ORIGINAL ARTICLE
Effect of the revision of the recommended vaccination schedule for preventing vertical transmission of hepatitis B virus on vaccination status of infants in Japan
2026 年 8 巻 3 号 p. 93-100
詳細
2026 年 8 巻 3 号 p. 93-100
BACKGROUND
In 1986, a strategy of vaccinating infants at 2, 3, and 5 months of age was implemented in Japan to prevent the vertical transmission of the hepatitis B virus. This strategy was revised in 2013 to vaccinate infants at birth, 1 month, and 6 months of age. We aimed to evaluate the effect of this policy change on the vaccination status of infants born to mothers with positive hepatitis B surface antigen.
METHODS
We identified infants born between April 2009 and March 2021 from the JMDC Claims Database. Administration of hepatitis B immunoglobulin at birth was used to identify infants who received preventive measures against vertical transmission. The timing of hepatitis B vaccine administration within 12 months of birth was compared between old (born between April 2009 and September 2013) and new (born between October 2013 and March 2021) groups.
RESULTS
Among the 77,797 and 510,584 infants born before and after October 1 2013, respectively, 190 (0.24%) and 732 (0.14%) were analyzed. The proportion of infants receiving at least one dose of the vaccine increased from 63% to 96% (p < 0.001). The proportion of infants who received timely first, second, and third doses of vaccines changed from 54% to 90% (p < 0.001), 46% to 59% (p = 0.002), and 39% to 31% (p = 0.034), respectively.
CONCLUSIONS
The change in strategy against the vertical transmission of hepatitis B virus resulted in an increased rate of receiving the first dose of the vaccine and a decreased rate of timely completion of the recommended doses.
Vertical transmission from mother to child is an important route of hepatitis B (HB) virus infection. Perinatal transmission results in chronic HB infection in 90% of cases. Most infected individuals become inactive carriers after HB e antigen (HBeAg) seroconversion. However, chronic hepatitis persists in some cases, causing cirrhosis, hepatocellular carcinoma, and liver failure1–3).
Different countries have adopted various timing of HB vaccine and HB immunoglobulin (HBIG) administration as preventive measures against vertical transmission of the HB virus4). In Japan, the vaccination strategy for infants born to mothers with positive serum HB surface antigen (HBsAg) and HBeAg started in 1986, involving HB vaccines scheduled at 2, 3, and 5 months of age and HBIG at birth and 2 months. The program was expanded in 1995 to all children of mothers who are HBsAg-positive, utilizing health insurance and applying the same protocol but excluding HBIG at 2 months in cases who are HBeAg-negative5–9). A further policy change in October 2013 recommended administering HB vaccines at birth, 1 month, and 6 months, and HBIG at birth to all infants born to HBsAg-positive mothers8),9).
Despite the considerable policy change in 2013, literature comparing strategies before and after the revision is scarce. A cohort study of 222 infants born to HBsAg-positive mothers reported comparable seropositive immunogenic responses in the two strategies10). However, to our knowledge, no study has evaluated the vaccination status of infants before and after the 2013 revision. It is unclear whether a change in the recommended vaccination schedule affects the complete and timely administration of vaccines. A large-scale, real-world evaluation is necessary to elucidate the possible effects of policy changes on clinical practice.
This study aimed to evaluate the effect on timing of infants receiving HB vaccine as a preventive measure against vertical transmission of HB virus in Japan by comparing the strategies in use before and after the 2013 revision.
This retrospective study utilized the JMDC Claims Database (JMDC Inc., Tokyo, Japan), an anonymized database of health insurance claims data provided by employer health insurance groups. The database covered employees of Japanese companies and their families, and the number of enrolled employees has been increasing. Basic enrollment information, including sex, year and month of birth, the period over which the data were obtained, and relationship to the main insured person within a family (e.g., employee himself/herself, spouse, and child), were contained in the database. Family members of the same insurance could be linked using family identification codes. All monthly claims data for medical services covered by health insurance were recorded in the database, including HB vaccine and HBIG for infants born to HBsAg-positive mothers. Diagnoses, drugs, and procedures were coded according to the International Statistical Classification of Diseases and Related Health Problems, 10th Revision, the World Health Organization Anatomical Therapeutic Chemical Classification System, and the Japanese code for reimbursement, respectively.
This study was approved by the Institutional Review Board of the Graduate School of Medicine, The University of Tokyo (Approval No. 10862-(3)). The requirement for informed consent was waived due to data anonymity.
STUDY POPULATIONWe identified all infants born between April 2009 and March 2021 with available data from the month of their birth and specified as children of the main insured person. From this cohort, we identified those who received preventive measures against vertical transmission of HB virus using claims data for HBIG (World Health Organization Anatomical Therapeutic Chemical Classification System code, J06BB04) in the month of their birth. Infants were categorized according to their birth period using 6-month intervals (April 2009–September 2009, October 2009–March 2010, etc.). Further analysis of HB vaccine use was conducted in infants who were observed in the database for 1 year or longer after birth. The cohort was divided into an old strategy group (born between April 2009 and September 2013) and a new strategy group (born between October 2013 and March 2021).
VARIABLESWe obtained data on low birth weight (<2,500 g) using diagnostic codes recorded in the birth month (International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes, P07.0 or P07.1). We also identified family members of the infants within the same insurance system using the family identification code, and data on the birth order of the infants and the birth year of their mothers were extracted. Data on HB vaccine (World Health Organization Anatomical Therapeutic Chemical Classification System code, J07BC01) administered to eligible infants was obtained, and the timing of vaccination was categorized according to the age in months. Details regarding HBsAg and anti-HBs antibody (HBsAb) testing were also obtained. The codes used to identify the diagnoses, drugs, and procedures are presented in Supplementary Table 1.
STATISTICAL ANALYSISFirst, we calculated the proportion of newborns born in different periods who received HBIG during the month of birth. The proportion of mothers born before 1986, when the nationwide immunoprophylaxis program began, was also calculated for each period. Next, we summarized the age (in months) at which eligible infants born in different periods received each dose of the HB vaccine. The number of HB vaccine doses administered within 1 year of birth and the number of infants who received each dose of HB vaccine as scheduled were compared between the two groups. Timely administration of the three doses of HB vaccine was defined as follows: by 2, 3, and 5 months in the old strategy group, and in the birth month, by 1 month, and by 6 months in the new strategy group. We also conducted analyses allowing additional 1 and 2 months after the schedule. Finally, we calculated the proportion of infants in the old and new strategy groups who underwent HBsAg and HBsAb testing each month after birth. The proportion of infants who underwent at least one test within 1 year of birth was derived for those who completed three doses of vaccines and those who did not.
We conducted a sensitivity analysis that excluded infants with low birth weight because four doses of vaccines may have been used in those with birth weight <2,000 g. This vaccination protocol for low birth weight infants aligns with the recommendation of the Japan Pediatrics Society11), although not approved by health insurance. Additionally, we compared infants born in March 2016 or earlier and those born in April 2016 or later within the new strategy group because universal HB vaccination of all infants, irrespective of their risk of contracting HB virus, started in October 2016 in Japan8),9). The chi-squared test was used to compare variables. Statistical analyses were performed using Stata/SE (version 17.0; StataCorp, College Station, USA).
A total of 588,381 newborns were identified from the JMDC Claims Database during the 12-year study period, including 77,797 born between April 2009 and September 2013 and 510,584 born between October 2013 and March 2021. The characteristics of these newborns are compared with those in the Vital Statistics of Japan in Supplementary Table 2. After adjusting for the number of births in each year, the study cohort had slightly younger mothers and larger proportion of first-born infants than the general Japanese population. HBIG was administered in the month of birth in 0.16% (922/588,381) of infants. The proportion of infants who received HBIG according to birth period is shown in Fig. 1, and a decreasing trend from approximately 0.3%–0.4% in 2009–2010 to 0.15% in 2019–2020 was observed. The cumulative proportions of infants receiving HBIG were 0.24% (190/77,797) and 0.14% (732/510,584) during the old and new strategy periods, respectively (p < 0.001). Fig. 1 shows the decreasing proportion of mothers born before 1986. Among those with available data on the birth year of mothers, the cumulative proportions of mothers with birth years before 1986 were 86% (42,595/49,473) and 52% (137,045/261,073) for the old and new strategy periods, respectively.
Each point represents the proportion of infants born during a 6-month period who received hepatitis B immunoglobulin in the month of birth, with a 95% confidence interval (left axis). The dashed line represents the proportion of mothers born before 1986 when the nationwide immunoprophylaxis program for hepatitis B was initiated (right axis).
Of the 922 infants who received HBIG during the month of birth, 43 were not observed for up to a year and were excluded. The characteristics of the included and excluded individuals are compared in Supplementary Table 3. Among the 879 infants eligible for analysis, there were 185 and 694 infants in the old and new strategy groups, respectively. Baseline characteristics of these infants are presented in Table 1. There were no significant differences in sex, birth order, or proportion of infants with low birth weight.
| Characteristic | Old strategy group, born 4/2009–9/2013 (N = 185) n (%) |
New strategy group, born 10/2013–3/2021 (N = 694) n (%) |
P value |
|---|---|---|---|
| Sex | |||
| Male | 103 (56) | 368 (56) | 0.521 |
| Female | 82 (44) | 326 (44) | |
| Birth order | |||
| 1st | 84 (45) | 323 (45) | 0.577 |
| 2nd | 78 (42) | 268 (42) | |
| 3rd or later | 23 (12) | 103 (12) | |
| Birth weight | |||
| ≥2,500 g | 172 (93) | 655 (94) | 0.471 |
| <2,500 g | 13 (7) | 39 (6) | |
| Birth year of mothera) | |||
| Before 1986 | 122 (94) | 280 (72) | <0.001 |
| 1986 or after | 8 (6) | 111 (28) |
a) N = 130 (old strategy group), N = 391 (new strategy group)
Fig. 2 shows the age (in months) at which eligible infants born at different periods received three doses of HB vaccines. Following the change in recommendation in October 2013, the common timing of the first dose changed from 2 months after birth to the birth month. Similar changes were observed for the second dose (old strategy: 3 months after birth; new strategy: 0–1 month after birth) and the third dose (old strategy: by 5 months after birth; new strategy: 6 months after birth).
(a) Age at vaccination with first dose
(b) Age at vaccination with second dose
(c) Age at vaccination with third dose
Table 2 shows the number of doses that infants in the old and new strategy groups received within 1 year of birth, as well as the number of infants who received vaccinations in accordance with the recommended schedule. At least one dose of the HB vaccine was administered to 63% (116/185) and 96% (669/694) of infants in the old and new strategy groups, respectively (p < 0.001). Three doses of HB vaccine were completed within 1 year of birth in 50% (93/185) and 57% (397/694) of infants in the old and new strategy groups, respectively (p = 0.092). The proportions of infants in the old and new strategy groups who received their first, second, and third doses of HB vaccine as scheduled were 54% and 90% (p < 0.001), 46% and 59% (p = 0.002), and 39% and 31% (p = 0.034), respectively.
| Vaccination status | Old strategy group, born 4/2009–9/2013 (N = 185) n (%) |
New strategy group, born 10/2013–3/2021 (N = 694) n (%) |
P value |
|---|---|---|---|
| Doses received within 1 year of birth | |||
| 0 | 69 (37) | 25 (4) | <0.001 |
| 1 | 9 (5) | 162 (23) | |
| 2 | 15 (8) | 210 (30) | |
| 3 | 90 (49) | 292 (42) | |
| 4 | 2 (1) | 5 (1) | |
| Vaccination as scheduled | |||
| 1st dose | 99 (54) | 622 (90) | <0.001 |
| 2nd dose | 86 (46) | 411 (59) | 0.002 |
| 3rd dose | 72 (39) | 213 (31) | 0.034 |
| Vaccination as scheduled plus 1 month | |||
| 1st dose | 112 (61) | 644 (93) | <0.001 |
| 2nd dose | 97 (52) | 443 (64) | 0.005 |
| 3rd dose | 88 (48) | 285 (41) | 0.112 |
| Vaccination as scheduled plus 2 months | |||
| 1st dose | 115 (62) | 659 (95) | <0.001 |
| 2nd dose | 105 (57) | 454 (65) | 0.030 |
| 3rd dose | 91 (49) | 295 (43) | 0.104 |
HBsAg and HBsAb testing status are shown in Fig. 3 and Supplementary Table 4. Tests were commonly conducted at months 0–1 and 6 in the old strategy group and months 9–12 in the new strategy group. Overall, HBsAg and HBsAb were tested in 73% (n = 135) and 57% (n = 105) of those in the old strategy group, respectively, whereas the respective proportions were 59% (n = 410) and 46% (n = 316) in the new strategy group. Tests were more likely to be conducted when the infants completed the three doses of the vaccine.
(a) Hepatitis B surface antigen test
(b) Anti-hepatitis B surface antibody test
The old and new strategy groups comprised those born between April 2009 and September 2013 (N = 185) and those born between October 2013 and March 2021 (N = 694), respectively.
The results of the sensitivity analysis, excluding 52 infants with low birth weights, are presented in Supplementary Table 5. These results were similar to those of the primary analysis. A comparison of the vaccination status within the new strategy group between infants born between October 2013 and March 2016 (N = 175) and those born between April 2016 and March 2021 (N = 519) is presented in Supplementary Table 6. Those born later were more likely to complete the three doses of the vaccination within one year. The proportion of timely vaccinations was also higher in the latter group, with the third dose being the only exception.
This study used a large-scale claims database to analyze 879 individuals from a cohort of over 500,000 infants born between April 2009 and March 2021. The administration of HBIG, which was recommended in both the old and new strategies, was used to identify those who received preventive measures against the vertical transmission of HB virus. The proportion of infants who received HBIG was consistent with the prevalence of HBsAg-positivity reported previously in a survey of mothers and an analysis of blood donors8),12),13). This proportion showed a decreasing trend, likely reflecting an increase in the number of mothers born after the implementation of immunoprophylaxis.
As shown in Fig. 2, vaccines were commonly administered at the time designated by the existing recommendations. Furthermore, there was a clear and immediate shift in the timing of the vaccination after 2013. Our analysis also revealed a significantly larger proportion of infants in the new strategy group receiving the first dose of the HB vaccine compared with those in the old strategy group (96% vs. 63%), as well as timely administration of the first dose (90% vs. 54%). Thus, this new strategy apparently succeeded in improving the receipt of the first dose of HB vaccine. This may be due to the new protocol recommending that the first dose of HB vaccine be administered immediately after birth.
Despite the favorable effects of the new strategy on the uptake of the first dose of HB vaccination, its effects on the second and third doses were limited. There was a considerable decrease in the proportion of infants who received timely administration compared to the first dose (59% and 31% for the second and third doses, respectively). Overall, there was no significant difference between the old and new strategy groups regarding the completion of the three doses within the first year of life. Additionally, the HBsAg and HBsAb tests were either delayed or not conducted in a considerable proportion of infants in the new strategy group. According to the new strategy, there is a 5-month gap between the second and third doses of the HB vaccine, and neither HBIG nor HBsAg/HBsAb testing is assigned during this period. Infants are recommended to receive multiple other vaccines during this period. Although the third dose of HB vaccine can be administered with other vaccines, routine vaccinations might have been prioritized.
Some limitations should be considered when interpreting the results of this study. First, this was a retrospective analysis using a health insurance claims database, and we had no information on the laboratory findings, including the HBsAg and HBeAg status of mothers. However, the old and new strategies recommend the same vaccination schedule for all mothers who are HBsAg-positive, regardless of HBeAg status. Therefore, the absence of these data does not affect the interpretation of our results. Nevertheless, a risk-based stratification may provide additional insights. Second, details on acquired immunity and infection status of the infants could not be determined. A comparison of the effectiveness of the two strategies was beyond the scope of this study, and our study was also underpowered to detect differences in infection and hepatitis in children. We could not identify infants with HBsAg positivity who were ineligible for the vaccination program. Thus, it is uncertain whether the reason for incomplete vaccination was in-utero infection, vaccine failure, or non-compliance. Tests for detecting HBsAg and HBsAb were not conducted often and were performed more frequently in those who completed the vaccinations, suggesting that the primary reason for missing vaccines may be non-compliance. Third, vaccines that are part of routine vaccinations are not subsidized by health insurance and, therefore, could not be identified. A small proportion of the participants may have received HB vaccines as part of their routine vaccinations. However, because infants born to mothers who were HBsAg-positive mothers are excluded from the routine HB vaccination, we anticipate the effect to be small. Our additional analysis of those born before and after 2016 also suggests that this effect is trivial. Fourth, the validity of the data was not assessed. Although procedure and prescription records are assumed to be accurate, disease records, such as low birth weight, may have low sensitivity, potentially leading to underestimation. Fifth, the exclusion of individuals lacking a 1-year follow-up data may have slightly affected the study population. Finally, the participants in this study were family members of employees of Japanese companies. Information on mothers was unavailable for approximately 40% of the participants, as the mothers were not enrolled in the same insurance. Furthermore, there was a small deviation in baseline characteristics compared to the general Japanese population. Vaccination status may vary based on health insurance schemes and healthcare systems.
The present study demonstrates the real-world status of HB vaccination as a preventive measure against vertical transmission of HB virus, with particular emphasis on the recommendation change in 2013. In conclusion, this new strategy successfully increased the uptake of the first dose of HB vaccine. However, it did not improve timely and complete administration of the three doses. Further efforts are necessary to increase compliance with the second and third doses of HB vaccines.
H. Yamana is married to an employee of Chugai Pharmaceutical Co., Ltd. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
This research was supported by Grants-in-Aid for Innovative Drug Discovery and Development Project from the Japan Agency for Medical Research and Development (Grant number JP21nf0101636), Cross-ministerial Strategic Innovation Promotion Program (SIP) on “Integrated Health Care System” (grant number JPJ012425), and grant from the Ministry of Health, Labor and Welfare, Japan (23AA2003). The funding sources had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
None.
H. Yamana conceived of the study. All authors contributed to the study design. S. Ono and H. Yasunaga acquired the data. H. Yamana analyzed the data, and all authors contributed to its interpretation. H. Yamana drafted the manuscript, and all other authors revised it critically for important intellectual content. All authors approved the submitted version.
H. Yamana and H. Yasunaga are the Editorial Board members of Annals of Clinical Epidemiology (ACE). They were not involved in the peer-review or decision-making process for this paper.
