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. 2019 Aug 29;16(1):16–20. doi: 10.1080/21645515.2019.1646575

Long-term protection at 20–31 years after primary vaccination with plasma-derived hepatitis B vaccine in a Chinese rural community

Jing-Chen Ma a, Zhi-Wei Wu a, Hai-Song Zhou b, Zhao Gao a, Zhi-Yong Hao b, Fei Jin a, Yan-Hong Zhang b, Min-Jie Li a, Feng Wang c, Qi Li a, Sheng-Li Bi c, Yu-Liang Zhao a,
PMCID: PMC7012072  PMID: 31339432

ABSTRACT

Background: To assess the long-term protection conferred by plasma-derived hepatitis B vaccine at 20–31y after primary immunization during infancy in Chinese rural community.

Method: Participants born between 1986 and 1996, who received a full course of primary vaccination with plasma-derived hepatitis B vaccine and had no experience with booster vaccination were enrolled. An epidemiological investigation was performed, and blood samples were collected to detect hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc). The positive rate of HBsAg, anti-HBs, and anti-HBc were calculated to evaluate the long-term protection of the plasma-derived hepatitis B vaccine.

Results: A total of 949 participants were enrolled in the final analysis. Six subjects were detected to be HBsAg-positive, resulting in a HBsAg carrier rate of 0.63% (6/949). A total of 468 (52.41%) participants maintained a level of anti-HBs antibody ≥10 mIU/mL, with a GMC of 112.20 mIU/mL (95%CI: 97.72 ~ 128.82 mIU/mL). A significant downtrend was observed in the anti-HBs positive rate (P < .001). The average anti-HBc positive rate was 5.90% (56/949), increased with prolongation of immunization (P < .001).

Conclusions: The plasma-derived hepatitis B vaccine maintained satisfactory protection at 20–31 y after primary immunization. These results indicate that a booster dose is not necessary. Further studies on the immune memory induced by the plasma-derived hepatitis B vaccine are needed.

KEYWORDS: Hepatitis B virus, vaccine, long-term protection, primary vaccination

Introduction

Hepatitis B virus (HBV) infection is a major public health concern worldwide. The World Health Organization estimated that approximately 257 million people worldwide had been infected with HBV,1 and about 887,000 people died of HBV-associated diseases, including cirrhosis and hepatocellular carcinoma in 2015.1,2 Immunization in infancy against HBV is currently the most effective and economical strategy to prevent HBV infection. In China, the universal immunization with hepatitis B vaccine at birth was integrated partially into National Expanded Immunization Program (EPI) in 1992, when parents had to pay for the vaccine, and added thoroughly to the EPI in 2002.3 With three decades of effort, the prevalence of hepatitis B virus surface antigen (HBsAg) in the entire population (1–59 y) dropped from 9.8% in 1992% to 7.2% in 2006,4 and 2.6% in 1–29 y in 2014.5 Although the safety and efficacy of hepatitis B vaccine were fully acknowledged, the long-term protection remained a question. Several published studies showed that vaccine-induced immune memory might begin to wane after of 15 y full primary immunization,6,7 while other studies indicated that immune memory might persist for up to 20 y or even longer.810 Continuous observation is required to assess the persistence of protection of the hepatitis B vaccine.

Hepatitis B vaccine was introduced in China in 1985. Large-scale demonstration studies to measure the effectiveness and explore the feasibility of universal immunization with hepatitis B vaccine were carried out in five sites in China. Zhengding County, Hebei Province, one of the five study sites, was immunized with a primary series of three doses (10ug/ml) of plasma-derived hepatitis B vaccine in 1986. The last cross-section survey conducted in 2009 in Zhengding County showed that the protection of hepatitis B vaccine after 13–23 y remained11 In order to evaluate the immune persistence at 20–31 y after primary vaccination, we repeated the survey in the same population in 2018.

Materials and methods

Study cohort and study design

Since 1986, all newborns from seven selected villages in Zhengding county were given vaccine according to a 0, 1, and 6 months schedule regardless of the mothers’ HBV infection status. Each dose contained 10 μg of surface antigen per milliliter derived from plasma. To minimize the number of blood draws for each child, serological follow-up was randomly rotated in a clockwise direction among participating villages. Each child was followed more than once of the follow-up dates, but none of the children were bled on every follow-up date. All identification information, vaccination-related information, as well as following serological follow-up information were collected and entered into a unique database. Based on this database, subjects born and completed the full course of primary vaccination with plasma-derived hepatitis B vaccine between 1986 and 1996 were followed again in 2018. After written inform consenting, a questionnaire including name, gender, date of birth, history of receiving an additional course of hepatitis B vaccine was required to complete for each subject. A 5 ml blood sample was collected and serum was isolated aseptically and stored at −20°C at the Zhengding Country Center for Disease Control and Prevention till testing.

Laboratory technique

Batch test for immunological biomarkers of HBV was performed in the reference laboratory at the Institute for Viral Disease, China Center for Disease Control and Prevention (Beijing, China) upon the completion of the follow-up. Abbott EIA AxSYM (Abbott, Abbott Park, IL, USA) was employed for detection of HBsAg (Lot: 82112FN00), anti-HBs (Lot: 84058FN00), and hepatitis B core antibody (anti-HBc) (Lot: 85025LI00). According to protocols provided by the manufacturer, positive and negative cutoffs were calculated, with the positive and negative controls as required by the diagnostic kits. The detection range of the kit was between 2.5 and 1000 mIU/mL, thus, samples with anti-HBs ≥1000mIU/mL were diluted. An anti-HBs concentration ≥10 mIU/mL, HBsAg ≥0.05 IU/mL and anti-HBc S/CO ≥1.0 were defined as positive.

Statistical analysis

The sample size was calculated based on Equation, in which p was the anti-HBs positive rate at 20–31 y after the immunization with the plasma-derived hepatitis B vaccine (35% was used according to references), and α was the significance level (5%), and d was the permissible error (0.1p).

n=zαd2p1p

After primary calculation, n was 743, considering that the sampling error and loss of follow-up, the total sample size was finally set to 900. The data were double-entered into custom-made data entry programs based on EpiData 3.1 (EpiData Association, Odense, Denmark). Statistical analysis was performed using SPSS software (IBM Corporation, Armonk, NY, USA). Antibody positive rate, geometric mean concentrations (GMCs) and their 95% confidence intervals were calculated. Antibody levels were log-transformed to calculate GMCs. The differences in the positive rate of HBV markers in different years after vaccination and gender groups were examined by the Chi-squared test or Fisher’s exact test. The trend of change in the prevalence of HBV markers with years after vaccination was evaluated using the χ2 trend test. GMCs of anti-HBs were calculated for participants with anti-HBs ≥10 mIU/mL. For comparison of GMCs in different years after vaccination groups, F-test was undertaken. Time after vaccination was defined as the interval between the time for blood collection during the cross-section survey in the present study and completion of full primary course. HBV infection was defined as HBsAg-positive, and new infection was defined as HBsAg positive in this survey, and HBsAg negative in any other previous surveys. The natural booster was defined as anti-HBc positive, while HBsAg negative. Subjects with either HBV infection, or HBV new infection, or natural booster, or vaccine booster were excluded from the calculation of anti-HBs persistence. P < .05 was considered to be statistically significant.

Ethical review

The study was approved by the Institutional Review Board of the Hebei Provincial Center for Disease Control and Prevention. Each subject voluntarily signed an informed consent form before the questionnaire survey and blood sample collection. The study was performed in accordance with the Helsinki Declaration of 1975 and its later amendments.

Results

Baseline characteristics of participants

In 1997, person who were born from 1986 to1996 and received the full course of primary vaccination with the plasma-derived hepatitis B vaccine were selected as study objects. Of them, 1,058 subjects were investigated, 939 were not participating in the study. The reasons for not participating were migration mainly, accounting for 90.10%. Study participants and eligible nonparticipants were similar with regard to sex, age, and anti-HBs level after the primary vaccination series. Of the participants, 109 subjects with a booster vaccination history were excluded, eventually, 949 participants were involved in the final analysis (Figure 1). The average age of enrolled participants was 27.06 y (95% CI: 26.85–27.27). The ratio of male to female was 1.17:1.00 (Table 1).

Figure 1.

Figure 1.

Assembly chart of participants through the study.

Table 1.

Distributions of age and gender of participants.

Age Male No. Female No. Total No. (%)
20 10 7 17 (1.79)
21 38 34 72 (7.59)
22 27 28 55 (5.80)
23 29 28 57 (6.01)
24 18 19 37 (3.90)
25 29 26 55 (5.80)
26 31 22 53 (5.58)
27 46 34 80 (8.43)
28 53 40 93 (9.80)
29 55 52 107 (11.28)
30 110 104 214 (22.55)
31 66 43 109 (11.49)
Total 512 437 949 (100.00)

Anti-HBs positive rate and gmcs

Fifty-six participants who were HBsAg and/or anti-HBc positive were excluded from the estimation of anti-HBs persistence. The overall anti-HBs positive rate of the 893 participants was 52.41% (468/893). The positive rate of anti-HBs showed a significant decline with time (P < .001), from 71.43% at 20 y to 44.44% at 31 y after the primary vaccination. The anti-HBs positive rate were 55.88% and 49.48% in female and male subgroups, respectively (P > 0.05). The average GMC in anti-HBs positive participants was 112.20 mIU/mL (95%CI: 97.72 ~ 128.82 mIU/mL) (Tables 2, 4). Among 468 anti-HBs-positive participants, 50.21% (235/468) showed low response (10 ≤ anti-HBs <100 mIU/mL), and 40.60% (190/468) showed moderate response (100 ≤ anti-HBs < 1000 mIU/mL), and 9.19% (43/468) showed high response (anti-HBs ≥ 1000 mIU/mL).

Table 2.

Anti-HBs positive rates and GMCs of participants at 20–31 years after primary vaccination.

Time after vaccination No. detected No. positive Positive rate (%) GMC* (95%CI)
20 42 30 71.43 138.04 (77.63 ~ 251.18)
21 73 47 64.38 213.80 (138.04 ~ 338.84)
22 47 32 68.08 190.55 (104.71 ~ 346.74)
23 55 32 58.18 117.49 (66.07 ~ 213.80)
24 34 17 50.00 69.18 (28.84 ~ 162.18)
25 55 29 52.73 117.49 (66.07 ~ 204.17)
26 64 35 54.69 89.13 (56.23 ~ 158.49)
27 80 44 55.00 128.83 (79.43 ~ 208.93)
28 96 46 47.92 107.15 (74.13 ~ 154.88)
29 147 61 41.50 100.00 (69.18 ~ 141.25)
30 164 79 48.17 95.50 (69.18 ~ 141.25)
31 36 16 44.44 109.65 (52.48 ~ 223.87)
total 893 468 52.41 112.20 (97.72 ~ 128.82)

*GMC of the anti-HBs-positive participants

Table 4.

The six HBsAg-positive cases list.

ID gender Date of birth Mother’s carrying status Time of primary immunization Time of
first discovery*
Time after vaccination$
1 male 1986/1/22 Negative 1986/8/30 1990/8/30 4
2 male 1987/12/18 Positive 1988/7/11 1990/5/9 1
3 female 1987/2/20 Positive 1987/8/25 1994/9/3 7
4 female 1987/4/6 Positive 1987/11/11 1988/5/28 0
5 male 1995/1/28 Positive 1995/7/29 1998/10/21 3
6 male 1988/10/2 Positive 1989/5/31 1989/6/2 0

*The HBsAg-positive was firstly confirmed time

$ Years after full primary course of vaccination when the HBsAg-positive was firstly confirmed

HBsAg and anti-hbc positive rate

The HBsAg-positive rate was 0.63% (6/949). The HBsAg-positive rate was 0.46% and 0.78% in female and male subgroup, respectively (P >.05). The anti-HBc positive rate was 5.90% (56/949), showing an increasing trend with the time prolonged after primary immunization (P < .001) (Table 3). The anti-HBc positive rate was 6.64% and 5.27% in female and male subgroup, respectively (P > .05)

Table 3.

HBsAg and anti-HBc positive rates of participants at 20–31 years after primary vaccination.

Time after vaccination No.
detected
HBsAg
Anti-HBc
No.
positive
Positive rate (%) No.
positive
Positive rate (%)
20 43 0 0.00 1 2.33
21 74 0 0.00 1 1.35
22 50 1 2.00 3 6.00
23 55 0 0.00 0 0.00
24 35 0 0.00 1 2.86
25 58 0 0.00 3 5.17
26 68 0 0.00 4 5.88
27 84 0 0.00 4 4.76
28 104 1 0.96 8 7.69
29 158 2 1.27 11 6.96
30 179 1 0.56 15 8.38
31 41 1 2.43 5 12.20
total 949 6 0.63 56 5.90

Analysis of HBsAg-positive cases

A total of six HBsAg-positive participants were found in this study, four males and two females. The mothers of five out of the six positive participants were also HBsAg-positive. By reviewing historical data, we found that the six people had shown to be HBsAg-positive between 0 and 7 y after primary vaccination. Therefore, there was no newly discovered HBsAg-positive case in this survey. (Table4)

Discussion

In this study, we found that after 20–31 y of the primary vaccination with plasm derived hepatitis B vaccine, the average positive rate of anti-HBs was 53.21%, in which decreasing trend was observed. Our previous survey based on the same cohort showed that, the anti-HBs positive rate was 60.82% at 13–23 y after the immunization with the plasma-derived hepatitis B vaccine.11 The results indicated that hepatitis B vaccine immune effect, determined by HBV markers seropositivity waned with time. Consistent with us, Bruce et al. showed that after 30 yof follow-up, the positive rate of anti-HBs was 56% after immunization with the plasma-derived hepatitis B vaccine.12 However, the study by Li et al. showed that the positive rate of anti-HBs at 22–28 y after immunization with the plasma-derived vaccine was only 24.95% in Long’an, Guangxi province.13 This difference was also found in a cross-sectional survey about the five surveillance sites carried in 200911 This might ascribe to some reasons. First of all, the deficiencies of vaccine implement, such as vaccine damage, vaccine freezing, on time inoculation and so on, resulted in the failure of vaccination. While, on the other hand, in China especially in Chinese underdeveloped districts, maternal-infant route accounted for the most of HBV transmission presently. Long’an county is a remote, undeveloped district in Guangxi province, the HBsAg prevalence (16.9%) was far higher than Zhengding(8.1%) in 198511 Therefore, if the baseline rate of HBsAg positivity was taken into consideration, the low rate of anti-HBs was reasonable. At the same time, a 30-year follow-up study in neonates born to HB carrier mothers also showed that 37.4% of subjects maintained anti-HBs positive at 30 y.14 In this study, we found 5.16% participants maintained anti-HBs concentrations ≥1000mIU/mL, higher than 1.05% reported by Li et al.13 which may be due to HBV natural infection (a potential natural booster), or to hepatitis B vaccine booster dose. The latter may be explained by recall bias during the investigation of booster vaccination history, so it failed to exclude the subject from the final analysis.

Hepatitis B vaccine has been used for nearly 30 y and its protective effect in the short- and medium- term has been fully recognized. However, the duration of the immunity protection of the vaccine was unknown, as well as the necessity for a booster vaccination.1519 Theoretically, anti-HBs level below 10 mIU/mL is considered as threshold for the effective protection against HBV infection. However, the individual with anti-HBs < 10 mIU/mL is not under the threat from HBV infection because of immune memory related to HBsAg.20

Studies showed that the incidence of breakthrough HBV infection (defined as HBV infection despite receiving three or more doses of hepatitis B vaccine) is low, which may be presented as anti-HBc-positive (1.0%-13.8%), transient HBsAg-positive (0.7%-5.4%) or HBV-DNA-positive (0.19%-0.9%), but few clinically significant infections diagnosed or few HBsAg carries reported.7,9,20,21 In this study, six participants were detected to be HBsAg-positive. But no new HBsAg-positive cases were discovered, and the mothers of five out of the six positive participants were also HBsAg-positive, so that the possibility was the failure to prevent mother-to-child transmission. There were several possible reasons could contribute to this failure. Firstly, the first dose was not given within 24 h; Secondly, hepatitis B immunoglobulin was not inoculated for immunoprophylaxis in these participants. Meanwhile, owing to the HBV markers had not been detected before vaccination as newborns, so that the intrauterine infection cannot be ruled out.

It was found that the average positive rate of anti-HBc was 5.90%, lower than 20.24% reported by Li,13 but both reported the increasing trend with time. Anti-HBc is traditionally recognized as an important serological marker in identifying patients infected or exposed to HBV. Momentous role of anti-HBc in occult HBV infection (OBI) has been explored widely.22 A study showed that the proportion of OBIs was 3.4% for patients with isolated anti-HBc and 4.2% for patients with both anti-HBc and anti-HBs seropositivity. Meanwhile, OBI is clearly recognized as a risk factor for cirrhosis and hepatocellular carcinoma.23 So that the clinically significant of anti-HBc could be more and more important. More studies should be taken to detect and clarify the HBV infection status in anti-HBc-positive subjects with active immunization, which would be important for the development of prevention and control measures against HBV infection.

There are couple of limitations in our study. Firstly, about 47% subjects were not catched in the last survey. Of these, around 90% of subjects emigrated. Even though, the baseline characteristics, as well as the antibody level from the first serological survey after full course between the followed and lost-to-followed groups were compared, and significant difference were not detected. Moreover, the numbers of subjects that included in the final analysis fulfilled the requirement of sample estimation. Secondly, since the experience of vaccine booster was derived from the questionnaire, there might be potential biased by the recall. However, hepatitis B is a well-known infectious disease, it had been associated with employment and marriage. As abovementioned, Zhengding is one of the five national hepatitis B study base, people’s awareness of hepatitis B and hepatitis B vaccine has been continuously strengthened by continuous research projects. To this end, the occurrence of underreported vaccine booster experience in this population seems to be less likely.

In summary, the positive rate of anti-HBs was 52.41% at 20–31 y after primary immunization with the plasma-derived hepatitis B vaccine. The positive rate of anti-HBs decreased with time. The anti-HBc positive rate was 5.90%, showing an increasing trend with the time prolonged after primary immunization. This indicates that immunity is on the wane. However, the positive rate of HBsAg was 0.63% and did not show a trend of increasing with time, and no new HBsAg-positive cases were identified.These results suggest that the protective effect of the plasma-derived hepatitis B vaccine still exists at 20–31 y after primary immunization, and booster immunization is not necessary widely. Meanwhile, immune memory induced by the plasma-derived hepatitis B vaccine needs to be further studied.

Acknowledgments

We thank the people of Zhengding County who participated in the study and the dedicated community health practitioners who made this study possible. This project titled “Study on protection conferred by hepatitis B vaccine 30 y. after initial immunization” (162777290) was supported by the Department of Science & Technology, Hebei Province.

Disclosure of potential conflicts of interest

The authors declare that they have no conflict of interest.

Authors’ Contributions

Yu-Liang Zhao, Qi Li, and Jing-Chen Ma contributed to the study’s conception and design. Zhi-Wei Wu, Hai-Song Zhou, Zhao Gao, Zhi-Yong Hao, Fei-Jin, Yan-Hong Zhang and Min-Jie Li conducted the field work. Zhi-Wei Wu, Zhi-Yong Hao, and Zhao Gao carried out the lab testing. Zhi-Wei Wu, Yu-Liang Zhao, and Jing-Chen Ma analyzed the data. Zhi-Wei Wu, and Jing-Chen Ma wrote the paper. Feng Wang, and Sheng-Li Bi provided important contributions in lab testing and the writing of the paper. All authors read and approved the final manuscript.

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Data Citations

  1. World health organization fact sheet published in July 2019. http://www.who.int/mediacentre/factsheets/fs204/en/.

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