Vaccine xxx (2018) xxx–xxx

Contents lists available at ScienceDirect

Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Antibody response to hepatitis B vaccine is independently associated

with hepatitis B breakthrough infection among adults: Results from a
three-year follow-up study in China
Li Zhang a,b,⇑, Bingyu Yan b, Jingjing Lv b, Jiaye Liu b, Wenlong Wu b, Yi Feng b, Aiqiang Xu a,b
a
Academy of Preventive Medicine, Shandong University, Jinan, China
b
Shandong Provincial Key Laboratory of Infectious Disease Control and Prevention, Shandong Center for Disease Control and Prevention, Jinan, China

a r t i c l e i n f o a b s t r a c t

Article history: Hepatitis B breakthrough infection (HBBI) and its risk factors are rarely reported among adults in China.
Received 11 December 2017 In 2009–2010 in three townships of China, hepatitis B vaccine (HepB) administration and anti-HBs detec-
Received in revised form 4 February 2018 tion after HepB were conducted among the residents aged 18–59 years. HBsAg, anti-HBs and anti-HBc
Accepted 6 February 2018
were detected for these vaccinees in 2013. A total of 252 out of 4701 vaccinees turned to be positive
Available online xxxx
for anti-HBc in 2013, but nobody was positive for HBsAg. The HBBI rate was 5.36% (95% CI 4.73, 6.04).
The highest rate was found in age-group of 18–29 years (7.33%, 95% CI: 5.31, 9.82). The rate was signif-
Keywords:
icantly different by the residential townships (P < 0.001) and by the antibody response to HepB
Hepatitis B vaccine
Hepatitis B breakthrough infection
(P = 0.003). Multivariate analysis showed that anti-HBs response to HepB was the independent risk factor
Antibody response of HBBI. The study documents the association between hyporesponse to HepB and HBBI among adults. It
Adult also suggests more attention should be given to new HBV infection among young adults.
Ó 2018 Published by Elsevier Ltd.

1. Introduction
Hepatitis B virus (HBV) infection remains an important global
public health issue, which is the leading cause of hepatocellular
carcinoma and leads to 650,000 deaths annually [1]. Hepatitis B
vaccine (HepB) is used since 1980 in the world [2]. The long-
term duration of antibody against hepatitis B surface antigen
(anti-HBs) and immune memory after HepB are documented
[3,4]. HepB immunization has achieved great succeeds in hepatitis
B control in many countries [5–7]. However, HBV breakthrough
infection including chronic infection has been reported to occur
after HepB administration [8].
HBV breakthrough infection is defined as ‘‘having HBV infection
despite receiving three or more doses of HepB” [9], which is usually
indicated by positive results of hepatitis B core antibody (anti-
HBc), hepatitis B surface antigen (HBsAg), or both among HepB
vaccinees. Among those who have completed HepB vaccination
as children or infants, the frequency of HBV breakthrough infection
was reported to be 12% in Thailand (20 years after HepB) [10], 6% in
Greenland (3–12 years after HepB) [11], 3.15% in mainland China
(1–14 years after HepB) [12], 1% in Gambia (3 years after HepB)
⇑ Corresponding author at: Shandong Center for Disease Control and Prevention,
Jinan, China.
E-mail address: ZL9127@163.com (L. Zhang).
[13] and 0.94% in Taiwan (18 years after HepB) [14]. HBV break-
through infection is also reported among adults. Acute hepatitis
B virus infection with delayed appearance of anti-HBc was
reported among an immunocompromised woman who received
HepB [15]. In an US study, 2.9% and 0.42% of homosexual men were
reported to seroconversion of anti-HBs and HBsAg respectively
within five years after HepB vaccination [8].
Anti-HBs 10 mIU/ml is usually regarded as protective level
after HepB [16]. In recent years, antibody response to HepB has
been further divided into four levels, including non-response (ant
i-HBs < 10mIU/ml), low response (10–99 mIU/ml), normal
response (100–999 mIU/ml) and high response (1000 mIU/ml)
[16,17]. Those who could not achieve normal and high response
are sometimes suggested to administrate another three doses of
HepB [17,18] because non-responders and low-responders have
been reported to be more likely to be infected by HBV [8,9,19].
Although immune response after HepB vaccination and risk factors
for HBV infection are different between children and adults, HBV
breakthrough infection among adult HepB vaccinees are not well
understood.
HBV is endemic in China and the prevalence of HBsAg was
7.18% among the general population according to the third
national serosurvey in 2006 [20]. HepB began to use in China in
1985 and was recommended to newborns in 1992 [21]. Although

https://doi.org/10.1016/j.vaccine.2018.02.039
0264-410X/Ó 2018 Published by Elsevier Ltd.

Please cite this article in press as: Zhang L et al. Antibody response to hepatitis B vaccine is independently associated with hepatitis B breakthrough infec-
tion among adults: Results from a three-year follow-up study in China. Vaccine (2018), https://doi.org/10.1016/j.vaccine.2018.02.039
2 L. Zhang et al. / Vaccine xxx (2018) xxx–xxx
great success has been achieved in HBV control among children in
the country [5,20], the prevalence of HBsAg is still high among
adults (8.57%) [20]. According to 2006 national serosurvey, the
coverage of HepB was 13.8% among population aged 15–59 years
in China [20]. To improve HepB coverage among adults, HepB
was recommended to all adults who had not completed the full
series by Chinese Center for Disease Control and Prevention
(CDC) and Chinese Preventive Medicine Association (CPMA) in
2012 [22].
We conducted this study to evaluate the frequency of HBV
breakthrough infection and its risk factors, especially antibody
response to HepB, among adult vaccinees in Chinese rural areas.
2. Methods
2.1. Study population
Shandong province is located in the east of China with the aver-
age prevalence of HBsAg of 2.49% according to the latest serosur-
vey in 2014 [23]. Zhangqiu is a city of Shandong, which has a
population of about 1.1 million. HBsAg, anti-HBs and anti-HBc
were detected among the residents who were aged 18–59 years
and had no history of hepatitis B vaccination and HBV infection
in three townships (Baiyunhu, Ningbu, Shuizai) of Zhangqiu city
during August and September of 2009. Three doses of HepB were
administrated to those who were negative for HBsAg, anti-HBs
and anti-HBc on 0–1–6 month schedule from September 2009 to
April 2010. Anti-HBs was detected one month after the third dose
and those who could not achieve anti-HBs titer above 10mIU/ml
were given another series of HepB on 0–1–6 month schedule dur-
ing June and December of 2010. Anti-HBs were also detected one
month after the second series. Those who completed one or two
series of HepB vaccination and anti-HBs detection after HepB were
involved in the study. The flow chart is shown in Fig. 1.
2.2. Questionnaire investigation
Questionnaire investigation was conducted by the staff at local
CDC when the first dose of HepB was administrated in 2009 and
when the follow-up was conducted in 2013 respectively. The stan-
dardized questionnaire was used and all investigators were trained
before interview. The basic information of the participants was col-
lected in 2009, including gender, birth date, occupation, ethnicity,
living place, history of HepB immunization and HBV infection, his-
tory of smoking and alcohol consumption. The information regard-
ing possible HBV exposure after HepB vaccination was investigated
in 2013, including having HBV infected family member, having his-
tory of possible sexual contact with HBV patients, dental treat-
ment, surgery treatment, transfusion, endoscope and
acupuncture therapy.
2.3. Specimen collection and laboratory testing
The volume of 5 ml blood sample was drawn from each partic-
ipant before HepB vaccination (in 2009), one month after vaccina-
tion (in 2010) and three years after vaccination (in 2013). All serum
specimens were stored at 20 °C at Shandong CDC before detec-
tion. For pre-vaccination samples, HBsAg and anti-HBs were
detected by enzyme-linked immunosorbent assay (ELISA, Xiamen
Xin Chuang Biotechnology Co., Ltd) and anti-HBc was detected by
Chemiluminescence Microparticle Imunoassay (CMIA, Abbott,
USA). For post-vaccination samples, all three indexes were
detected by CMIA (Abbott, USA). To decrease the rate of false pos-
itivity of anti-HBc, the blood positive for anti-HBc in the first test
was retested and a positive result was defined as being positive
Please cite this article in press as: Zhang L et al. Antibody response to hepatitis B vaccine is independently associated with hepatitis B breakthrough infec-
tion among adults: Results from a three-year follow-up study in China. Vaccine (2018), https://doi.org/10.1016/j.vaccine.2018.02.039
in both tests. All detection was conducted according to the manu-
facture’s instruction.
2.4. Statistical analyses
HBV breakthrough infection rate across different group of age,
gender, and anti-HBs level were assessed with Pearson Chi-
square test. Pairwise Comparison of HBV breakthrough infection
rate among the groups with different anti-HBs responders was
conducted by Bonferroni correction method. Multivariable logistic
regression model was built to assess the independent contribution
of different risk factors to HBV breakthrough infection. HBV break-
through infection was defined as positive result for anti-HBc with
or without positive result for HBsAg after HepB vaccination [11].
The body mass index (BMI) was categorized into three levels (nor-
mal: BMI < 24 kg/m2; overweighed: 24 kg/m2  BMI < 28 kg/m2;
and obese: BMI  28 kg/m2) based on the national data collected
in China [24]. Anti-HBs response to HepB was categorized to
non-response (anti-HBs < 10 mIU/ml), low-response (10 mIU/ml
 anti-HBs < 100 mIU/ml), normal response (100 mIU/ml  anti-H
Bs < 1000 mIU/ml) and high response (anti-HBs  1000 mIU/ml)
[25]. All analyses were conducted with SPSS 18.0. The
P value < 0.05 was considered to be statistically significant, except
that P value < 0.008 was considered to be significantly different
when pairwise comparison was performed according to the rule
of Bonferroni correction method.
2.5. Ethical concern
The protocol was approved by Shandong CDC Ethics Committee
and a written informed consent form was obtained from each par-
ticipant before investigation.
3. Results
3.1. General information of participants
A total of 6250 adults completed one or two series of HepB vac-
cination and anti-HBs detection in 2009–2010. Of them, 4701 sub-
jects (75.22%) participated in the follow-up visit in 2013 and were
involved in the final analysis. Their mean age was 39.72 ± 7.46 ye
ars at the first dose of HepB. The ratio of male to female was
0.83:1 (2129: 2572). Among them, 3932 participants (83.64%)
completed one series vaccination and 769 participants (16.36%)
completed two series. A total of 52.12% participants were resided
in Baiyun township, 40.80% in Ningbu township and 7.08% in Shui-
zai township. The non-, low-, normal- and high-responders
accounted for 3.19% (150/4701), 6.83% (321/4701), 40.25%
(1892/4701) and 49.73% (2338/4701) of the total participants
respectively. Nobody reported to have HBV infected family mem-
ber, nor did they report to have possible sexual exposure with
HBV patients, or have received dental treatment, surgery treat-
ment, transfusion, endoscope or acupuncture therapy.
3.2. HBV Breakthrough Infection Rate by Age, Sex, Living Place and
Anti-HBs Response to HepB
A total of 252 participants were tested positive for anti-HBc and
nobody was tested positive for HBsAg. The rate of breakthrough
infections was 5.36% (252/4701, 95% CI 4.73, 6.04). The highest
infection rate was found in age-group of 18–29 years (7.33%, 95%
CI: 5.31, 9.82), but the difference was not statistically significant
by age (v2 = 5.45, P = 0.167). The similar rate was observed
between males and females (v2 = 0.14, P = 0.709). The infection
rates were 6.41% (95% CI: 5.47, 7.45), 4.74% (95% CI: 3.84, 5.79)
 L. Zhang et al. / Vaccine xxx (2018) xxx–xxx 3

20118 parcipants screening for HBsAg, an-HBs and an-HBc

8431 parcipants negave 11687 parcipants posive

Excluded
for all three indexes for at least one index

6761 parcipants completed 1670 parcipants not completed

three doses of HepB and three doses of HepB or an-HBs Excluded
an-HBs detecon detecon

5025 parcipants with 1736 parcipants with non-

normal and high response or low-response

1225 parcipants completed 511 parcipants not

the second series of HepB completed the second series Excluded
and an-HBs detecon of HepB and an-HBs
detecon

6250 parcipants involved in the study

Fig. 1. The flow chart of study population. HBsAg: hepatitis B surface antigen; anti-HBs: antibody against hepatitis B surface antigen; anti-HBc: antibody against hepatitis B
core antigen; non-response: anti-HBs < 10 mIU/ml; low-response: 10 mIU/ml  anti-HBs < 100 mIU/ml; normal-response: 100 mIU/ml  anti-HBs < 1000 mIU/ml; high-
response: anti-HBs  1000 mIU/ml.

and 1.20% (95% CI: 0.33, 3.05) among participants resided in Baiyun
township, Ningbu township and Shuizai township respectively and
the difference was significant (v2 = 18.09, P < 0.001). The details
are shown in Table 1.
The breakthrough infection rate was 12.00% (95% CI: 7.27–
18.30), 4.67% (95% CI: 2.64, 7.59), 4.60% (95% CI: 3.70, 5.64) and
5.65% (95% CI: 4.74, 6.66) among non-responders, low-
responders, normal-responders and high-responders respectively
and the difference was significant (v2 = 16.22, P = 0.003). Pairwise
comparison showed that the breakthrough infection rate was
much higher among non-responders than among low-responders,
normal-responders and high- responders (v2 = 8.42, 15.61, 10.04;

Table 1
Prevalence of HBV breakthrough infection rate among adult hepatitis B vaccinees by age, sex and living place.

Number detected Number with breakthrough infection Infection rate (%, 95% CI) v2 P value
Total 4701 252 5.36 (4.73, 6.04)
Age (years)
18–29 559 41 7.33 (5.31, 9.82) 5.45 0.167
30–39 1352 74 5.47 (4.32, 6.82)
40–49 2683 132 4.92 (4.13, 5.81)
50–59 107 5 4.67 (1.53, 10.57)
Gender
Male 2129 117 5.50 (4.56, 6.55) 0.14 0.709
Female 2572 135 5.25 (4.42, 6.18)
Living place
Baiyun 2450 157 6.41 (5.47, 7.45) 18.09 <0.001
Ningbu 1918 91 4.74 (3.84, 5.79)
Shuizai 333 4 1.20 (0.33, 3.05)

Please cite this article in press as: Zhang L et al. Antibody response to hepatitis B vaccine is independently associated with hepatitis B breakthrough infec-
tion among adults: Results from a three-year follow-up study in China. Vaccine (2018), https://doi.org/10.1016/j.vaccine.2018.02.039
4 L. Zhang et al. / Vaccine xxx (2018) xxx–xxx

P = 0.004, <0.001, =0.002), but no significant difference was found 14.00

Breakthrougn infecon rate (%)

in breakthrough infection rate among the other three groups 12.00
(v2 = 0.003, 0.512, 2.338; P = 0.953, 0.474, 0.126). The details are
10.00
shown in Table 2 and Fig. 2.
The infection rate in participants with only one series (5.93%, 8.00
95% CI: 5.19, 6.74) was similar with the rate in participants with 6.00
two series (4.34%, 95% CI: 2.99, 6.07), (v2 = 2.607, P = 0.106). The 4.00
breakthrough infection rate was higher in two-series group than
2.00
in one-series group among non-responders, low-responders and
normal-responders, and was similar among high-responders, but 0.00

10000
1000
1200
1400
1600
1800
2000
2500
3000
4000
5000
6000
7000
8000
9000
100
200
300
400
500
600
700
800
900
10
all differences were not statistically significant (all P > 0.05). The
details are shown in Table 3. An-HBs ter (mIU/ml)

3.3. Multivariable analysis of risk factors associated with HBV Fig. 2. HBV breakthrough infection rate among adult hepatitis B vaccinees in 3-year
follow-up by anti-HBs titer one month after hepatitis B vaccination.
breakthrough infection

Multivariable analysis showed that the living place and anti-

HBs response to HepB were the independent risk factors of HBV
breakthrough infection. Residing in Shuizai township decreased
the risk of HBV breakthrough infection when compared with
Baiyun township [OR (95% CI): 0.26 (0.10–0.73), P = 0.010], and
non-responders had the higher risk of breakthrough infection than
low-responders [OR (95% CI): 2.89(1.40, 5.96), P = 0.004]. We did
not find hepatitis B doses (one series or two series) was indepen-
dent associated with breakthrough infection rate (P = 0.470). We
did not find the deference in HBV infection rate between low-
responders and normal-responders (P = 0.956) and between low-
responders and high-responders (P = 0.523). The details are shown
in Table 4.
3.4. Natural booster by HBV breakthrough infection
A total of 55 participants with HBV breakthrough infection were
found to have higher anti-HBs titer at follow-up when compared
with the titer one month after HepB vaccination, accounting for
21.82% (55/252) of participants with breakthrough infections and
1.17% (55/4701) of the total participants. Among the participants
with breakthrough infection, the anti-HBs titer at following was
60.31 mIU/ml, 34.47 mIU/ml, 77.51 mIU/ml, and 76.92 mIU/ml
among non-, low-, normal- and high-responders respectively
(F = 0.52, P = 0.67). The corresponding positive rate of anti-HBs
was 66.67%, 73.33%, 72.41% and 78.79% (v2 = 13.56, P = 0.14). The
details are shown in Table 5.
4. Discussion
Our results documented the widespread existence of HBV
breakthrough infection among adults in Chinese rural areas. HBV
breakthrough infection was found among 5% adult general popula-
tion after HepB vaccination, the proportion is higher than that in
children <15 years of age in the country (3%) [12]. It is known that
approximately 5% adults would turn to chronic patients after HBV
infection [2]. However, 252 participants were found to have HBV
infection after HepB vaccination in the present study, while
nobody was found to be positive for HBsAg, which might indicate
the role of HepB vaccination.
Although we did not find the significant difference in HBV infec-
tion rate by age group, our study showed the trend that the young
adults aged 18–29 years might undergo high risk of HBV break-
through infection. According to the fourth national serosurvey of
hepatitis B in China in 2014, the peak prevalence of both HBsAg
and anti-HBc was at age-group of 20–29 years and a rapid increase
of HBsAg and anti-HBc prevalence was also found in this age-group
[5,23]. HIV infection has been reported to increase sharply among
young adults in China in recent years [23], which shared the sim-
ilar transmission mode (blood and sex) with HBV. More attention
should be taken on the newly infection of diseases transmitted
by sex or blood among the youngsters in China.
Our study documented the association between high rate of
HBV breakthrough infection and lack of anti-HBs response to HepB
among adults, which is in accordance with Hadler SC’s study [8]
and Whittle HC’s study [19]. Although HepB was documented to
induce good antibody response among adults, approximately 10%
adult vaccinees could not achieve anti-HBs above protective level
(10 mIU/ml) after one or two series of HepB vaccination [26,27].
As the results, post-vaccination testing of anti-HBs should be rec-
ommended to adult HepB vaccinees who are under high risk of
HBV infection as suggested by World Health Organization [2].
Given our study found the higher breakthrough infection rate in
non-responder, we think all adult HepB vaccinees should be tested
for anti-HBs response after HepB so long as they could afford it.
In the practice of HepB vaccination, low-responders were usu-
ally suggested to receive another dose to avoid higher risk of
HBV breakthrough infection [17,18]. In the study by Hadler SC,
the rate of HBV infection was 16.7%, 8.9%, 8.9%, 2.7% and 0.74%
among the homosexual men whose anti-HBs were 0, 2.1–9.9,
10–49, 50–59 and >100 sample ratio unites (SRU) respectively

Table 2
HBV breakthrough infection rate by anti-HBs response to hepatitis B vaccination.

Anti-HBs response Number detected Number with breakthrough infection Infection rate (%, 95% CI) v2 P value
Non-response (group 1) 150 18 12.00 (7.27, 18.30) 16.22 0.003
Low-response (group 2) 321 15 4.67 (2.64, 7.59)
Normal response (group 3) 1892 87 4.60 (3.70, 5.64)
High response (group 4) 2338 132 5.65 (4.74, 6.66)
Group 1 vs 2 8.424 0.004
Group 1 vs 3 15.610 <0.001
Group 1 vs 4 10.045 0.002
Group 2 vs 3 0.003 0.953
Group 2 vs 4 0.512 0.474
Group 3 vs 4 2.338 0.126

Please cite this article in press as: Zhang L et al. Antibody response to hepatitis B vaccine is independently associated with hepatitis B breakthrough infec-
tion among adults: Results from a three-year follow-up study in China. Vaccine (2018), https://doi.org/10.1016/j.vaccine.2018.02.039
 L. Zhang et al. / Vaccine xxx (2018) xxx–xxx 5

Table 3
HBV breakthrough infection rate between one-series group and two-series group by anti-HBs response.

Anti-HBs response Complete only one series Complete two series v2 P value
Number detected Number with HBV infection Infection rate Number detected Number with Infection rate
(%, 95% CI) HBV infection (%, 95% CI)
Total 3932 220 5.93 (5.19, 6.74) 769 32 4.34 (2.99, 6.07) 2.607 0.106
Non-response 117 16 15.84 (9.33, 24.45) 33 2 6.45 (0.79, 21.42) 1.155 0.282
Low-response 184 11 6.36 (3.22, 11.09) 137 4 3.01 (0.83, 7.52) 1.509 0.219
Normal-response 1559 77 5.20 (4.12, 6.45) 333 10 3.10 (1.49, 5.62) 2.164 0.141
High-response 2072 116 5.93 (4.92, 7.07) 266 16 6.40 (3.70, 10.19) 0.068 0.794

Table 4 homosexual men while our study was in the general population,
Multi-variate analysis of risk factors associated with hepatitis B breakthrough while the antibody response after HepB vaccination [8,28] and risk
infection.
factors for HBV infection [28] were reported to be difference
Variable OR (95% CI) Z P>z between them. The further studies should be carried out to docu-
Gender ment it.
Male Ref. The possible route of HBV infection was investigated in our
Female 0.93 (0.68, 1.26) 0.48 0.630 study, while no participants reported to have exposed to HBV by
Age (yrs)a household contact, sexual contact and other routes including den-
18–29 Ref. tal treatment, surgery treatment, transfusion, endoscope or
30–39 0.81 (0.54, 1.20) 1.05 0.293
acupuncture therapy, no matter in HBV-infection group or in those
40–49 0.73 (0.50, 1.06) 1.65 0.098
50–59 0.89 (0.33, 2.36) 0.24 0.807 without HBV infection. The results might be due to the following
reasons. First, the discrimination against hepatitis B patients is still
Living placea
Ningbu village Ref. serious in China [29]. The persons with HBV family members usu-
Baiyun village 1.34 (0.99, 1.82) 1.90 0.057 ally would not attend HBV studies to avoid being asked about the
Shuizhai village 0.26 (0.10, 0.73) 2.57 0.010 family contact. Second, most of our participants are farmers who
BMI (kg/m2)a are relatively poor and usually take less care of their health. They
<24 Ref. usually would not go to the hospital if they could endure the pain.
24–27 0.79 (0.60, 1.05) 1.63 0.103 Third, Chinese persons are usually shy to talk about sex, especially
28 0.90 (0.53, 1.54) 0.39 0.697
out-of-wedlock sex contact, which might hide the real difference
Smoking historya between the participants with and without breakthrough infection.
Yes Ref.
Smoking cessation 1.74 (0.65, 4.66) 1.09 0.275
Risk factors for new HBV infection are important for policy-making
Never 1.18 (0.71, 1.94) 0.63 0.528 and further studies should be conducted regarding it.
Drink historya
Natural booster after HBV infection is helpful to keep long-term
Yes Ref. immunity in HBV endemic areas [10]. According to a 20-year
Abstinence 0.89 (0.56, 1.40) 0.52 0.606 follow-up study, natural booster response of anti-HBs was
Never 0.74 (0.38, 1.45) 0.88 0.380 observed in 5% (11/222) participants who completed HepB primary
Anti-HBs response to hepatitis B vaccine vaccination as infants [10]. In our study, 1% participants with HBV
Non-response 2.89 (1.40, 5.96) 2.87 0.004 breakthrough infection showed increase in anti-HBs concentration
Low-response Ref. – –
three years after HepB vaccination, indicating anti-HBs booster
Normal-response 0.98 (0.56, 1.74) 0.06 0.956
High-response 1.20 (0.68, 2.11) 0.64 0.523 response, which is lower than the result in the above study. Not
all participants with HBV breakthrough infection showed anti-
Hepatitis B doses
One series Ref. HBs increases in our study. It might be due to the rapid decreasing
Two series 0.86 (0.58, 1.28) 0.72 0.470 of anti-HBs concentration after booster response [10]. In our study,
a blood samples positive for anti-HBc have been tested for two times
The value wasmeasured when the first dose of hepatitis B vaccine was
administrated. and only those who were positive for both tests were defined as
positive samples, which could decrease the false positive or incor-
rect testing result effectively. Therefore, false positive or incorrect
[8], indicating the relatively higher infection rate in low- testing result might not be the main reason for the fact that anti-
responders than the normal- and high-responders. However, we HBs titer did not increase in some participants with HBV break-
did not find higher risk of HBV breakthrough infection among through infection.
low-responders, normal-responders and high-responders. The It would be noticed that both the proportion of participants and
reason might lie in that Hadler SC’s study was conducted in the the breakthrough infection rate are much lower in Shuizai town-

Table 5
Anti-HBs titer three years after hepatitis B vaccination by antibody response to hepatitis B vaccine.

Anti-HBs titer after HepB (mIU/ml) Anti-HBs titer at follow-up (mIU/ml)

<10 10–99 100–999 1000 Total
<10 6 (33.33) 3 (16.67) 8 (44.44) 1 (5.56) 18 (100.00)
10–99 4 (26.67) 8 (53.33) 3 (20.00) 0 (0.00) 15 (100.00)
100–999 24 (27.59) 21 (24.14) 26 (29.89) 16 (18.39) 87 (100.00)
1000 28 (21.21) 47 (35.61) 35 (26.52) 22 (16.67) 132 (100.00)
Total 62 (24.60) 79 (31.35) 72 (28.57) 39 (15.48) 252 (100.00)

Please cite this article in press as: Zhang L et al. Antibody response to hepatitis B vaccine is independently associated with hepatitis B breakthrough infec-
tion among adults: Results from a three-year follow-up study in China. Vaccine (2018), https://doi.org/10.1016/j.vaccine.2018.02.039
6 L. Zhang et al. / Vaccine xxx (2018) xxx–xxx
ship than in the other two townships. A rumor that the blood
samples collected in this study would be sold spread in Shuizai,
which caused a panic and the decline to the study in the residents.
The participants from this township might be more healthy and
strong to neglect this rumor, which might be the reason for the
low breakthrough rate in Shuizai. The reason should be further
studied.
There are some limitations in our study. First, approximately
25% subjects have been lost in our study, which might mainly be
due to population floating. The participants in our study are adults
living in Chinese rural area, who often leave their hometown and
work in the urban areas to earn more money. Second, some per-
sons at high risk of HBV infection such as those with HBV infected
family member are not involved in the study, which might under-
estimate the prevalence of breakthrough infection among adults.
In conclusion, HBV breakthrough infection could occur among
adult HepB vaccinees. Non-response to HepB might play an impor-
tant role in HBV breakthrough infection and the difference in
breakthrough infection rate among low-responders, normal-
responders and high-responders should be further studies.
Although no significant difference in the rate of breakthrough
infection was found by age in our study, new HBV infection among
young adults should be taken more attention and further studies
should be conducted regarding it.
Acknowledgments
We thank our colleagues at Zhangqiu county CDC for their help in
questionnaire survey and blood collection.
Funding
This work was supported by the grants from the Major Project
of National Science and Technology (No. 2013ZX10004902),
Taishan Scholar Program of Shandong Province (No. ts20151105)
and the Shandong Medical Health Science and Technology
Development Program (No. 2011HD006, 2014WS0373). The
funders had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
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