ARTICLE IN PRESS

REVIEW ARTICLE

Immunogenicity of Hepatitis B Vaccine in Preterm or

Low Birth Weight Infants: A Meta-Analysis
Wei Fan, MMed,1,2,3 Miao Zhang, MBBS,1,2,3 Yi-Min Zhu, MBBS,1,2,3 Ying-Jie Zheng, PhD1,2,3

Context: The study aims to quantitatively assess the immune response to hepatitis B vaccine in
infants born preterm or with low birth weight.

Evidence acquisition: In December 2018, a literature search was conducted in 4 databases with-
out date restrictions. The pooled ORs, mean differences, and their corresponding 95% CIs were cal-
culated with random-effects models using the DerSimonian−Laird estimator. The potential risk of
bias of each study was assessed using the Newcastle−Ottawa Scale. The stability and publication
bias of the pooled estimates were also evaluated. Analyses were completed in 2019.

Evidence synthesis: A total of 27 studies including 22,202 infants were eligible for analysis. The
studies found that infants born preterm had significantly poorer immune responses to the hepatitis
B vaccine. Preterm infants were 1.36 times more likely to exhibit nonresponse to the hepatitis B vac-
cine (95% CI=1.12, 1.65, p=0.002) compared with their full-term counterparts. The pooled esti-
mates for preterm birth may be subject to a potential publication bias. However, these results were
stable, as suggested by the leave-one-out analysis and fail-safe number. The association between
low birth weight and impaired immune response to the hepatitis B vaccine was not statistically sig-
nificant when birth weight was dichotomized at 2,500 g.
Conclusions: These findings suggest an association between preterm birth and lowered immune
responses to hepatitis B vaccine.
Am J Prev Med 2020;000(000):1−10. © 2020 American Journal of Preventive Medicine. Published by Elsevier
Inc. All rights reserved.

CONTEXT developmental immaturity.6−8 Although preterm infants

are generally capable of mounting a comparable immune

T
he hepatitis B vaccine (HBvac) is highly effective
for preventing perinatal transmission of hepati-
tis B virus and infection in infants. Thus far, it is
the only vaccine suggested by the Advisory Committee
on Immunization Practices (ACIP) to be administered
within 24 hours of birth.1 However, the effectiveness of
HBvac is often challenged by vaccination program acces-
sibility, delayed first-dose administration, preterm birth,
and many other factors.2−5 According to the WHO, it
was estimated that approximately 15 million babies are
born preterm every year; in recent years, this number
has continued to rise.6 Compared with full-term infants,
preterm infants are often vulnerable to newborn infec-
tions and respiratory problems. These may result in
other severe outcomes such as neurodevelopmental
impairment and death, possibly owing to the interferen-
tial nature of life-saving medical interventions and
response to most vaccines like inactivated polio vaccine
and acellular pertussis vaccine compared with those of
full-term infants, the situation may be different when
HBvac is administrated.9−13
In recent decades, some researchers have investigated
the immunogenicity of HBvac in preterm infants; how-
ever, these results were not conclusive.5,14−16 Interestingly,
From the 1Department of Epidemiology, School of Public Health, Fudan
University, Shanghai, China; 2Key Laboratory for Health Technology
Assessment, National Commission of Health and Family planning, Fudan
University, Shanghai, China; and 3Key Laboratory of Public Health Safety,
Ministry of Education, Fudan University, Shanghai, China.
Address correspondence to: Ying-Jie Zheng, PhD, School of Public
Health, Fudan University, No. 130 Dong’an Road, Xuhui District, Shang-
hai 200032, China. E-mail: zhengshmu@gmail.com.
0749-3797/$36.00
https://doi.org/10.1016/j.amepre.2020.03.009

© 2020 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights Am J Prev Med 2020;000(000):1−10 1
reserved.
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2 Fan et al / Am J Prev Med 2020;000(000):1−10
although some studies supported the lowered hepatitis B
surface antibody (anti-HBs) response to vaccines adminis-
tered in preterm infants, the difference in seropositivity
proportions between the preterm and full-term groups
was often not statistically significant.17,18 In addition, pre-
term infants are likely to have a salient low birth weight
(LBW), which was often underaddressed among the stud-
ies assessing the immunogenicity of HBvac in infants.
However, being preterm and having LBW may coincide in
the potential causal pathway of immunogenicity.
There have been some reviews available addressing
HBvac immunogenicity in preterm infants, but these
reviews did not involve quantitative analyses.9,19,20 To
overcome the limitations of subjective reviews and indi-
vidual studies with small sample sizes, as well as limited
ability to generalize, this study quantitatively examines
the association of preterm birth and LBW with HBvac
immunogenicity in infants.
EVIDENCE ACQUISITION
This meta-analysis was conducted in accordance with the PRISMA
checklist. The study protocol was registered on PROSPERO with
the registration number CRD42019128253.
Search Strategy
A relatively loose search strategy was launched on December 18,
2018 to capture more hits and avoid omissions. A total of 4 data-
bases including PubMed, Embase, Web of Science, and Cochrane
Library were searched without date restrictions. The 3 of 5 ele-
ments of the PICOS model (Population, Intervention/Exposure,
and Outcome) were addressed in the search strategy. The search
terms included hepatitis B; variants of vaccine, low birth weight,
preterm, infants, and immune response; along with the Medical
Subject Headings and Embase Subject Headings.
Selection Criteria
All studies on the immunogenicity of HBvac in preterm or LBW
infants were considered for possible inclusion. However, studies
were excluded if they met the following criteria: (1) were pub-
lished as a review, editorial, patent report, protocol, case report,
book chapter, clinical guideline/news, meeting abstract, or trial
registration report; (2) were irrelevant to the topic of interest; (3)
were published in neither English nor Chinese; (4) had a lack of
control groups, such as full-term infants (gestational age [GA]
≥37 weeks) or non-LBW infants (≥2,500 g); (5) were involved
with plasma-derived vaccines; (6) full text was unavailable; (7)
had unclear or inappropriate exposure/outcome definitions; (8)
failed to complete the full course of vaccination series or to report
unclear completion statuses; or (9) had limited information for
extraction or duplicate data.
Exposure and Outcome of Interest
The primary objective of this meta-analysis was to determine
whether there is a difference in immunogenicity between preterm
and full-term infants. As premature infants often also have
significant LBW, studies on the association between birth weight
and immune response were also included.
In this study, the infants were defined as preterm if they were born
before 37 weeks of gestation. Some studies did not provide a clear defi-
nition of preterm birth but reported the range of GA in each group. For
these studies, they were considered as eligible if the 37th week of gesta-
tion was between the upper bound of GA in the preterm group and the
lower bound of GA in the control (full-term) group. The difference in
both range bounds was ignored. LBW infants were defined as those
who had birth weight <2,500 g.21
In this study, HBvac immunogenicity was evaluated through
observation of anti-HBs concentration. Infants were defined as
nonresponders if their anti-HBs titers were <10 mIU/mL.
Screening of Studies and Data Extraction
Two researchers screened the papers obtained through the above
search strategy (WF and YMZ) and extracted the data (WF and
MZ) independently. Any disagreements were reconciled by a third
researcher (YJZ) if a consensus was not reached. Extracted data
included study design, study region, vaccine used, vaccination
doses, dosage, schedule, hepatitis B immunoglobulin administra-
tion, maternal infection status, total evaluated participants in each
group, number of nonresponders in each group, geometric mean
titers (GMTs) of anti-HBs in each group, timing of first-dose
administration, timing of post-vaccination serologic testing
(PVST), and assessment methods.
Risk of Bias Assessment
Potential risk of bias was assessed using the Newcastle−Ottawa
Scale for all included studies.22 An adapted version of the scale
was created for evaluating the risk of bias in cross-sectional stud-
ies.23,24 Each study can be scored with a maximum of 9 stars, and
studies rated <5 stars were considered to have a high risk of bias.
Statistical Analysis
The primary statistical analyses were separated into the following
2 parts: (1) comparing the immunogenicity of HBvac between
preterm infants and full-term infants (estimated by the pooled
ORs, mean differences, and their corresponding 95% CIs) and (2)
comparing the immunogenicity of HBvac between LBW infants
and non-LBW infants (estimated by the pooled OR, mean differ-
ences, and their corresponding 95% CIs). Heterogeneity was
assessed by Q-test, t 2, and I2. A random-effects model was used to
determine the main pooled estimates using the DerSimonian
−Laird estimator, irrespective of the heterogeneity between studies.
The dose−response relationship between birth weight and the loga-
rithmic OR was also evaluated with the covariance matrix, estimated
by the Hamling method.25 Publication bias was assessed using a
trim-and-fill funnel plot and Egger’s test. The sensitivity of the
results was further assessed with both the leave-one-out analysis and
Rosenberg fail-safe number.26 The significance level was set to
p<0.05 for all statistical tests. All statistical analyses were performed
using SAS, version 9.4 and R, version 3.5.2. The SAS macro
(%metaanal) created by Spiegelman was used for calculating the
pooled estimates, and results were cross-checked with those found
by the R metafor package.27 The dose-response meta-analysis was
performed with the R dosresmeta package, and a quadratic regres-
sion model was fitted for the trend estimation.28
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Fan et al / Am J Prev Med 2020;000(000):1−10
EVIDENCE SYNTHESIS
Literature Search
The search returned 1,263 records from 4 databases, of
which 121 were from Cochrane Library, 408 from
Embase, 249 from PubMed, and 485 from Web of Sci-
ence. After removing duplicates, the remaining 811
records were considered for screening. Among these
records (Figure 1), 784 were excluded owing to publica-
tion type (385), irrelevance (314), language (28), lack of
comparable controls (27), full-text unavailability (7),
plasma-derived vaccine (2), unclear completion status
(1), unclear or inappropriate exposure/outcome defini-
tion (12), and duplicate data or insufficient information
for extraction (8).
Summary of the Enrolled Studies
The screening returned 27 studies eligible for calculating
the pooled estimates.5,14−18,29−49 The study metadata
are summarized in Appendix Table 1 (available online).
The meta-analysis included 22,202 infants, and these
studies were mainly conducted in Europe, Asia, and the
3
Americas. The reported GA ranged from 23 to 43 weeks,
and birth weight ranged from 810 to 4,420 g. A total of
22 studies were cohort based (including prospective
comparative studies), whereas all others were cross-sec-
tional. A total of 24 studies involved recombinant HBvac
(monovalent), of which 2 did not mention any detail
regarding which vaccine was used. However, this could
be judged by referring to the immunization policy where
the study was conducted.50,51 One reported monovalent
vaccine was administered within 24 hours, followed by a
pentavalent vaccine thereafter.48 A total of 4 studies
reported the immunogenicity and safety of combination
vaccines, which contained 10 mg hepatitis B surface
antigen (HBsAg).
Risk of Bias Assessment
The Newcastle−Ottawa Scale results showed that one-
third of the studies were scored 5 stars, 9 were scored
higher than 5 stars, and the remaining 9 studies may
be involved with a significantly high risk of bias
(Appendix Figure 1, available online). In addition, 12
of the enrolled studies addressing preterm birth did

Figure 1. Overview of screening process. Records were returned from 4 databases, including PubMed, Embase, Cochrane Library,
and Web of Science.

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4 Fan et al / Am J Prev Med 2020;000(000):1−10
not mention how the GA was estimated, and most
studies did not confirm undetectable anti-HBs titers
before administration of the first dose. A total of 5
studies did not control for sufficient critical factors for
assessing HBvac immunogenicity, such as timing of
the first dose and PVST, timing of the first dose, vacci-
nation doses, dosage, schedule, and maternal infection
status. Most studies had relatively low bias on outcome
assessment.
Immunogenicity of HBvac in Preterm Infants
A total of 22 studies provided dichotomous data for calcu-
lating the pooled OR of nonresponse to HBvac in preterm
and full-term infants. Of these studies, 4 were involved
with multiple comparisons and 2 were excluded from the
calculation owing to lack of events in both preterm and
full-term groups. Low heterogeneity was shown among
the studies (Q=23.27, p=0.445, I2=1.2), and the pooled OR
suggested that preterm infants were 1.36 times more likely
to exhibit nonresponse to HBvac than full-term infants
(95% CI=1.12, 1.65, p=0.002, Figure 2).
A funnel plot indicated that the above estimate may
have a potential publication bias (Egger’s test: p=0.037)
(Appendix Figure 2, available online). The leave-one-out
analysis showed that the pooled OR was quite stable,
and removing the most influential study by Zhao et al.49
(Appendix Figure 3, available online) could increase the
estimate from 1.36 to 1.46 (95% CI=1.18, 1.80). The fail-
safe number was 28, indicating that 28 studies with sta-
tistically nonsignificant results were required to reverse
the conclusion.
Subgroup analysis was performed on the basis of vari-
ous univariate stratifications, including delayed or non-
delayed administration (beyond 24 hours after birth),
types of vaccine (combination or single antigen), timing
of PVST, study design, dosage, and maternal infection
status (Appendix Figure 4, available online). It seemed
that preterm infants were less likely to respond to HBvac
than full-term infants in all subgroups. However, the
pooled estimates were not statistically significant when
the first dose was given at birth, when using combination
vaccines, when the timing of PVST was >6 months,
when there was a cross-sectional study design, when a
dosage of 5 mg was given, and when mothers were
HBsAg-positive (p>0.05). Motivated by the number of
studies suggested in each subgroup, it was decided to
further delve into the association between preterm birth
and nonresponse to HBvac. This association was
observed when the study had a cohort based on a full
series of monovalent HBvac, delayed first dose, timing of
PVST not beyond 6 months, a dose of 10 mg HBsAg,
and with HBsAg−negative mothers. These conditions
limited the analyses to only 1 study conducted by Belloni
et al.30 In this study, the association estimate for preterm
birth and nonresponse to HBvac was 0.98 (95% CI=0.41,
2.32, p=0.957). Furthermore, bivariate stratification anal-
yses were also conducted regarding the timing of first-
dose administration and PVST. Similar estimates were
returned in the stratum, with the first dose given at birth
irrespective of the timing of PVST. However, none of
the stratum-specific estimates were statistically signifi-
cant (p>0.05) (Appendix Figure 5, available online).
In addition, the logarithmic GMT of anti-HBs
between preterm infants and full-term infants was com-
pared. It was found that all eligible studies measuring
the GMT of anti-HBs were cohort based. The pooled
mean difference of the logarithmic GMT was 0.186
(95% CI= 0.291, 0.080, p<0.001) (Figure 3), indicat-
ing that logarithmic anti-HBs were on an average of
0.186 mIU/mL lower in preterm infants than those in
full-term infants. In other words, the anti-HBs GMTs
were 1.20 times higher in full-term infants than those in
their preterm counterparts.
Immunogenicity of HBvac in LBW Infants
When the birth weight was dichotomized into LBW
(<2,500 g) and non-LBW (≥2,500 g), the pooled OR
obtained using a random-effects model did not suggest a
significant association between LBW and nonresponse
to HBvac (OR=1.39, 95% CI=0.92, 2.12, p=0.121; hetero-
geneity: Q=8.89, p=0.113, I2=43.8) (Figure 4).
The funnel plot was symmetric, and Egger’s test did not
yield statistically significant results (p=0.223) (Appendix
Figure 6, available online). The study conducted by Hassan
et al.39 had the greatest influence on the overall estimate,
and the pooled OR changed from 1.39 to 1.10 (95%
CI=0.75, 1.62) after this study was removed (Appendix
Figure 7, available online). This study had 3,758 valid sub-
jects, which were greater than other study populations for
the calculation of this measure. The blood samples were
assessed at the age of 5.5‒6.0 years.
Trend analysis for the birth weight on the OR of not
developing a protective anti-HBs titer was also per-
formed to estimate the birth weight-specific ORs, with
infants who had birth weight ≥2,500 g serving as the ref-
erence group. A total of 3 studies15,34,48 were originally
eligible for this analysis, but only the study by Sood
et al.15 provided sufficient nonresponse events for trend
estimation. Though a downward trend in the logarith-
mic OR was observed followed by an increase in birth
weight, the results of the trend analysis were not statisti-
cally significant (chi-squared=3.479, p=0.176) (Appen-
dix Figure 8, available online).
A study conducted by Faldella et al.31 was identified to
calculate the mean difference of the logarithmic GMT
between infants with LBW and non-LBW. The estimated
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Fan et al / Am J Prev Med 2020;000(000):1−10 5

Figure 2. The association between preterm birth and nonresponse to HBvac in infants.
Notes: The black bars on the left panel of the plot show the proportion of infants with anti HBs <10 mIU/mL in preterm groups, whereas the white
bars show the corresponding proportions in full-term groups.
a
Early blood sample (1‒3 months after third dose).
b
Late blood sample (2.5‒3 years after third dose).
c
After third dose (4‒6 weeks).
d
After fourth dose (11‒12 weeks).
e
Anti-HBs tested at age 18‒20 months.
f
Anti-HBs tested after the first booster dose in the second year of life (Post DTaP-HBV-IPV/Hib booster at 18‒20 months).
g
After primary immunization.
h
After revaccination for non and low responders in primary immunization.
anti-HBs, anti-hepatitis B surface antigen; DTaP-HBV-IPV/Hib, hexavalent diphtheria−tetanus−acellular pertussis−hepatitis B virus−inactivated
polio and Haemophilus influenzae type b vaccine; HBvac, hepatitis B vaccine.

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6 Fan et al / Am J Prev Med 2020;000(000):1−10

Figure 3. The mean difference of logarithmic GMT of anti-HBs between preterm and full-term infants.
a
Early blood sample (1‒3 months after third dose).
b
Late blood sample (2.5‒3 years after third dose).
c
After third dose (4‒6 weeks).
d
After fourth dose (11‒12 weeks).
e
Anti-HBs tested at age 18‒20 months.
f
Anti-HBs tested after the first booster dose in the second year of life (Post DTaP-HBV-IPV/Hib booster at 18‒20 months).
anti-HBs, anti-hepatitis B surface antigen; DTaP-HBV-IPV/Hib, hexavalent diphtheria−tetanus−acellular pertussis−hepatitis B virus−inactivated
polio and Haemophilus influenzae type b vaccine; GMT, geometric mean titers.

mean difference of the logarithmic GMT was
(95% CI= 0.364, 0.004, p=0.050).
DISCUSSION
This meta-analysis quantitatively assessed the immuno-
genicity of HBvac between infants born preterm or with
LBW and their full-term or non-LBW counterparts. The
findings suggest that preterm birth is associated with an
impaired immune response to HBvac. Though some
measures may be subject to potential publication bias,
the funnel plots suggest that the filled pseudo studies
have relatively high SEs. In addition, the fail-safe num-
ber indicates that a moderate number of unpublished
studies are required to alter the conclusion. The sub-
group analyses results suggest that a difference in HBvac
immunogenicity still exists in most strata with seven or
0.180 more study comparisons. However, the difference was
not statistically significant when fewer comparisons
were present. This might suggest that the association
estimates of preterm birth on nonresponse to HBvac are
greatly affected by the sample sizes of the studies.
As timing of hepatitis B vaccination may influence the
measurement of anti-HBs titers, a bivariate subgroup
analysis based on the timing of first-dose administration
and PVST was also performed for further illustration of
how the association would be affected by the timing fac-
tors. It was noted that although all the substrata showed
results with wide CIs, the direction of these estimates has
not changed and the estimates in 2 of the strata were
close to the overall estimate returned from all the eligible
studies. This suggests that HBvac timing may not
completely abrogate the relationship between prematurity
and nonresponse to HBvac. However, there is a caveat to

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Fan et al / Am J Prev Med 2020;000(000):1−10 7

Figure 4. The association between LBW and nonresponse to HBvac in infants.

Note: The black bars on the left panel of the plot show the proportion of infants with anti-HBs <10 mIU/mL in LBW groups, whereas the white bars
suggest the corresponding proportions in non-LBW groups.
anti-HBs, anti-hepatitis B surface antigen; HBvac, hepatitis B vaccine; LBW, low birth weight; non-LBW, non−low birth weight.

this conclusion. A delayed first dose was defined as being
>24 hours after birth for meta-analytic feasibility. How-
ever, the recommendations from the American Academy
of Pediatrics (AAP) for infants with birth weight
<2,000 g are to delay the first dose until age 1 month or
until hospital discharge if their mothers are HBsAg−neg-
ative, which spans a broad timing range. Therefore, it is
possible that the conclusion will change when switching
to another cutoff for the definition of a delayed first dose.
In addition, the findings of this meta-analysis also
showed that quite a few studies assessing immunogenicity
in preterm infants were not statistically significant. The
following reasons might be ascribed to this phenomenon.
Firstly, as data were combined from various studies, the
sample size and power increased with the increment of
study subjects. Secondly, because most currently available
HBvac were highly immunogenic, few infants with nonre-
sponse events could be observed from a single study, and
thus, differences between preterm and full-term infants
may be indiscernible. Thirdly, as multiple studies were
incorporated, the characteristics of preterm and full-term
infants may be more balanced and more likely to repre-
sent the general infant population. This may lead to a
population that differs somewhat from any of the individ-
ual studies enrolled. For example, some studies only
enrolled preterm infants with no or very low risk of
immune deficiency (e.g., born between GA of 26 and 37
weeks with no signs of disease). However, this may rarely
be the case in general clinical practice.
Although the overall estimates for LBW on the immu-
nogenicity of HBvac did not reach the significance level,
it was noted that the estimates were also close to the
overall estimates for that of prematurity. This might
mirror the overlap issue between the preterm and LBW
exposures to some extent. By contrast, as the standard
definition of LBW (<2,500 g) was used in this study,
results might be different if another cutoff of birth
weight was chosen for comparison. The results from the
trend analysis suggest that there is a possibility that
infants with very LBW might be likely to suffer from
the problem of poor immunogenicity as evidenced by
the ascending trend of logarithmic OR followed by the
decrease of birth weight.
Safety Issues in Relation to Preterm or LBW
The safety of the hepatitis B vaccination in relation to
prematurity or LBW was briefly reviewed on the basis of
the included studies. It was observed that studies with
Engerix-B, Butang, and Shanvac B did not report any
adverse event after administration that could be attribut-
able to the vaccine.5,14,15,29,32,34,35,38 By contrast, among
the studies using combination vaccines, one reported that
irritability and drowsiness were more frequently observed
in preterm infants, but a difference was not observed dur-
ing revaccination.37,40 Therefore, there is still a lack of
strong evidence to support the presence of safety issues
related to HBvac in preterm or LBW infants.
Current Guidelines and Suggestions for
Immunization Programs
Current guidelines for HBvac from ACIP/AAP do not
provide special suggestions for infants born before 37

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8 Fan et al / Am J Prev Med 2020;000(000):1−10
weeks. However, it is recommended that infants with
birth weight <2,000 g should be administered 1 dose of
single-antigen HBvac and hepatitis B immunoglobulin
for the birth dose and 3 additional intramuscular doses
beginning at age 1 month if the infants were born to
women who are HBsAg-positive or with unknown status
and should receive 3 doses of HBvac with the first dose
delayed to the time of hospital discharge or age 1 month
if they are born to HBsAg−negative women.1,11,52
Although birth weight and prematurity may not cast
great effects on the immunogenicity of other vaccines
such as inactivated polio vaccine and acellular pertussis
vaccine, HBvac seems to be an exception, and decreased
seroconversion rates might occur among certain preterm
infants after given HBvac at birth.9,12,13 The findings of
this meta-analysis supported this conclusion.
Currently, the fundamental mechanism underlying
the attenuation of the immune response has not been
thoroughly studied. Although an impaired immune
response may not be observed in all clinically stable
infants, innate immune response attenuation is not
unusual. Therefore, preterm infants may be more likely
to experience attenuation of pro-inflammatory cytokine
responses, abnormal composition of circulating white
blood cells, and lack of trans-placental transfer of mater-
nal antibodies, thus, becoming more susceptible to hepa-
titis B infection.8,53,54 Considering that many preterm
infants often experience serious clinical complications,
they may need closer observation for achieving a clini-
cally stable status to receive the first dose timely and
take regular surveillance after administration. This is
particularly important for those who are living in epi-
demic areas such as Africa, the Arabian region, China,
and Eastern Europe.55 It may also be advisable for the
preterm infants born in epidemic areas to have a similar
4-dose schedule as those with birth weight <2,000 g in
ACIP/AAP guideline because it is often not feasible to
dissever prematurity and LBW in a single baby. Specifi-
cally, preterm infants with birth weight >2,000 g are
underaddressed in most currently available guidelines
although their risk of infection is not negligible. For
those who may inevitably have delayed first dose of
HBvac, it might be expected that the requirements for
the start of vaccination program be loosened to a list of
options beyond the 30 day postnatal age and hospital
discharge. The weight-based policy offers the possibility
for vaccinating the infants with very LBW,56 which gives
the referential experience for increasing the immunoge-
nicity of HBvac in preterm infants, especially for those
at very young GA. Besides, as one booster dose is gener-
ally applied for remedying an impaired immune
response to HBvac, 1 additional dose or revaccination
may also be effective for the preterm infants who have
not achieved a desired immune response during the pri-
mary vaccination program.
Nonetheless, as many nuanced findings that led to
specific recommendations regarding HBvac are lost in
the meta-analytic methodology, further studies remain
necessary to better understand the underlying reason for
the association before policy recommendations may be
made on the basis of these results. Furthermore, the lim-
itations of currently available data reveal the demand for
a standardized and consistent data report on the study
topic, especially for the LBW infants. For example, there
is a gap between the definition used in ACIP/AAP guide-
lines (<2,000 g) and WHO for LBW (<2,500 g), leading
to a different normal group to be referred to in practice.
Perhaps, a consistent reference group (birth weight
>2,500 g and GA >37 weeks) accompanied with multi-
ple potential risk groups with reported medians of GA
and birth weight would be more preferable for the com-
parative analysis.
There were several strengths to this meta-analysis.
Firstly, multiple subgroup analyses with potential influ-
encing factors were performed to further elaborate on
the general relationship between prematurity and the
immunogenicity of HBvac. Secondly, a comprehensive
sensitivity analysis was performed for the overall esti-
mates. The results suggest that the association between
infants being born preterm and a lowered immune
response is stable, but its association with LBW may not
be. Thirdly, to further illustrate the relationship between
birth weight and immune response to the vaccine, a
dose-response meta-analysis was performed to evaluate
the relationship of increasing birth weight with the odds
of nonresponse to HBvac.
Limitations
These strengths aside, there are also several limitations
to this study. First, the reference group of non-LBW was
defined as those who had birth weight >2,500 g. Thus,
studies that did not include infants with these subjects
were excluded from this study, potentially leading to
fewer studies being eligible for the thorough assessment
of the effect of birth weight on HBvac immunogenicity.
Second, the dose of birth weight on the logarithmic OR
of nonresponse to HBvac may not be robust. This is
because only one study with arithmetic means was avail-
able for the trend estimation. Third, the study-level data
restricted the main analysis to binary traits and expo-
sures. Therefore, situations with more extreme condi-
tions may be poorly addressed. For example, infants
with birth weight >4,000 g may be included in the non-
LBW groups. Clinical heterogeneity across the studies
could not be perfectly reconciled for the same reason.
However, the results may reflect a general phenomenon
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Fan et al / Am J Prev Med 2020;000(000):1−10
in preterm or LBW infants who have completed the full
series of hepatitis B vaccination. Finally, the findings of
this study are observational and do not control suffi-
ciently for potential confounders, meaning that causality
cannot be established.
CONCLUSIONS
Preterm birth is associated with an impaired immune
response to HBvac. A statistically significant association
between LBW and impaired response to HBvac was not
found when birth weight was dichotomized at 2,500 g.
ACKNOWLEDGMENTS
This study was supported by the National Key Research and
Development Program of China (2017YFC1200203) and the
National Natural Science Foundation of China (81373065,
81773490).
YJZ conceived the study and revised the manuscript drafted
by WF. WF and YMZ screened the search results. WF and MZ
performed data extraction for the screened records. WF con-
ducted the statistical analysis and drafted the manuscript. All
authors critically reviewed the manuscript and approved the
final version of the manuscript.
No financial disclosures were reported by the authors of this
paper.
SUPPLEMENTAL MATERIAL
Supplemental materials associated with this article can be
found in the online version at https://doi.org/10.1016/j.
amepre.2020.03.009.
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