《(62)--医学微生物学mainRubellavirusneutralizinganti.pdf》由会员分享，可在线阅读，更多相关《(62)--医学微生物学mainRubellavirusneutralizinganti.pdf（6页珍藏版）》请在taowenge.com淘文阁网|工程机械CAD图纸|机械工程制图|CAD装配图下载|SolidWorks_CaTia_CAD_UG_PROE_设计图分享下载上搜索。
1、Rubella virus neutralizing antibody response after a third dose ofmeasles-mumps-rubella vaccine in young adultsHuong Q.McLeana,Amy Parker Fiebelkornb,Adaeze Ogee-Nwankwoc,1,LiJuan Haoc,Laura A.Colemana,2,Adebola Adebayoc,Joseph P.IcenoglecaCenter for Clinical Epidemiology&Population Health,Marshfiel
2、d Clinic Research Institute,1000 North Oak Ave,Marshfield,WI 54449,USAbImmunization Services Division,National Center for Immunization and Respiratory Diseases,Centers for Disease Control and Prevention,1600 Clifton Rd NE,Atlanta,GA 30329,USAcDivision of Viral Diseases,National Center for Immunizati
3、ons and Respiratory Diseases,Centers for Disease Control and Prevention,1600 Clifton Rd NE,Atlanta,GA 30329,USAa r t i c l ei n f oArticle history:Received 13 December 2017Received in revised form 21 June 2018Accepted 3 August 2018Available online 11 August 2018Keywords:RubellaThird-dose measles-mum
4、ps-rubella(MMR)vaccineImmune responsea b s t r a c tBackground:Third doses of measles-mumps-rubella(MMR)vaccine have been administered duringmumps outbreaks and in various non-outbreak settings.The immunogenicity of the rubella componenthas not been evaluated following receipt of a third dose of MMR
5、 vaccine.Methods:Young adults aged 1831 years with documented two doses of MMR vaccine received a thirddose of MMR vaccine between July 2009 and October 2010.Rubella neutralizing antibody titers wereassessed before,1 month,and 1 year after receipt of a third dose of MMR vaccine.Results:Among 679 par
6、ticipants,1.8%had rubella antibody titers less than 10 U/ml,immediately beforevaccination,approximately 15 years after receipt of a second dose of MMR vaccine.One month afterreceipt of a third dose of MMR vaccine,average titers were 4.5 times higher and 50%of participantshad a 4-fold boost.Response
7、was highest among those with titers less than 10 U/ml prior to vaccination(geometric mean titer ratio=18.8;92%seroconversion)and decreased with increasing pre-vaccinationtiters.Average titers declined 1 year postvaccination but remained significantly higher than pre-vaccination levels.The proportion
8、 classified as low-positive antibody levels increased from 3%1 monthpostvaccination to 24%1 year postvaccination.Conclusions:Vaccination with a third dose of MMR vaccine resulted in a robust boosting of rubella neu-tralizing antibody response that remained elevated 1 year later.Young adults with low
9、 rubella titers aremore likely to benefit from a third dose of MMR vaccine.?2018 Elsevier Ltd.All rights reserved.1.BackgroundAcute infection with rubella virus often results in a mild feverand rash.However,rubella infection in pregnant women,espe-cially during the first trimester,can result in misc
10、arriages,still-births,and congenital rubella syndrome(CRS),a constellation ofbirth defects that often includes cataracts,hearing loss,congenitalheart defects,and developmental delay 1.Rubella vaccines have been available since the late 1960s andare highly effective in preventing clinical disease 24.
11、In theUnited States,rubella vaccine was combined with measles andmumps vaccines as measles-mumps-rubella(MMR)vaccine in1971.Although only 1 dose of rubella-containing vaccine is cur-rently recommended in the United States by the Advisory Commit-tee on Immunization Practices(ACIP)5,most people receiv
12、e 2doses of MMR vaccine as a result of the recommended 2-doseMMR vaccine schedule for school-aged children(age 1215months and 46 years)for improved measles control starting in1989 6.High 2-dose MMR vaccination coverage contributed tothe end of endemic transmission of rubella and CRS in the UnitedSta
13、tes,which was declared in 2004 7.In 2011,an expert panelreviewed available data and unanimously agreed that rubella andCRS elimination has been maintained in the United States 8.Serologic studies have shown nearly all(?99%)children havedetectable rubella antibody and over half have a fourfold increa
14、sein rubella titer following receipt of a second dose of MMR vaccine911.Additionally,between 2004 and 2011,a median of 10 caseswere reported annually in the United States,of which,88%werehttps:/doi.org/10.1016/j.vaccine.2018.08.0100264-410X/?2018 Elsevier Ltd.All rights reserved.Corresponding author
15、 at:Center for Clinical Epidemiology&Population Health,Marshfield Clinic Research Institute,1000 North Oak Ave ML2,Marshfield,WI54449,USA.E-mail address:mclean.huongmarshfieldresearch.org(H.Q.McLean).1Present affiliation:Office of the Director,Center for Global Health,Centers forDisease Control and
16、Prevention,Atlanta,GA,USA.2Present affiliation:Novartis Institutes for Biomedical Research,Cambridge,MA,USA.Vaccine 36(2018)57325737Contents lists available at ScienceDirectVaccinejournal homepage: or had unknown vaccination status 8.Although it isunlikely a third dose is currently needed to maintai
17、n elimination ofendemic rubella transmission,information on a third dose in theUnited States may be important in the future for maintenance ofrubella elimination,since population immunity may change.Illus-trating the evolution of MMR vaccination recommendations is thefact that a third dose of MMR va
18、ccine has been administered duringmumps outbreaks 1214 and recently recommended for personsidentified by public health as being at increased risk during mumpsoutbreaks 15.A third dose has also been administered innon-outbreak settings to healthcare personnel,military recruits,international travelers
19、,and college students who may have beenvaccinated with two doses previously but lacked documentationof receipt 16,17.Additional vaccination is also recommended forwomen of childbearing age or pregnant women with a negativerubella titer(after delivery for pregnant women)even if they havehad two previ
20、ous doses of MMR vaccine 5.The immunogenicityof the rubella component following receipt of a third dose of MMRvaccine has not been systematically evaluated among persons withdocumentedreceiptoftwodosesofMMRvaccine.Wemeasuredtherubella neutralizing antibody response one month after receipt of athird
21、dose of MMR vaccine in a healthy,young adult population andpersistence of the response one year after receipt.We also assessedpersistence of rubella neutralizing antibody levels among youngadults who have received two doses of MMR vaccine in childhood.2.Methods2.1.Study population and proceduresFrom
22、 July 2009 throughOctober 2010,young adults aged 1831years were contactedby mail and telephone to assess study eligibil-ity and invite participation.Individuals were eligible for the study ifthey(1)had previously participated in a longitudinal study at theMarshfield Clinic examining immunogenicity a
23、nd adverse eventsfollowing the second dose of MMR vaccine(MMR2 study)9,1820,or(2)were aged 1825 years and lived in or around Marshfield,Wisconsin with two doses of MMR vaccine documented in theMarshfield Clinics electronic immunization registry(www.recin.org).Details of study procedures,including sa
24、mple size determina-tion and exclusion criteria were previously described 21,22.Briefly,participants received a third dose of MMR vaccine(M-M-R II,Merck&Co)at the enrollment visit,and serum samples werecollected for antibody testing immediately before vaccination,andapproximately 1 month and 1 year
25、postvaccination.Participantswho had documented titers of?121 mIU/mL for measles,10 formumps,and 10 U/ml for rubella 21 during the follow-up periodfor the previous MMR2 study were not offered a third dose of MMRvaccine,but provided serum samples at the enrollment visit andapproximately one year after
26、 enrollment.All participants wereadministered a survey to obtain information on demographics,clinical history(e.g.,current illness and medications),history ofpotential exposures(e.g.,military,university/college attendance),living conditions(e.g.,type of housing,number of household mem-bers),and hist
27、ory of foreign travel at the enrollment visit.Historyof rash,exposure to measles,mumps,or rubella,and illness frommeasles,mumps,and rubella were assessed at every visit.The study was approved by the Institutional Review Boards atthe Marshfield Clinic and Centers for Disease Control and Preven-tion(C
28、DC).2.2.Laboratory methodsSerum samples were processed and stored at the MarshfieldClinic Research Institute at?80?C until shipping to CDC for testing.Samples collected before receipt of the third dose of MMR vaccine(or at enrollment among those who did not receive a third dose),and approximately 1
29、month and 1 year postvaccination/enroll-ment were tested after completion of the 1 year postvaccinationvisit.All samples from the same individuals were tested in thesame run.A soluble immunocolorimetric neutralization assay(sICNA)wasused to assess rubella neutralization titer at each time point as p
30、re-viously described 23.Briefly,the ability of each serum to neutral-ize 30 plaque forming units of HPV-77 rubella virus was assessedas follows.Sera were serially diluted in duplicate in a 2-fold seriesbeginning from 1:20 and continuing through 1:160 for pre-vaccination and 1 year postvaccination se
31、ra,and from 1:80through 1:640 for 1 month postvaccination.Control sera werediluted similarly.The amount of remaining infectivity in theserum-virus mixtures was determined by infecting Vero cellmonolayers.The standard control sera with known neutralizationtiters were included with each test.The end-p
32、oint was defined asa 50%reduction in infectivity as measured 3 days postinfection.Serum-virus mixtures that had less than 50%of the input infectiv-ity at the last dilution were retested in a more dilute dilution ser-ies.Serum-virus mixtures that had more than 50%of inputinfectivity at the first dilu
33、tion were retested using a less dilutedilution series.The lowest dilution tested was 1:10.To confirmreproducibility,a total of 480 sera were retested 1 week to 1month after the original tests.Final neutralization titers were cal-culated according to the previously described LOESS method 23.2.3.Stati
34、stical analysisAntibody titers were categorized into four groups:negative(titer 10 U/ml),low-positive(titers 10 U/ml to less than40 U/ml),medium-positive(titers 40 U/ml to less than 120 U/ml),and high-positive(titers?120 U/ml).Titers measured for specimens collected at enrollment for allparticipants
35、 were used to assess long-term persistence of rubellaantibodies following receipt of a second dose of MMR vaccine.Toassess antibody response and short term persistence followingreceipt of a third dose of MMR vaccine,only participants whoreceived a third dose in this study were included(5 participant
36、swere excluded because they only had titer data at enrollment).The following endpoints were assessed:(1)geometric mean titer(GMT),using log2-transformed titers and reported as back-transformed value;(2)geometric mean of the titer ratio(GMTratio),defined as the geometric mean of the difference betwee
37、npostvaccinationlog2-transformedtiterandpre-vaccinationlog2-transformed titer(reported as back-transformed value);and(3)4-fold boost,defined as a ratio of?4 for 1 month postvaccina-tion titer to pre-vaccination titer.GMT ratio was assessed for boththe 1 month and 1 year postvaccination visits.Logist
38、ic regressionusing backwards elimination(factors retained if p .05)was usedto assess factors associated with a 4-fold boost following vaccina-tion with a third dose.Potential factors assessed included sex,ageat first MMR dose(categorized as 1215 and?16 months),timebetween second and third dose(categ
39、orized into tertiles:14,1418,and?18 years),age at third dose(1822 and 2331 years),and prevaccination titer(continuous log2transformed value).Sec-ondary analysis was also conducted restricting to participants who(1)received their first dose of MMR vaccine at age 1215 monthsand second dose at age 46 y
40、ears,the ages recommended by ACIP5,and(2)had rubella titer data for all three study visits.Differences in characteristics between groups were assessedusingv2tests for categorical variables,ANOVA for normally dis-tributed continuous variables,and Wilcoxon rank-sum test forlog-transformed variables.Al
41、l analyses were performed using SAS9.4(SAS Institute,Cary,North Carolina).H.Q.McLean et al./Vaccine 36(2018)5732573757333.Results3.1.Study populationOf the 685 participants enrolled,baseline rubella antibody datawere available for 679(659 who received a third dose and 20 whodid not receive a third d
42、ose).The median age of participants atenrollment was 20.8 years(range 1828 years)and 56%were male.A higher proportion of new enrollees were age 2331 years(26%vs16%,p=0.03)versus 1822 years,and received their second doseof MMR vaccine at age 46 years(97%vs 83%,0.001)versus otherages compared to parti
43、cipants who were enrolled from the previ-ous MMR2 study(Table 1).Participants were enrolled a medianof 15.6 years(range:6.720.3 years)after receipt of the seconddose of MMR vaccine.3.2.Long-term persistence of rubella antibodies following receipt ofthe second dose of MMR vaccineAt enrollment or appr
44、oximately 15 years following receipt ofthe second dose of MMR vaccine,12(1.8%)of 679 participantshad undetectable rubella titers(10).By design,recruits from theMMR2 study who did not receive a third dose of MMR vaccinehad higher rubella GMT than those who received a third dose(74.9 vs 39.3 U/ml,p=0.
45、004)(Table 2).Among participants whoreceived a third dose of MMR vaccine,there were no differencesin the distribution by antibody titer categories or GMT betweenrecruits from the previous MMR2 study vs new recruits(Table 2).There were also no significant differences in antibody titer cate-gories by
46、time since the second dose.3.3.Rubella antibody response following receipt of a third dose ofMMR vaccineOne month after receipt of the third dose of MMR vaccine,50%of 654 recipients had a 4-fold boost and rubella antibody titerswere an average of 4.5 times higher than pre-vaccination titers(Table 2
47、and Fig.1).None of the participants had titers less than10 U/ml.Antibody response varied by rubella antibody titer cate-gory pre-vaccination.Although all groups experienced an increasein antibody titer with GMTs above 150 U/ml following vaccination,the response was highest among those with titers le
48、ss than10 U/ml prior to vaccination(GMT ratio=18.8 and 92%serocon-version)and decreased with increasing pre-vaccination titers(Table 3).No one with high-positive titers prior to vaccinationhad a 4-fold boost following vaccination.Pre-vaccination titerwas the only factor associated with a 4-fold boos
49、t 1 month afterreceipt of a third dose in the logistic regression model.A 2-foldincrease in pre-vaccination titer was associated with 76%lowerodds of a 4-fold boost(95%CI,5487%).3.4.Short-term persistence of rubella antibody 1 year after a third doseof MMR vaccineOne year after receipt of the third
50、dose,all recipients continuedto have detectable rubella antibody titers(?10 U/ml),but antibodylevels declined from levels at one month postvaccination.The pro-portion with low-positive antibody levels increased from 3%1month postvaccination to 24%1 year postvaccination.However,antibodylevelsremained