(2.6)--感染病学Thetransferanddecayofmaternalant.pdf

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1、 Published online October 5,2020 https:/doi.org/10.1016/S1473-3099(20)30480-1 1ArticlesThe transfer and decay of maternal antibodies against enterovirus A71,and dynamics of antibodies due to later natural infections in Chinese infants:a longitudinal,paired motherneonate cohort studySummaryBackground

2、 Since 1997,epidemics of hand,foot,and mouth disease associated with enterovirus A71(EV-A71)have affected children younger than 5 years in the Asia-Pacific region,including mainland China.EV-A71 vaccines have been licensed for use in children aged 671 months in China,but not for infants younger than

3、 6 months.We aimed to assess the dynamics of maternal EV-A71 antibodies to inform choice of potential vaccination strategies to protect infants younger than 6 months,because they have a substantial burden of disease.Methods We did a longitudinal cohort study with motherneonate pairs in local hospita

4、ls in southern China during 201318.We collected cord blood from neonates and venous blood from mothers at delivery.We followed up and collected blood samples from the children at ages 2,4,6,12,24,and 36 months and tested for the presence of neutralising antibodies against EV-A71 with virus neutralis

5、ation assays.Seropositivity,or protective titre,was defined as a neutralisation antibody titre of 16 or higher.We estimated the seroprevalence,geometric mean titre(GMT),and transfer ratio of maternal antibodies.We used a binomial distribution to derive the 95%CIs of seroprevalence.Seropositivity bet

6、ween mothers and neonates was compared by use of an agreement(),while GMTs were compared by use of paired Students t tests.Findings Between Sept 20,2013,and Oct 14,2015,1054 mothers with 1066 neonates were enrolled.The EV-A71 GMT was similar among pairs of neonates(227,95%CI 208249)and mothers(221,9

7、5%CI 202241;p=020).The mean transfer ratio of maternal antibodies was 103(95%CI 098108).Although 705(66%)of 1066 neonates acquired protective concentrations of EV-A71 antibodies from mothers,these declined rapidly,with a half-life of 42 days(95%CI 4044).The time to loss of protective immunity was ex

8、tended to 5 months in neonates with mothers who had titres of 128 or higher.By age 30 months,28%of children had become seropositive because of natural infection.Interpretation EV-A71 maternal antibodies were efficiently transferred to neonates,but declined quickly to below the protective threshold,p

9、articularly among those whose mothers had low antibody titres.Our findings suggest that maternal vaccination could be explored to provide neonatal protection against EV-A71 through maternal antibodies.Catch-up vaccination between ages 6 months to 5 years could provide protection to the approximately

10、 3090%of children that have not had natural EV-A71 infection by that age.Funding National Science Fund for Distinguished Young Scholars,National Natural Science Foundation of China.Copyright 2020 Elsevier Ltd.All rights reserved.Lancet Infect Dis 2020Published Online October 5,2020 https:/doi.org/10

11、.1016/S1473-3099(20)30480-1See Online/Comment https:/doi.org/10.1016/S1473-3099(20)30452-7For a Chinese translation of the abstract see Online for appendix 1*Contributed equallyContributed equallySchool of Public Health,Fudan University,Key Laboratory of Public Health Safety,Ministry of Education,Sh

12、anghai,China(X Wei MD,J Yang PhD,L Wang MSc,Q Liao MSc,Q Qiu MPH,Y Zhou MSc,J Zhang PhD,J Zhou BS,X Chen MD,L Ren MD,J Guo MD,Prof H Yu PhD);Hunan Provincial Center for Disease Control and Prevention,Changsha,China(L Gao MSc,K Luo MPH,H Yang MPH);Institut Pasteur of Shanghai,Chinese Academy of Scien

13、ces,Shanghai,China(L Wang);Key Laboratory of Surveillance and Early Warning on Infectious Disease,Division of Infectious Disease,Chinese Center for Disease Control and Prevention,Beijing,China(Q Liao,F Liu MD,S Yu PhD,Q Chen MPH,W Xing PhD,L Luo MSc,Prof H Yu);Hubei Provincial Center for Disease Con

14、trol and Prevention,Wuhan,China(Q Chen);Anhua County Center for Disease Control and Prevention,Yiyang,China(B Dai MD,M He MD,Z Chen MD);School of Public Health,Shandong First Medical University and Shandong Academy of Medical Sciences,Taian,China(W Xing);WHO Collaborating Centre for Infectious Disea

15、se Epidemiology and Control,IntroductionSince 1997,large epidemics of hand,foot,and mouth disease(HFMD)associated with enterovirus A71(EV-A71)among children younger than 5 years have been reported throughout the Asia-Pacific region,including mainland China.14 The estimated case-severity risk is 174%

16、and case-fatality risk is 0055%in mainland China.Younger age and living in rural areas were associated with greater risk of fatal outcomes.24 In the past 5 years,increased circulation of EV-A71 and outbreaks of HFMD have been described outside of Asia,which poses a growing global public health conce

17、rn.57In China,HFMD poses a substantial burden to health,with more than 1 million cases per year,with EV-A71 associated with the most severe and fatal outcomes.3,4 The case-fatality risk is highest among children younger than 1 year,especially among those younger than 6 months(about 017%in children y

18、ounger than 6 months vs 011%in those aged 611 months).3 No specific antiviral treatment is available for HFMD.Three licensed inactivated EV-A71 vaccines are available Articles2 Published online October 5,2020 https:/doi.org/10.1016/S1473-3099(20)30480-1 School of Public Health,Li Ka Shing Faculty of

19、 Medicine,The University of Hong Kong,Hong Kong,China(P Wu PhD,Prof B J Cowling PhD);Oxford University Clinical Research Unit,Hospital for Tropical Diseases,Ho Chi Minh City,Vietnam(H R van Doorn PhD);Nuffield Department of Medicine,University of Oxford,Oxford,UK(H R van Doorn);and Mathematical Mode

20、lling of Infectious Diseases Unit,Institut Pasteur,UMR2000,Centre National de la Recherche Scientifique,Paris,France(Prof S Cauchemez PhD)Correspondence to:Prof Hongjie Yu,School of Public Health,Fudan University,Key Laboratory of Public Health Safety,Ministry of Education,Shanghai 200032,China for

21、use in children aged 671 months in China.8,9 Infants younger than 6 months remain susceptible before they receive the first dose of EV-A71 vaccination.EV-A71 vaccines are used in the private sector in mainland China.To promote their introduction into the National Immunisation Programme,optimal timin

22、g and value of catch-up vaccination should be assessed.Information is needed on the presence and persistence of maternal antibodies and dynamics of antibodies from natural infection in early life.Several cross-sectional studies reported correlation of EV-A71 antibody levels in motherneonate pairs.10

23、13 However,only one longitudinal cohort study presented the half-life(42 days)from blood samples collected at birth and at age 6 months.14 Another study found 33%seropositivity in babies aged 3 months and 7%in those aged 6 months,but had high drop-out rates of 68%at age 3 months and 90%at age 6 mont

24、hs.15 Mao and colleagues16 reported seropositivity and antibody titre in babies aged 2 and 7 months,but could not estimate the dynamics of maternal antibodies because the blood samples were not collected for neonates at birth.In our study,we quantified antibody concentrations for EV-A71 in paired ma

25、ternal and cord serum samples from a large cohort of mothers and neonates,assessed the transplacental transfer efficiency of maternal antibodies,and analysed the antibody kinetics from birth to age 3 years,including the decline in maternal antibodies and subsequent increases due to natural infection

26、.MethodsStudy design and participantsWe established a longitudinal,paired motherneonate cohort in three townships(Tianzhuang,Jiangnan,and Qingtang)in Anhua county,Hunan Province,southern China from September,2013,to August,2018(appendix 2,p 3).Neonates were eligible for inclusion if Research in cont

27、extEvidence before this studyEnterovirus A71(EV-A71)is responsible for a substantial disease burden of hand,foot,and mouth disease(HFMD)in young children in the Asia-Pacific region,particularly in mainland China.An increased circulation of EV-A71 was described in European and North American countrie

28、s,leading to outbreaks of severe neurological illness,which poses a growing global public health concern.A 2015 systematic review showed that 30%of children in China were seronegative against EV-A71 and thus remained susceptible at age 5 years.Available licensed EV-A71 vaccines in China cannot be gi

29、ven to infants younger than 6 months,among whom a substantial burden of severe disease occurs.Necessity and timing of vaccination in early life is highly related with maternal-derived antibody levels and their persistence.We searched PubMed,Web of Science,China National Knowledge Infrastructure,and

30、Wanfang up to Feb 10,2020,using the following search terms:(enterovirus 71 OR EV-A71 OR EV-71 OR EV71)AND(seroepidemiology OR seroepidemiologic OR seroepidemiological OR serosurvey OR seroprevalence OR seroprevalent OR seronegative OR seropositive OR serologic OR serological OR seroincidence OR sero

31、conversion OR seroconvert OR GMT)AND(maternal OR maternally OR mother OR transplacental OR placental OR infant OR newborn OR neonate OR neonatal OR child OR children).Only four cross-sectional studies and one longitudinal cohort study reported the correlation between EV-A71 maternal and neonate anti

32、bodies in motherneonate pairs,with one study presenting the transfer ratio.Of these studies,the cohort study alone characterised the half-life of EV-A71 maternal antibodies,but obtained only two blood specimens from neonates within 6 months of age(ie,the cord blood and venous blood at age 6 months).

33、Another cohort study found that 33%of infants aged 3 months and 7%of infants aged 6 months were positive for EV-A71 antibodies.One study reported the seropositivity and antibody titres in neonates aged 2 and 7 months,but could not estimate the dynamics of maternal antibodies because the blood sample

34、s were not collected for neonates at birth.No studies were found that addressed the duration of protection conferred by maternal-transferred antibodies.Added value of this studyIn this study,we assessed the transplacental transfer ratio of EV-A71 antibodies,calculated the half-life of maternal-deriv

35、ed EV-A71 antibody titres,and the time to loss of protective immunity in neonates(with a cutoff titre of 16 or higher for protective titres).To our knowledge,this was the largest population-based study of motherneonate pairs followed up from birth to age 36 months that quantified the transplacental

36、transfer efficiency of EV-A71 antibodies,and measured the dynamics of EV-A71 antibodies in neonates.Our findings show that the mean transplacental transfer ratio was 103(95%CI 098108).Although the majority of neonates acquired protective concentrations of EV-A71 antibodies from their mothers,this pr

37、otection declined rapidly.After the disappearance of maternal antibodies,antibody titres rose because of natural infection,with about a third of children infected by the age of 25 years.Implications of all the available evidenceOur study showed that protective titres of EV-A71 antibodies could be ef

38、ficiently transferred to neonates from mothers through the placenta.However,maternal antibodies declined rapidly.The findings provide helpful information to guide EV-A71 vaccination programmes and suggest that maternal vaccination could be explored to provide protection to neonates and infants young

39、er than 6 months against EV-A71 through maternal antibodies.Catch-up vaccination between ages 6 months to 5 years could provide protection to the approximately 3090%of children that have not had natural EV-A71 infection by that age.See Online for appendix 2 A Published online October 5,2020 https:/d

40、oi.org/10.1016/S1473-3099(20)30480-1 3they were born after Sept 20,2013,and their mothers had resided in the study sites in the preceding 3 months or longer.Well trained nurses enrolled motherneonate pairs in six local hospitals.89%of pregnant women from these three townships give birth in these hos

41、pitals.The study was approved by the Institutional review board from WHO Western Pacific Regional Office(2013.10.CHN.2.ESR),the Chinese Centre for Disease Control and Prevention(201224),and Fudan University(2019050756).We obtained written informed consent from all enrolled mothers for themselves and

42、 their neonates.ProceduresWe collected a peripartum venous blood sample(2 mL)from each woman around the time of delivery and a cord blood sample(2 mL)from each neonate(baseline).Mothers were interviewed within 1 week of delivery to obtain information including demographics,gestational weeks,delivery

43、 method,and birthweight of neonates.Infant blood samples were taken at 2,4,6,12,24,and 36 months.The first three follow-ups(at 2,4,and 6 months)were done allowing 1 week before or after the scheduled age.The last three follow-ups(at 12,24,and 36 months)were done in FebruaryMarch or AugustNovember of

44、 201418,whichever was closer to the babys birthday.At each follow-up visit,we interviewed caregivers face to face about hygiene,vaccination,hospitalisation,and breastfeeding(up to 6 months)of the enrolled children.In FebruaryMarch,2017,we did a supple-mentary investigation to collect information on

45、mothers,including self-reported underlying diseases and health status during pregnancy.Aggregated data on all deliveries in the townships during the study period was retrieved from the Hunan Rural Population Health Information System.EV-A71 activity was identified through enhanced virological survei

46、llance of HFMD in Anhua17 and national notifiable disease surveillance data in Hunan3(appendix 2,pp 36).An EV-A71 vaccine was introduced in 2016,after recruitment and baseline visits were completed.For enrolled children who were vaccinated against EV-A71 during the study period,we excluded from the

47、analyses the antibody titres of blood samples collected after vaccination.Laboratory proceduresThe neutralisation assays are described in appendix 2(pp 68).Briefly,we used the EV-A71 FY573 strain(GenBank accession number HM064456.1),belong ing to the same subgenogroup C4 as the circulating strains i

48、n Anhua.Serum samples were serially diluted four-fold(1/8 to 1/2048)in duplicate.Neutralising titres were defined as the reciprocal of the highest dilution capable of inhibiting 50%of the cytopathic effect and calculated by use of the Karber method.18 Neutralisation titres lower than eight were assi

49、gned as four,and those higher than 2048 were assigned as 4096.Statistical analysisWe calculated that a sample size of 900 motherneonate pairs would allow a 10%annual risk of EV-A71 infection to be estimated to within 25%,with a statistical significance level of 5%,allowing for a drop-out rate of 39%

50、.We estimated the seroprevalence,geometric mean titre(GMT),and transfer ratio of maternal antibodies.The ratio of neonate-to-mother titre was log-transformed to obtain normal distribution.The geometric mean of the ratio is a frequently used metric to assess the transfer efficiency of maternal antibo