Vaccines 2013, 1, ; doi: /vaccines Article. Deanna Kruszon-Moran 1, *, R. Monina Klevens 2 and Geraldine M.

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1 Vaccins 2013, 1, ; doi: /vaccins Articl OPEN ACCESS vaccins ISSN X Chang in Hpatitis A Sroprvalnc among U.S. Childrn and Adolscnts: Rsults from th National Halth and Nutrition Examination Survy and Danna Kruszon-Moran 1, *, R. Monina Klvns 2 and Graldin M. McQuillan Division of Halth and Nutrition Examination Statistics, National Cntr for Halth Statistics (NCHS), Cntrs for Disas Control and Prvntion, 3311 Toldo Rd., Room 4308 Hyattsvill, MD 20782, USA Division of Viral Hpatitis, National Cntr for HIV/AIDS, Viral Hpatitis, STD, and TB Prvntion (NCHHSTP), Cntrs for Disas Control and Prvntion,1600 Clifton Rd., MS G-37, Atlanta, GA 30333, USA; rmk2@cdc.gov Division of Halth and Nutrition Examination Statistics, National Cntr for Halth Statistics (NCHS), Cntrs for Disas Control and Prvntion, 3311 Toldo Rd., Room 4204 Hyattsvill, MD 20782, USA; gmm2@cdc.gov * Author to whom corrspondnc should b addrssd; ddk0@cdc.gov; Tl.: ; Fax: Rcivd: 29 January 2013; in rvisd form: 13 March 2013 / Accptd: 5 April 2013 / Publishd: 10 April 2013 Abstract: To xamin changs in sroprvalnc of antibodis to hpatitis A virus (HAV) during a priod in which univrsal vaccin rcommndations for all U.S. childrn wr implmntd, rsults from srologic tsting from th National Halth and Nutrition Examination Survy (NHANES) from wr analyzd among 7,989 participants ag 6 19 yars, born in th U.S. in two birth cohorts ( and ). Ovrall prvalnc incrasd ovr tim from 24.4% in to th highst vr rportd (37.6%) in Spcifically, incrass rachd statistical significanc in th birth cohort born in th yars aftr implmntation of vaccin rcommndations ( ), among thos of rac/thnicity othr than whit, non-hispanic, and among stats whr rcommndations wr implmntd latr. Th gratst incras ovr tim was among th subgroup of prsons in stats with arly implmntation who wr of rac/thnicity othr than whit, non-hispanic. Gographic rgion and birth cohort basd on vaccin rcommndations as wll as rac/thnicity wr th main prdictors of sropositivity in

2 Vaccins 2013, Th incras in Hpatitis A sroprvalnc occurrd during a tim of dcrasing incidnc and incrasing vaccination, howvr rac/thnic disparitis prsist. Kywords: Hpatitis A virus; HAV; NHANES; vaccination; sroprvalnc; birth cohort 1. Introduction Hpatitis A virus (HAV) is transmittd through th fcal-oral rout and sprad primarily through clos prsonal contact with an HAV-infctd prson. Hpatitis A was onc on of th most frquntly rportd notifiabl disass in th Unitd Stats (U.S.) with a rportd incidnc of 10.7 cass pr 100,000 population from , with incidnc varying by ag, gndr, rac/thnicity and gographic rgion [1]. In 1995, th first Hpatitis A vaccins wr licnsd in th Unitd Stats and by 1996 th Advisory Committ on Immunization Practics (ACIP) mad rcommndations for routin vaccination of childrn agd 2 18 yars living in communitis with th highst rats of infction and disas [2]. By 1999, pidmiologic vidnc suggstd that th stratgy had a limitd impact on national disas incidnc [3]. Thrfor in 1999, th ACIP rcommndd routin vaccination for childrn living in 11 mostly wstrn stats, with man incidnc rats that wr at last twic th national man (i.., 20 cass pr 100,000 population). In addition, th ACIP rcommndd considration of routin vaccination of childrn in an additional six stats, whr man incidnc rats wr highr than th national avrag, but lss than twic that valu (i.., cass pr 100,000 population [3]. By 2003, acut hpatitis A disas had dclind ovrall by 76%, from a rat of 10.7 pr 100,000 population during to 2.6 pr 100,000 population in 2003 [1]. In 2006, ACIP rcommndd intgration of HAV vaccin into th routin childhood vaccination schdul, with HAV vaccin administrd for all childrn at ag 12 months [4]. By 2007, th rat of acut Hpatitis A again dclind to 1.0 pr 100,000 population [5] and by 2009 th rat was th lowst vr rportd at 0.6 cass pr 100,000 population [6]. Th Halthy Popl 2020 goal is to rduc incidnt Hpatitis A cass to 0.3 cass pr 100,000 population [7]. Population-basd sroprvalnc survys play a critical rol in supplmnting data systms for disas incidnc, vaccination covrag, and vaccin advrs vnts in th dvlopmnt of vaccination policy [8]. Bfor th availability of vaccin, sroprvalnc of antibody to HAV (anti-hav) in th population solly rflctd prior infction [9]. Currntly, sroprvalnc can rflct immunity du to ithr prvious infction or to vaccination. Earlir studis of data from th National Halth and Nutrition Examination Survys dscribd HAV sroprvalnc and prdictors of sropositivity for th yars prior to any vaccination ( ) and prior to th 2006 ACIP rcommndation of univrsal vaccination of all childrn ( ) [9,10]. Studis of vaccination covrag show incrasd covrag sinc 2006, variability in covrag by rac/thnicity, highr covrag in th stats whr vaccin rcommndations wr initiatd arly (1999) but th gratst incras in covrag occurs among stats in which vaccination rcommndations wr initiatd latr [11]. Our objctiv was to dscrib chang in sropositivity to HAV in th U.S. among childrn and adolscnts from th pr-vaccin ra ( ) to th post-vaccin ra ( ) for thos ag 6 19 yars during a tim of dcrasing HAV incidnc. W also valuatd sociodmographic factors associatd with

3 Vaccins 2013, sroprvalnc in th post vaccin ra ( ), and compard ths findings with thos of prvious studis basd on data bfor a vaccin bcam availabl. 2. Exprimntal Sction 2.1. Data Sourc and Sampl Dsign Data for this study cam from Th National Halth and Nutrition Examination Survys (NHANES), a sris of survys conductd by th U.S. Cntrs for Disas Control and Prvntion s (CDC) National Cntr for Halth Statistics that obtains nationally rprsntativ data on th halth and nutritional status of th non-institutionalizd, civilian population of th Unitd Stats. NHANES uss a complx, stratifid, multistag probability sampl dsign and collcts information using standardizd houshold intrviws, physical xaminations conductd in mobil xamination cntrs, and tsting of biologic sampls. Th continuous NHANES bgan in 1999 and data fils ar rlasd in two-yar cycls. W analyzd data from ight yars of th continuous NHANES, groupd into two four yar cycls ( and ). For NHANES , non-hispanic blacks, Mxican Amricans, adolscnts, and low incom prsons wr sampld at highr frquncis than othr prsons to provid mor prcis stimats for ths groups. Starting in 2007, adolscnts ar no longr ovrsampld and all Hispanic prsons wr targtd for ovrsampling rathr than just Mxican Amrican prsons. Mor dtaild information on survy dsign for NHANES survys, including approval from th Ethics Rviw Board for data collction and analysis, is availabl from th survy documntation [12] Laboratory Tsting Blood spcimns from prsons 6 yars of ag (for ) and 6 19 yars of ag ( ) wr procssd, stord, and shippd to CDC s Division of Viral Hpatitis Laboratory. A qualitativ dtrmination of total anti-hav in srum or plasma was masurd using a solid-phas comptitiv nzym immunoassay (HAVAB-EIA, Abbott Laboratoris, Abbott Park, IL, USA). Srologic rsults for thos ag 6 19 yars wr usd in this analysis Dfinitions th FIPR An anti-hav positiv prson was considrd immun to HAV infction through ithr vaccination or natural infction. Rac and thnicity wr catgorizd, basd on a subjcts slf-rportd information, as non-hispanic whit, non-hispanic black, or Mxican Amrican. Subjcts that wr not classifid into on of ths catgoris wr classifid as othr. Country of birth was catgorizd as U.S. or non-u.s. birth. Povrty indx was calculatd by dividing family incom by a povrty thrshold spcific for family siz. Th US Dpartmnt of Halth and Human Srvics povrty guidlins wr usd as th povrty masur to calculat th povrty indx [13]. Education lvl was masurd as last yar of school compltd using had of houshold ducation and groupd into thr lvls: lss than a high school graduat, high school compltd, and mor than high school compltd. Halth insuranc status was catgorizd as having any insuranc or having non.

4 Vaccins 2013, Analyss wr rstrictd to U.S.-born prsons to bst rflct U.S.-acquird immunity. Basd on rstrictd us NHANES gographic data, prsons wr groupd by stat of rsidnc into two groups, according to th 1999 ACIP hpatitis A vaccination rcommndations and consistnt with othr analyss [3]: (1) th 17 arly vaccinating stats, whr hpatitis A vaccination was rcommndd (AK, AZ, CA, ID, NM, NV, OK, OR, SD, UT, WA) or whr vaccination was considrd (AR, CO, MO, MT, TX, WY), and (2) th rmaining 33 latr vaccinating stats, whr no routin childhood vaccination was rcommndd in 1999 (AL, CT, DE, FL, GA, HI, KS, KY, IA, IL, IN, LA, MA, MD, ME, MI, MN, MS, NC, ND, NE, NH, NJ, NY, OH, PA, RI, SC, TN, VA, VT, WI, WV). Prsons wr also catgorizd into birth cohorts basd on rstrictd data using actual dat of birth and into two groups basd on initiation of vaccin rcommndations; thos born btwn (bfor vaccin rcommndations) and thos born btwn (aftr vaccin rcommndations). Thr wr 936 sampl prsons ag born bfor 1987 in survy yars that wr not includd in ithr birth cohort and thrfor wr not includd in this analysis Statistical Analysis Sroprvalnc stimats wr wightd to rprsnt th total civilian, non-institutionalizd U.S. houshold population and to account for ovrsampling and non-rspons to th houshold intrviw and physical xamination [14]. Bcaus w utilizd a variabl basd on U.S. gography, w wr unabl to us th publically rlasd maskd stratum and primary sampling units (PSU s) to dsignat th complx sampl dsign in our analyss. Th tru stratum and PSU dsignations wr usd instad. Ninty-fiv prcnt confidnc intrvals (95% CI) wr stimatd by using th xact binary mthod [15]. Statistical comparisons btwn subgroups wr valuatd using a t-statistic obtaind from a linar contrast procdur in SUDAAN (rlas vrsion 10.0, Rsarch Triangl Institut, Rsarch Triangl Park, NC, USA), a statistical packag dsignd to analyz complx survy data. P-valus of lss than 0.05, with dgrs of frdom qual to th minimum calculatd for ithr subgroup in th comparison, wr considrd significant. No adjustmnts for multipl comparisons wr mad. Bcaus prvalnc was vry low (lss than 10%) in som smallr subgroups as wll as vry high (approaching 90%) in othrs, th stability of an stimat was basd on both th prcnt positiv and prcnt ngativ as wll as th numbr of positiv and ngativ individuals. An stimat was dsignatd as unstabl whn th rlativ standard rror of th stimat was gratr than 30% (RSE = standard rror of th prcnt/prcnt xprssd as a prcnt) or whn th numbr of ngativ or positiv individuals was <10. Bcaus of small numbrs in ach survy cycl for svral rac/thnic subgroups whn stratifying on gographic rgion, w collapsd rac/thnic catgoris to whit, non-hispanic and all othr rac/thnic groups combind (all othrs). A logistic modling procdur in SUDAAN was usd to valuat intractions btwn chang in sroprvalnc by survy cycl and ithr rac/thnic group or birth cohort within ach gographic rgion. Logistic modling was also usd to dtrmin cofactors indpndntly associatd with anti-hav sroprvalnc for th data from Modl trms with a Sattrthwait-adjustd F statistic with a p < 0.05 wr considrd to b significant prdictors of HAV sropositivity.

5 Vaccins 2013, Rsults 3.1. HAV Tsting Rspons Rats Thr wr 4,955 prsons agd 6 19 yars born in th U.S. btwn , intrviwd in NHANES , and 4,622 in NHANES Ninty svn prcnt of thos intrviwd in both (n = 4,788) and (n = 4,488) wr xamind and 87% of thos xamind in (n = 4,185) and 85% in (n = 3,805) had blood drawn and wr tstd for Hpatitis A virus antibody. Rspons to HAV tsting varid by many prdictors of sropositivity including gographic rgion and rac/thnic group by 5%. Diffrnc in rspons was gratst for birth cohort (89% for birth cohort and 79% for birth cohort in NHANES and 89% and 80% rspctivly for birth cohorts and in NHANES , p < 0.001). All analyss wr rpatd with nw wights adjustd for th diffrncs in non-rspons by th thr main prdictors of sropositivity, gographic rgion, birth cohort and rac/thnic group. Estimats diffrd by lss than 1% and thr wr no changs in any rsults. All rsults rportd wr calculatd using original wights Chang in Sropositivity ovr Tim (Survy Cycl) by Birth Cohort, Gographic Rgion, and Rac/Ethnicity Prvalnc of anti-hav among U.S. born individuals ag 6 19 yars incrasd ovr tim by 13.1 prcntag points from 24.4% (95% CI %) in NHANES to 37.6% (95% CI %) in NHANES (p < 0.05) (Tabl 1). Prvalnc of antibody incrasd ovr tim in th rgion with latr vaccin rcommndations (11.5 prcntag points, p < 0.01). A similar ffct was found in th rgion with arly rcommndations (18.5 prcntag points) but it did not rach statistical significanc. Ovrall sropositivity was significantly highr in th rgion with arlir rcommndations as compard to th rgion with latr rcommndations in both four yar survy cycls (p < for both). Prvalnc incrasd significantly ovr tim in th post vaccin birth cohort ( ) (18.9 prcntag points p < 0.01) (Tabl 1). Thr was not a significant incras in prvalnc ovr tim among prsons in th pr-vaccin birth cohort ( ). Prvalnc was significantly highr in th post vaccin birth cohort as compard to th pr-vaccin birth cohort but only in th latr survy cycl (p < 0.001). Prvalnc incrasd significantly ovr tim among non-hispanic blacks (19.1 prcntag points, p < 0.01) and among Mxican Amricans (23.3 prcntag points, p < 0.001) as wll as among all prsons combind who wr not non-hispanic whit (24.0 prcntag points, p < 0.001). Thr was no incras in prvalnc among whit, non-hispanic prsons (Tabl 1). Sroprvalnc was lowr among whit, non-hispanic prsons compard to all othrs combind and compard to Mxican Amricans in both survy cycls (Tabl 1). Sroprvalnc was also lowr among whit, non-hispanic prsons as compard to black, non-hispanic prsons but only in th survy cycl (p < 0.01). Black, non-hispanic prsons had lowr sroprvalnc compard to Mxican Amricans in both survy cycls (p < for both).

6 Vaccins 2013, Bcaus chang in sropositivity ovr tim and initiation of vaccin rcommndation policy wr both strongly associatd with gographic rgion, additional analyss wr conductd stratifid on rgion. Du to small numbrs and unstabl stimats with th multi-lvl stratification ndd to tst for ths intractions, diffrncs in rac/thnicity wr limitd to th two catgory variabl for ths analyss whit, non-hispanics and all othrs combind. Significanc tsts for chang ovr tim and possibl intractions with rac/thnicity or yar of birth cohort wr conductd using logistic rgrssion stratifying on gographic rgion and adjusting for th othr cofactor. Th incras in sropositivity ovr tim, although it did not rach statistical significanc, was similar in both birth cohorts in th gographic rgion with arly rcommndations (p > 0.05 for both, p > 0.05 for intraction trm, Figur 1). This was not tru in th rgion with latr rcommndations. In th latr rgion, th incras ovr tim was gratr in th post-vaccin birth cohort (p < 0.001) as compard to th pr-vaccin cohort (p < 0.05) (p < for th intraction trm). Not th rlativ standard rror for th stimat for th first survy cycl for thos in th post vaccin birth cohort in this rgion was high (>30%) making th stimat unstabl; thrfor, rsults should b intrprtd with caution. Th incras in sropositivity was similar btwn whit, non-hispanics (p < 0.05) and all othrs combind (p < 0.01) in th gographic rgion with latr vaccin rcommndations (Figur 2). Thr was no significant intraction btwn chang in sropositivity (survy cycl) and rac/thnic group in this rgion (p > 0.10 for intraction trm). In contrast, in th rgion with arly vaccin rcommndations, th incras in sropositivity ovr tim was much gratr among th all othrs combind rac/thnic group (p < 0.001) as compard to th whit, non-hispanic rac/thnic group (p > 0.05) (p < 0.05 for th intraction trm) Prdictors of Sropositivity Using Logistic Modls for To dtrmin significant socio-dmographic prdictors of currnt HAV antibody sropositivity in th U.S. for th most rcnt point in tim, data from th survy cycl was analyzd using logistic rgrssion modling. Possibl prdictors valuatd wr dtrmind from prvious analyss publishd using data [10]. Significant prdictors wr dfind as thos with a p < 0.05 in th full modl (Tabl 2). As xpctd gographic rgion basd on arly vaccin rcommndations, yar of birth cohort and rac/thnicity wr significant prdictors of sropositivity. Additional prdictors of gratr sropositivity includd fmal gndr. Bcaus vaccin rcommndations wr initiatd at diffrnt tims by rgion of th U.S. and changs in sropositivity ovr tim by rac and birth cohort also varid by rgion, modls wr run stratifid by this variabl. Highr sropositivity in among thos in th all othrs combind rac/thnic group as compard to whit, non-hispanic sampl prsons was much gratr in th gographic rgion with arly vaccin rcommndations (odds ratio (OR) 5.1 (95% CI ) as compard to th rgion with latr rcommndations (OR 2.2 (95% CI ). Othr than rac/thnicity, yar of birth cohort was th only othr significant prdictor in th rgion with arly vaccin rcommndations. Thr wr no othr significant prdictors of sropositivity for this rgion. Possibl intractions of ach cofactor with yar of birth cohort wr also xamind but stimats wr too unstabl in many subgroups to stratify on yar of birth cohort.

7 Vaccins 2013, Tabl 1. Prvalnc of HAV antibody among U.S. born 6 19 yar old childrn and adolscnts: NHANES and NHANES NHANES n Prcnt Lowr Uppr n Prcnt Lowr Uppr Incras Prvalnc 95% CI 95% CI Prvalnc 95% CI 95% CI Ovr tim p-valu All 4, , p < 0.05 Rgion of th U.S. * Early rgion (rf) 1, , NS Latr rgion 2, a , a p < 0.01 Birth Cohort ^ Pr-vaccin (rf) 3, , NS Post vaccin , a p < 0.01 Rac/thnicity Whit, non-hispanic (rf) 1, , NS Black, non-hispanic 1, b p < 0.01 Mxican Amrican 1, a a p < Whit, non-hispanic (rf) 1, , NS All othrs + 3, c , a p < HAV = Hpatitis A virus; NHANES = National Halth and Nutrition Examination Survy; CI = confidnc intrval; * Early rgion includs thos stats in which th ACIP rcommndd or considrd rcommnding HAV vaccin in 1999 (Alaska, Arizona, California, Idaho, Nw Mxico, Nvada, Oklahoma, Orgon, South Dakota, Utah, Washington, Arkansas, Colorado, Missouri, Montana, Txas, and Wyoming). Latr rgion includ thos stats with latr HAV vaccin rcommndations starting in 2006; (Alabama, Conncticut, Dlawar, Florida, Gorgia, Hawaii, Kansas, Kntucky, Iowa, Illinois, Indiana, Louisiana, Massachustts, Maryland, Main, Michigan, Minnsota, Mississippi, North Carolina, North Dakota, Nbraska, Nw Hampshir, Nw Jrsy, Nw York, Ohio, Pnnsylvania, Rhod Island, South Carolina, Tnnss, Virginia, Vrmont, Wisconsin, and Wst Virginia); rf = rfrnc group; NS = not statistically significant; a = p < 0.001, b = p < 0.01, c = p < 0.05 from t-tst comparing subgroup to rfrnc group within ach survy cycl. ^ Pr-vaccin birth cohort wr thos born from and post vaccin birth cohort wr thos born from All othrs rfrs to th combind rac/thnic group that includs all thos othr than non-hispanic whit. All othrs includs non-hispanic blacks, Mxican Amricans, othr Hispanics, and othr racs including multi-racial.

8 Vaccins 2013, Figur 1. HAV sropositivity ovr tim among U.S. born childrn and adolscnts 6 19 yars old stratifid by birth cohort and rgion of th U.S.: NHANES and P r c n t S r o p o s i t i v NHANES NHANES Post-vaccin birth cohort * in rgion ^ with arly vaccin rcommndations Pr-vaccin birth cohort * in rgion ^ with arly vaccin rcommndations Post-vaccin birth cohort * in rgion ^ with latr vaccin rcommndations Pr-vaccin birth cohort * in rgion ^ with latr vaccin rcommndations Incras in 95% CI for P - valu for Prvalnc Incras incras NS NS p < p < 0.05 HAV = Hpatitis A virus; NHANES = National Halth and Nutrition Examination Survy; * Pr-vaccin birth cohort wr thos born from and post-vaccin birth cohort wr thos born from ^ Early rgion includs thos stats in which th ACIP rcommndd or considrd rcommnding HAV vaccin in 1999 (Alaska, Arizona, California, Idaho, Nw Mxico, Nvada, Oklahoma, Orgon, South Dakota, Utah, Washington, Arkansas, Colorado, Missouri, Montana, Txas, and Wyoming). Latr rgion includs thos stats with latr HAV vaccin rcommndations starting in 2006 (Alabama, Conncticut, Dlawar, Florida, Gorgia, Hawaii, Kansas, Kntucky, Iowa, Illinois, Indiana, Louisiana, Massachustts, Maryland, Main, Michigan, Minnsota, Mississippi, North Carolina, North Dakota, Nbraska, Nw Hampshir, Nw Jrsy, Nw York, Ohio, Pnnsylvania, Rhod Island, South Carolina, Tnnss, Virginia, Vrmont, Wisconsin, and Wst Virginia). CI = confidnc intrval; NS = not significant (p > 0.05); + high rlativ standard rror (>30%) for NHANES stimat for post-vaccin birth cohort in rgion with latr vaccin rcommndations.

9 Vaccins 2013, Figur 2. HAV sropositivity ovr tim among U.S. born childrn and adolscnts 6 19 yars old stratifid by rac/thnic group and rgion of th U.S.: NHANES and P r c n t S r o p o s i t i v NHANES NHANES All othrs combind* in rgion^ with arly vaccin rcommndations Whit, non-hispanic in rgion^ with arly vaccin rcommndations All othrs combind* in rgion^ with latr vaccin rcommndations Whit, non-hispanic in rgion^ with latr vaccin rcommndations Incras in 95% CI for P-valu for Prvalnc Incras Incras p< NS p< p<0.05 HAV = Hpatitis A virus; NHANES = National Halth and Nutrition Examination Survy; * All othrs rfrs to th combind rac/thnic group that includs all thos othr than non-hispanic whit. All othrs includs: non-hispanic blacks, Mxican Amricans, othr Hispanics, and othr racs including multi-racial. ^ Early rgion includs thos stats in which th ACIP rcommndd or considrd rcommnding HAV vaccin in 1999 (Alaska, Arizona, California, Idaho, Nw Mxico, Nvada, Oklahoma, Orgon, South Dakota, Utah, Washington, Arkansas, Colorado, Missouri, Montana, Txas, and Wyoming). Latr rgion includs thos stats with latr HAV vaccin rcommndations starting in 2006 (Alabama, Conncticut, Dlawar, Florida, Gorgia, Hawaii, Kansas, Kntucky, Iowa, Illinois, Indiana, Louisiana, Massachustts, Maryland, Main, Michigan, Minnsota, Mississippi, North Carolina, North Dakota, Nbraska, Nw Hampshir, Nw Jrsy, Nw York, Ohio, Pnnsylvania, Rhod Island, South Carolina, Tnnss, Virginia, Vrmont, Wisconsin, and Wst Virginia). CI = confidnc intrval; NS = not significant (p > 0.05).

10 Vaccins 2013, Tabl 2. Prdictors of HAV sropositivity from logistic rgrssion modls among U.S. born childrn and adolscnts 6 19 yars of ag by rgion basd on HAV vaccin rcommndations and birth cohort: NHANES Pr-vaccin Post-vaccin Birth cohort in Birth cohort in All Rgion with Early Vaccin Rcommndations a Rgion with Latr Vaccin Rcommndations b Rgion with Latr Vaccin Rcommndations Rgion with Latr Vaccin Rcommndations Charactristics OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) Rgion of th U.S. Early a 6.7 ( ) c NA NA NA NA Latr b rf Birth Cohort * Pr-vaccin rf rf rf NA NA Post-vaccin 1.6 ( ) c 1.9 ( ) 1.5 ( ) c Rac/thnicity Non-Hispanic whit rf rf rf rf rf All othrs ^ 3.0 ( ) c 5.1 ( ) c 2.2 ( ) c,f 1.5 ( ) 3.2 ( ) c Gndr Mal rf rf rf rf rf Fmal 1.2 ( ) d 1.0 ( ) 1.3 ( ) 1.3 ( ) 1.4 ( ) d Povrty Indx < ( ) 1.0 ( ) 1.0 ( ) 1.0 ( ) 0.9 ( ) 1.0 rf rf rf rf rf Education of had of houshold <High school 1.1 ( ) 1.0 ( ) 1.1 ( ) 1.0 ( ) 1.3 ( ) High school graduat 0.8 ( ) 0.9 ( ) 0.7 ( ) f 0.5 ( ) d 1.0 ( ) >High school rf rf rf rf rf Houshold siz 4 prsons rf rf rf rf rf 5 or mor prsons 1.3 ( ) 1.3 ( ) 1.2 ( ) 1.2 ( ) 1.1 ( )

11 Vaccins 2013, Tabl 2. Cont. Pr-vaccin Post-vaccin Birth cohort in Birth cohort in All Rgion with Early Vaccin Rcommndations a Rgion with Latr Vaccin Rcommndations b Rgion with Latr Vaccin Rcommndations Rgion with Latr Vaccin Rcommndations Halth Insuranc Any 1.7 ( ) 1.6 ( ) 2.0 ( ) d 1.9 ( ) d,r 1.9 ( ) Non rf rf rf rf rf HAV = Hpatitis A virus; NHANES = National Halth and Nutrition Examination Survy; OR = odds ratio; CI = confidnc intrval. a Early rgion includs thos stats in which th ACIP rcommndd or considrd rcommnding HAV vaccin in 1999 (Alaska, Arizona, California, Idaho, Nw Mxico, Nvada, Oklahoma, Orgon, South Dakota, Utah, Washington, Arkansas, Colorado, Missouri, Montana, Txas, and Wyoming). b Latr rgion includs thos stats with latr HAV vaccin rcommndations starting in 2006 (Alabama, Conncticut, Dlawar, Florida, Gorgia, Hawaii, Kansas, Kntucky, Iowa, Illinois, Indiana, Louisiana, Massachustts, Maryland, Main, Michigan, Minnsota, Mississippi, North Carolina, North Dakota, Nbraska, Nw Hampshir, Nw Jrsy, Nw York, Ohio, Pnnsylvania, Rhod Island, South Carolina, Tnnss, Virginia, Vrmont, Wisconsin, and Wst Virginia). NA = not applicabl; rf = rfrnc group. * Pr-vaccin birth cohort wr thos born from and post-vaccin birth cohort wr thos born from ^ All othrs rfrs to th combind rac/thnic group that includs all thos othr than non-hispanic whit. All othrs includs: non-hispanic blacks, Mxican Amricans, othr Hispanics, and othr racs including multi-racial. c p < for comparison of subgroup and rfrnc group in modl; d p < 0.05 for comparison of subgroup and rfrnc group in modl; p < 0.01 for comparison of subgroup and rfrnc group in modl; f p < 0.05 for intraction of cofactor and yar of birth cohort within gographic rgion; r = RSE > 30% in univariat analysis stimats may b unstabl.

12 Vaccins 2013, In th rgion with latr vaccin rcommndations, bsids rac/thnicity, post vaccin birth cohort, fmal gndr and having halth insuranc wr associatd with gratr sropositivity to HAV. In addition, a significant intraction with birth cohort and both rac/thnicity and had of houshold ducation was found. Logistic modls for this rgion stratifid by birth cohort dmonstratd largr rac/thnic diffrncs (highr sropositivity among all othrs ) in th post-vaccin birth cohort (OR 3.2 (95% CI ), p < 0.001) as compard to th pr-vaccin birth cohort (OR 1.5 (95% CI ), p > 0.05). Thr was no diffrnc btwn thos whos had of houshold had lss than a high school ducation as compard to thos with gratr than a high school ducation in ithr cohort. Individuals whos had of houshold ducational lvl was qual to high school had lowr sropositivity than thos with gratr than a high school ducation but this was only tru in th pr-vaccin cohort (p < 0.05). 4. Discussion W rport hr th highst vr prvalnc of immunity to hpatitis A among U.S. childrn (37.6%) through 2010; prvalnc was spcially high (66%) among childrn rsiding in aras with an arly rcommndation (1999) or considration of vaccination. This prvalnc is almost fiv tims highr than th 8% lvl found in childrn during th NHANES [9], i.., bfor th vaccin bcam availabl. Givn th stady dclin in disas incidnc [16] our findings of an incras in sroprvalnc ar consistnt with th obsrvd incras in vaccination covrag [17]. In a prvious NHANES study priod, pr-dating vaccination, childrn who livd in povrty, in housholds of lss ducatd adults, or in crowdd homs, wr mor frquntly immun bcaus of infction [9]. In this study of U.S. born childrn in NHANES , w documnt that socio-conomic factors wr not associatd with immunity. This might b rlatd to th Vaccins for Childrn Program (VFC), which has bn providing vaccins at no cost to childrn in familis unabl to pay, sinc 1994 [18]. Th incras in sroprvalnc btwn and was similar in both th rgion with arly vaccin rcommndations as compard to th rgion with latr vaccin rcommndations although it only rachd statistical significanc in th lattr rgion. Although not statistically significant, th chang in sroprvalnc in both birth cohorts in th rgion with arly rcommndations wr similar in magnitud to th significant incras found in th post vaccin birth cohort in th rgion with latr vaccin rcommndations. Th lack of statistical significanc in th arly rgion was partly du to th fact that thr wr fwr sampl prsons and fwr stratum and PSU s in this rgion thrby rsulting in largr standard rrors for ths stimats and lss powr to dtct statistical significanc. Th incras in sroprvalnc was similar btwn th two birth cohorts in th rgion with arly rcommndations. In contrast, in th rgion with latr rcommndations, th incras in sroprvalnc was gratr in th post-vaccin birth cohort. Thr appard to b no diffrnc in prvalnc of antibody by birth cohort in this rgion in but bcaus of th gratr incras in sroprvalnc in th post-vaccin cohort, diffrncs btwn birth cohorts wr sn in Th smallr chang in sroprvalnc in th cohort born bfor implmntation in th rgion with latr rcommndations may b du to a varity of factors including: oldr ag of this cohort at th tim

13 Vaccins 2013, vaccin rcommndations wr implmntd and th fact that initial rcommndations wr risk-basd and this group may not hav bn prcivd to b at risk. W did obsrv on disparity: childrn rsiding in aras with arly rcommndations in th all othr combind rac/thnic group had a significantly highr prvalnc of immunity (82% by ) and a significantly gratr incras in sroprvalnc compard to whit, non-hispanic childrn. In , controlling for othr variabls, childrn in th all othrs combind rac/thnic group in stats with an arly vaccination rcommndation wr 5 tims mor likly to b protctd from hpatitis A than whit, non-hispanic childrn. In rgions with latr rcommndations, ths childrn wr 2 tims mor likly to b immun to hpatitis A. Ths findings ar consistnt with a survy of vaccination covrag among tnagrs in 2009 [19] that found that covrag was low ovrall (two doss 30%) and that whit, non-hispanic tns had th lowst covrag of all racial/thnic groups (66% in stats with arly rcommndations and 25% in stats with no rcommndation in 1999). No such disparity has bn obsrvd among infants. Vaccination covrag with 2 doss was not significantly diffrnt btwn whit and black, non-hispanic infants; howvr, covrag among Hispanic and Asian infants was significantly highr than among whit, non-hispanic childrn [17]. Slf-rportd vaccination with hpatitis A vaccin was similar among whit, black, and Hispanic adults agd yars in th 2010 National Halth Intrviw Survy [20]. It is possibl that th prcption of risk for hpatitis A among whit childrn is lowr than among childrn in othr rac/thnic groups. Th Unitd Stats is not alon in adopting hpatitis A vaccination with succss. Isral was th first country to initiat routin vaccination with a two-dos rgimn of hpatitis A vaccin in Thr, th incidnc of hpatitis A droppd ovr 95% in childrn and adolscnts by 2007 [21]. In Argntina, th introduction of a singl dos rgimn for childrn 12 months of ag was followd by an 83% rduction in th avrag incidnc rat by 2007 [22], In Puglia (Southrn Italy), vaccination of toddlrs and pradolscnts was initiatd in 1998 aftr an HAV pidmic in th yars Incidnc of HAV infction dclind by 95% by 2009 du to both vaccination and rducd circulation although prsnc of antibody to HAV rmaind low in som ag groups [23]. A strngth of this study was that thr wr sufficint data to allow a mor in-dpth analysis of immunity within gographic aras with and without arly vaccination rcommndations (i.., to vaccinat in 1999) as wll as by th birth cohorts ffctd by ths rcommndations. A limitation of all NHANES data ar that findings ar gnralizabl to th U.S. non-institutionalizd civilian population of th Unitd Stats, and do not rprsnt prsons rsiding in institutions (.g., illicit drug usrs in prisons). A limitation of th assay usd to dtct antibodis to HAV is that thy ar unabl to distinguish immunity rlatd to infction or to vaccination. 5. Conclusions In summary, U.S. childrn agd 6 19 yars through 2010 had th highst vr prvalnc of immunity to hpatitis A (37.6%) and immunity rachd 66% among childrn in th rgion with arly rcommndations. Prvalnc incrasd ovr tim and this incras was gratst among thos of th all othr rac/thnic group othr than non-hispanic whit. Continud monitoring of immunity, vaccination covrag, and incidnc of disas will hlp guid nxt stps in th U.S. hpatitis A vaccination policy.

14 Vaccins 2013, Th findings and conclusions in this papr ar thos of th author(s) and do not ncssarily rprsnt th official position of th National Cntr for Halth Statistics, Cntrs for Disas Control and Prvntion. Conflict of Intrst Th authors dclar no conflict of intrst. Rfrncs 1. Wasly, A.; Samandari, T.; Bll, B.P. Incidnc of hpatitis a in th Unitd Stats in th ra of vaccination. JAMA 2005, 294, Rcommndations of th Advisory Committ on Immunization Practics (ACIP). Prvntion of hpatitis a through activ or passiv immunization: Rcommndations of th Advisory Committ oniimmunization Practics (ACIP). MMWR Rcomm. Rp. 1996, 45, Rcommndations of th Advisory Committ on Immunization Practics (ACIP). Prvntion of hpatitis a through activ or passiv immunization: Rcommndations of th Advisory Committ on Immunization Practics (ACIP). MMWR Rcomm. Rp. 1999, 48, Fior, A.E.; Wasly, A.; Bll, B.P. Prvntion of hpatitis a through activ or passiv immunization: Rcommndations of th advisory committ on immunization practics (ACIP). MMWR Rcomm. Rp. 2006, 55, Danils, D.; Grytdal, S.; Wasly, A.; Cntrs for Disas Control and Prvntion. Survillanc for acut viral hpatitis Unitd Stats, MMWR Survill. Summ. 2009, 58, Cntrs for Disas Control and Prvntion. Viral Hpatitis Survillanc Unitd Stats, Availabl onlin: (accssd on 18 January 2012). 7. Cntrs for Disas Control and Prvntion, U.S.D.H.H.S. Availabl onlin: halthypopl.gov/2020/topicsobjctivs2020/objctivslist.aspx?topicid=23/ (accssd on 17 May 2012). 8. Bgg, N.; Millr, E. Rol of pidmiology in vaccin policy. Vaccin 1990, 8, Bll, B.P.; Kruszon-Moran, D.; Shapiro, C.N.; Lambrt, S.B.; McQuillan, G.M.; Margolis, H.S. Hpatitis a virus infction in th Unitd Stats: Srologic rsults from th Third National Halth and Nutrition Examination Survy. Vaccin 2005, 23, Klvns, R.M.; Kruszon-Moran, D.; Wasly, A.; Gallaghr, K.; McQuillan, G.M.; Kuhnrt, W.; Tshal, E.H.; Drobniuc, J.; Bll, B.P. Sroprvalnc of hpatitis a virus antibodis in th U.S.: Rsults from th National Halth and Nutrition Examination Survy. Public Halth Rp. 2011, 126, Cntrs for Disas Control and Prvntion. Hpatitis a vaccination covrag among childrn agd months Unitd Stats, 2006 and MMWR Morb. Mortal. Wkly. Rp. 2009, 58, Cntrs for Disas Control and Prvntion. NHANES fil documntation. Availabl onlin: (accssd on 16 March 2012).

15 Vaccins 2013, US Dpartmnt of Halth and Human Srvics. Povrty Guidlins, Rsarch, and Masurmnt. US Dpartmnt of Halth and Human Srvics wbsit. Availabl onlin: POVERTY/indx.shtml/ (accssd 16 March 2012). 14. National Cntr for Halth Statistics, CDC. National Halth and Nutrition Examination Survys Analytic Guidlins. Availabl onlin: analytical_guidlins.htm/ (accssd on 16 March 2012). 15. Korn, L. Confidnc intrvals for proportions with small xpctd numbr of positiv counts stimatd from survy data. Surv. Mthodol. 1998, 24, Klvns, R.M.; Millr, J.T.; Iqbal, K.; Thomas, A.; Rizzo, E.M.; Hanson, H.; Swt, K.; Phan, Q.; Cronquist, A.; Khudyakov, Y.; t al. Th volving pidmiology of hpatitis a in th Unitd Stats: Incidnc and molcular pidmiology from population-basd survillanc, Arch. Intrn. Md. 2010, 170, Cntrs for Disas Control and Prvntion. National, Stat, and Local ara vaccination covrag among childrn agd months Unitd Stats, MMWR Morb. Mortal. Wkly. Rp. 2012, 61, Cntrs for Disas Control and Prvntion. Vaccin for Childrns Prgram. Availabl onlin: (accssd on 5 Sptmbr 2012). 19. Dorll, C.G.; Yanky, D.; Byrd, K.K.; Murphy, T.V. Hpatitis a vaccination covrag among adolscnts in th Unitd Stats. Pdiatrics 2012, 129, Cntrs for Disas Control and Prvntion. Adult vaccination covrag Unitd Stats, MMWR Morb. Mortal. Wkly. Rp. 2012, 61, Chodick, G.; Hymann, A.D.; Ashknazi, S.; Kokia, E.; Shalv, V. Long-trm trnds in hpatitis a incidnc following th inclusion of hpatitis a vaccin in th routin nationwid immunization program. J. Viral Hpat. 2008, 15, Vacchino, M.N. Incidnc of hpatitis a in Argntina aftr vaccination. J. Viral Hpat. 2008, 15, Chironna, M.; Prato, R.; Sallustio, A.; Martinlli, D.; Tafuri, S.; Quarto, M.; Grminario, C. Hpatitis a in Puglia (South Italy) aftr 10 yars of univrsal vaccination: Nd for strict monitoring and catch-up vaccination. BMC Infct. Dis. 2012, 12, by th authors; licns MDPI, Basl, Switzrland. This articl is an opn accss articl distributd undr th trms and conditions of th Crativ Commons Attribution licns (