Analysis of epidemiological serosurvey of hepatitis B virus among people under 29 years of age in Jiangsu Province, China

ABSTRACT

Background: The purpose of this paper was to analyze the prevalence of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core anti-body (anti-HBc)in1-29 years old living in the most populous eastern province of China,22 years after introduction of hepatitis B vaccine (HepB) vaccination of infants and provide provincial baseline data for developping a better prevention and control plan for hepatitis B virus (HBV)in Jiangsu Province, China

Methods: The incidence rates of HBV in Jiangsu province from 2004 to 2014 were obtained from the National Notifiable Disease Reporting System (NNDRS). A stratified cluster random sampling method was used to select 3,002 participants aged 1–29 years across 13 HBV monitoring points throughout the province, which had been classified as either urban or rural. HBV serological markers were measured by Abbott microparticle enzyme immunoassay (MEIA) kits (Abbott Laboratories, Chicago, Illinois).

Results: The incidence of hepatitis B decreased by approximately 71.44% in Jiangsu province between 2004 and 2014. Serological assessments showed that the prevalence of the HBsAg, anti-HBc, and anti-HBsin the 1–29 age group were 1.20%, 5.33%,and 66.89%, respectively. There was a significantly lower prevalence of HepB who were vaccinated than in unvaccinated subjects (0.46% vs 14.93%, p < .0001). Among these the ages of 1–29, the coverage rate drops from 97.7% to 56.6% with age,andthe timely rate among people aged 1–14 years was 90.93%.

Conclusions: Since the HepB was integrated into the immunization programme in Jiangsu province,the rate of hepatitis B reported and the prevalence of HBsAg decreased significantly, and the coverage of HepB and the vaccination rate within 24 hours after birth have played an important role in reducing HBV infection.

KEYWORDS:

• Hepatitis B
• serosurvey
• immunization

1. Background

Hepatitis B is an infectious disease that is caused by the HBV in humans.Among the 6 billion people in the world, almost 2 billion people each year are infected worldwide with HBV, and more than 350 to 400 million people world wide are infected with HBV, accounting for approximately 6% of the global population. According to a global report from the World Health Organization (WHO), HBV remains a serious public health problem worldwide, resulting in approximately 1 million deaths from liver failure, liver cirrhosis and primary hepatocellular carcinoma each year.^1,2

The HepB is the most economical and effective way to prevent HBV infection.HBV seriously threatens human life and health, the Chinese government integrated HepB into the routine immunization management programme in 1992.^3,4 Then, in 2002, HepB was integrated into the national expanded immunization programme. However, parents were still required to pay for the cost of the vaccination. Since 2005, the Chinese government has provided the vaccine and vaccination without charge to all newborns, and it must be administered within 24 hours of birth⁵

After 20 years of unremitting efforts, the prevalence of HBsAg in China has dropped drastically, especially among children under 5 years of age. According to the 1992 and 2014 national hepatitis B serological surveys, under-5 HBsAg positive rate declined from 9.67% to 0.32% during the period of survey.⁶ China has achieved the target for hepatitis B control proposed by the World Health Organization in the Western Pacific Region in September 2005, which states the prevalence of HBsAg among children under-5 in the western Pacific Region should be 1% or less.

Jiangsu is a developed province in the eastern of China and there were about 80 million people in 2014 .The HepB management strategy in Jiangsu Province is consistent with the country, a 5ug recombinant HepB was introduced by 1995 in Jiangsu province, In 2013, the antigen content of HepB was increased from 5ug to 10ug for all newborns. According to the historical statistics of Jiangsu Province, the incidence of hepatitis B in our province has decreased from 242.00/100,000 to 15.42/100,000. The1992 serological surveys that 20.0% of the general population were carriers of HBV(data unreleased). The results of the 2006 serological survey showed that the prevalence rate of HBsAg among people aged 1 − 29 years was 7.7%.^7,8The coverage rate of the 3-dose and timely rate for children have increased each year. However, while Jiangsu province is committed to preventing the spread of the hepatitis B virus, the seroprevalence of HBV remains underreported. It’s been a long time since we conducted the provincial serosurvey, the result of this survey can provide provincial baseline data for developping a better prevention and control plan for HBV in Jiangsu Province, China.

2. Methods

2.1. Study design and participants

We conducted a cross-sectional serological study in Jiangsu Province, China. 13 monitoring sites⁹ were selected from throughout the province basing on geography. A stratified, two-stage cluster random sampling method was adopted. In the first stage, the village committee was selected and each county (district) where the monitoring points were to be selected was assigned to a layer (group). The village committees in each layer were the primary sampling units. A capacity ratio probability sampling method was adopted for each layer, and two village committees were randomly selected. In the second stage, the survey objects were selected, according to the sample size assigned by each village committee. A simple random sampling method was used to randomly select the indicated number of resident populations of 1 to 4, 5 to 14 and 15 to 29 year olds for the study. A return visit was made to initial non-responders (any person who did not respond to the first survey). Participants who did not respond after three consecutive visits were considered lost to follow-up, and the relevant information (reason for non-response, name, age, gender, etc.) was recorded in detail. The epidemiological investigation was conducted in residents of Jiangsu province (defined as residing in the province for >6 months). Blood samples were collected for HBV serological testing.

2.2. Investigation method

The centralized or house-to-house interviews were conducted by trained study personnel. Investigators used a standardized questionnaire for the survey. Professional nurses and medical laboratory science officers collected and prepared biological samples. The survey covered basic participant characteristics, patient history of hepatitis, vaccination history, and the detection of maternal HBsAg. Participants’ vaccination histories were obtained through vaccination cards, and if they hadn’t vaccination cards, vaccination history would be obtained via self-reported.

2.3. Specimen collection

After the face-to-face interview, 5 ml of venous blood was collected from participants 5 years or older, and 3 ml of venous blood was collected from under5years. A bar code was pasted on each participant’s survey form and blood sample tube. All surveys and whole blood samples were then returned to the county-level CDC laboratory for serum separation. County-level CDC staff transported the interviews forms, the separated serum and the blood clot samples to the provincial CDC for testing.

2.4. Ethical issues

The surveys were approved by the Chinese CDC’s Ethics Review Committee (No 201339). Participants and children’s guardians provided their written informed consent before the blood collection and interview. The participants were asked to anonymously fill out a questionnaire.

2.5. Laboratory testing

All samples were tested with MEIA kits (Abbott Laboratories, Chicago, Illinois) for HBsAg, anti-HBs and anti-HBc. The sample was defined as positive if the S/N value of HBsAg was >2.0, the CO/S value of anti-HBc was <1.0, or the value of anti-HBs was >10 mIU/ml.¹⁰

2.6. Statistical analysis

EpiData 3.1 was used to establish a case interview database. All data were entered into the database in duplicate. SPSS 22.0 (IBM, Armonk, New York, USA) was used for all statistical analyses.We calculated the prevalence of HBV serological markers and its 95% CI. Meanwhile,univariateand multivariate logistic regression analysis were used to identify factors related to the positive rate of HBsAg. Chi-square tests were used for comparison of rates. P < .05 was defined as statistical significance.

3. Results

3.1. Demographic characteristics

A total of 3,002 participants aged 1 to 29 years were investigated, among which there were 1,583 males (52.73%) and 99.00% were of the Han ethnicity. The group under 5 years old contained 1,232 participants, the 5- to 15-year-old group contained 944 participants, and the group between 15 and 29 years of age contained 826 participants. There was a disproportionate number of participants under 5 years of age, accounting for 41.04% of the total number. In additional, 269 participants (37.31%) had middle school education level or lower (Table 1).

Table 1. Seroprevalence of HBV markers by sociodemographic characteristics

	n/N(%)	HBsAg prevalence (%[95%CI])	P value	Anti-HBs prevalence (%[95%CI])	P value	Anti-HBc prevalence (%[95%CI])	P value
All partcipants	3002(100)	1.20(0.84–1.66)		66.89(65.17–68.57)		5.33(4.55–6.19)
Age
1–4 years	1232(41.04)	0.41(0.13–0.94)	0.000	76.38(73.91–78.73)	.000	1.38(0.81–2.20)	.000
5–14 years	944(31.45)	0.32(0.07–0.93)		61.97(58.79–65.08)		1.80(1.05–2.87)
15–29 years	826(27.51)	3.39(2.26–4.86)		58.35(54.91–61.74)		15.25(12.87–17.89)
Residential area
Urban	1544(51.43)	0.91(0.50–1.52)	0.128	63.84(61.39–66.24)	.000	4.79(3.78–5.98)	.173
Rural	1458(48.57)	1.51(0.95–2.28)		70.12(67.70–72.47)		5.91(4.75–7.24)
Sex
Male	1583(52.73)	1.33(0.82–2.02)	0.498	68.16(65.80–70.45)	.118	5.44(4.37–6.67)	.778
Female	1419(47.27)	1.06(0.59–1.74)		65.47(62.93–67.94)		5.21(4.12–6.50)
Region
South	872(29.05)	0.92(3.97–1.80)	0.216	61.35(58.03–64.60)	.000	5.40(3.99–7.11)	.000
Central	643(21.42)	0.78(0.25–1.81)		64.39(60.55–68.09)		2.80(1.67–4.39)
North	1487(49.53)	1.55(0.98–2.31)		71.22(68.84–73.51)		6.39(5.20–7.75)
Ethnic origin
Han	2972(99.00)	1.18(0.82–1.63)	0.280	66.96(65.23–68.65)	.420	5.25(4.48–6.11)	.049
Others	30(1.00)	3.33(0.08–17.22)		60.00(40.60–77.34)		13.33(3.76–30.72)
Education(>18 years)
Illiterate	19(2.64)	5.26(0.13–26.02)	0.038	42.11(20.25–66.50)	.092	21.05(6.05–45.57)	.000
Primary school	23(3.19)	4.35(0.11–21.95)		47.83(26.82–69.41)		30.43(13.21–52.92)
Middle school	227(31.48)	9.69(6.17–14.31)		52.31(45.43–59.13)		23.61(18.11–29.85)
High school	229(31.76)	5.68(3.06–9.51)		59.39(52.72–65.81)		16.59(12.02–22.06)
College	223(30.93)	0.45(0.01–2.47)		62.78(56.08–69.14)		8.85(5.49–13.33)
Immunization history of HBV
Yes	2590(86.54)	0.46(0.24–0.81)	0.000	68.95(67.13–70.73)	0.000	3.16(2.51–3.90)	0.000
No	67(2.24)	14.93(7.40–25.74)		55.22(42.58–67.40)		38.81(27.14–51.50)
Unknown	336(11.23)	4.17(2.30–6.89)		53.27(47.78–58.71)		15.48(11.78–19.79)
Fullimmunization(<15 years)
Vaccinated within 24 h after birth	1904(90.93)	0.05(1.49–7.44)	0.000	70.59(68.48–72.63)	0.126	0.95(0.56–1.49)	0.000
Vaccinated more than 24 h after birth	190(9.07)	3.68(1.49–7.44)		65.26(58.03–72.01)		6.32(3.31–10.77)

3.2. Distribution of seroprevalence of HBV markers by sociodemographic characteristics

The overall prevalence of HBsAg in the 1 to 29 age group was 1.20% (95%CI:0.84–1.66). The prevalence of HBsAg was higher in the 15–29-year-old age group(3.39%) than in the 1–4 years old age group(0.41%) and 5–14 years old age group(032%).The positive rate of anti-HBc was the highest rate (15.25%) in the 15–29-year-old group, which was significantly higher than the other two age groups . The highest rate of anti-HBs was found in the 1-year-old group (95.00%), and the anti-HBs seroprevalence in the 1–4 years old age group was significantly higher than the other two age groups (Figure 1 and Table 1).

Figure 1. Seroprevalence of HBV markers among participants by age group

The prevalence of HBsAg was highest in participants with a junior high school education level (9.69%) and was lower in those with a university education (0.45%, p < .0001).The anti-HBs rate was significantly higher for participants who lived in rural areas compared with those who lived in urban areas (p < .0001, Table 1). The seroprevalence of anti-HBswas significantly higher in the northern regions than the southern and central regions (71.22% vs 64.39%/61.35%, p < .0001). There was no significant difference in the seroprevalence of all HBV markers based on sex (Table 1).

3.3. Distribution of seroprevalence of HBV markers by immunization history

Table 1 shows that the HBsAg positive rate was significantly lower among participants who were vaccinated than among those who were not (0.46%, 95% CI: 0.24–0.81 vs 14.93%, 95% CI: 7.40–25.74, respectively, p < .0001), which was consistent in different age groups, the history of HepB vaccination was also an independent protective factor through the multivariate regression analysis (Table 2). The prevalence of anti-HBs in vaccinated people was 68.95% (95% CI: 67.13–70.73), which was significantly different from the prevalence in unvaccinated participants (p < .0001). In all age groups, the HBsAg positive rate of the immunized group was much lower than that of the non-immunized group,this difference was more obvious

Table 2. Multinomial logistic regression analysis of HBsAg-positive rate among population aged 15–29 years

	Category	Frequency	OR (95% CI)	P value
Age group (yrs)	15～	196	1
	20～	272	0.31 (0.09–1.08)	.066
	25～	358	0.61 (0.26–1.44)	.261
Residential area	Urban	422	1
	Rural	402	1.92 (0.88–4.21)	.103
Sex	Male	385	1
	Female	441	0.47 (0.22–1.04)	.062
Region	South	244	1
	Central	172	0.34 (0.15–1.02)	.054
	North	410	0.62 (0.23–1.68)	.343
Ethnic origin	Han	815	1
	Others	11	1.20 (0.84–1.69)	.315
Immunization history of HBV	Yes	491	1
	No and unknown	335	3.07 (1.80–5.23)	.000

in the 20-year-old age group (Table 3).

Table 3. Relationship between hepatitis B vaccination and HBsAg seropositivity

	Immunization history
Age group (yrs)	Yes	No + Unknown (%)	P-value*
1～	1205 (0.41%)	27
5～	591 (0.34%)	86
10～	235 (0.43%)	23 (4.34)	.046
15～	209 (0.96%)	40 (5.00)	.062
20～	166 (0.60%)	86 (8.14)	.002
25～	184 (0.54%)	141 (9.93)	.001

* P value is the result of comparing vaccination status

3.4. Incidence rates of HBV in Jiangsu province between 2004 and 2014

Figure 2 shows that the incidence of HBV in the 1–29 age group demonstrated a decreasing trend after 2004 (P < .001). The incidence rate was 197.65/100,000 in 2004 and 56.44/100,000 in 2014, with average incidence rate of 99.10/100,000.The incidence of hepatitis B decreased by approximately 71.44% in Jiangsu province between 2004 and 2014. In the 0- to 4-year-old age group, the reported incidence was 17.00/100,000 in 2004 and 5.01/100,000 in 2014, a decrease of 70.53%. In the 5- to 14-year-old and the 15- to 29-year-old groups, the reported incidence of hepatitis B decreased by 81.03% and 70.42%, respectively. The incidence of hepatitis B was significantly higher in the 15–29-year-old age group than in either the 1-4-year-old age group or the 5- to 14-year-old age group.

Figure 2. The incidence rates of HBV in Jiangsu province between 2004 and 2014

3.5. Vaccination coverage according to age and region

The HepB coverage rate was shown in Table 4. In general, the self-reported vaccination coverage rate in urban areas was about 88.9%, and the vaccine coverage rate in rural areas was 83.5%. Among these the ages of 1–29, the coverage rate drops from 97.7% to 56.6% with age. The vaccination coverage rate (96.1%) in urban areas (under 14 years of age) was higher than that in rural areas (92.5%).

Table 4. Vaccination coverage according to age and region

	Urban		Rural		Total
Age group (yrs)	N	%	N	%	N	%
1～	620	98.1	585	97.3	1205	97.7
5～	325	90.0	266	84.2	591	87.2
10～	135	91.2	100	90.9	235	91.1
<14	1124	96.1	951	92.5	2075	95.4
15～	131	87.9	78	78.0	209	83.9
20～	96	69.1	70	53.1	166	65.9
25～	65	56.5	119	56.7	184	56.6
Total	1372	88.9	1218	83.5	2590	86.3

4. Discussion

As hepatitis B had seriously endangered the lives and health of its people, the Chinese government integrated the hepatitis B vaccine into its routine immunization management programme in 1992, and the HepB was included in the national expanded immunization programme in 2002.^3,4 With these steps, the prevention and control of HBV entered a new era. According to the NNDRS report, from 2004 to 2014, the incidence of hepatitis B among people aged 1 to 29 in Jiangsu Province decreased significantly. In particular, the incidence of children aged 1–14 dropped from 10.51‰ to 2%.The incidences of acute and chronic HBV dropped significantly with the implementation of the hepatitis B vaccine immunization programmes in Jiangsu province. In order to maintain HBV at a low epidemic level, we cannot slacken our efforts in the slightest with regards to the prevention and control of HBV.

Due to different terrain and climate, economic development level, population structure and people’s different understanding of HBV transmission, this may lead to different HBsAg prevalence in different provinces.¹¹The survey found that the prevalence rate of HBsAg was 0.41% in people aged 1 to 4 years, while the rate was 3.39% in the >15 years age group in 2014. HBsAg positive rate was significantly higher in the people aged 15–29 years. The main reasons may be that these people did not have the opportunity to be vaccinated in childhood, or may due to increase social activities and occupational exposure, indicating that this group of people is at accumulated risk of hepatitis B infection. The result was significantly lower than those recorded in the 1992 and 2006.^9,12 This was also significantly lower than the result reported by other provinces in China. According to the results of two surveys in Zhejiang and Jilin province, the prevalence of HBsAg in the corresponding population was 1.70% and 3.43%, respectively.^13,14 Meanwhile,our results also showed that the positive rate of anti-HBc in 1–14 year old was significantly lower than that in 15–29 year old in this serologic survey, which might be attributed to the coverage of HepB.¹⁵ Moreover, the anti-HBc positive rate was increased with age, as other studies have observed,^16,17 which might due to the antibody level attenuation and increase exposure in this age group. In addition, adult vaccinations still need to pay for themselves, which also indirectly affects the vaccination coverage rate. The survey data showed that the prevalence of HBsAg was no significant difference in the gender, region,residential area and ethnicity

The survey also showed that the prevalence rates of anti-HBs in Jiangsu province for people ages 1 to 4, 5 to 15, and 15 to 29 years were 76.38% (95% CI: 73.91–78.73%), 61.97% (95% CI: 58.79–65.08%), and 58.35% (95% CI: 54.91–61.74%), respectively.Children infected within the age of one or six have an 80–90% and 30–50% chance of developing chronicity, respectively, while less than 5% of adolescents and adults developed a chronic infection.¹⁸ Therefore, the high level of anti-HBs in children under 6 years old plays an important role in controlling HBV. In addition, we found that antibody positive rate(76.38%) in the 1–4 age group were significantly higher than those in the 15–29 age group(58.35%), which may be due to the decline of antibody levels, and low coverage rate among those age groups in some areas,¹⁹ therefore, revaccination of such populations is recommended.

The positive rate of HBsAg among people with history of HepB vaccination was significantly lower than that of people without history of vaccination. Multivariate logistic regression analysis showed that HepB vaccination was significantly negatively correlated with HBsAg positive rate,which reflects the critical role of HepB in controlling HBV. In addition, our research showed that the positive rate of HBsAg in the unvaccinated group had a significant upward trend, while the positive rate of HBsAg in the vaccinated group had no upward trend (15–29 year old). Vaccination of HepB among 15–29 year old can slow the increase of the rate of hepatitis B infection. We found that the HBsAg positive rate was 0.46% in people with history of immunization, and the HBsAg positive rate was higher in the 15–29 age group, suggesting that they may not have developed an immune response or have been infected with HBV when they were vaccinated. We suggest that serological markers can be tested before vaccination, and that pre-vaccination testing should be used as routine screening for high-risk populations in areas with high prevalence of hepatitis B.In addition to the individual with no immune response can be replaced with other types of HepB for vaccination.

In a hepatitis B serological survey conducted in Jiangsu Province in 2006, the vaccine coverage rate of participants aged 1–29 years was 85.1% (data unreleased).Vaccine coverage rate in urban areas was slightly higher than that in rural areas in this survey. The main reason was that economic conditions inurbanareasare better,many cities have implemented free vaccination policies and residents are more willing to vaccinate. Meanwhlie, the first dose coverage rate and timely rate have been continuously improved, these improvements are conducive to the reduction of perinatal transmission.^20–23

This study had three key limitations. First, although this seroepidemiological survey used a cross-sectional design, they were strictly involved random sampling according to the rules. Second, the participants were people who had lived in the surveillance points for six months. Many migrants or unregistered children outside of family planning were excluded, especially in some urban areas, HBsAg prevalence rates in these groups may be higher than those reported in this study, so we may have underestimated the overall prevalence in the province. Third, because the adults included in this study did not have their vaccination records, the acquisition of adult immunization history was done by individual recall.

5. Conclusions

In conclusion,the implementation of the hepatitis B vaccine immunization strategy in Jiangsu Province over the last 22 years has been critical in improving the coverage rate of the HB vaccine, reducing the rate of HBV infection and protecting the susceptible population. To maintain a low-level prevalence of HBsAg in the whole population, we should continue to maintain high coverage rate of the HepB and the vaccination rate within 24 hours after birth. In addition, vaccination needs to be expanded in order to prevent HBV infection in older children and adults.

Authors’ contributions

Conceived and designed the experiments: XS,FT, YL,MZ. Performed the experiments: YH, XD.Analysed the data: XS,YL. Contributed reagents/materials/analysis tools: XS,YH, XD. Wrote and revised the paper: XS, YZ,ZW.All authors read and approved the final manuscript.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

We would like to thank all of the municipal CDCs (Pukou, Yunlong, Wujin, Ganyu, Zhangjiagang, Jinhu, Xiangshui, Rugao, Baoying, Danyang, Jiangyin, Taixing, Siyang) in Jiangsu province for their field work.

Additional information

Funding

This work was supported by Chinese Foundation For Hepatitis Prevention and Control under grant number [YGFK20190027].