーno. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82,279 (47.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20,174 (53.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e497 (52.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9,289 (53.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10,624 (48.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12,549 (44.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e29,146 (42.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical risk factorsーno. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e781 (0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e147 (0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e42 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e62 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e120 (0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e407 (0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2,909 (1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e436 (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e220 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e322 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e493 (1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1,421 (2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic obstructive pulmonary disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e516 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e81 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e33 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e57 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e69 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e267 (0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsthma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4,531 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,166 (3.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e473 (2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e587 (2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e650 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1,623 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic kidney disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e906 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e175 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e57 (0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e93 (0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e142 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e432 (0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiovascular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,540 (0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e268 (0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e90 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e135 (0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e249 (0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e785 (1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e*F-test for continuous age, chi-squared test for binomial or ordinal categorical variables.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eCOVID-19: Coronavirus disease 2019\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTime-dependent Cox regression analysis for the incidence of COVID-19 and COVID-19-related hospitalization\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eIncidence of COVID-19\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eHospitalization of COVID-19\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003cp\u003e(95% confidence interval)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003cp\u003e(95% confidence interval)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eUnivariable analysis\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOne-dose COVID-19 vaccine group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.68 (0.57, 0.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.51 (0.26, 0.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.045\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTwo-dose COVID-19 vaccine group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.78 (0.74, 0.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.54 (0.43, 0.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThree-dose COVID-19 vaccine group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.57 (0.54, 0.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.58 (0.46, 0.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFour-dose COVID-19 vaccine group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.55 (0.52, 0.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.37 (0.26, 0.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFive-dose COVID-19 vaccine group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.41 (0.35, 0.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.21 (0.027, 1.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMultivariable analysis\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOne-dose COVID-19 vaccine group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.76 (0.63, 0.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.42 (0.21, 0.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTwo-dose COVID-19 vaccine group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.89 (0.85, 0.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.44 (0.35, 0.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThree-dose COVID-19 vaccine group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.80 (0.76, 0.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.38 (0.30, 0.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFour-dose COVID-19 vaccine group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.93 (0.88, 1.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.20 (0.14, 0.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFive-dose COVID-19 vaccine group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.72 (0.62, 0.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.11 (0.014, 0.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.98 (0.98, 0.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.04 (1.03, 1.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale sex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.04 (1.01, 1.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.66 (0.58, 0.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical risk factors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.18 (0.91, 1.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.19 (0.53, 2.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.94 (0.82, 1.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.92 (0.56, 1.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic obstructive pulmonary disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.24 (0.91, 1.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.86 (0.28, 2.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsthma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.30 (1.19, 1.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.16 (0.76, 1.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic kidney disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.41 (1.12, 1.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.44 (0.74, 2.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiovascular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.32 (1.11, 1.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.04 (0.56, 1.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eCOVID-19: Coronavirus disease 2019\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents the results of the subgroup analyses performed according to the age categories (0\u0026ndash;9, 19\u0026ndash;19, 20\u0026ndash;29, 30\u0026ndash;39, 40\u0026ndash;49, 50\u0026ndash;59, 60\u0026ndash;69, 70\u0026ndash;79, 80\u0026ndash;89, and \u0026ge;\u0026thinsp;90 years) for the overall effectiveness of the COVID-19 vaccine based on time-dependent univariable Cox regression analysis. Subgroup analyses revealed that the incidence of COVID-19 was inconsistent. The effectiveness against COVID-19-related hospitalization was significant among older individuals except among those aged\u0026thinsp;\u0026ge;\u0026thinsp;90 years.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSubgroup analysis according to the age categories for overall effectiveness of the COVID-19 vaccine in the no-vaccine group vs. vaccine group including all dose groups based on time-dependent univariable Cox regression analysis for the incidence of COVID-19 and COVID-19-related hospitalization\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eIncidence of COVID-19\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eCOVID-19-related hospitalization\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003cp\u003e(95% confidence interval)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003cp\u003e(95% confidence interval)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eOverall effectiveness of the COVID-19 vaccine in non-vaccine group vs. vaccine group including all dose groups\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.62 (0.60, 0.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.52 (0.44, 0.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eSubgroup analysis based on age (years)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.63 (0.45, 0.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e- (-, -)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u0026ndash;19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.77 (0.67, 0.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e- (-, -)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u0026ndash;29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.80 (0.68, 0.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.23 (0.022, 2.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30\u0026ndash;39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.03 (0.90, 1.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.57 (0.11, 2.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e40\u0026ndash;49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.08 (0.95, 1.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.18 (0.056, 0.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50\u0026ndash;59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.16 (1.00, 1.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.050\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.20 (0.096, 0.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e60\u0026ndash;69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.85 (0.73, 0.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.19 (0.11, 0.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e70\u0026ndash;79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.94 (0.82, 1.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.27 (0.18, 0.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e80\u0026ndash;89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.29 (1.11, 1.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.56 (0.40, 0.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.07 (2.29, 4.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.59 (0.82, 3.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eCOVID-19: Coronavirus disease 2019\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFigures \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003ea and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003eb present the probability of the outcomes estimated using the univariable analyses. The estimated probability of the incidence of COVID-19 was lower in the vaccinated groups. The incidence of COVID-19 decreased as the frequency of vaccination increased. The estimated probability of COVID-19-related hospitalization was lower in the vaccinated groups. The incidence of COVID-19-related hospitalization decreased as the frequency of vaccination increased (four- and five-dose vs. one-, two-, and three-dose groups).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents the effectiveness of the vaccine against the incidence of COVID-19 according to the multivariable analysis based on the time-dependent piecewise Cox proportional hazard model. The effectiveness of two and three doses waned by approximately 4 months. The point estimate of the hazard ratio ranged from 0.29\u0026ndash;0.83 by 4 months and from 0.86\u0026ndash;1.21 thereafter. The preventive effects were statistically significant at 0\u0026ndash;1, 1\u0026ndash;2, 2\u0026ndash;3, 3\u0026ndash;4, 7\u0026ndash;8, and \u0026ge;\u0026thinsp;12 months. \u003cb\u003eSupplemental Table\u0026nbsp;1\u003c/b\u003e presents the time dependency of the effectiveness of the vaccine for all dose groups in the univariable analysis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e4\u003c/span\u003e presents the effectiveness of the vaccine in preventing COVID-19-related hospitalization according to multivariable analysis based on the time-dependent piecewise Cox proportional hazard model. The point estimates of the hazard ratio for two or three doses gradually increased in later months; however, they were \u0026lt;\u0026thinsp;1 throughout the observation period. The preventive effects were significant at 0\u0026ndash;1, 1\u0026ndash;2, 2\u0026ndash;3, 3\u0026ndash;4, 4\u0026ndash;5, 5\u0026ndash;6, 7\u0026ndash;8, and 9\u0026ndash;10 months. \u003cb\u003eSupplemental Table\u0026nbsp;2\u003c/b\u003e presents the time dependency of the effectiveness of the vaccine for all dose groups in the univariable analysis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eA population-based retrospective cohort study was conducted using a linked database of healthcare administrative claims data and vaccination records of a city in Japan for a period extending from April 1, 2020, to December 31, 2022. Assessment of the effectiveness of one, two, three, four, and five doses of the COVID-19 vaccine on the two co-primary outcomes revealed the more definitive effectiveness against COVID-19-related hospitalization than against the incidence of COVID-19 in each dose group. The effectiveness of the vaccine against severe disease became more evident as the number of booster doses administered increased, which may be attributed to the recovery of effectiveness owing to the increase in antibody titers. Consistent with the findings of previous studies, the findings of the present study underscore the critical role of continuous and periodic booster vaccinations, especially in reducing the severity of COVID-19, even amidst the emergence of new variants, such as Omicron JN.1.\u003c/p\u003e \u003cp\u003eThe duration of effectiveness of the COVID-19 vaccine in preventing the incidence of COVID-19 and COVID-19-related hospitalization was investigated in this study. The effectiveness of the vaccine showed gradual attenuation with time after vaccination and the protective effectiveness was maintained for 4 months for the incidence of COVID-19 and \u0026ge;\u0026thinsp;6 months for COVID-19-related hospitalization. The waning of the protective effectiveness against COVID-19-related hospitalization was milder than that against incidence. These findings are consistent with the trends reported by existing studies on the attenuation of the effectiveness of the first vaccine without booster vaccination and the second or third booster vaccination over time [\u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Furthermore, the present study indicated that the effectiveness against severe disease after the second or third booster vaccination persisted for \u0026gt;\u0026thinsp;6 months. The trends shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e suggest that the effectiveness persisted for up to 1 year. Vaccinating younger individuals and individuals at low risk of severe disease every year, instead of every 6 months, may be sufficient. The findings of the present study may be useful for formulating routine vaccination plans after a pandemic.\u003c/p\u003e \u003cp\u003eThe present study has a few limitations. First, although the primary outcome was the incidence of COVID-19, the data did not include information on the results of COVID-19 antigen or polymerase chain reaction tests. Second, there may have been unmeasured confounding factors. Individuals who received a greater number of booster doses may have been biased toward individuals who were more likely to be infected or hospitalized. Third, the duration of the study was until December 31, 2022; thus, the follow-up period after the fourth and fifth doses was insufficient.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe present study identified a more definite effectiveness of the vaccine against COVID-19-related hospitalization, regardless of the number of booster doses administered; the effectiveness against the incidence of COVID-19 was not as strong. Vaccine effectiveness showed a gradual attenuation with time after vaccination and maintained effectiveness against the incidence of COVID-19 for 4 months and \u0026ge;\u0026thinsp;6 months for COVID-19-related hospitalization. These findings will aid in identifying the optimal timing for the formulation of a routine vaccination plan after a pandemic.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCI, Confidence Interval; COVID-19, Coronavirus Disease 2019; Hazard Ratio, HR;\u003c/p\u003e\n\u003cp\u003eICD-10, International Classification of Diseases, 10th revision\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eThis study was approved by the Research Ethics Committee of the Graduate School of Medicine and Faculty of Medicine, The University of Tokyo (approval no. 2021187NI-(3)). Because our analyses involved the secondary use of anonymized data that had been routinely collected by the local government in Japan, the need for individual informed consent was waived in accordance with the current ethical guidelines for medical and health research involving human participants in Japan.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eThe database used in this study is maintained by a city in the Kanto region of Japan. Restrictions applied to the availability of data were applied with permission for this study. Accordingly, these data are not publicly available.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe\u0026nbsp;authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis study was supported by the Grants-in-Aid for Innovative Drug Discovery and Development Project from the Japan Agency for Medical Research and Development (grant number: 21nf0101636h0001). The funding source played no role in the analysis, interpretation, or writing of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u0026nbsp;\u003c/strong\u003eUK, OS, MN and Yasunaga H: Study concDeption and design. UK: Analysis of data. All authors: Interpretation of data. KU drafted the manuscript. OS, MN, Yamana H and Yasunaga H: Revising the manuscript critically for important intellectual content. All authors approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eWe would like to thank Editage (www.editage.com) for English language editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGoldberg Y, Mandel M, Bar-On YM, Bodenheimer O, Freedman L, Haas EJ, et al. Waning Immunity after the BNT162b2 Vaccine in Israel. N Engl J Med. 2021;385:e85. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/NEJMoa2114228\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2114228\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKobashi Y, Takebayashi Y, Yoshida M, Kawamura T, Shimazu Y, Kaneko Y, et al. 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Lancet. 2021;398:2093\u0026ndash;100. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S0140-6736(21)02249-2\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(21)02249-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"administrative claims data, cohort study, COVID-19 vaccination, time-dependent effectiveness","lastPublishedDoi":"10.21203/rs.3.rs-4023571/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4023571/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMost evidence of the waning of vaccine effectiveness is limited to a relatively short period after vaccination.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eData obtained from a linked database of healthcare administrative claims and vaccination records maintained by the municipality of a city in the Kanto region of Japan were used in this study. The study period extended from April 1, 2020, to December 31, 2022. The duration of the effectiveness of the COVID-19 vaccine was analyzed using a time-dependent piecewise Cox proportional hazard model using the age, sex and history of cancer, diabetes, chronic obstructive pulmonary disease, asthma, chronic kidney disease, and cardiovascular disease as covariates.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong the 174,757 eligible individuals, 14,416 (8.3%) were diagnosed with COVID-19 and 936 (0.54%) were hospitalized for COVID-19. Multivariate analysis based on the time-dependent Cox regression model revealed a lower incidence of COVID-19 in the one-dose group (hazard ratio, 0.76 [95% confidence interval, 0.63\u0026ndash;0.91]), two-dose (0.89 [0.85\u0026ndash;0.93]), three-dose (0.80 [0.76\u0026ndash;0.85]), four-dose (0.93 [0.88\u0026ndash;1.00]), and five-dose (0.72 [0.62\u0026ndash;0.84]) groups. A lower incidence of COVID-19-related hospitalization was observed in the one-dose group (0.42 [0.21\u0026ndash;0.81]), two-dose (0.44 [0.35\u0026ndash;0.56]), three-dose (0.38 [0.30\u0026ndash;0.47]), four-dose (0.20 [0.14\u0026ndash;0.28]), and five-dose (0.11 [0.014\u0026ndash;0.86]) groups. Multivariable analyses based on the time-dependent piecewise Cox proportional hazard model revealed significant preventive effects of the vaccine at 0\u0026ndash;1, 1\u0026ndash;2, 2\u0026ndash;3, 3\u0026ndash;4, 7\u0026ndash;8, \u0026ge;\u0026thinsp;12 months for the incidence of COVID-19 and 0\u0026ndash;1, 1\u0026ndash;2, 2\u0026ndash;3, 3\u0026ndash;4, 4\u0026ndash;5, 5\u0026ndash;6, 7\u0026ndash;8, and 9\u0026ndash;10 months for hospitalization.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eVaccine effectiveness showed gradual attenuation with time after vaccination; however, protective effects against the incidence of COVID-19 and hospitalization were maintained for 4 months and \u0026ge;\u0026thinsp;6 months, respectively. These results may aid in formulating routine vaccination plans after the COVID-19 pandemic.\u003c/p\u003e","manuscriptTitle":"Duration of effectiveness of the COVID-19 vaccine in Japan: A retrospective cohort study using large- scale population-based registry data","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-19 16:17:52","doi":"10.21203/rs.3.rs-4023571/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-04-03T13:21:07+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-26T14:05:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"4aa1cb60-e48c-4e2b-96db-3f4076a31d3d","date":"2024-03-20T07:50:56+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-19T16:43:11+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-15T08:57:39+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-15T08:18:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2024-03-07T08:16:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cac0e244-5fd6-4fc7-9398-9397e89c81a1","owner":[],"postedDate":"March 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-06-10T03:36:20+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-19 16:17:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4023571","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4023571","identity":"rs-4023571","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}