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 2a and 2b 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.