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OPEN Immune Persistence After

Infant Hepatitis-B Vaccination:
A Systematic Review and Meta-
Received: 16 March 2017
Accepted: 27 July 2018 Analysis
Published: xx xx xxxx
Sajid Mahmood1, Kifayat Ullah Shah1 & Tahir Mehmood Khan 2,3

A systematic review was performed to estimate the duration of protection of Hepatitis-B vaccine after
primary vaccination during infancy. The number of seropositive participants with anti-HBs antibody
titer ≥ 10 mIU/ml and seronegative participants who had anti-HBs antibody titer ≤ 10 mIU/ml after
booster dose was the main outcome criteria to find out the protection time of Hepatitis-B vaccine.
Twelve studies were selected for systematic review. Overall, results from the meta-analysis have
revealed that the risk of Anti-HBs Titer ≤ 10 mIU/ml reduced by 50%. Upon performing the sub-group
analysis it was revealed that the overall risk of having Anti-HBs Titre ≤ 10 mIU/ml was reduced up to
62% among the subjects age 21–30 years (0.38 [0.34, 0.44]; I2 = 0.0%, p = 0.938). Furthermore, it was
observed that the risk of having titre level less than 10 mIU/ml for plasma derived vaccines were to be
56% [0.44, CI 0.33–0.57, I2 90.9%, p = <0.001]. Vaccination in early infancy does not ensure protection
against Hepatitis-B infection. There is a strong correlation between the duration of protection and time
elapsed after primary immunization during infancy.

Hepatitis-B is a serious health problem worldwide. According to World Health Organization (WHO) in year 2016
about 240 million people were infected with Hepatitis-B1, and about 686,000 death were reported2,3. Countries
with the highest disease burden are China, Indonesia, Nigeria, parts of Africa and Asia4,5. Norway and United
Kingdom are observed to be the countries with the prevalence of hepatitis-B, as low as 0.01%, while the highest
prevalence is observed in Sudan where it is up to 22.70%6.
In South Asia the prevalence rate of chronic Hepatitis-B is 2–5%1. A decrease in hepatitis-B prevalence has
been seen in countries where routine immunization plan have been implemented7.
Vaccination with Hepatitis-B has been considered as a very important tool for protection against HBV infec-
tion8. The protective response to Hepatitis-B vaccine is quantified by measuring anti-HBS level in 6–8 weeks after
vaccination, for successful immunization the anti-HBS level should be greater than 10 mIU/ml. According to
WHO the Hepatitis-B vaccination should produce the protective level of antibodies in ≥95% of the individuals
after completion of the recommended vaccination schedule9. However, in some cases primary and secondary
vaccination failure led to occurrence of hepatitis B infection among the individual. When the Infections occur in
short time after the vaccination, it is termed as primary vaccination failures. However, in the case when there is
loss of seroprotective response that is termed as secondary vaccination failure due to loss of immunity10, which
is due to decline in the immunological memory which wane over time11. The individual whose anti-HBS level
falls below 10 mIU/ml is not protected anymore. However the individual is not under the threat from hepatic
disease because of immune memory related to Hepatitis-B surface antigen (HBsAg). The specific memory after
Hepatitis-B vaccination is due to an anamnestic anti-HBs response after booster dose of vaccine. The booster
dose lead to spontaneous rise in anti-HBs level in the population who have completed their initial vaccination
series12,13. According to European consensus group on Hepatitis-B immunity the duration of protection among
fully vaccinated children is 15 years12.

1
Faculty of Pharmacy, Quaid-e-Azam University, Islamabad, 45320, Pakistan. 2School of Pharmacy, Monash
University, Bandar Sunway, 45700, Selangor, Malaysia. 3The Institute of Pharmaceutical Sciences (IPS), University
of Veterinary & Animal Sciences (UVAS), Outfall road, Lahore, Pakistan. Correspondence and requests for materials
should be addressed to K.U.S. (email: [email protected]) or T.M.K. (email: [email protected])

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The protection period of Hepatitis-B vaccine (either derived from plasma or recombinant vaccine) is not
well understood8,14–16. According to WHO global immunization coverage data sheet 2014 highest coverage for
Hepatitis-B vaccine is seen in western pacific where it is estimated to be 92%,while lowest is 10% in African
region.

Study Question and Aim

The duration of protection of Hepatitis-B vaccine is still variable and a very limited data is available on this topic
especially in developing countries. Most regions/countries have different vaccination schedule, this results in fail-
ure to develop the policies and procedures to control the spread of Hepatitis-B in the world, particularly in under
developed countries. Currently available vaccines are highly safe and effective but the available data shows that
antibody titer declines with time17,18. Secondary vaccination failure is one of the main concern for the most of the
policy makers in order to ensure the decline in mortality and morbidity of.
Therefore, this systematic review aims at assessing the duration of protection of Hepatitis-B vaccine after
primary vaccination during infancy/childhood as well as the need for booster dose in case the antibody titer is
below immunoprotection level. Findings in this regard will assist the policy makers to develop guidelines for
booster dose.

Method
A systematic review of the scientific literature was performed. All studies published from 1st Jan 2000 till 31st
December 2016 was assessed for potential inclusion in this systematic review.

Search Strategy. The syntax used for literature survey is Immune Memory OR immunopersistence AND
Hepatitis-B AND Vaccine OR vaccination OR Immunization AND infants OR newborn OR birth OR cohort.
The relevant studies were identified through Pubmed, Medline, Embase, Google Scholar and Cochrane Library.
Population, intervention, comparator and outcomes
Population = Seronegative children/adults
Intervention = Hepatitis-B vaccine
Comparator = None
Outcome = The outcomes studied in this systematic review include the percentage of the children/adults with
antibody titer ≥10 mIU/ml and percentage of seronegative children/adults who have seroprotective antibody
titer ≥10 mIU/ml in response to single booster dose. In addition, continuous data i.e. antibody titer, standard
deviation and number patients before and after the booster dose will also be extracted to estimate the differences
in the titer before and after vaccination.

Inclusion Exclusion Criteria. All observational studies reporting the antibody titer after primary vaccina-
tion with Hepatitis-B vaccine during infancy with or without the information regarding the administration of
booster dose were included for further assessment.
We excluded all case studies/reports, letter to the editors, review papers, personal opinions or any other type
of study with inconsistent data or not reporting original data. Similarly the studies were excluded if primary
vaccination was done six months after birth. All studies with follow up duration less than two years were also
excluded. Studies were excluded if the booster dose was administered between the primary vaccination series and
follow up study.

Data extraction. The titles, abstracts and the contents of the study were reviewed according to our inclusion
and exclusion criteria. Any question/concern regarding the selection of articles was settled through consensus.
The data collected was Name of investigator, Country of study, Year of study, Study population, No. of patients
with Hepatitis-B antibody titer ≥ 10 mIU/ml, No. of patients with Hepatitis-B antibody titer ≥ 10 mIU/ml after
booster dose, Vaccine type, Dosage of vaccine and Dosage schedule. Two investigators independently evaluated
the identified research studies and extracted the relevant outcomes of the studies. The outcomes of the studies
were extracted by using the data extraction table especially designed for this purpose (Table 1). Any confusion
regarding the results of selected study was resolved through mutual consensus.

Data analysis. ®
Meta-analysis was carried out by using STATA version 14.3 . Risk ratios were estimated
using random effect model. The binary data was analyzed to estimate the risk of having Hepatitis-B antibody
titer ≥ 10 mIU/ml after booster dose. Subgroup analysis was performed to address heterogeneity. Age and type of
vaccines were used as the grouping variables. Tau2 was used to interpret the heterogeneity at a confidence inter-
val of 95%. In addition, quality of studies was also performed using New Castel Ottawa scale for observational
studies.

Results
A total of N = 576 studies were identified for the initial assessment and potential inclusion in this systematic
review. Upon applying the inclusion criteria n = 12 studies were eligible for the qualitative synthesis. Upon
screening the extracted data, n = 6 studies were selected for the meta-analysis. Details illustration of the screen-
ing the selected articles are shown in the Fig. 1.

Persistence of seroprotective Anti-HBs Titer. A total of N = 5805 patients were presented across the
twelve studies8,19–29. Only six studies have reported the anti HBS titer after booster dose of hepatitis-B vaccine,
with a follow up of two years8,19,20,22,25,26. A single booster dose of vaccine was administered only to those par-
ticipants who had antibody titer ≤ 10 mIU/ml at the time of follow up, antibody titer was again determined
one month after challenge dose. However Su et al. administered two subsequent booster doses of Hepatitis-B

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Age at Anti-HBS Vaccination

Country of Year of Follow up Study Patients with anti- antibody Titer Dosage of Schedule 1 s
Authors Study Study Design Study (Years) Population HBS ≥ 10 mIU/ml After Boosting Vaccine Type Vaccine 2nd 3rd
Vaccinated at 06
Bruce et al. Alaska Prospective Cohort 2011 30 243 51% 88% Plasma Derived Standard
months age.
Randomized
Wu et al. China placebo controlled 2010 23 126 48.1% 84% Plasma Derived Standard 00 01 06
cohort
Poovorawan
Thailand Cohort Study 2009 20 109 60.5% 83.9% Recombinant Standard 00 01/02 12
et al.
Al-Ghamdi Cross Sectional
Saudi Arabia 2012 20 238 58.8% Not Specified Standard
et al. Cohort Study
Cross Sectional
Su et al. Taiwan 2012 18 1734 35.9% 95% Plasma Derived Standard 01 02 12
Study
Cross Sectional
Al Faleh et al. Saudi Arabia 2008 18 1355 38.0% Not Specified Recombinant Standard 00 01 06
Study
Spada et al. Italy Follow up Study 2010 17 571 72.9% Not Specified Standard
Middleman Cross Sectional
U.S.A 2014 16–19 420 24.0% 92% Recombinant Standard 00 01 12
et al. Study
Avidoca et al. Slovakia Longitudinal Study 2010 10–11 31 48.4% 96% Standard 03 05 12
Cross Sectional
Gold et al. Israel 2000 08 122 77.1% Not Specified Recombinant Standard 00 01 06
Study
Tsega et al. Ethiopia Longitudinal Study 2010 05 314 89% Not Specified Recombinant Standard 00 01 06
97% (Children) 82%
Amini et al. Iran Longitudinal Study 1999 02 542 Not Specified Recombinant Standard 00 01 06
(Adults)

Table 1. Anti-HBs Titer ≥ 10 mIU/ml before and after Booster Dose.

Figure 1. PRISMA 2009 Flow Diagram.

vaccine. Second booster dose was administered six months after the first dose, if the participant had ant-HBV
titer ≤ 10 mIU/ml after the first challenge dose. Anti-HBV antibody titer was again determined one month after
the second challenge dose22. An increase in anti HBS titer ≥ 10 mIU/ml after booster dose ranging from 23.4%
to 68.0% of participants than the anti HBS titer before booster dose. Details are given in Table 1. Among the
eligible studies one was randomized placebo controlled study19, one study was Phase-4 Open follow up and
Challenge Study26, three were Cohort Studies8,20,21. Three were follow up studies24,28,29 four were cross sectional
studies22,23,25,27.

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Selection Outcomes
Authors/ Representative of Selection of Non- Ascertainment of Outcomes not Assessment of Sufficient Follow Adequate Total
reference Exposed Cohort Exposed Cohort Exposure Present at Baseline Comparability Outcomes up Duration Follow up Score
Bruce et al. 1 0 1 1 2 1 1 1 8
Wu et al. 1 0 1 1 1 1 1 1 7
Poovorawan et al. 1 0 1 1 2 1 1 1 8
Al-Ghamdi et al. 1 0 1 1 1 1 1 1 7
Su et al. 1 0 1 1 1 1 1 1 7
Al Faleh et al. 1 0 1 1 1 1 1 1 7
Spada et al. 1 0 1 1 2 1 1 1 8
Middleman et al. 1 0 1 1 2 1 1 1 8
Avidoca et al. 1 0 1 1 2 1 1 1 8
Gold et al. 1 0 1 1 2 1 1 1 8
Tsega et al. 1 0 1 1 1 1 1 1 7
Amini et al. 1 0 1 1 1 1 1 1 7

Table 2. Quality assessment using New Castel Ottawa Scale.

All participants of the study were fully immunized during infancy with either recombinant or plasma derived
hepatitis-B vaccine. Bruce et al. in a long term prospective cohort study conducted in Alaska, data was collected
after thirty years of the primary vaccination with plasma derived vaccine on 243 participants. Of whom 51%
of the participants has anti-HBs titer above seroprotection level (titer ≥ 10 mIU/ml)8. In a randomized pla-
cebo controlled trial cohort study conducted in China on 126 persons immunized with plasma derived vaccine
during infancy it was observed that 48.1% of subjects were seroprotective with an antibody titer ≥ 10 mIU/ml
after 23 years19. In a cohort study conducted in Thailand by Poovorawan et al. reported data of 109 participants
with recombinant Hepatitis-B vaccine, of whom 60.5% of participants were maintained with the seroprotective
level of Anti-HBs anti-bodies20. Al-Ghamidi et al. reported data of 238 participants from a cross sectional study
conducted in Saudi Arabia, it was observed that 58.8% participants were seroprotected after twenty years after
primary vaccination with recombinant hepatitis-B vaccine21. During an eighteen years cross sectional study in
Taiwan on 1734 participants, only 35.9% of participants were seroprotected22. In eighteen years cross sectional
cohort study in Saudi Arabia by Al-Faleh et al. on 1355 participants, only 38% of the participant had seropro-
tective anti-HBs tier ≥ 10 mIU/ml23. Spada et al. conducted a 17 years follow up study on 571 participants in
Italy and noticed that 72.9% of participants were seroprotected24. In a recent cross sectional study conducted
by Middleman et al. in USA among 420 Participants, of whom only 24% of the participants were seroprotected,
16–19 years after primary vaccination with Recombinant Hepatitis-B vaccine during infancy25. In an eleven years
phase-4 open follow up and challenge study on 31 participants in Slovakia by Avidoca et al., the seroprotection
level was to be 48.4%26. Gold et al. in a cross sectional study in Israel found that 77.1% of the participants were
seropotected27. Tsega et al. in a follow up study carried out five years after primary vaccination with recombinant
Hepatitis-B vaccine in Ethiopia revealed that 89% of participants were still seroprotected28. In a two years follow
up study conducted by Amini et al. in Iran on 542 participants establish that 97% of the participants had anti-HBs
titer ≥ 10 mIU/ml after primary immunization with recombinant Hepatitis-B vaccine during infancy29.

Response to Booster Dose. The antibody titer ≤ 10 mIU/ml does not always means the loss of immunity
because the vaccine protection persists beyond the time during which antibody titer is above seroprotective level.
The rise in anti-HBs titer above seroprotection level after the booster dose means that anamnestic response to
vaccine still persists30. For example, results Bruce et al. revealed that Anti-HBs antibody titer above seroprotection
level raised from 51% to 88% after booster dose which shows that immune memory still persists even though
the Anti-HBs level is below seroprotection level8. Similarly in the randomized placebo controlled trial cohort
study carried out by Qian Wu et al. the number of seroprotected individuals rise from 48.1% to 84% after booster
dose19. Poovorawan et al. in a cohort study in Thailand observed that number of seroprotected individuals rose
from 60.5% to 83.9% after a single booster dose20. Su et al. in across sectional study in Taiwan observed a rise in
Anti-HBs level above seroprotection level from 35.9% to 95% after booster dose which shows the persistence of
immune memory22. Middleman et al. in a cross sectional study conducted in USA observed an increase in the
number of seroprotected individuals from 24% to 92% after single booster dose25. Avidoca et al. in a phase-4 open
follow up and challenge study in Slovakia observed that the number of seroprotected individuals rose from 48.4%
to 96% showing the persistence of immune memory Eleven years after primary vaccination during infancy26.

Quality of studies. All the studies included in this systematic review were observational studies. New castle
Ottawa scale was used to estimate the quality. Overall most studies were of good quality with a NOS score ranging
from 7 to 8. Details are shown in Table 2.

Meta-analysis for the post booster titer comparison. Quantitative data from six studies were con-
sidered suitable for the Meta-analysis. Number of subjects with Anti-HBs Titer ≥ 10 mIU/ml before and after
the booster dose was used to estimate the overall effect of the booster dose. Upon initial analysis it was revealed
that after receiving the booster dose the risk of having Anti-HBs Titer ≤ 10 mIU/ml reduced by 50% [RR 0.50, CI

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Figure 2. Number of subjects with Anti-HBs Titer ≥ 10 mIU/ml before and after the booster dose.

Figure 3. Number of subjects with Anti-HBs Titer ≥ 10 mIU/ml before and after the booster dose using age as
the grouping variable.

0.40–0.63, I2 88.9%, Tau2 0.0608, p = <0.001] after receiving the booster dose. The decline in the risk of having
Anti-HBs Titer ≤ 10 mIU/ml was variable across all studies, ranging from 17% to 62%. The decline in risk was
highest for the study by Bruce et al. (2011) and Qian Wu et al. (2010) details are shown in Fig. 2.
Keeping in view the heterogeneity subgroups analysis was performed using age group 10–20 years and 21–30
years respectively. Four studies have recruited subjects from the age of 10–20 years upon receiving the booster
dose20,22,25,26. While only two studies were from the age group 21–30 years8,19. Upon performing the sub-group
analysis it was revealed that the overall risk of having Anti-HBs Titer ≤ 10 mIU/ml was reduced up to 42% among
the subjects age 10–20 years (0.0.58 [0.44, 0.76]). However, heterogeneity was still 86.5%, while for the age 21–30
years were observed to have 62% decline in the risk of having Anti-HBs Titer ≤ 10 mIU/ml (0.38 [0.34, 0.44];
I2 = 0.0%, p = 0.938), In addition, all the studies from the subgroup of 10–20 years of age have adapted a 12 month
vaccination schedule in comparison to the 21–30 years of age group who adapted a 6 month vaccination schedule.
Details are shown in Fig. 3. Furthermore, it was also observed that the risk of having titer level less than 10 mIU/ml
was 39% (RR 0.61 CI 95% 0.36–1.04) less in the recombinant vaccines than the plasma derived vaccines. It is
observed that the risk of having titer level less than 10 mIU/ml for plasma derived vaccines were to be 56% [0.44,
CI 0.33–0.57, I2 90.9%, p = <0.001]. Details are shown in the Fig. 4.

Discussion
The current systematic review is perhaps the first to explore the dosing frequency impact on the anti-HBs anti-
body titer. Anti-HBs antibody titer ≥ 10 mIU/ml and response to booster dose are considered as protection
markers against Hepatitis-B infection. Overall, results from the meta-analysis have revealed that the risk of
Anti-HBs Titer ≤ 10 mIU/ml reduced by 50%. In addition it was observed that likelihood of the having Anti-HBs

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Figure 4. Anti-HBs Titer ≥ 10 mIU/ml before and after the booster dose using types of vaccines as a grouping
variable.

Titer ≤ 10 mIU/ml reduced by 42% among the subjects age 10–20 years (0.58 [0.44, 0.76]. Furthermore, with
the use of plasma derived vaccines the risk of having Anti-HBs Titer ≤ 10 mIU/ml reduced by 56%. In the stud-
ies referred above the protective antibody concentration decreases with time since primary vaccination and
booster dose is required to keep antibody titer above seroprotective level. A decrease in anamnestic response
has been observed after twenty years of primary vaccination. The response to booster dose decreases with age.
This decrease in vaccine protection level is accelerated by vaccination with lower vaccine dose than currently
recommended dose at the time of primary vaccination. Therefore without the administration of booster dose the
duration of protection in fully vaccinated individuals remains under question.
Data studied for review reveals that after two years of primary vaccination more than 95% of individuals were
seroprotected with anti-HBs level ≥ 10 mIU/ml. The level of protection continue to decrease with passage of time
as after five years of primary vaccination only 80–90% individuals were found to be seroprotected with anti-HBs
level more than 10 mIU/ml. This protection level drops further to 70% ten years after primary vaccination with
Hepatitis-B vaccine. Booster dose presents viral challenge in previously immunized individuals which result in
spontaneous rise in anti-HBs antibody level due to immunological memory. This rise in antibody level suggests
that there is no need for booster dose administration. From the data it is evident that no booster dose is required
until 10 years after primary vaccination with Hepatitis-B vaccine.
Limited data is available on duration of protection in adults after the primary vaccination during infancy. Several
studies in high risk population show the persistence of immunological memory for as much as 12 years after primary
vaccination. Studies on duration of action of Hepatitis-B vaccine is important for healthcare authorities in order to plan
for the immunization programs and to make booster dose policy. Lower dose of vaccine and the gap between two con-
secutive doses seem to be contributing factors in the duration of protection of Hepatitis-B vaccine. The individuals who
received the primary vaccination during infancy are better protected. The differences between recombinant vaccine and
plasma derived vaccine are also under debate in many countries which require further investigations. No connection
is found between the endemic status of the region and duration of protection. The persistence of vaccine immunity
requires further studies because large scale seroepidemiological studies in adults are still not been conducted, who
are born after the implementation of Hepatitis-B vaccination program. The studies in different ethnic populations are
required to determine that same observations are replicable in other ethnic populations as well.

Limitations
A higher heterogeneity among the studies is one of the main issues that should be kept in view while interpreting
the results of the meta-analysis. The heterogeneity among the studies was not statistical and can be due to the
clinical and demographics related factors among the participants from the included studies. Secondly we did not
investigate the data on duration of protection of Hepatitis-B vaccine in children born with Hepatitis B antigen
carrier mothers. The effects of under dose of vaccine and gap between the last dose and the preceding dose during
primary vaccination should also be studied for the duration of protection of Hepatitis-B vaccine. Finally the entire
analysis was performed using published data, and due to variability of data reporting among the studies further
analysis to estimate the dose response relationship was not possible to estimate.

Conclusion
Results have revealed that risk of having Anti-HBs Titer ≤ 10 mIU/ml reduced by 50% after receiving the booster
dose. Use of plasma derived vaccines and participant age of 21–30 years were identified to be the other two factors
resulting in higher Anti-HBs titer.

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Recommendations
The protection of an individual remains under question without the administration of booster dose 12 years
after primary vaccination during infancy. After this period a booster dose should be administered to check the
persistence of immune memory. If the anti-HBS tier remains less than 10 mIU/ml even after the administration
of booster dose, revaccination should be done.

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Author Contributions
S.M., T.M.K. conceived the idea; K.U.S., S.M. performed the search and data extraction; S.M. and K.U.S. devised
the method and analyzed the data; TMK verified the data and analysis. S.M. and T.M.K. wrote the initial draft;
K.U.S., S.M. and T.M.K. finalized the draft for submission.

Additional Information
Competing Interests: The authors declare no competing interests.
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ScIenTIfIc REPOrTS | (2018) 8:12550 | DOI:10.1038/s41598-018-30512-8 8