| ObjectivesPreterm birth(PTB)infants have immature immune system and may not induce a good immune response after Hepatitis B vaccine(Hep B)vaccination,and the immune persistence after vaccination may also be lower than that of full-term infants.Some scholars have proposed booster vaccination for PTB infants,but the necessity and timing of booster vaccination were controversial,and whether a booster vaccination is cost-effective remains to be elucidated.Therefore,this study investigated the necessity and optimal timing of booster vaccination for PTB infants from the perspectives of dynamic changes in HBs Ab levels after Hep B vaccination and the long-term immune persistence of Hep B.Besides,we also conducted a health economic evaluation to determine whether the booster vaccination strategy is cost-effective.The final goal of this study was to provide data to support further optimization of Hep B immunization strategies in China.MethodsPart 1:A cross-sectional study was conducted to collect information related to PTB infants born in 2016-2021 at obstetric outpatient clinics in 24 hospitals in Lu’an,Anhui Province.The main contents collected included maternal and child demographic information at birth,current address,contact information,mode of delivery,feeding type,gestational week,birth weight,complications of infants,fetal times,maternal HBs Ag,and HIV and syphilis test results.In addition,the immunization history of Hep B and HBIG was collected for PTB infants born to HBs Ag-positive mothers.The descriptive epidemiological method was used to describe the prevalence of PTB and the immunization history of Hep B and HBIG in PTB infants born to HBs Ag-positive mothers.Logistic regression was used to analyze the factors influencing the occurrence of preterm birth,and the OR and its 95%CI were calculated.Part 2:Based on the first part survey combined with the later supplemental survey results,PTB infants born to HBs Ag-positive mothers from 2016 to 2021 were selected as study subjects,while one normal full-term child was selected as a control child in the same township in a 1:1 ratio for each study subject.We followed up all participants and conducted on-site surveys and blood specimen collection during July-August,2022.The main contents of the survey included demographic information of mothers and children,date of birth,gestational week,birth weight,mode of delivery,feeding type,the timing of Hep B and HBIG vaccination,etc.After the survey was completed,blood specimens were collected from children for HBs Ag,HBs Ab,HBe Ag,HBe Ab,HBe Ab,and HBc Ab testing.The dynamic changes of HBs Ab after Hep B vaccination were explored by comparing the positive rate and GMC of HBs Ab in two groups by different time intervals and different age groups.Time-dependent ROC curves were constructed to determine the AUC and 95%CI,sensitivity,specificity,and cut-off value for each group.We used ROC curves to assess the predictive value of the time interval after Hep B vaccination and the age of the child on HBs Ab non-response.We compared the difference in HBs Ab seropositivity rate and GMC between the PTB and control groups at the cut-off value.Part 3:We constructed a retrospective cohort which consisted of PTB infants with an interval of at least 5 years after only 3-dose of Hep B vaccination(exposure group)as well as normal full-term infants also with an interval of at least 5 years after only 3-dose of Hep B vaccination(control group).All participants were investigated in the survey field and blood specimens were also collected.The main contents of the surveys included maternal and child demographic information at birth,mode of delivery,feeding type,contact information,gestational week,birth weight,time of Hep B vaccination,current address,complications of infants,etc.After completion of the survey,blood specimens were collected from children for HBs Ab testing.The basic characteristics of the two groups were analyzed using descriptive epidemiological methods.The risk of HBs Ab non-response in the exposure group was analyzed using logistic regression,and OR values and 95%CI were calculated.Subgroup analysis was conducted to compare the differences in GMC of HBs Ab between the two groups at different time intervals,different birth weights,and different types of PTB.Part 4:A decision tree-Markov model was constructed using Tree Age pro 2022software to assess the cost-effectiveness of Hep B booster vaccination.Based on the results of Study 2 and Study 3,two candidate Hep B booster vaccination strategies for PTB infants were proposed.Strategy 1:Screen all PTB infants for HBs Ag and HBs Ab at age of 3 years,and provide a 1-dose Hep B booster vaccination for HBs Ab-negative and HBV-uninfected children.Strategy 2:Screen only PTB infants born to HBs Ag-positive mothers for HBs Ag and HBs Ab at age of 3 years,and provide a 1-dose Hep B booster vaccination for HBs Ab-negative and HBV-uninfected children.The comparison strategy:the current no screening and no Hep B booster vaccination for PTB infants was used as the comparison strategy.The parameters of the model were mainly obtained from the field investigation,literature search,authoritative institution release,and expert consultation.The two candidate strategies were compared with the comparison strategies respectively,and the CER and ICER were calculated to determine whether the candidate booster vaccination strategies were cost-effective.We performed one-way deterministic and probabilistic sensitivity analyses to assess the robustness of our findings.ResultsPart 1:A total of 4126 PTB infants were reported in Lu’an during 2018-2021,with an incidence of 4.49%(95%CI:4.36-4.63)and an annual growth rate of 9.83%for PTB infants.The incidence of extreme preterm,very preterm,moderate preterm,and late preterm was 0.05%,0.27%,0.92%,and 3.25%,respectively.Among 4126 PTB infants,the proportion of the above four PTB types were 1.19%,6.03%,20.50%,and 72.27%,respectively.The overall incidence of PTB was significantly higher in multiparous pregnancies(42.42%,95%CI:40.22-44.62)than in singleton pregnancies(3.68%,95%CI:3.55-3.80),with a statistically significant difference(χ~2=619.807,P<0.001).The logistic regression model analysis showed that maternal age,multiparous pregnancies,and syphilis infection were potential risk factors for the occurrence of PTB.The risk of PTB was highest in multiple pregnancies(OR=19.33,95%CI:17.53-21.31).The risk of PTB was significantly increased in the 30-34 years(OR=1.25,95%CI:1.15-1.91),35-39years(OR=1.71,95%CI:1.53-1.91),and 40+years age groups(OR=1.99,95%CI:1.62-2.43)compared to 25-29 years.The risk of PTB tended to increase with maternal age.The risk of PTB was 1.62 times higher in the syphilis-infected mothers than in the control group(OR=1.62,95%CI:1.12-2.34),and no significant association was found between HBV-infected mothers and PTB.Only four children(2.40%)received the 4-dose Hep B as recommended by Immunization Schedules and Instructions for Vaccines of the National Immunization Program-version 2016.Part 2:A total of 390 participants were included in this study,including 195 PTB born to HBs Ag-positive mothers(preterm group)and 195 full-term children(control group).Seven mothers of children in the control group self-reported as HBs Ag positive,accounting for 3.59%.All children born to HBs Ag-positive mothers have received HBIG immunization at birth in two groups.The proportion of HBV infection in PTB children born to HBs Ag-positive mothers was 1.54%.However,the rates of nature childbirth(χ~2=14.043,P<0.001),breastfeeding(χ~2=41.748,P<0.001),and timely birth dose of Hep B(χ~2=19.476,P<0.001)were significantly lower in the preterm group than that in the control group.Overall,the HBs Ab seropositivity rate(71.28%vs.77.44%)and GMC(35.29 m IU/m L vs.42.31 m IU/m L)were lower in the preterm group than that in the control group,but none of the differences were statistically significant(P>0.05).The HBs Ab seropositivity rate and GMC of children tended to decrease with increasing age of children and time interval of Hep B vaccination,but the decreasing trend was faster in the preterm group.The ROC curve showed that the use of time intervals to predict HBs Ab non-response in children in the preterm group had a good application value with an AUC of 0.73(95%CI:0.68-0.80).Stratified analysis showed that there was no statistical difference in seropositivity and GMC between the preterm group and control group when the time interval of Hep B vaccination was less than 2.5 years and when the children were under 3 years of age(P>0.05).However,when the time interval of Hep B vaccination exceeded 2.5 years,the GMC in the preterm group had dropped below the protective level(9.43 m IU/m L),significantly lower than that in the control group(21.29 m IU/m L,P=0.006).When the age of participants was older than 3 years,the GMC in the preterm group was only 9.89 m IU/m L,significantly lower than that in the control group(21.51m IU/m L,P=0.007).In addition,our study also found that the GMC of children who received only 3 doses of Hep B was 35.68 m IU/m L(95%CI:27.46-46.37),while the GMC of children in the booster vaccination group was 390.50 m IU/m L(95%CI:126.5-1206),suggesting that the HBs Ab in the booster vaccination group were at the adequate response level.Part 3:A total of 1027 participants were included in this study,including 505 in the preterm exposure group and 522 in the control group.Sixteen(3.17%)were very preterm infants,60(11.88%)were moderate preterm infants,and 429(84.95%)were late preterm infants.A total of 190(37.62%)were preterm low birth weight(PLBW)children,in the exposure group.A total of 242 children in the exposed group were HBs Ab-negative,with a no-response rate of 47.92%.A total of 216 children in the control group were HBs Ab-negative,with a no-response rate of 41.38%.We found that the no-response rate of children in the exposure group was significantly higher than that of the control group,with statistically significant differences(χ~2=4.445,P=0.035).The risk of occurrence of HBs Ab-negative was 1.51 times higher than that of the control group(OR=1.51,95%CI:1.12-2.02).The GMC of HBs Ab was 9.31 m IU/m L(95%CI:7.69-11.28)and 12.41m IU/m L(95%CI:10.29-14.97)for children in the exposure group and control group,respectively.We found that the GMC in the exposure group children was below the protective antibody(10 m IU/m L)level and was significantly lower than the control group(Z=-2.182,P=0.029).The stratified analysis revealed that GMCs in the very preterm,moderate preterm,and late preterm groups of children was 3.24 m IU/m L(95%CI:0.94-11.13),9.94 m IU/m L(95%CI:5.74-17.22)and 9.60 m IU/m L(95%CI:7.80-11.82),respectively.Although the difference between the three groups was not statistically significant(χ~2=3.345,P=0.188),the very preterm children were relatively lower than the other two groups.We also found that the GMC in PTB infants weighing less than 2000 g was lower than in PTB infants weighing 2000-2499 g(7.93 m IU/m L vs.11.49 m IU/m L),but the difference was not statistically significant(Z=-1.096,P=0.273).Part 4:This study assumed a birth cohort of 100 000 PTB infants and used a decision tree-Markov model to analyze the cost-effectiveness of Hep B booster vaccination for this birth cohort.The results of the decision tree-Markov model analysis showed that implementation of strategy 1 resulted in 942 fewer cases of acute hepatitis B,8178 fewer cases of chronic HBV infection,24 fewer cases of cirrhosis,2 fewer cases of hepatocellular carcinoma,and 1475 fewer cases of HBV infection-related deaths compared with existing strategies.Implementation strategy 2 could reduce 97 cases of acute hepatitis B,274 cases of chronic HBV infection,and 9 cases of liver cirrhosis,and could avoid 65 cases of HBV infection-related deaths,respectively.The results of the cost-effectiveness analysis showed that the cost of strategy 1 and strategy 2 was 1653.03RMB/person and 2848.83 RMB/person,respectively.Both immunization strategies saved costs compared to the existing strategies,saving 1428.29 RMB/person and 232.49RMB/person,respectively.The QALYs available per capita in strategy 1 and strategy 2were 70.03 and 69.81,with an increase of 0.27 and 0.06 QALYs,respectively,compared with the existing strategy.We found that the ICERs of Strategy 1 and Strategy 2 were-5209.97 RMB/QALYs and-4170.78 RMB/QALYs,respectively,indicating that both study strategies were significantly economical,saving costs and increasing effects.One-way deterministic sensitivity analysis found that the discount rate was the most influential parameter on the ICER in both strategy 1 and strategy 2.Probabilistic sensitivity analysis found that the probability of having a cost effect was 100%and72.80%for strategy 1 and strategy 2,respectively,when willingness to pay was set at 3times GDP per capita.ConclusionsPTB infants born to HBs Ag-positive mothers have a lower rate of timely Hep B vaccination.The 4-dose of Hep B for PTB infants born to HBs Ag-positive mothers recommended by Immunization Schedules and Instructions for Vaccines of the National Immunization Program-version 2016 was not fully implemented,suggesting a strong public health intervention should be taken to close the policy-practice gap in China in the future.The GMC of HBs Ab in PTB infants decreased more rapidly and significantly with longer time intervals after Hep B vaccination and with increasing age of the child than that in full-term infants.Once the time interval after vaccination exceeded 2.5 years or when the child was older than 3 years,the GMC in the PTB infants group decreases to a non-responsive level,while term infants maintain a low response level.These results suggested that booster vaccination appears to be necessary for PTB infants and that booster vaccination at the age of 3 years seems to be appropriate.The results of long-term immune persistence analysis showed that prematurity had a significant effect on the persistence of Hep B,with the risk of HBs Ab-negative in PTB infants being 1.51 times higher than that in normal-term infants.The GMC in PTB infants was significantly lower than those in the control group after 5 years of Hep B vaccination and had dropped below protective levels.One dose of Hep B booster vaccination given to PTB children at the age of 3 years after completion of routine immunization would be cost-effective. |
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