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© 2020 American Journal of Preventive Medicine. Publishreserved.

REVIEW ARTICLE

From the 1DepUniversity, ShAssessment, NaUniversity, ShaMinistry of Edu

Address coHealth, Fudanhai 200032, Ch

0749-3797/$https://doi.o

ed by Elsevier Inc. All right

Immunogenicity of Hepatitis B Vaccine in Preterm orLow 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 ininfants 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 ofbias of each study was assessed using the Newcastle−Ottawa Scale. The stability and publicationbias 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. Thestudies found that infants born preterm had significantly poorer immune responses to the hepatitisB 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 werestable, as suggested by the leave-one-out analysis and fail-safe number. The association betweenlow 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 immuneresponses to hepatitis B vaccine.Am J Prev Med 2020;000(000):1−10. © 2020 American Journal of Preventive Medicine. Published by ElsevierInc. All rights reserved.

CONTEXT

artment of Epidemiology, School of Public Health, Fudananghai, China; 2Key Laboratory for Health Technologytional Commission of Health and Family planning, Fudannghai, China; and 3Key Laboratory of Public Health Safety,cation, Fudan University, Shanghai, China.rrespondence to: Ying-Jie Zheng, PhD, School of PublicUniversity, No. 130 Dong’an Road, Xuhui District, Shang-ina. E-mail: zhengshmu@gmail.com.36.00rg/10.1016/j.amepre.2020.03.009

The hepatitis B vaccine (HBvac) is highly effectivefor preventing perinatal transmission of hepati-tis B virus and infection in infants. Thus far, it is

the only vaccine suggested by the Advisory Committeeon Immunization Practices (ACIP) to be administeredwithin 24 hours of birth.1 However, the effectiveness ofHBvac is often challenged by vaccination program acces-sibility, delayed first-dose administration, preterm birth,and many other factors.2−5 According to the WHO, itwas estimated that approximately 15 million babies areborn preterm every year; in recent years, this numberhas continued to rise.6 Compared with full-term infants,preterm infants are often vulnerable to newborn infec-tions and respiratory problems. These may result inother severe outcomes such as neurodevelopmentalimpairment and death, possibly owing to the interferen-tial nature of life-saving medical interventions and

developmental immaturity.6−8 Although preterm infantsare generally capable of mounting a comparable immuneresponse to most vaccines like inactivated polio vaccineand acellular pertussis vaccine compared with those offull-term infants, the situation may be different whenHBvac is administrated.9−13

In recent decades, some researchers have investigatedthe immunogenicity of HBvac in preterm infants; how-ever, these results were not conclusive.5,14−16 Interestingly,

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although some studies supported the lowered hepatitis Bsurface antibody (anti-HBs) response to vaccines adminis-tered in preterm infants, the difference in seropositivityproportions between the preterm and full-term groupswas 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 LBWmay coincide inthe potential causal pathway of immunogenicity.There have been some reviews available addressing

HBvac immunogenicity in preterm infants, but thesereviews did not involve quantitative analyses.9,19,20 Toovercome the limitations of subjective reviews and indi-vidual studies with small sample sizes, as well as limitedability to generalize, this study quantitatively examinesthe association of preterm birth and LBW with HBvacimmunogenicity in infants.

EVIDENCE ACQUISITIONThis meta-analysis was conducted in accordance with the PRISMAchecklist. The study protocol was registered on PROSPERO withthe registration number CRD42019128253.

Search StrategyA 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 CochraneLibrary 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 searchterms included hepatitis B; variants of vaccine, low birth weight,preterm, infants, and immune response; along with the MedicalSubject Headings and Embase Subject Headings.

Selection CriteriaAll studies on the immunogenicity of HBvac in preterm or LBWinfants were considered for possible inclusion. However, studieswere 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 trialregistration report; (2) were irrelevant to the topic of interest; (3)were published in neither English nor Chinese; (4) had a lack ofcontrol groups, such as full-term infants (gestational age [GA]≥37 weeks) or non-LBW infants (≥2,500 g); (5) were involvedwith 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 reportunclear completion statuses; or (9) had limited information forextraction or duplicate data.

Exposure and Outcome of InterestThe primary objective of this meta-analysis was to determinewhether there is a difference in immunogenicity between pretermand full-term infants. As premature infants often also have

significant LBW, studies on the association between birth weightand immune response were also included.

In this study, the infants were defined as preterm if they were bornbefore 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. Forthese 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 thelower bound of GA in the control (full-term) group. The difference inboth range bounds was ignored. LBW infants were defined as thosewho had birth weight<2,500 g.21

In this study, HBvac immunogenicity was evaluated throughobservation of anti-HBs concentration. Infants were defined asnonresponders if their anti-HBs titers were <10 mIU/mL.

Screening of Studies and Data ExtractionTwo researchers screened the papers obtained through the abovesearch strategy (WF and YMZ) and extracted the data (WF andMZ) independently. Any disagreements were reconciled by a thirdresearcher (YJZ) if a consensus was not reached. Extracted dataincluded study design, study region, vaccine used, vaccinationdoses, dosage, schedule, hepatitis B immunoglobulin administra-tion, maternal infection status, total evaluated participants in eachgroup, number of nonresponders in each group, geometric meantiters (GMTs) of anti-HBs in each group, timing of first-doseadministration, timing of post-vaccination serologic testing(PVST), and assessment methods.

Risk of Bias AssessmentPotential risk of bias was assessed using the Newcastle−OttawaScale for all included studies.22 An adapted version of the scalewas 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, andstudies rated <5 stars were considered to have a high risk of bias.

Statistical AnalysisThe primary statistical analyses were separated into the following2 parts: (1) comparing the immunogenicity of HBvac betweenpreterm infants and full-term infants (estimated by the pooledORs, mean differences, and their corresponding 95% CIs) and (2)comparing the immunogenicity of HBvac between LBW infantsand non-LBW infants (estimated by the pooled OR, mean differ-ences, and their corresponding 95% CIs). Heterogeneity wasassessed by Q-test, t2, and I2. A random-effects model was used todetermine 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, estimatedby the Hamling method.25 Publication bias was assessed using atrim-and-fill funnel plot and Egger’s test. The sensitivity of theresults was further assessed with both the leave-one-out analysis andRosenberg fail-safe number.26 The significance level was set top<0.05 for all statistical tests. All statistical analyses were performedusing SAS, version 9.4 and R, version 3.5.2. The SAS macro(%metaanal) created by Spiegelman was used for calculating thepooled estimates, and results were cross-checked with those foundby the R metafor package.27 The dose-response meta-analysis wasperformed with the R dosresmeta package, and a quadratic regres-sion model was fitted for the trend estimation.28

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EVIDENCE SYNTHESIS

Literature SearchThe search returned 1,263 records from 4 databases, ofwhich 121 were from Cochrane Library, 408 fromEmbase, 249 from PubMed, and 485 from Web of Sci-ence. After removing duplicates, the remaining 811records were considered for screening. Among theserecords (Figure 1), 784 were excluded owing to publica-tion type (385), irrelevance (314), language (28), lack ofcomparable 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 informationfor extraction (8).

Summary of the Enrolled StudiesThe screening returned 27 studies eligible for calculatingthe pooled estimates.5,14−18,29−49 The study metadataare summarized in Appendix Table 1 (available online).The meta-analysis included 22,202 infants, and thesestudies were mainly conducted in Europe, Asia, and the

Figure 1. Overview of screening process. Records were returned frand Web of Science.

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Americas. The reported GA ranged from 23 to 43 weeks,and birth weight ranged from 810 to 4,420 g. A total of22 studies were cohort based (including prospectivecomparative studies), whereas all others were cross-sec-tional. A total of 24 studies involved recombinant HBvac(monovalent), of which 2 did not mention any detailregarding which vaccine was used. However, this couldbe judged by referring to the immunization policy wherethe study was conducted.50,51 One reported monovalentvaccine was administered within 24 hours, followed by apentavalent vaccine thereafter.48 A total of 4 studiesreported the immunogenicity and safety of combinationvaccines, which contained 10 mg hepatitis B surfaceantigen (HBsAg).

Risk of Bias AssessmentThe Newcastle−Ottawa Scale results showed that one-third of the studies were scored 5 stars, 9 were scoredhigher than 5 stars, and the remaining 9 studies maybe involved with a significantly high risk of bias(Appendix Figure 1, available online). In addition, 12of the enrolled studies addressing preterm birth did

om 4 databases, including PubMed, Embase, Cochrane Library,

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not mention how the GA was estimated, and moststudies did not confirm undetectable anti-HBs titersbefore administration of the first dose. A total of 5studies did not control for sufficient critical factors forassessing HBvac immunogenicity, such as timing ofthe first dose and PVST, timing of the first dose, vacci-nation doses, dosage, schedule, and maternal infectionstatus. Most studies had relatively low bias on outcomeassessment.

Immunogenicity of HBvac in Preterm InfantsA total of 22 studies provided dichotomous data for calcu-lating the pooled OR of nonresponse to HBvac in pretermand full-term infants. Of these studies, 4 were involvedwith multiple comparisons and 2 were excluded from thecalculation owing to lack of events in both preterm andfull-term groups. Low heterogeneity was shown amongthe studies (Q=23.27, p=0.445, I2=1.2), and the pooled ORsuggested that preterm infants were 1.36 times more likelyto 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-outanalysis 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 theestimate 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 reversethe 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), timingof PVST, study design, dosage, and maternal infectionstatus (Appendix Figure 4, available online). It seemedthat preterm infants were less likely to respond to HBvacthan full-term infants in all subgroups. However, thepooled estimates were not statistically significant whenthe first dose was given at birth, when using combinationvaccines, when the timing of PVST was >6 months,when there was a cross-sectional study design, when adosage of 5 mg was given, and when mothers wereHBsAg-positive (p>0.05). Motivated by the number ofstudies suggested in each subgroup, it was decided tofurther delve into the association between preterm birthand nonresponse to HBvac. This association wasobserved when the study had a cohort based on a fullseries of monovalent HBvac, delayed first dose, timing ofPVST not beyond 6 months, a dose of 10 mg HBsAg,and with HBsAg−negative mothers. These conditionslimited the analyses to only 1 study conducted by Belloni

et al.30 In this study, the association estimate for pretermbirth 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 werereturned in the stratum, with the first dose given at birthirrespective of the timing of PVST. However, none ofthe 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 measuringthe GMT of anti-HBs were cohort based. The pooledmean 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 of0.186 mIU/mL lower in preterm infants than those infull-term infants. In other words, the anti-HBs GMTswere 1.20 times higher in full-term infants than those intheir preterm counterparts.

Immunogenicity of HBvac in LBW InfantsWhen the birth weight was dichotomized into LBW(<2,500 g) and non-LBW (≥2,500 g), the pooled ORobtained using a random-effects model did not suggest asignificant association between LBW and nonresponseto 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) (AppendixFigure 6, available online). The study conducted by Hassanet 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 (AppendixFigure 7, available online). This study had 3,758 valid sub-jects, which were greater than other study populations forthe calculation of this measure. The blood samples wereassessed 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, withinfants who had birth weight ≥2,500 g serving as the ref-erence group. A total of 3 studies15,34,48 were originallyeligible for this analysis, but only the study by Soodet al.15 provided sufficient nonresponse events for trendestimation. Though a downward trend in the logarith-mic OR was observed followed by an increase in birthweight, 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 GMTbetween infants with LBW and non-LBW. The estimated

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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 whitebars show the corresponding proportions in full-term groups.aEarly blood sample (1‒3 months after third dose).bLate blood sample (2.5‒3 years after third dose).cAfter third dose (4‒6 weeks).dAfter fourth dose (11‒12 weeks).eAnti-HBs tested at age 18‒20 months.fAnti-HBs tested after the first booster dose in the second year of life (Post DTaP-HBV-IPV/Hib booster at 18‒20 months).gAfter primary immunization.hAfter 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−inactivatedpolio and Haemophilus influenzae type b vaccine; HBvac, hepatitis B vaccine.

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Figure 3. The mean difference of logarithmic GMT of anti-HBs between preterm and full-term infants.aEarly blood sample (1‒3 months after third dose).bLate blood sample (2.5‒3 years after third dose).cAfter third dose (4‒6 weeks).dAfter fourth dose (11‒12 weeks).eAnti-HBs tested at age 18‒20 months.fAnti-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−inactivatedpolio and Haemophilus influenzae type b vaccine; GMT, geometric mean titers.

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mean difference of the logarithmic GMT was �0.180(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 withLBW and their full-term or non-LBW counterparts. Thefindings suggest that preterm birth is associated with animpaired immune response to HBvac. Though somemeasures may be subject to potential publication bias,the funnel plots suggest that the filled pseudo studieshave relatively high SEs. In addition, the fail-safe num-ber indicates that a moderate number of unpublishedstudies are required to alter the conclusion. The sub-group analyses results suggest that a difference in HBvacimmunogenicity still exists in most strata with seven or

more study comparisons. However, the difference wasnot statistically significant when fewer comparisonswere present. This might suggest that the associationestimates of preterm birth on nonresponse to HBvac aregreatly affected by the sample sizes of the studies.As timing of hepatitis B vaccination may influence the

measurement of anti-HBs titers, a bivariate subgroupanalysis based on the timing of first-dose administrationand PVST was also performed for further illustration ofhow the association would be affected by the timing fac-tors. It was noted that although all the substrata showedresults with wide CIs, the direction of these estimates hasnot changed and the estimates in 2 of the strata wereclose to the overall estimate returned from all the eligiblestudies. This suggests that HBvac timing may notcompletely abrogate the relationship between prematurityand nonresponse to HBvac. However, there is a caveat to

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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 barssuggest 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.

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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 Academyof Pediatrics (AAP) for infants with birth weight<2,000 g are to delay the first dose until age 1 month oruntil hospital discharge if their mothers are HBsAg−neg-ative, which spans a broad timing range. Therefore, it ispossible that the conclusion will change when switchingto 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 immunogenicityin preterm infants were not statistically significant. Thefollowing reasons might be ascribed to this phenomenon.Firstly, as data were combined from various studies, thesample size and power increased with the increment ofstudy subjects. Secondly, because most currently availableHBvac were highly immunogenic, few infants with nonre-sponse events could be observed from a single study, andthus, differences between preterm and full-term infantsmay be indiscernible. Thirdly, as multiple studies wereincorporated, the characteristics of preterm and full-terminfants may be more balanced and more likely to repre-sent the general infant population. This may lead to apopulation that differs somewhat from any of the individ-ual studies enrolled. For example, some studies onlyenrolled preterm infants with no or very low risk ofimmune deficiency (e.g., born between GA of 26 and 37weeks with no signs of disease). However, this may rarelybe the case in general clinical practice.Although the overall estimates for LBW on the immu-

nogenicity of HBvac did not reach the significance level,

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it was noted that the estimates were also close to theoverall estimates for that of prematurity. This mightmirror the overlap issue between the preterm and LBWexposures to some extent. By contrast, as the standarddefinition of LBW (<2,500 g) was used in this study,results might be different if another cutoff of birthweight was chosen for comparison. The results from thetrend analysis suggest that there is a possibility thatinfants with very LBW might be likely to suffer fromthe problem of poor immunogenicity as evidenced bythe ascending trend of logarithmic OR followed by thedecrease of birth weight.

Safety Issues in Relation to Preterm or LBWThe safety of the hepatitis B vaccination in relation toprematurity or LBW was briefly reviewed on the basis ofthe included studies. It was observed that studies withEngerix-B, Butang, and Shanvac B did not report anyadverse event after administration that could be attribut-able to the vaccine.5,14,15,29,32,34,35,38 By contrast, amongthe studies using combination vaccines, one reported thatirritability and drowsiness were more frequently observedin preterm infants, but a difference was not observed dur-ing revaccination.37,40 Therefore, there is still a lack ofstrong evidence to support the presence of safety issuesrelated to HBvac in preterm or LBW infants.

Current Guidelines and Suggestions forImmunization ProgramsCurrent guidelines for HBvac from ACIP/AAP do notprovide special suggestions for infants born before 37

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weeks. However, it is recommended that infants withbirth weight <2,000 g should be administered 1 dose ofsingle-antigen HBvac and hepatitis B immunoglobulinfor the birth dose and 3 additional intramuscular dosesbeginning at age 1 month if the infants were born towomen who are HBsAg-positive or with unknown statusand should receive 3 doses of HBvac with the first dosedelayed to the time of hospital discharge or age 1 monthif they are born to HBsAg−negative women.1,11,52

Although birth weight and prematurity may not castgreat effects on the immunogenicity of other vaccinessuch as inactivated polio vaccine and acellular pertussisvaccine, HBvac seems to be an exception, and decreasedseroconversion rates might occur among certain preterminfants after given HBvac at birth.9,12,13 The findings ofthis meta-analysis supported this conclusion.Currently, the fundamental mechanism underlying

the attenuation of the immune response has not beenthoroughly studied. Although an impaired immuneresponse may not be observed in all clinically stableinfants, innate immune response attenuation is notunusual. Therefore, preterm infants may be more likelyto experience attenuation of pro-inflammatory cytokineresponses, abnormal composition of circulating whiteblood 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 preterminfants often experience serious clinical complications,they may need closer observation for achieving a clini-cally stable status to receive the first dose timely andtake regular surveillance after administration. This isparticularly 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 thepreterm infants born in epidemic areas to have a similar4-dose schedule as those with birth weight <2,000 g inACIP/AAP guideline because it is often not feasible todissever prematurity and LBW in a single baby. Specifi-cally, preterm infants with birth weight >2,000 g areunderaddressed in most currently available guidelinesalthough their risk of infection is not negligible. Forthose who may inevitably have delayed first dose ofHBvac, it might be expected that the requirements forthe start of vaccination program be loosened to a list ofoptions beyond the 30 day postnatal age and hospitaldischarge. The weight-based policy offers the possibilityfor vaccinating the infants with very LBW,56 which givesthe referential experience for increasing the immunoge-nicity of HBvac in preterm infants, especially for thoseat very young GA. Besides, as one booster dose is gener-ally applied for remedying an impaired immuneresponse to HBvac, 1 additional dose or revaccinationmay 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 inthe meta-analytic methodology, further studies remainnecessary to better understand the underlying reason forthe association before policy recommendations may bemade on the basis of these results. Furthermore, the lim-itations of currently available data reveal the demand fora standardized and consistent data report on the studytopic, especially for the LBW infants. For example, thereis a gap between the definition used in ACIP/AAP guide-lines (<2,000 g) and WHO for LBW (<2,500 g), leadingto 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 GAand 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 onthe general relationship between prematurity and theimmunogenicity of HBvac. Secondly, a comprehensivesensitivity analysis was performed for the overall esti-mates. The results suggest that the association betweeninfants being born preterm and a lowered immuneresponse is stable, but its association with LBW may notbe. Thirdly, to further illustrate the relationship betweenbirth weight and immune response to the vaccine, adose-response meta-analysis was performed to evaluatethe relationship of increasing birth weight with the oddsof nonresponse to HBvac.

LimitationsThese strengths aside, there are also several limitationsto this study. First, the reference group of non-LBW wasdefined as those who had birth weight >2,500 g. Thus,studies that did not include infants with these subjectswere excluded from this study, potentially leading tofewer studies being eligible for the thorough assessmentof the effect of birth weight on HBvac immunogenicity.Second, the dose of birth weight on the logarithmic ORof nonresponse to HBvac may not be robust. This isbecause only one study with arithmetic means was avail-able for the trend estimation. Third, the study-level datarestricted the main analysis to binary traits and expo-sures. Therefore, situations with more extreme condi-tions may be poorly addressed. For example, infantswith birth weight >4,000 g may be included in the non-LBW groups. Clinical heterogeneity across the studiescould not be perfectly reconciled for the same reason.However, the results may reflect a general phenomenon

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in preterm or LBW infants who have completed the fullseries of hepatitis B vaccination. Finally, the findings ofthis study are observational and do not control suffi-ciently for potential confounders, meaning that causalitycannot be established.

CONCLUSIONS

Preterm birth is associated with an impaired immuneresponse to HBvac. A statistically significant associationbetween LBW and impaired response to HBvac was notfound when birth weight was dichotomized at 2,500 g.

ACKNOWLEDGMENTSThis study was supported by the National Key Research andDevelopment Program of China (2017YFC1200203) and theNational Natural Science Foundation of China (81373065,81773490).

YJZ conceived the study and revised the manuscript draftedby WF. WF and YMZ screened the search results. WF and MZperformed data extraction for the screened records. WF con-ducted the statistical analysis and drafted the manuscript. Allauthors critically reviewed the manuscript and approved thefinal version of the manuscript.

No financial disclosures were reported by the authors of thispaper.

SUPPLEMENTAL MATERIALSupplemental materials associated with this article can befound in the online version at https://doi.org/10.1016/j.amepre.2020.03.009.

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