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Vaccine 28 (2010) 5332–5337

Contents lists available at ScienceDirect

Vaccine

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bsence of endemic measles transmission in a highly vaccinated population from999 to 2008: Implications of sustained measles elimination in Taiwan

u-Kang Changa, Jacky Y.H. Chenb, Hsiao-Ling Changc,d, Mei-Ching Yue, Hsu-Feng Hsiaof,hing-Cheng Houg, Shyun-Yeu Liuh, Kow-Tong Cheni,∗

Department of Radiology, Liouying Campus, Chi-Mei Medical Center, Tainan, TaiwanDepartment of Anesthesiology, Liouying Campus, Chi-Mei Medical Center, Tainan, TaiwanDivision of Surveillance, Center for Disease Control, Department of Health, Taipei, TaiwanSchool of Public Health, National Defense Medical Center, National Defense University, Taipei, TaiwanDepartment of Chemical Engineering, Tatung University, Taipei, TaiwanDepartment of Family Medicine, Liouying Campus, Chi-Mei Medical Center, Tainan, TaiwanDepartment of Intensive Care Medicine, Liouying Campus, Chi-Mei Medical Center, Tainan, TaiwanChi-Mei Medical Center, Tainan, TaiwanDepartment of Public Health, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 70101, Taiwan

r t i c l e i n f o

rticle history:eceived 29 March 2010eceived in revised form 13 May 2010ccepted 14 May 2010vailable online 31 May 2010

eywords:easles

pidemiologymported case

a b s t r a c t

Background: Measles remains a leading vaccine-preventable cause of child mortality worldwide. Theimpact of vaccination programs can be seen in the increasingly low incidence of measles. However, casesof measles continue to occur in low numbers every year in Taiwan. We assessed the epidemiology ofmeasles in Taiwan from 1999 to 2008 with a focus on domestic versus imported cases.Methods: We analyzed the data reported to surveillance systems at the Taiwan Center for Disease Control,where viral isolation was performed.Results: A total of 84 measles cases were reported from 1999 to 2008 in Taiwan with the incidence ofmeasles varying from 0 to 1.5 per 1,000,000 people per year, peaking in 2002 and again in 2008. Theincidence decreased with increasing age in both males and females. Among the 84 reported measlescases, 39 (46%) originated internationally, 8 (10%) were epidemiologically linked to imported cases and

accine

aiwan the source was unknown in 37 (44%) of the cases. The unknown-source cases were analyzed for potentialevidence of endemic measles transmission. Most of the measles cases that occurred in Taiwan from1999 to 2008 were associated with imported cases. No endemic transmission of measles in Taiwan wasidentified.Conclusions: This study suggests that maintaining the high rate of vaccination coverage is needed to

nd su

prevent future outbreak a

. Introduction

Measles is a highly infectious, acute viral disease that canause rashes, fevers, diarrhea, pneumonia, encephalitis, and death.he World Health Organization (WHO) estimates that there were64,000 deaths attributable to measles worldwide in 2008; theseeaths occurred primarily in developing nations where the measlesaccine was underutilized [1]. In contrast, less than 140 measles

ases have occurred annually in the United States since 1998 [2–4].he WHO and the United Nations Children’s Fund (UNICEF) devel-ped a comprehensive strategy for sustainable measles mortalityeduction, setting the goal of a 90% reduction in global measles

∗ Corresponding author. Tel.: +886 6 2353535x5563; fax: +886 6 2359033.E-mail address: ktchen@mail.ncku.edu.tw (K.-T. Chen).

264-410X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.oi:10.1016/j.vaccine.2010.05.047

stain the elimination of measles in Taiwan.© 2010 Elsevier Ltd. All rights reserved.

deaths by 2010 relative to levels observed in 2000. The strat-egy aims to either maintain a high rate of vaccination coverage(95%) with two doses of the measles-containing vaccine (MCV1 andMCV2) through routine immunization or provide supplementaryimmunization activities (SIAs)—or both. It also seeks to maintainsensitive and timely case-based measles surveillance and provideaccess to an accredited measles laboratory network to test sus-pected measles cases and identify measles virus genotypes [5].

An epidemic of measles infection in Taiwan occurred every 2years before a mass vaccination was initiated in 1978 [6]. Sincethen, mortality due to measles has decreased significantly. How-

ever, the virus persisted in Taiwan and, on the whole island,outbreaks continued to occur periodically in both 1984–1985 and1988–1989 [7,8]. The live attenuated measles vaccine was licensedfor use in Taiwan in 1968. Mass vaccination programs with onedose of vaccine for children between the ages of 5 and 21 months

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ere initiated in 1978. Since 1978, the recommended ages for vac-ination have been changed several times. From 1984 to 1987,ass vaccination programs with one dose of vaccine for children

etween the ages of 9 and 15 months were instituted. In early 1988,ne dose of the vaccine at 12 months of age was scheduled, but aaccination schedule including two doses at 9 and 15 months ofge was initiated in 1988 because of a measles outbreak. This pol-cy was implemented until 1991. After the 1988–1989 outbreak, thelimination of measles in Taiwan by 2000 was established as a gov-rnment goal. To reach this goal, one dose of the measles vaccineas given at 9 months and a second dose of the measles, mumps,

nd rubella (MMR) vaccine has been given to 15-month-old chil-ren since 1992. In addition, a mass campaign in which a singleose of the MMR vaccination was administered to all preschoolnd junior high-school children was conducted between 1992 and994, while a campaign from 2001 to 2004 was aimed at primarychool children. Since 2006, two doses of the MMR vaccine weredministered: one at 12–15 months of age and the other when chil-ren first attended primary school (approximately 6 years of age)7–9].

The coverage rate for the first dose of measles vaccine amonghildren aged 13–24 months was 84% in 1993–1994. The coverageate for the second dose of MMR was 69% in 1993–1994 and 80–85%n 1995. Immunization was verified for all children entering pri-

ary school in 1991 and, by 1995, the overall vaccine coverage ofhildren receiving at least one dose of MMR in primary school was6% [8].

Despite these efforts, cases of measles continue to occur at veryow numbers every year in Taiwan. We reviewed the epidemiologyf measles cases reported from 1999 to 2008, focusing on domesticases relative to imported cases to determine whether measles isndemic in Taiwan.

. Methods

.1. Data source

Taiwan has a population of approximately 22.7 million people.ith a land area of 36,188 km2, this large population results in a

opulation density of 627 people/km2. The main island is dividednto 22 cities and counties that are grouped into 4 regions. Each citynd county has a health bureau and a varying number of health sta-ions. The central department of health is the highest public healthuthority. The majority (95%) of the population lives in the west-rn part of Taiwan, which we divided into northern, central, andouthern regions for the purposes of this study. Only 5% of theopulation lives in eastern Taiwan, where medical care and socioe-onomic status are classified as inadequate. The National Notifiableiseases Surveillance System (NNDSS) has reported measles cases

o the Center for Disease Control, Taiwan (Taiwan CDC), since 1990,s has been previously described in the literature [10]. Measless a reportable disease in Taiwan. Physicians reported all cases of

easles to the Center for Disease Control (CDC) at the Departmentf Health. Data were entered into local databases and electronicallyorwarded to the Taiwan CDC within 24 h using software developedy the Taiwan CDC [11].

We analyzed data regarding confirmed measles cases reportedo NNDSS at the Taiwan CDC from 1999 to 2008. The reportednformation included the patient’s age, gender, area of residence,eographic location of occurrence, vaccination status, and date

f rash onset. Clinical details were also reported, including theutcome of the disease (complications and death), the source ofxposure, the site of transmission, the patient’s history of travel,he importation status of the disease, the country of exposure (formported cases), any links to other cases, and the results of sero-

8 (2010) 5332–5337 5333

logical testing. Virological testing of measles was completed by theCDC measles virus laboratory, Taiwan, and included informationon the measles genotype. A genetic analysis was conducted on 55measles cases occurring from 1999 to 2008. The methods that wereused to identify the measles virus and genotypes have been previ-ously described [12]. Serum specimens were tested for measles IgMand IgG antibodies using Enzygnost Anti-Marsen-Virus/IgG (DadeBehring, Marburg, Germany) following the manufacturer’s instruc-tions. Clinical specimens such as throat swab, urine sediments,and lymphocytes were inoculated onto B95a cells (a marmoset B-lymphoblastoid cell line transformed by the Epstein-Barr virus),and observed for the presence of a cytopathic effect (CPE). Inocu-lated cells were passaged blindly up to two times before discardingthose with no evidence of CPE. RNA was extracted from infectedcells or directly from clinical specimens using the Viral RNA mini kit(Qiagen Inc., Chatsworth, CA) following the manufacturer’s instruc-tions. The wild-type measles virus isolates and genotype sequencesfrom Taiwan were named according to WHO recommendations.The WHO-designed reference sequences for each genotype wereobtained from GenBank.

2.2. Case definitions and classifications

Reported measles cases were confirmed in accordance with thecriteria established by the Taiwan CDC [11] based on the clinicalcase description and the criteria for laboratory confirmation. A clin-ical case of measles is defined as an illness characterized by allof the following: a generalized maculopapular rash lasting for ≥3days, a temperature of ≥38.3 ◦C, and cough, coryza, or conjunctivi-tis. The criteria for laboratory confirmation of measles include thedetection of the serum measles IgM antibody, a significant rise inserum IgG antibodies between acute and convalescent phase titers,or the isolation of the measles virus. A confirmed case of measles isdefined as a case that is either laboratory-confirmed or a case thatmeets the clinical case definition and is epidemiologically linked toa laboratory-confirmed case.

Cases of measles were classified epidemiologically, according tothe source of infection, as follows [13]:

Internationally imported case. An internationally imported caseof measles is defined as a case that results from exposure to themeasles virus outside Taiwan, as evidenced by the onset of a rashwithin 21 days after the patient entered Taiwan. These cases showno link to the local transmission of measles.

Indigenous case. An indigenous case of measles is the one thatresults from exposure to the measles virus in Taiwan. All measlescases without evidence of international importation were classifiedas indigenous.

Indigenous cases were sub-classified into two mutually exclu-sive groups: (1) a case that is epidemiologically linked to animported case is defined as a case of measles in a patient who hadknown contact or likely contact with an imported case or witha chain of transmission that was epidemiologically linked to animported case; and (2) an unknown-source case is a measles casefor which an epidemiological or virological link to an imported casecannot be established.

Importation-associated cases. Cases were further classified asimportation-associated cases if they were either imported cases orwere epidemiologically linked to imported cases. Unknown-sourcecases are not importation-associated and must be evaluated todetermine whether they represent an endemic chain of transmis-

sion.

We defined endemic measles transmission as the existence of atleast one chain of measles virus transmission persisting anywherein Taiwan for one full year. To document the absence of endemictransmission, we focused our analysis on unknown-source cases.

5334 Y.-K. Chang et al. / Vaccine 28 (2010) 5332–5337

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Fig. 2. Age-specific incidence of measles in Taiwan, 1999–2008.

imported from the following five countries: China (24 cases), Japan(7 cases), the Philippines (5 cases), Thailand (2 cases), and Germany(1 case). Eight cases were epidemiologically linked to importedcases. From 1999 to 2008, there were 55 isolates from patients.

Table 1Distribution of measles virus genotype by source in Taiwan, 1999–2008.

Source Genotypes

D3 D5 D9 H1 Total

China 15 15Philippines 3 1 4Thailand 1 1 2German 1 1Japan 4 1 5Epidemiologically linked to imported case 1a 7b 8

ig. 1. Reported incidence and importation status of measles cases by year in Tai-an, 1999–2008.

.3. Statistical analysis

We analyzed the NNDSS database of confirmed measles caseseported in Taiwan from 1999 to 2008 to identify epidemiolog-cal patterns of transmission, importation status, temporal andeographic distribution of cases, age distribution, and vaccinationtatus.

The annual incidence of measles cases by age group was cal-ulated by dividing the number of cases of measles by the totalopulation in that age group from 1999 to 2008 as reported in Tai-anese census data. The annual incidences of measles cases were

xpressed as the number of measles cases per 1,000,000 people. Alltatistical analyses were performed using STATA Statistical Soft-are version 8.0 [14]. We used a Chi-squared test with a Yates’

orrection for categorical data and tests for linear trends. The levelf significance for all analyses was designated as P < 0.05. Relativeisks were calculated using a Poisson regression analysis [15].

. Results

From 1999 to 2008, a total of 84 confirmed cases of measlesere reported to the Taiwan CDC. The median patient age was 5

ears (range: 3 months to 44 years), and the male-to-female ratioas 1:1.2. The mean number of cases reported per year was 8.4

range: 0–24 cases), representing an annual incidence of less thanne case per one million people (Fig. 1). The median number ofases reported for the 10-year period was 6 (range: 0–24 cases).rom 1999 to 2008, cases of measles were observed in 20 (91%) ofhe 22 counties in Taiwan.

The annual incidences of measles cases (the number of measlesases per 1,000,000 people) were as follows: 0.06 in 1999, 0.37 in000, 0.63 in 2001, 1.51 in 2002, 0.38 in 2003, 0.0 in 2004, 0.046

n 2005, 0.26 in 2006, 0.66 in 2007, and 1.08 in 2008 (�2 for linearrend = 2.86; P = 0.09). The incidence of measles peaked in 2002 andgain in 2008 (Fig. 1). There was a measles outbreak in 2002. In thisutbreak, a person who was infected in China imported the diseasento Taiwan and then infected at least seven schoolchildren. All ofhese cases were associated with an H1 sequence imported fromhina.

The age-specific annual incidences of measles cases by year arehown in Fig. 2. From 1999 to 2008, the measles incidence wasighest among children < 1-year-old and lowest among adults aged0–44 years. The annual incidence decreased as age increased.

dults (>19 years of age) accounted for 36% of reported measlesases, whereas 35% of cases occurred in infants younger than 12onths; 13% of cases occurred in preschool-aged children, and 17%

ccurred in school-aged children and adolescents (Fig. 3).

Fig. 3. Age distribution and vaccination status of reported measles cases by sourcein Taiwan, 1999–2008.

The vaccination status of cases varied depending on the infec-tious source. Importation-associated cases were more likely to beunvaccinated than unknown-source cases. Overall, 85% (40/47)of importation-associated cases occurred in unvaccinated indi-viduals compared to 54% (20/37) among unknown-source cases(�2 = 6.88; P < 0.01; Fig. 3). A high proportion (77%) of unknown-source patients with measles had received two doses of the measlesvaccine between 5 and 19 years of age.

From 1999 to 2008, internationally imported cases accountedfor 46% (39 cases) of all reported cases of measles. The mean num-ber of imported cases per year was four (Fig. 1). Measles cases were

Unknown 1 2 17 20Total 4 8 4 39 55

a Household infection linked to imported cases from Thailand.b Cases linked to imported cases from China.

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ig. 4. Extent of measles transmission and outbreak spread in Taiwan, 1999–2008.TR: transmission rate).

he distribution of measles virus genotypes by infected countriess shown in Table 1. Among those cases, four different genotypes

ere detected (D3, D5, D9, and H1); H1 accounted for 71% of theiruses isolated. Overall, importation-associated cases (imported,pidemiologically linked cases) accounted for 47 (56%) of the 84ases reported during this period. The proportion of importation-ssociated cases increased from 0% of all reported cases in 1999 to0% in 2008 (�2 for linear trend = 8.57; P < 0.01; Fig. 1).

Fig. 4 shows the extent of secondary transmission and outbreakpread. Among the reported cases, 64 were recognized as primaryases. Of these, 55 produced no secondary infection cases, 6 pro-uced 6, 1 produced 3, 1 produced 4, and 1 produced 7 secondary

nfection cases.Imported measles cases resulted in two epidemiologically

inked cases, accounting for 10% (8/84) of the total reported cases18% of indigenous cases). The number of epidemiologically linkedases originating from the spread of an imported case ranged fromto 7 (with a mean of 0.2 cases transmitted per imported case). For

5% of imported cases, no transmission in Taiwan was reported.

Among the reported measles cases, 37 (44%) were indige-ous and were consequently sub-classified as unknown-sourceases. An average of four unknown-source cases was reported

ig. 5. Maps of unknown source and importation-associated cases of measles in Taiwanounty, Taoyuan County, and Hsinchu County; the central region includes Taichung, Miaegion includes Kaohsiung, Tainan, Chiayi, Yunlin County, Chiayi County, Tainan County, Kualien County, and Taitung County.

8 (2010) 5332–5337 5335

each year (range: 0–18 cases; Fig. 3). Sixteen counties reportedunknown-source cases during this 10-year surveillance period. Anunknown-source case occurred somewhere in Taiwan for an aver-age of 48 weeks (range: 38–52 weeks) per year. From 1999 to 2008,there were 29 chains of transmission that included measles cases ofunknown source; 25 of these chains were isolated cases (unlinkedto any other cases) and 4 were chains including 2–4 cases (threeoccurred in Taichung County and one in Hsinchu County). Thelargest unknown-source outbreak included four cases and lastedfor 1 week. Taichung County reported the most unknown-sourcecases (11 cases) and had the largest number of weeks in whichunknown-source cases were reported (4/520 weeks with an aver-age of 0.8 weeks per year).

From 1999 to 2008, a total of 16 (70%) of the 22 counties inTaiwan reported unknown-source cases. Of these counties, seven(44%) reported only one unknown-source case. The remaining ninecounties reported 2–11 unknown-source cases over the 10-yearperiod. All of the counties had at least one calendar year in which nounknown-source cases were reported. No county had > 5 weeks inwhich unknown-source cases were reported in any year during thestudy period. In general, unknown-source cases tended to clusterin counties in which imported measles cases were also reported(Fig. 5).

4. Discussion

Epidemiological evidence supports the conclusion that measlesis no longer transmitted endemically in Taiwan. Of the reportedmeasles cases from 1999 to 2008, 56% (47 cases) were importation-associated. Among these cases, 46% (39 cases) were importedcases, and 10% (8 cases) were epidemiologically linked to importedcases. Most imported cases (95%) did not result in an indigenous

the limited proportion of cases that spread from imported casesindicate that effective preventive measures had been performed.This implies that the immunity of the Taiwanese population tomeasles is too high to allow for sustained measles virus transmis-

, 1999–2008. Note: the northern region includes Taipei, Keelung, Hsinchu, Taipeioli County, Taichung County, Nantou County, and Changhua County; the southernaohsiung County, and Pintung County; and the eastern region includes Ilan County,

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ion [16,17]. Additionally, viral genotyping data indicate that therere no endemic measles strains circulating in Taiwan [18].

In 2003, the WHO Regional Committee for the Western Pacificormally declared the goal of eliminating measles [19]. Progressas been made, and 24 of the 37 countries in the region haveither eliminated or nearly eliminated the disease. However, in008, 131,441 confirmed measles cases were reported in Chinand 11,015 cases were reported in Japan; these two countriesccount for 97% of the confirmed cases in the region [20]. It haseen reported that the importation of the measles virus into Tai-an was first initiated by foreign laborers from Indonesia, Malaysia,

he Philippines, Thailand, and Vietnam in early 1989 [12]. Multipleenotypes were documented (D3, D5, D9, G2, H1, and H2) [12].he H1 virus genotype was isolated in the majority (71%) of casesrom 1999 to 2008 in Taiwan. From 1995 to 2003, the major wild-ype measles virus in China was the H1 genotype [17,21]; a similar

easles virus genotype was isolated from imported cases in Tai-an. This similarity indicates that measles cases in Taiwan were

elated to those from Mainland China.This study found that the incidence of measles in Taiwan was

ighest in 2002. Did this constitute an endemic transmission in Tai-an? According to further investigation, there were 24 confirmedeasles cases in 2002. Among these cases, 10 occurred in a school

utbreak that occurred from September to October. There were 17ases with sequence information, and 15 of the H1 sequences weremported from China. Of the 15 H1 sequences, 3 were importedrom China, and 9 of the H1 isolates associated with the outbreakad identical sequences to those isolated from Japan and China.hese data therefore suggest that these viruses were introduced bymportation [12].

This study found that there were many importation-associatedases without vaccination below the age of 1 year and many two-ose vaccine failures among the unknowns aged 5–19 years. Thereas been uncertainty about the efficacy of the 6-month dose of theeasles vaccine [22,23]. The period from 1978 to 1984, when Tai-anese children began measles vaccination at 5 months of age,ould be responsible for a significant vaccine failure due to the per-

istence of maternal transplacental measles IgG antibodies blockinghe vaccine virus replication in many of those children younger than–12 months of age [22,23]. Some children in the 5–19 year age-roup cluster in our study may represent the residual cases of thateriod.

However, unknown-source cases for which no link to importedeasles cases could be detected were reported every year with

he exception of 2004 and 2007. We present four possible rea-ons for the failure to detect the international importation of theseases. First, some unknown-source cases are misclassified and areot actually measles. Because rash-causing illnesses are commonnd intensive surveillance causes many suspected cases of measleso be tested using imperfect laboratory tests, some false-positiveesults will inevitably occur. Misclassification is an especially likelyxplanation for isolated unknown-source cases that have no link tony other measles cases—despite active surveillance efforts seek-ng source or spread cases. Second, virus specimens are not alwaysbtained and submitted for testing in isolated measles cases, mak-ng the detection of an imported virus difficult. Third, it is difficulto detect every imported measles case. Imported measles cases

ay spread the measles virus, especially those resulting from for-ign visitors who depart from Taiwan without seeking health care.etecting such imported cases is practically impossible. Fourth,nknown-source cases represent the endemic transmission of the

easles virus. However, our data show that this explanation is

nlikely. Long periods elapsed during which no unknown-sourceases were reported at any county in Taiwan. No county in Taiwanad a sufficient number of unknown-source cases to represent anndemic chain of transmission.

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8 (2010) 5332–5337

Some researchers have suggested that individuals with a mildor asymptomatic measles virus infection may transmit the measlesvirus and that such chains of transmission could go undetected [24].Although asymptomatic measles infections have been reported[25,26], there is little evidence that such infections effectivelytransmit the measles virus. However, these infections do occasion-ally occur when an immune individual acquires the virus from anexcreting contact. The immune subject may then demonstrate ananamnestic measles antibody boost due to the abortive replicationof the transmitted virus.

From 1999 to 2008, the incidence of measles was lower than thethreshold of an epidemic. Endemic measles transmission was notsustained in any year, in any county, or in Taiwan as a whole. Themajority of reported measles cases are importation-associated, andthe transmission of the disease from these cases is extremely lim-ited. This limited spread indicates very high population immunity,which is the result of a highly effective immunization program. Thesustained elimination of measles in Taiwan will require this highlevel of immunity to be maintained through the timely delivery oftwo doses of the measles vaccine according to the recommendedschedule.

Acknowledgements

We would like to thank Dr. Wen-Yueh Cheng (LaboratoryDivision of Center for Disease Control, Taiwan) for her critical com-ments. We would also like to thank the staff of the Center for DiseaseControl, Taiwan, for their assistance in collecting the epidemiolog-ical data.

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