
==== Front
Hum Vaccin Immunother
Hum Vaccin Immunother
Human Vaccines & Immunotherapeutics
2164-5515
2164-554X
Taylor & Francis

39247981
10.1080/21645515.2024.2395087
2395087
Version of Record
Research Article
Licensed Vaccines
Time interval distribution of hepatitis B vaccine immunization among infants in China from 2017 to 2021
S. ZHANG ET AL.
HUMAN VACCINES & IMMUNOTHERAPEUTICS
Zhang Sihui a b *
Tian Xiaoling c *
Wang Li d *
Liu Ming e *
Wang Chao b
Zhao Tianshuo a b
Cai Xianming a b
Zhang Xiyu a b
Wang Mingting a b
Du Juan b
Liu Yaqiong b
Lu Qingbin b
Wu Jiang f
Huang Ninghua b g h
Cui Fuqiang b g h
a Department of Epidemiology and Biostatistics, School of Public Health, Peking University , Beijing, P. R. China
b Department of Laboratorial Science and Technology & Vaccine Research Center, School of Public Health, Peking University , Beijing, P. R. China
c Institute for Immunization and Prevention, Inner Mongolia Center for Disease Control and Prevention , Hohhot City, People’s Republic of China
d Institute for Immunization and Prevention, Suzhou Center for Disease Control and Prevention , Suzhou, China
e Department of Infectious Disease, Guizhou Provincial Center for Disease Control and Prevention , Guiyang, China
f Institute for Immunization and Prevention, Beijing Center for Disease Prevention and Control, Beijing Research Center for Preventive Medicine , Beijing, China
g Key Laboratory of Epidemiology of Major Diseases, Ministry of Education, Peking University , Beijing, China
h Center for Infectious Diseases and Policy Research & Global Health and Infectious Diseases Group, Peking University , Beijing, P. R. China
CONTACT Jiang Wu wj81732@hotmail.com Institute for Immunization and Prevention, Beijing Center for Disease Prevention and Control, Beijing Research Center for Preventive Medicine, No. 16, HePingli Middle Street, DongCheng District, Beijing 100013, China.
Ninghua Huang hnh@bjmu.edu.cn Department of Laboratorial Science and Technology & Vaccine Research Center, School of Public Health, Peking University, Beijing 100191, P. R. China.
* Authors contributed equally to this work.

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https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

ABSTRACT

Infant hepatitis B vaccine coverage in China is high, with over 95% of infants immunized; however, high vaccine coverage can often mask low timeliness. The vaccination interval between the second and third doses is not clearly defined by immunization guidelines in China. This retrospective cohort study assessed the time interval distribution of hepatitis B vaccination among a cohort of randomly selected live births from the Centers for Disease Control and Prevention across four provinces or municipalities in China between January 2017 and December 2021. Among the infants analyzed, 163,224 received the first dose of hepatitis B vaccine with 146,905 (90.0%) and 135,757 (83.2%) infants receiving the second and third doses, respectively. A total of 132,577 (90.2%) infants received the second dose between 28 and 61 days after the first dose. Of the 119,437 (88.0%) infants that completed the hepatitis B series between 61 and 214 days after the second dose 87,067 (64.1%) infants were vaccinated with the third dose between 151 and 180 days after the second dose. The time interval distribution varied across the four provinces or municipalities (p < .001). Of the 58,077 infants who completed the hepatitis B vaccine series, 36,377 (62.6%) infants used the same type of hepatitis B vaccine for all three doses. Overall, the timeliness of hepatitis B vaccination for infants was lower than expected, with regional disparities observed. This highlights the need for improved timeliness through the introduction of a defined timeframe for the last two doses of vaccine and training for obstetricians and related personnel.

KEYWORDS

Time interval
hepatitis B vaccination
infants
type of vaccine
last two dose
Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education Center for Infectious Diseases and Policy Research & Global Health and Infectious Diseases Group, Peking University Development and Application Promotion of Inner Mongolia Immunization Planning Information Management System This work was supported by the Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education; Center for Infectious Diseases and Policy Research & Global Health and Infectious Diseases Group, Peking University; Development and Application Promotion of Inner Mongolia Immunization Planning Information Management System. This study was also funded by Sanofi. Sanofi was not involved in the study design, including protocol development, the data analysis plan, data interpretation, and manuscript writing. Sanofi also provided funding for editorial support.
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pmcIntroduction

The global HBV infection rate was 3.9%, equivalent to approximately 292 million HBV-infected individuals. Perinatal transmission is a major mode of hepatitis B virus (HBV) transmission worldwide. Approximately 1.8 million cases (1.4%) of infections occur in 5-year-old children. According to the latest data, 85% of infants received three doses of hepatitis B vaccine before the age of 1, 46% received the first dose of the vaccine timely, and 14% received hepatitis B immunoglobulin and a complete vaccination regimen.1 In the Southeast Asia Region and the Western Pacific Region, the incidence of mother-to-child transmission (MTCT) in infants of mothers with negative hepatitis B e-antigen is 0.0–5.2%, while the incidence of MTCT in infants of mothers with positive hepatitis B e-antigen is 2.7–53.0%.2 China has the highest infection rate in Perinatal transmission.3 In response, China has implemented efforts to reduce transmission through universal infant immunization. In 2002, China integrated a hepatitis B vaccine into the Expanded Program on Immunization and provided all neonates with free HBV immunization,4 resulting in high vaccine coverage, with over 95% of infants receiving three doses.5 The schedule recommended in the 2021 immunization program of the National Health Commission of People’s Republic of China6 involves administration of the first dose within 24 hours after birth and administration of subsequent doses at 1 and 6 months of age, respectively, and it is the birth dose that is really impactful on MTCT, and the subsequent doses are to establish longer-term protection for other modes of transmission.4,7

Preventing perinatal by providing hepatitis B vaccine for infants was a safe and effective strategy to eliminate HBV transmission.8–10 The Global Alliance for Vaccines and Immunization (GAVI), established in the early 21st century, has played an important role in promoting universal hepatitis B vaccination in low- and middle-income countries. Between 2011 and 2020, children from 73 countries were vaccinated.11 This has led to a sharp increase in the age of vaccine coverage for infants from 1% in 1990 to 84% in 2015.12 By the end of 2021, 190 countries adopted the policy of universal hepatitis B vaccination, and the global coverage rate of three doses of hepatitis B vaccine is estimated to be 85%.13

In recent years, research on measuring vaccine timeliness has become increasingly frequent, and it is recommended that, according to the recommendations of the World Health Organization (WHO),8 the first dose of hepatitis B vaccine should be administered within 24 hours after birth, regardless of the mother’s HBV status.8,14–18 The United States Advisory Committee on Immunization Practices (ACIP) recommends the use of a three-dose series at 0 months, 1–2 months, and 6–18 months of age.19 In addition, 111 member countries provided hepatitis B vaccine of “birth dose” to newborns within the first 24 hours after birth.13 Moreover, infants who received the first dose of hepatitis B vaccine at birth were more likely to complete the three-dose and other recommended vaccinations.20

Multiple factors influence coverage and timely administration of hepatitis B vaccines, including immigrant populations,4 regions,21 locations of birth,7,21 parental attitudes to vaccination,22–24 health care providers,25 and restricted medical resources or limited health consciousness.26 A nationwide study from China demonstrated that three-dose vaccine coverage was lower in those born before 2001, residing in western provinces or rural locations, home-birthed, or with Tibetan or Uigur ethnicity.4 Vaccination coverage and timeliness of vaccine administration are related; however, high coverage can sometimes mask low timeliness. In 2012, the WHO verified that China achieved the hepatitis B surface antigen 1% prevalence control goal among children <5 years of age through universal hepatitis B immunization of newborns.27 As such, it is important for future research to focus on further enhancing the effectiveness and economic benefits related to hepatitis B immunization.

Currently, the vaccination interval between the second and third doses of the hepatitis B vaccine is not clearly defined in the Chinese immunization guidelines, nor is the timely vaccine series completion defined in China. The aim of this study was to analyze the time interval distribution of three doses of hepatitis b vaccine administration across four provinces of China to further optimize the immunization schedule and the vaccine type used.

Materials and methods

Study design and study setting

We conducted a retrospective cohort study to assess vaccination status among randomly sampled live births with immunization records across four provinces or municipalities (Beijing, Anhui, Guizhou, and Inner Mongolia) between 1 January 2017 and 31 December 2021. Four regions are located in the eastern (Beijing), central (Anhui), and western (Guizhou, and Inner Mongolia) regions of China. A total of 3% of infants from at least three counties were randomly selected from each province or city.

Study population and data sources

The study population included all infants born from 1 January 2017 to 30 June 2021, who had immunization records between 1 January 2017 and 31 December 2021, allowing infants born at the end of June sufficient time to complete the three-dose hepatitis B vaccination program. Notably, data may not have been complete for internal migrants (e.g., those who have moved from one county or province to another) due to electronic medical records not having been transferred. Exclusion criteria included incomplete or inconsistent data, such as missing or incorrect birth dates (such as birth after vaccination), vaccination time (or inconsistent vaccination sequence, such as the date of the third dose being earlier than the first dose), or vaccination dose (data only available for the first or third dose, but no information for the second dose).

Variables of interest

The primary endpoint was the proportion of infants who received three doses of hepatitis B vaccine at different intervals and was derived from two variables: date of birth and date of receiving hepatitis B vaccination. For the first dose of vaccine, timely vaccination was limited to 24 hours after birth, following international recommendations. Any vaccination after 24 hours of birth was considered delayed.

For the second and the third dose, guidelines recommend vaccination at 1 and 6 months of age, respectively, but a specific time interval is not defined. The time interval between the first and second dose was divided into three groups: 28–42 days, 43–61 days, and ≥62 days after the first dose. The time interval between the second and third dose was divided into seven groups: <60 days, 61–90 days, 91–120 days, 121–150 days, 151–180 days, 181–214 days, and ≥215 days after the second dose.

Sampled data from Beijing and Anhui was used to analyze the usage of three types of vaccines, coded as A, B, and C, differentiated by the technological platform used in their production, including the percentage of infants using the same or different types of vaccine between the various doses of the three-dose schedule. Data for the other provinces was not available due to data privacy restrictions. Floating population is defined as residing in an area for less than 6 months.

Statistical analysis

The total number of infants for each dose and the corresponding time interval between doses were presented as numbers and percentages. Chi-squared test/Fisher exact tests were used to compare the percentages of infants with different vaccination schedules and different types of vaccines. The level of statistical significance was set at 0.05, and Stata 16.0 (Stata Corp LP, College Station, TX) was used for all statistical analyses.

Ethical approval

The study was approved by the Ethics Committee of Peking University Health Science Center (IRB00001052–23084) and Guizhou Center for Disease and Prevention and Control (Q2023–10).

Results

Dose uptake

Descriptions of the sociodemographic characteristics stratified by province are presented in Table 1. Among the infants analyzed, 163,224 received the first dose of hepatitis B vaccine. Vaccination grade decreased for the subsequent two doses, with 146,905 (90.0%) and 135,757 (83.2%) infants receiving the second and third doses, respectively.Table 1. Doses of vaccines administered within the pre-defined timeframe.

Provinces or province-level municipality	Doses	Total	Administered within the custom time interval	Administered after the custom time interval	
N	n (%)	n (%)	
Beijing*	1	32,532	30,518 (93.8)	2014 (6.2)	
 	2	32,515	27,798 (85.5)	4717 (14.5)	
 	3	29,955	21,736 (72.6)	8163 (27.3)	
 	1 to 3	29,955	17,617 (58.8)	12,338 (41.2)	
Anhui*	1	29,533	23,990 (81.2)	5543 (18.8)	
 	2	29,230	26,858 (91.9)	2372 (8.1)	
 	3	28,122	25,989 (92.4)	2085 (7.4)	
 	1 to 3	28,122	19,533 (69.5)	10,000 (30.5)	
Inner Mongolia*	1	39,650	34,255 (86.4)	5395 (13.6)	
 	2	29,516	28,126 (95.3)	1390 (4.7)	
 	3	28,449	28,393 (99.8)	8 (0.03)	
 	1 to 3	28,449	25,049 (88.0)	14,601 (12.0)	
Guizhou*	1	61,509	56,491 (91.8)	5018 (8.2)	
 	2	55,644	49,795 (89.5)	5849 (10.5)	
 	3	49,231	43,319 (88.0)	5563 (11.3)	
 	1 to 3	49,231	38,235 (77.7)	23,274 (22.3)	
Total	1	163,224	145,254 (89.0)	17,970 (11.0)	
 	2	146,905	132,577 (90.2)	14,328 (9.8)	
 	3	135,757	119,437 (88.0)	15,819 (11.7)	
 	1 to 3	135,757	100,434 (74.0)	60,213 (26.0)	
The custom time interval for the first dose was within 24 hours after birth, for the second dose was 28–61 days after the first dose, and the third dose was 61–214 days after the second dose; administered after the custom time interval for the first dose was >24 hours after birth, for the second dose was ≥62 days after the first dose, and the third dose was ≥215 days after the second dose.

*p < .001, comparison of the proportion between different doses in the same provinces or province-level municipality.

Time interval distribution of the three doses of vaccine

Of the 135,757 infants who completed the three doses hepatitis B vaccination schedule, a total of 100,434 (74.0%) infants received the first dose within 24 hours, the second dose 28–61 days after the first dose, and the third dose 61–214 days after the second dose.

For the first dose of hepatitis B vaccine, 145,254 (89.0%) received within 24 hours after birth.

The time interval distribution for the second dose of hepatitis B vaccine across the four regions is shown in Table 2. Among the 146,905 infants who received two doses of the hepatitis B vaccine, 132,577 (90.2%) received the second dose between 28 and 61 days after the first dose. The proportion of infants vaccinated between 43 and 61 days after the first dose was higher than those vaccinated ≥62 days after the first dose (19.2% vs. 9.8%, respectively).Table 2. Distribution of time intervals of the second dose vaccination.

Provinces or province-level municipality	Total	Between 28 and 42 days after the first dose	Between 43 and 61 days after the first dose	≥62 days after the first dose	
N	n (%)	n (%)	n (%)	
Beijing*	32,515	22,180 (68.2)	5618 (17.3)	4717 (14.5)	
Anhui*	29,230	22,940 (78.5)	3918 (13.4)	2372 (8.1)	
Inner Mongolia*	29,516	21,094 (71.5)	7032 (23.8)	1390 (4.7)	
Guizhou*	55,644	38,136 (68.5)	11,659 (21.0)	5849 (10.5)	
Total	146,905	104,350 (71.0)	28,227 (19.2)	14,328 (9.8)	
*p < .001, comparison of the proportion between different doses in the same provinces or province-level municipality.

Of the 135,757 infants who received the third dose of hepatitis B vaccine, 119,437 (88.0%) completed the full series between 61 and 214 days after the second dose, 87,067 (64.1%) were vaccinated between 151 and 180 days after the second dose, and 17,210 (12.7%) were vaccinated between 181 and 214 days after the second dose (Table 3). The proportion of infants who received the third dose of hepatitis B vaccine between 121 and 214 days after the second dose reached 85.6% (n = 116,266; Table 3). Only around 1% (n = 1,386) of infants were immunized ≤91 days after the second dose.Table 3. Distribution of time intervals for the third dose.

Provinces or province-level municipality	 	Days after the second dose	
Total	≤60	61–90	91–120	121–150	151–180	181–214	≥215	
N	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	
Beijing	29,955	56 (0.2)	321 (1.1)	749 (2.5)	3234 (10.8)	14,393 (48.1)	3039 (10.2)	8163 (27.3)	
Anhui	28,122	48 (0.2)	128 (0.5)	638 (2.3)	4203 (15.0)	17,935 (63.8)	3085 (11.0)	2085 (7.4)	
Inner Mongolia	28,449	48 (0.2)	51 (0.2)	162 (0.6)	1067 (3.8)	25,290 (88.9)	1823 (6.4)	8 (0.03)	
Guizhou	49,231	349 (0.7)	385 (0.8)	737 (1.5)	3485 (7.1)	29,449 (59.8)	9263 (18.8)	5563 (11.3)	
Total	135,757	501 (0.3)	885 (0.7)	2286 (1.7)	11,989 (8.8)	87,067 (64.1)	17,210 (12.7)	15,819 (11.7)	

Dose uptake within the specific time interval by region

The proportion of infants who received the first dose of hepatitis B vaccine within 24 hours, the second dose between 28 and 61 days after the first dose, and the third dose between 61 and 214 days after the second dose, was higher in Inner Mongolia (n = 25,049, 88.0%) and Guizhou (n = 38,235, 77.7%), compared with Beijing (n = 17,617, 58.8%) and Anhui (n = 19,533, 69.5%) (Table 1).

The time interval of the first dose

The proportion of infants receiving the first hepatitis B dose varied significantly across the four regions (Beijing, Anhui, Inner Mongolia, and Guizhou; p < .001; Table 1). In Anhui and Inner Mongolia, 23,990 (81.2%) and 34,255 (86.4%) infants received the first dose of hepatitis B vaccine within 24 hours after birth, respectively, compared with 30,518 (93.8%) and 56,491 (91.8%) infants born in Beijing and Guizhou, respectively (Table 1).

The time interval of the second dose

Conversely, the proportion of infants receiving the second dose of hepatitis B vaccine between 28 and 61 days after the first dose was 26,858 (91.9%) and 28,126 (95.3%) in Anhui and Inner Mongolia, respectively, compared with 27,798 (85.5%) and 49,795 (89.5%) of infants born in Beijing and Guizhou, respectively (Table 1). The proportion of infants who received the second dose between 28 and 42 days after the first dose was the highest in Anhui (n = 22,940, 78.5%) and lowest in Beijing (n = 22,180, 68.2%); however, the proportion of infants who received the second dose between 43 and 61 days after the first dose was higher in Inner Mongolia (n = 7032, 23.8%) compared to the other three regions (Beijing n = 5618, 17.3%; Anhui n = 3918, 13.4%; Guizhou n = 11,659, 21.0%) (Table 2).

The time interval of the third dose

Similarly, those receiving the third dose of hepatitis B vaccine between 61 and 214 days after the second dose were higher in Inner Mongolia (n = 28,393, 99.8%) and Anhui (n = 25,989, 92.4%), compared with Guizhou (n = 43,319, 88.0%) and Beijing (n = 21,736, 72.6%; Table 1). Furthermore, proportionally more infants in Inner Mongolia (n = 25,290, 88.9%) received the third dose of hepatitis B vaccine between 151 and 180 days after the second dose compared with Anhui (n = 17,935, 63.8%), Guizhou (n = 29,449, 59.8%), or Beijing (n = 14,393, 48.1%; Table 3).

Analysis of three doses of immunization using different types of hepatitis B vaccines

A total of 58,077 children from Beijing and Anhui who received all three doses of hepatitis B vaccine were analyzed to assess the type of vaccine used for each dose. Of those included, 36,377 (62.6%) infants used the same type of vaccine for all three doses, 21,613 (37.2%) infants used two different types of vaccines for the three doses, and only 87 (0.2%) infants used completely different types of vaccines for the three doses (Table 4). Furthermore, 12,590 (21.7%) infants used a different type of hepatitis B vaccine for the second dose than for the first dose.Table 4. Use of different types of hepatitis B vaccines.

First dose	 	Second dose	Using different type of vaccine for second dose	Third dose	Using two different types of vaccine to complete the course	Using three different types of vaccine to complete the course	Using the same type of vaccine to complete the course	
Type	N (%)	Type	N (%)	N (%)	Type	N (%)	N (%)	N (%)	N (%)	
A	313 (0.5)	A	127 (40.6)	186 (0.3)	A	83 (65.4)	199 (0.3)	31 (0.05)	83 (0.1)	
B	13 (10.2)	
C	31 (24.4)	
B	56 (17.9)	A	1 (1.8)	
B	38 (67.9)	
C	17 (30.4)	
C	130 (41.5)	A	3 (2.3)	
B	14 (10.8)	
C	113 (86.9)	
B	24540(42.3)	A	54 (0.2)	6687 (11.5)	A	24 (44.4)	11644 (20.0)	38 (0.1)	12858 (22.1)	
B	20 (37.0)	
C	10 (18.5)	
B	17853 (72.8)	A	54 (0.3)	
B	12858 (72.0)	
C	4941 (27.7)	
C	6633 (27.0)	A	28 (0.4)	
B	1331 (20.1)	
C	5274 (79.5)	
C	33224 (57.2)	A	66 (0.2)	5717 (9.8)	A	35 (53.0)	9770 (16.9)	18 (0.03)	23436 (40.4)	
B	12 (18.2)	
C	19 (28.8)	
B	5651 (17.0)	A	6 (0.1)	
B	3116 (55.1)	
C	2529 (44.8)	
C	27507 (82.8)	A	31 (0.1)	
B	4040 (14.7)	
C	23436 (85.2)	
Total	58,077	 	 	12590 (21.6)	 	 	21613 (37.2)	87 (0.2)	36377 (62.6)	

Univariate analysis of vaccination using different types of hepatitis B vaccines

A univariate analysis of the 58,077 infants who completed all three doses of hepatitis B vaccine showed that several factors influenced the number of different vaccine types used. The proportion of Han that received the same type of vaccine was higher than for other ethnic groups (64.9% vs. 53.9%), respectively. Additionally, in 2018 and 2019, 57.5% and 57.2%, respectively, received the same type of vaccine, which were lower compared with other years included in this analysis. However, the proportion of infants vaccinated with all doses at the same location was higher than those who received subsequent hepatitis B vaccines at an alternative location (79.2% vs. 62.1%). Furthermore, a higher proportion of second-born children (64.6%) received the same type of vaccine compared with those born in any other birth order (Table 5, p < .001).Table 5. Characteristics of infants who received all three doses of hepatitis B vaccine.

Characteristics	Using the same type of hepatitis B vaccine	Using the different types of hepatitis B vaccine	RR	P Value	
N (%)	N (%)	95% CI	
Birth order	
 1	25,493 (62.1)	15,577 (37.9)	Reference	 	
 2	6103 (64.6)	3350 (35.4)	1.04 (1.02, 1.06)	<.001	
 3 or more	4782 (63.3)	2772 (36.7)	1.02 (1.001, 1.04)	.042	
Ethnicity	
 Han	29,872 (64.9)	16,133 (35.1)	Reference	 	
 Other	6506 (53.9)	5566 (46.1)	0.83 (0.82, 0.85)	<.001	
Year of birth	
 2017	9993 (66.2)	5106 (33.8)	Reference	<.001	
 2018	7939 (57.5)	5877 (42.5)	0.87 (0.85, 0.88)	<.001	
 2019	7174 (57.2)	5380 (42.9)	0.86 (0.85, 0.88)	<.001	
 2020	7449 (70.4)	3128 (29.6)	1.06 (1.05, 1.08)	<.001	
 2021	3823 (63.4)	2208 (36.6)	0.96 (0.94, 0.98)	<.001	
Vaccination at the same location	
 Yes	1435 (79.2)	377 (20.8)	Reference	 	
 No	34,961 (62.1)	21,322 (37.9)	0.78 (0.77, 0.80)	<.001	
Floating population	
 Yes	8650 (63.3)	5015 (36.7)	Reference	 	
 No	27,728 (62.4)	16,684 (37.6)	0.99 (0.97,1.001)	.067	
 Total	36,378 (62.6)	21,699 (37.4)	 	 	
CI, confidence interval; RR, Risk ratio.

Vaccination coverage of other national immunization program vaccines

A total of 69,183 immunization records for infants from Anhui and Inner Mongolia who had received at least the first dose of hepatitis B vaccine were analyzed to determine the coverage rates of other vaccines, including the diphtheria, tetanus, and pertussis vaccine (DTP), oral poliovirus vaccine (OPV), inactivated polio vaccine (IPV), meningococcal conjugate vaccines (MCV), and bacillus Calmette-Guerin vaccine (BCG). Vaccination coverage rates for DTP, MCV, and BCG all exceeded 90%; however, vaccine coverage rates were lower for subsequent doses. The coverage rates of the first and second doses of OPV also exceeded 90%; however, coverage for the third dose reached only 16.7%. Similarly, the coverage rate for the first dose of IPV was 82.1% but decreased to 56.3% for the second dose (Table 6).Table 6. Vaccination coverage rate for other vaccines in Anhui and Inner Mongolia.

 	Total number	Number of vaccinations	Coverage rate (%)	
DTP	
DTP1	69,183	65,413	94.6	
DTP2	69,183	64,958	93.9	
DTP3	69,183	64,566	93.3	
OPV	
OPV1	69,183	65,340	94.5	
OPV2	69,183	65,076	94.1	
OPV3	69,183	11,536	16.7	
IPV	
IPV1	69,183	56,800	82.1	
IPV2	69,183	38,972	56.3	
MCV	69,183	66,697	96.4	
BCG	69,183	66,295	95.8	
BCG, Bacillus Calmette-Guerin Vaccine; DTP, diphtheria, tetanus, and pertussis mixed vaccine; IPV, inactivated polio vaccine; MCV, meningococcal vaccine; OPV, oral polio vaccine.

Discussion

In this retrospective cohort study conducted in the four provinces or municipalities in China, (Anhui, Inner Mongolia, and Guizhou, and one province-level municipality Beijing), China, we found that vaccine coverage and timeliness of hepatitis B vaccination differed among the four regions analyzed (Anhui Inner Mongolia, Guizhou, and Beijing).

These data showed that the proportion of infants who received all three doses hepatitis B vaccine within the pre-defined time intervals did not reach 95%. These findings are similar to a previous study conducted in Hohhot, China, which found that timely vaccination with the first dose of hepatitis B vaccine was achieved in only 90% of newborns in 2019 and 2021.28 Conversely, a study in Guangxi, China, found that the timely vaccination was achieved in 94.88% of newborns, with delayed vaccination attributed to low birth weight, preterm delivery, and dystocia.29 This suggests that training should be strengthened so that vaccination personnel can correctly master the contraindications of hepatitis B vaccination, and health education should be enhanced to further improve the timely vaccination rate of newborn infants with the first dose of hepatitis B vaccine.

Under- or delayed vaccination is a significant, avoidable public health risk and contributes to the low overall vaccine coverage (40–60%) observed in some population subgroups.30,31 As low vaccine coverage increases the overall susceptibility of the population to outbreaks of vaccine-preventable diseases, it is important that medical resources are readily accessible across all areas. Local health departments should be encouraged to assess vaccination coverage so that they can use it as a baseline for designing and implementing interventions in the region, with the aim of increasing vaccination rates. Although a previous study on hepatitis B vaccine coverage rate in the central and western regions of China showed that timely full and complete coverage increased from 46.6% in 2011 to 59.3% in 2016, this study was conducted earlier and may underestimate the full coverage rate.32 Overall, our data show that the majority of infants who received both the second and third doses of hepatitis B vaccine were clustered between 28 and 61 days (90.2%) after the first dose and between 121 and 214 days (85.6%) after the second dose, respectively. Timely administrated hepatitis B birth dose is an effective way to prevent the vertical transmission, and delaying the first hepatitis B vaccination would reduce the efficacy of immunoprophylaxis.33 Failure to receive the second and the third dose timely may result in missing the vaccination time for the second and third dose, affecting the persistent immunogenicity and future protective efficacy unless within a certain vaccination time range the immunoprophylaxis efficacy is not affected.34–36 Finally, it affects the integrity of the immunization program. This indicates that setting a clear vaccination schedule would further improve vaccination uptake and timely vaccination rate.

This study found that there were differences in the proportion of children vaccinated within the prescribed time interval in four regions. In terms of full vaccination, the proportion of children vaccinated within the prescribed time interval in Guizhou and Inner Mongolia was higher than that in Beijing and Anhui. However, the highest proportion of children vaccinated within 24 hours of the first dose in Beijing might be the high-level medical institutions and professional medical staff. This has provided a solid guarantee for hepatitis B vaccination and ensured the accessibility and quality of the first dose of vaccination service. The reason for the low vaccination rate of the second and third doses within the defined time interval might be the difficulty of vaccination for migrant children. We should strengthen the management and services for migrant children. By establishing files of migrant children and carrying out active search and follow-up, it is ensured that migrant children can be vaccinated with hepatitis B vaccine in a timely manner. On the other hand, the proportion of infants who received three doses of the vaccine varied depending on their year of birth. In 2021, the proportion of infants who received the three doses was decreased. Our research mainly focused on the proportion of children who received the vaccine within the prescribed time interval, so the impact on the results was minimal.

In terms of the different types of vaccines used, we found that the majority of infants were immunized with the same type of vaccine. However, although the vaccination procedure for all three doses of hepatitis B vaccine is not clearly stipulated by the Chinese hepatitis B vaccination procedure, our study also revealed that 21.7% of infants received a different type of hepatitis B vaccine for their first two doses, and 37.2% of infants received two types of hepatitis B vaccine for over the three doses; this may due to convenience and availability of vaccines. This reflects real-world clinical practice, whether for newborns or other populations, as an individual may receive two different vaccines for sequential immunizations due to issues with vaccine procurement and supply. However, it is important to note that multiple studies have shown that different types of hepatitis B vaccines display comparable effects in terms of safety and immunogenicity,37,38 with no significant difference in immunization of effect noted between schedules using the same of different hepatitis B vaccines for the three-dose schedule.38,39 Notably, our data also revealed that infants were more likely to receive the same type of vaccine if they were of Han nationality, vaccinated in the same location, or second-born children or later. This is likely related to the accessibility of hepatitis B vaccine, parents’ knowledge, and previous experience of the hepatitis B vaccine.

Lastly, our data also showed that infants vaccinated with hepatitis B vaccines were more than 90% likely to receive the DTP, OPV, MCV, and BCG vaccines. However, the proportion of those who received OPV3 was lower because China implemented an updated immunization program incorporating bivalent IPV and bivalent OPV on 1 May 2016.40 To understand the coverage rate of other vaccines for children inoculated with hepatitis B vaccine, publicity and education on specific vaccines can be carried out when hepatitis B vaccine is inoculated, so as to improve the coverage rate of other vaccines.

This study had multiple limitations that warrant discussion. First, this study cannot use the logistic regression to analyze the factors affecting timely vaccination, and this analysis could provide valuable insights into the barriers to timely vaccination and help in developing strategies to overcome these barriers. At present, we cannot obtain these data at the individual level. If we have access to data at the individual level in the future, a logistic regression analysis will be used to understand the impact of various factors on vaccination timely rates. Second, we should use sampled data from Beijing and Anhui to analyze the usage of three types of vaccines. Data for other provinces were not available due to data privacy restrictions. Including data from all provinces could enhance the comprehensiveness and representativeness of the study.

Conclusions

As there are currently large regional disparities in the timeliness of infant hepatitis B vaccination, it is necessary to precisely define the time of vaccination for the last two doses of hepatitis B vaccine, to further investigate the factors affecting timely vaccination, and to strengthen training for obstetricians and related personnel. Additionally, our study showed the interchangeability of hepatitis B vaccine that exists in real-world clinical practice, with different types of hepatitis B vaccine used for immune prophylaxis, which may also help improve full vaccination coverage and timeliness of hepatitis B vaccination.

Acknowledgments

The authors also thank Roopsha Brahma, PhD for editorial assistance and manuscript coordination on behalf of Sanofi. Yurong Mao and Juan Camilo Vargas Zambrano also be acknowledged due to discussions they had with the study team. Editorial support with the preparation of the manuscript was provided by Holly McAlister and Nichola Cruickshanks, inScience Communications, Springer Healthcare Ltd, UK, and was funded by Sanofi.

Jiang Wu, Director and Chief Physician of the Immune Prevention Institute of the Beijing Center for Disease Control and Prevention, and Chief Expert of Immune Prevention at the municipal level in Beijing. Presided over the major projects of the 11th Five Year Plan of the Beijing Municipal Science and Technology Commission, such as “Research on the Low/Non response Test Standard System of hepatitis B Vaccine” and “Research on Immune Prevention of Pneumonia with High Incidence of Infectious Diseases in Children”, the 12th Five Year Plan, “Investigation and Analysis of the Current Situation of the Horizontal Transmission of Hepatitis B Virus in Beijing and Research on Control Strategies”. In terms of vaccine clinical research, he has successively presided the research of H5N1, H1N1, H7N9, and other vaccines. Published over 60 papers and 2 monographs. Serving as a member of the Expert Guidance Committee for Abnormal Vaccination Response Identification of the Chinese Medical Association and the Beijing Food and Drug Safety Expert Committee, among other social positions.

Ninghua Huang, a Ph.D. graduate and Assistant Researcher at Peking University’s School of Public Health, is dedicated to the study of infectious disease control, vaccine efficacy, and health policy evaluation. Holding the position of Secretary for the Chinese Preventive Medicine Association’s Committee on the Eradication of Viral Hepatitis, she has spearheaded projects funded by the Beijing Natural Science Foundation and engaged in multiple national and provincial research initiatives, with a publication record that includes over 10 scholarly articles in prestigious international journals such as the Journal of Medical Virology.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Conceptualization, F.C., J.D., Q.L., C.W., and H.N.; collected and analyzed the data and prepared tables, S.Z., X.T., L.W., T.Z., X.C., M.W., Y.L., X.Z., M.L., and J.W.; funding acquisition, X.T., and F.C.; writing – original draft preparation, S.Z., T.Z., X.C., M.W., X.Z., and J.D.; writing – review and editing, F.C., N.H., X.T., L.W., Y.L., C.W., M.L., Q.L., and J.W. All authors have read and agreed to the published version of the manuscript. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Data availability statement

Original data are available on request. Readers who wish to gain access to the data can contact the corresponding author. Requests to access these datasets should be directed to FC, cuifuq@bjmu.edu.cn.

Institutional review board statement

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Peking University Health Science Center IRB00001052-23084) and Guizhou Center for Disease and Prevention and Control (Q2023-10).
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