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Journal of Microbiology, Immunology and Infection (2014) xx, 1e6
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.e-jmii.com
ORIGINAL ARTICLE
Seroepidemiology for measles among elementary school children in Northern Taiwan Yu-Chun Lin a, Yu-Chia Hsieh a,*, Ya-Ling Huang b, Yu-Chiau Huang b, Yung-Tai Hung c, Yhu-Chering Huang a,* a Department of Pediatrics, Chang Gung Children’s Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan b Department of Laboratory Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan c Department of Political Science, National Taiwan University, Taipei, Taiwan
Received 30 April 2014; received in revised form 21 August 2014; accepted 23 August 2014
Available online - - -
KEYWORDS measles; schoolchildren; seroepidemiology
Background: Despite the high vaccination coverage in Taiwan, sporadic cases or small cluster of measles still occur every year. Nevertheless, few studies provided information about the serostatus for measles in recent years. This cross-sectional survey aimed to establish the seroepidemiologic data of measles among elementary school children in New Taipei City, Taiwan during 2012e2013. Methods: A multistage stratified sampling design using 14 variables was employed to obtain samples. All selected schoolchildren were bled for the serologic tests of measles by both chemiluminescence immunoassay (CLIA) and enzyme immunoassay (EIA). Results: A total of 856 schoolchildren from 14 schools were recruited in this study. Among these individuals, the overall seropositive rates for measles were 82.24% and 92.17% by the Liaison and NovaLisa assays, respectively. For schoolchildren in each grade, the seropositive rates were > 90% for Grade 1, and then decreased gradually to 70 e80% for Grade 6 (p < 0.001 for both methods). A decay of measles-specific immunoglobulin G titers was also observed with the maximum drop between Grade 1 and Grade 2 (declining trend of p < 0.001 for both).
* Corresponding authors. Department of Pediatrics, Chang Gung Children’s Hospital, Number 5, Fu-Hsin Street, Kweishan 333, Taoyuan, Taiwan. E-mail addresses: [email protected] (Y.-C. Hsieh), [email protected] (Y.-C. Huang). http://dx.doi.org/10.1016/j.jmii.2014.08.015 1684-1182/Copyright ª 2014, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. All rights reserved.
Please cite this article in press as: Lin Y-C, et al., Seroepidemiology for measles among elementary school children in Northern Taiwan, Journal of Microbiology, Immunology and Infection (2014), http://dx.doi.org/10.1016/j.jmii.2014.08.015
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Y.-C. Lin et al. Conclusion: Although the seropositive rate of measles was > 90% for Grade 1, the rate for Grade 6 was only in the range of 70e80%, which may be a challenge to prevent outbreaks of measles in the future and should be monitored meticulously. Copyright ª 2014, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. All rights reserved.
Introduction Measles is an acute viral disease which is highly infectious in nature. It brings about a large body of illnesses, including fever, rash, conjunctivitis, diarrhea, pneumonia, encephalitis, and even death. In Taiwan, measles occurred epidemically with a 2-year cyclic fluctuation in the prevaccination era.1 To diminish the burden of this disease, the Taiwanese government has been making a great effort by the use of measles-containing vaccines over the past 3 decades. In Taiwan, the live attenuated measles vaccine (Schwarz strain) was first licensed for use in 1968 and a nationwide mass vaccination program with a two-dose schedule for children aged 9 months and 15 months was started in 1978. In January 1988, the immunization program was switched to a single dose of vaccine at 12 months of age, but was soon changed back to a two-dose schedule administered at 9 months and 15 months of age in May 1988, because of an outbreak of measles.2 This strategy was continuously employed until 1991. Since 1992, the second dose of measles vaccine at 15 months of age was substituted with a measles, mumps, and rubella (MMR) vaccine on account of the policy for the elimination of measles, congenital rubella syndrome, poliomyelitis, and neonatal tetanus. Furthermore, a catch-up campaign with one dose of MMR vaccination targeting school students aged 7e13 years was conducted from 1992 to 1994. Since 2001, giving the second dose of MMR vaccine when first attending primary school was started. Another catch-up campaign was carried out for children aged 8e13 years from 2001 to 2004 due to outbreaks.3 Since 2006, the first dose of measles vaccine was ceased, and a schedule of two doses of MMR vaccine was adopted: one at 12e15 months of age and the other at elementary school entry. However, the schedule for the first MMR vaccine was changed to 12 months of age in April 2009 in response to a reappearance of measles resulting from imported cases during the period of November 2008 to February 2009.4,5 The second dose of MMR vaccine was switched to be given to children aged 5e6 years before they entered primary school, in September 2012. According to data from the Taiwan Centers for Disease Control, the coverage rate for the first dose of measles vaccine reached 97.31% by 2012. However, domestic cases as well as imported cases of measles were still identified in low numbers every year in Taiwan. Seroepidemiologic data were very beneficial in understanding the epidemiology of infectious disease and determining the control strategy. Although seroprevalence for measles in Taiwan was previously well documented, the childhood serostatus was no longer well understood as measles became a sporadic
disease, especially in the past 3 years. Therefore, we carried out this survey to investigate the immunity status against measles in elementary school students in Northern Taiwan. The survey will be the pilot study of an ongoing nationwide study, and will be provided as the reference for a national immunization program.
Materials and methods Ethics statement The study proposal was reviewed and approved by the Institutional Review Board at Chang Gung Memorial Hospital, Taoyuan, Taiwan in 2012. Informed consents were obtained from all participants as well as their guardians. All informed consents were in the written form.
Study populations and selection of participants A cross-sectional survey of measles-specific immunoglobulin (Ig)G antibody in the population of elementary schoolchildren in New Taipei City was conducted from September 2012 to June 2013. New Taipei City comprises 29 administrative districts and is the second largest special municipality in Northern Taiwan. A total of 225,234 pupils resided in this city, which accounted for 16.5% of all primary school children in Taiwan in 2012. A multistage stratified method with probability proportional to size sampling was employed to obtain samples. The 29 administrative districts of New Taipei City were classified into five strata based on 14 variables, which included four demographic variables [population density (persons/km2), proportion of population aged > 65 years, < 15 years, and < 6 years], four socio-educational variables (number of physicians, nursing staff, low-income households, and nearpoor households/10,000 people), and six medical facilities’ variables (nursing staff/10,000 people, medical personnel/ 10,000 people, all staff in health centers/10,000 people, number of colleges or universities/10,000 people, proportion of agriculture population, and proportion of population with a college degree or above). From each stratum, elementary schools were selected as the primary sampling unit, and then classes were selected as the second sampling unit. One class was drawn from each grade in a sampled school, that is, a total of six classes were drawn from each sampled school. Students were selected at the final stage of the sampling scheme. Selected students were bled for the serologic tests of measles. All participants were manifestly healthy without acute illness as blood drawing. Past medical histories were obtained by a questionnaire from
Please cite this article in press as: Lin Y-C, et al., Seroepidemiology for measles among elementary school children in Northern Taiwan, Journal of Microbiology, Immunology and Infection (2014), http://dx.doi.org/10.1016/j.jmii.2014.08.015
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each participant and information on vaccination status was reliably obtained by vaccination records.
Determination of measles-specific antibodies Sera were stored at 20 C before measurements. Two different methods were employed to determine measlesspecific IgG: (1) chemiluminescence immunoassay (CLIA; Liaison, DiaSorin, Italy); and (2) enzyme immunoassay (EIA; NovaLisa, NovaTec, Dietzenbach, Germany). Sera were tested following the directions of the manufacturers. The results were interpreted based on the respective manufacturer’s instructions. For the Liaison method, the antibody titers were calculated in arbitrary unit (AU)/mL. Samples with an antibody titer of > 16.5 AU/mL were classified as positive, a titer between 13.5 AU/mL and 16.5 AU/mL was grouped as equivocal, and a titer of < 13.5 AU/mL was considered as negative. With respect to the NovaLisa assay, antibody titers were acquired using NovaTec Units (NTU). An NTU was defined as patient (mean) absorbance value 10/ cut-off value. The results were considered positive for titers > 11 NTU. Titers < 9 NTU and in the range of 9e11 NTU were negative and equivocal, respectively.
Statistical analysis Measles-specific antibody titers were presented as geometric mean titers (GMT). Differences in seropositive
Table 1
percentages between different groups and the two assays were tested by the Chi-square test. The unpaired t test was used to compare the statistic deviances between GMT levels in different grades. The trend of decreasing GMTs was assessed by a linear regression method. Data analyses were performed using SPSS software version 17.0 (SPSS Inc., Chicago, IL, USA). A p value < 0.05 was considered statistically significant.
Results Selected schools and the number of individuals in each stratum are shown in Table 1. In total, 856 schoolchildren from 14 schools were recruited and bled for the serologic tests of measles; 416 (48.5%) were male. From each school, the difference of seropositivity or sex distribution was not statistically apparent. There was a statistically significant difference in seropositivity among five strata by the NovaLisa method (p Z 0.03), but not by the Liaison assay (p Z 0.86). When measured by the Liaison method, a total of 704 (82.24%) samples were positive for measles-specific IgG, whereas 789 (92.17%) were seropositive when the NovaLisa assay was used (Table 1). A statistically significant difference was observed in the seropositive rate between the two assays (p < 0.001). Grade-specific measles seroprevalence and the change of GMTs are shown in Fig. 1. When tested by the Liaison assay, the seropositive rate was 94.96% for Grade 1 but
Seroprevalence among 856 primary school children in five strataa
School (administrative district)
1st stratum Zhong-Shan (Ban-Qiao) San-Zhong (San-Zhong) Zhong-Gang (Xin-Zhuang) Lu-Zhou (Lu-Zhou) Ji-Mei (San-Zhong) Ju-Guang (Ban-Qiao) 2nd stratum Cheng-Fu (San-Xia) Xin-Xing (Dan-Shui) 3rd stratum Jin-Mei (Jin-Shan) Jin-Long (Xi-Zhi) 4th stratum Gan-Yuan (Shu-Lin) Wu-Gu (Wu-Gu) 5th stratum Shi-Ding (Shi-Ding) Shuang-Xi (Shuang-Xi) Total
Schoolchildren, n
517 89 92 86 77 89 84 109 59 50 66 35 31 140 70 70 24 12 12 856
Sex (M/F)
0.99 0.82 0.96 0.83 1.2 1.23 1 0.85 0.64 1.17 0.61 0.67 0.55 0.94 1 0.89 2 5 1 0.95
Positive, n (%) Liaison (CLIA)
NovaLisa (EIA)
429 67 79 72 65 70 72 89 46 43 52 30 22 115 54 61 19 10 9 704
486 84 88 81 73 83 77 92 47 45 62 34 28 127 61 66 22 11 11 789
(82.98) (75.28) (85.87) (83.72) (84.42) (78.65) (90.48) (81.65) (77.97) (86.00) (78.79) (85.71) (70.97) (82.14) (77.14) (87.14) (79.17) (83.33) (75.00) (82.24)
(94.00) (94.38) (95.65) (94.19) (94.81) (93.26) (91.67) (84.40) (79.66) (90.00) (93.94) (97.14) (90.32) (90.71) (87.14) (94.29) (91.67) (91.67) (91.67) (92.17)
a The five strata were classified according to 14 variables (see text). CLIA Z chemiluminescent immunoassay; EIA Z enzyme immunoassay. b The p values for seropositivity among 14 schools were p Z 0.25 and p Z 0.07 by the Liaison and NovaLisa assays, respectively. c The p values for seropositivity among five strata were p Z 0.86 and p Z 0.03 by the Liaison and NovaLisa methods, respectively. d A p value < 0.001 for seropositive rate between the two assays.
Please cite this article in press as: Lin Y-C, et al., Seroepidemiology for measles among elementary school children in Northern Taiwan, Journal of Microbiology, Immunology and Infection (2014), http://dx.doi.org/10.1016/j.jmii.2014.08.015
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A
B
Figure 1. Grade-specific seropositivity and geometric mean titers of measles among 856 schoolchildren by (A) the Liaison assay and (B) the NovaLisa assay. The p values for declining seropositivity and geometric mean titers (GMTs) by both assays were all p < 0.001.
declined to 82.88% for Grade 2 (p Z 0.001). Thereafter, seroprevalence decreased gradually to a nadir of 70.63% for Grade 6. Similarly, seropositivity determined by the NovaLisa assay also had a declining tendency from 100% for Grade 1 to 81.12% for Grade 6 (p < 0.001). In addition, the number of schoolchildren with equivocal serostatus increased over time, either tested by the Liaison or the NovaLisa assay. Similar to seroprevalence, both assays also showed a decay of measles-specific IgG titers (both p for declining trend < 0.001) with the maximum drop between Grade 1 and Grade 2 (both p < 0.001). Among 856 participants, 24 had an unclear vaccination status, all but one of whom had received at least one dose of MMR vaccine, and were excluded when the association between seroprevalence and vaccination doses was further analyzed. A total of 798 (93.2%) received two doses of measles vaccine. Participants with two-dose vaccination had a significantly higher seropositive rate than those who
only received one dose of MMR vaccine (2 doses, 92.5% vs. 1 dose, 82.4 by NovaLisa, p Z 0.047; and 2 doses, 82.8% vs. 1 dose, 64.7 by Liaison, p Z 0.001). The comparisons of seropositivity between the two different methods according to vaccination doses are displayed in Table 2.
Discussion This study revealed an overall anti-measles IgG seropositive rate of 82.3e92.2% via two different serological tests in the population of elementary school students in New Taipei City in Taiwan. Even though both the Liaison and NovaLisa assays disclosed seropositive rates of measles > 90% for Grade 1, the rates for Grade 6 were only in the range of 70e80%. The difference in the seropositivity rates between the tests by Liaison CLIA and NovaLisa EIA was statistically
Please cite this article in press as: Lin Y-C, et al., Seroepidemiology for measles among elementary school children in Northern Taiwan, Journal of Microbiology, Immunology and Infection (2014), http://dx.doi.org/10.1016/j.jmii.2014.08.015
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Table 2 The comparisons of seropositivity between enzyme immunoassay (EIA) and chemiluminescent immunoassay (CLIA), according to measles, mumps, and rubella (MMR) vaccination status Vaccination doses
2 (n Z 798)
1 (n Z 34)
p
Positive, n (%)
738 (92.5)
28 (82.4)
0.032
662 (82.8)
22 (64.7)
0.007
EIA (NovaLisa) CLIA (Liaison)
significant. CLIAs have been reported to provide equal, even greater, sensitivity and specificity in serologically diagnosing a variety of infectious diseases when compared to traditional EIAs.6e11 Liaison measles IgG is a new semiqualitative, fully automated method for determination of measles-specific IgG, and the sensitivity and specificity provided by the manufacturer were 94.7% and 97.4%, respectively. To the best of our knowledge, almost all studies use conventional EIA to measure specific IgG for measles. In the literature to date, only two studies employed this new automated Liaison CLIA to determine measles IgM, in which diagnostic performances of Liaison measles IgM were excellent.7,8 It is hard to distinguish which method is more sensitive or specific, but the result of a seroprevalence of 82.24% revealed by the Liaison assay is lower than expected, considering that all participants in our study received a second dose of MMR vaccine just before or at elementary school entry. Further investigation to resolve this question is warranted. Although measles-specific IgG titers were at a high level for Grade 1, antibody titers declined rapidly at Grade 2 from 171.05 AU/mL to 102.55 AU/mL by the Liaison method and from 29.99 NTU to 24.5 NTU by the NovaLisa method, respectively. In agreement with our findings, other research observed a rapid drop of the antibody level within the 1st year of vaccination.12 Since a nationwide childhood immunization program was implemented in 1978, the incidence of measles has declined rapidly in Taiwan. From 2000 to 2013, the incidence of measles was low, varying from 0 people/year to < 3/1,000,000 people/year (Taiwan Center for Disease Control). As a result, participants in the present study had a low possibility of exposure to wild measles virus and got immunity mainly from vaccination. In our survey, we found a declining seropositivity among primary school students despite the fact that there was somewhat of a discrepancy in the seroprevalence examined by two measurements. The seropositive rate significantly declined to a nadir of 70e80% for Grade 6, whereas schoolchildren with antibody titers in the equivocal range increased gradually as their grade increased. These findings presumably reflected a waning vaccine-evoked immunity with increasing age. Without a natural booster of measles, a rapid decay of vaccine-induced antibody titers in the Taiwanese population was also reported in several studies.12e14. It appeared as though immunity obtained from natural infection provided longer lasting protection. In two previous measles seroepidemiological studies in Taiwan, the seroprevalence in the population born before 1978 was in the range of 95e100%.2,15 Another study in Taiwan reported that infection-induced immunity can even be
lifelong. According to the study, a high level of seropositive rate > 95% remained in people > 65 years old.12 A two-dose regime of MMR vaccination was generally considered appropriate and has been introduced into many countries to eliminate measles infection successfully.16e19 Our study also showed that individuals with two-dose vaccination had a significantly higher seropositive rate than those who only received one dose of MMR vaccine. However, the seropositive rate in Asian countries was substantially lower when compared to Western countries. In addition to a seropositive rate of 70e80% for Grade 6 students in our study, a study conducted in southern mainland China in 2008 revealed that 84.4% of the group aged 2e3 years old were seropositive, whereas the seropositivity decreased to 58.8% in the 15e29-year-old group, despite two dose vaccination coverage data being reported as high (> 90%) since 1986.20 In Korea, a survey revealed that the seropositive rate was 75.3% in the population aged 11e13 years old.21 A cohort study in Finland, however, found that the seropositive rate in vaccinees for MMR was 95% after the 20-year follow-up.22 Similarly, in a national serosurvey in the United States, the rate of measles seropositivity in the population overall was as high as 95.9% during 1999e2004.23 Race difference may play a role in this seroprevalent discrepancy and should be taken into consideration in making vaccination plans. Measles was thought to be a highly contagious disease with an estimated prevaccination reproductive number in the range of 4.78 to 8.0 in Taiwan.24 Hence, a seroprevalence of about 95% in the population was presumed to interrupt measles transmission.25 Although several studies delineated that clinically vaccinees with undetectable or low antibody titers may not necessarily be susceptible to symptomatic measles infection because immune memory and cellular immunity also had an influence against measles infection,26e28 this may be a challenge to prevent outbreaks of measles in the future, since immunity prevalence did not reach the requirement for Grade 6 students. This population is potentially at risk of infection with measles and then plays a role in transmitting the disease. A booster vaccination has been reported to be useful in decreasing the proportion of vaccinees with low antibody titers.29 A revaccination approach for schoolchildren of Grade 5 or 6 deserves further investigation but might not be a matter of great urgency, because the incidence of measles in Taiwan has been low in recent years. The present study had several limitations. First, although we employed a multilevel design using 14 variables to minimalize selecting bias, our participants may not accurately represent all schoolchildren nationwide. Second, serologic results can be confounded by previous measles infection. All participants were not on the list of reporting cases and we used questionnaires to obtain the past medical histories from all schoolchildren. Modified measles can be difficult to diagnose and the questionnaires are still not a thoroughly reliable method. Therefore, we cannot completely exclude the possibility of getting measles before, although the chance was very low. Furthermore, someone may question the results of seroprevalence because there was an inconsistency between the two assays. Indeed, we did not put much effort into analyzing which assay had a better diagnostic performance in this
Please cite this article in press as: Lin Y-C, et al., Seroepidemiology for measles among elementary school children in Northern Taiwan, Journal of Microbiology, Immunology and Infection (2014), http://dx.doi.org/10.1016/j.jmii.2014.08.015
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6 study. Nevertheless, the fact that there was a decay of seropositivity was convincing enough, because both of the assays disclosed the same tendency. In conclusion, the present survey demonstrated a seroepidemiologic profile for measles in elementary school students in Northern Taiwan. A low seroprevalence, around 70e80%, was apparent for schoolchildren above Grade 5 and two-dose vaccines had a higher seropositivity than onedose vaccines. Our findings may provide guidance for national medical authorities in determining a vaccination strategy to reach the goal of measles elimination and also point out that the seroepidemiologic status for measles should be monitored meticulously in the future.
Conflicts of interest All authors declare that they have no conflicts of interest associated with the materials discussed in the article.
Acknowledgments This study was supported in part by a grant from the Centers for Disease Control, Taiwan (DOH101-DC-1016). We would like to thank Ms. Kun-Ju Tsai, a member of the Public Health Department of New Taipei City Government, for her helpful support.
References 1. Chen CJ, Lin TM, Yeh YL. Analysis of the secular trend and seasonal variation of measles mortality rate in Taiwan. Ann Acad Med Singapore 1984;13:136e41. 2. Lee MS, King CC, Jean JY, Kao CL, Wang CC, Ho MS, et al. Seroepidemiology and evaluation of passive surveillance during 1988-1989 measles outbreak in Taiwan. Int J Epidemiol 1992; 21:1165e74. 3. Cheng WY, Lee L, Rota PA, Yang DC. Molecular evolution of measles viruses circulated in Taiwan 1992e2008. Virol J 2009; 6:219. 4. Chen JH, Tsou TP, Liu DP. Measles resurgence in Taiwanelessons learned. J Formos Med Assoc 2009;108:267e9. 5. Cheng WY, Yang CF, Hou YT, Wang SC, Chang HL, Chiu HY, et al. Imported measles and implications for its elimination in Taiwan. Emerg Infect Dis 2011;17:1523e6. 6. de Ory F, Minguito T, Echevarria JE, Del Mar Mosquera M, Fuertes A. Comparative evaluation of tests for detection of parvovirus B19 IgG and IgM. APMIS 2014;122:223e9. 7. Haywood B, Patel M, Hurday S, Copping R, Webster D, Irish D, et al. Comparison of automated chemiluminescence immunoassays with capture enzyme immunoassays for the detection of measles and mumps IgM antibodies in serum. J Virol Methods 2014;196:15e7. 8. Sampedro A, Rodriguez-Granger J, Gomez C, Lara A, Gutierrez J, Otero A. Comparative evaluation of a new chemiluminiscent assay and an ELISA for the detection of IgM against measles. J Clin Lab Anal 2013;27:477e80. 9. Maters AW, Wright CV, Lee MT, Schwichtenberg G, Detrick B. Detection of type-specific antibodies to HSV-1 and HSV-2: comparative analysis of a chemiluminescence immunoassay with a conventional ELISA. Diagn Microbiol Infect Dis 2012;73: 273e4.
Y.-C. Lin et al. 10. Alonso R, Lopez Roa P, Suarez M, Bouza E. Evaluation of a new automated chemiluminescence immunoassay for simultaneous but separate detection of human immunodeficiency virus antigens and antibodies. J Clin Microbiol 2014;52:1467e70. 11. Knight CS, Crum MA, Hardy RW. Evaluation of the LIAISON chemiluminescence immunoassay for diagnosis of syphilis. Clin Vaccine Immunol 2007;14:710e3. 12. Chen CJ, Lee PI, Hsieh YC, Chen PY, Ho YH, Chang CJ, et al. Waning population immunity to measles in Taiwan. Vaccine 2012;30:6721e7. 13. Ho TS, Wang SM, Wang LR, Liu CC. Changes in measles seroepidemiology of healthcare workers in southern Taiwan. Epidemiol Infect 2012;140:426e31. 14. Huang CL, Yang YH, Wang LC, Lin YT, Tsai YY, Chiang BL. Humoral and cellular immune response after measles vaccination in Taiwan. J Microbiol Immunol Infect 2005;38:169e75. 15. Lee MS, Chien LJ, Yueh YY, Lu CF. Measles seroepidemiology and decay rate of vaccine-induced measles IgG titers in Taiwan, 1995e1997. Vaccine 2001;19:4644e51. 16. Hall R, Jolley D. International measles incidence and immunization coverage. J Infect Dis 2011;204(Suppl. 1):S158e63. 17. Katz SL, Hinman AR. Summary and conclusions: measles elimination meeting, 16e17 March 2000. J Infect Dis 2004; 189(Suppl. 1):S43e7. 18. Peltola H, Jokinen S, Paunio M, Hovi T, Davidkin I. Measles, mumps, and rubella in Finland: 25 years of a nationwide elimination programme. Lancet Infect Dis 2008;8:796e803. 19. Ramsay ME, Jin L, White J, Litton P, Cohen B, Brown D. The elimination of indigenous measles transmission in England and Wales. J Infect Dis 2003;187(Suppl. 1):S198e207. 20. Fu C, Xu J, Liu W, Zhang W, Wang M, Nie J, et al. Low measles seropositivity rate among children and young adults: a seroepidemiological study in southern China in 2008. Vaccine 2010;28:8219e23. 21. Kim ES, Choe YJ, Cho H, Kim YJ, Yoon HS, Yang JS, et al. Seroprevalence of measles among children affected by national measles elimination program in Korea, 2010. Vaccine 2012;30:3355e9. 22. Davidkin I, Jokinen S, Broman M, Leinikki P, Peltola H. Persistence of measles, mumps, and rubella antibodies in an MMRvaccinated cohort: a 20-year follow-up. J Infect Dis 2008; 197:950e6. 23. McQuillan GM, Kruszon-Moran D, Hyde TB, Forghani B, Bellini W, Dayan GH. Seroprevalence of measles antibody in the US population, 1999e2004. J Infect Dis 2007;196:1459e64. 24. Chen SC, Chang CF, Jou LJ, Liao CM. Modelling vaccination programmes against measles in Taiwan. Epidemiol Infect 2007; 135:775e86. 25. Thacker SB, Millar JD. Mathematical modeling and attempts to eliminate measles: a tribute to the late Professor George Macdonald. Am J Epidemiol 1991;133:517e25. 26. Whittle HC, Aaby P, Samb B, Jensen H, Bennett J, Simondon F. Effect of subclinical infection on maintaining immunity against measles in vaccinated children in West Africa. The Lancet 1999;353:98e102. 27. Lee MS, Nokes DJ, Hsu HM, Lu CF. Protective titres of measles neutralising antibody. J Med Virol 2000;62:511e7. 28. Ward BJ, Boulianne N, Ratnam S, Guiot MC, Couillard M, De Serres G. Cellular immunity in measles vaccine failure: demonstration of measles antigen-specific lymphoproliferative responses despite limited serum antibody production after revaccination. J Infect Dis 1995;172:1591e5. 29. Tischer A, Gerike E. Immune response after primary and revaccination with different combined vaccines against measles, mumps, rubella. Vaccine 2000;18:1382e92.
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Journal of Microbiology, Immunology and Infection (2014) xx, 1e6
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.e-jmii.com
ORIGINAL ARTICLE
Seroepidemiology for measles among elementary school children in Northern Taiwan Yu-Chun Lin a, Yu-Chia Hsieh a,*, Ya-Ling Huang b, Yu-Chiau Huang b, Yung-Tai Hung c, Yhu-Chering Huang a,* a Department of Pediatrics, Chang Gung Children’s Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan b Department of Laboratory Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan c Department of Political Science, National Taiwan University, Taipei, Taiwan
Received 30 April 2014; received in revised form 21 August 2014; accepted 23 August 2014
Available online - - -
KEYWORDS measles; schoolchildren; seroepidemiology
Background: Despite the high vaccination coverage in Taiwan, sporadic cases or small cluster of measles still occur every year. Nevertheless, few studies provided information about the serostatus for measles in recent years. This cross-sectional survey aimed to establish the seroepidemiologic data of measles among elementary school children in New Taipei City, Taiwan during 2012e2013. Methods: A multistage stratified sampling design using 14 variables was employed to obtain samples. All selected schoolchildren were bled for the serologic tests of measles by both chemiluminescence immunoassay (CLIA) and enzyme immunoassay (EIA). Results: A total of 856 schoolchildren from 14 schools were recruited in this study. Among these individuals, the overall seropositive rates for measles were 82.24% and 92.17% by the Liaison and NovaLisa assays, respectively. For schoolchildren in each grade, the seropositive rates were > 90% for Grade 1, and then decreased gradually to 70 e80% for Grade 6 (p < 0.001 for both methods). A decay of measles-specific immunoglobulin G titers was also observed with the maximum drop between Grade 1 and Grade 2 (declining trend of p < 0.001 for both).
* Corresponding authors. Department of Pediatrics, Chang Gung Children’s Hospital, Number 5, Fu-Hsin Street, Kweishan 333, Taoyuan, Taiwan. E-mail addresses: [email protected] (Y.-C. Hsieh), [email protected] (Y.-C. Huang). http://dx.doi.org/10.1016/j.jmii.2014.08.015 1684-1182/Copyright ª 2014, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. All rights reserved.
Please cite this article in press as: Lin Y-C, et al., Seroepidemiology for measles among elementary school children in Northern Taiwan, Journal of Microbiology, Immunology and Infection (2014), http://dx.doi.org/10.1016/j.jmii.2014.08.015
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Y.-C. Lin et al. Conclusion: Although the seropositive rate of measles was > 90% for Grade 1, the rate for Grade 6 was only in the range of 70e80%, which may be a challenge to prevent outbreaks of measles in the future and should be monitored meticulously. Copyright ª 2014, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. All rights reserved.
Introduction Measles is an acute viral disease which is highly infectious in nature. It brings about a large body of illnesses, including fever, rash, conjunctivitis, diarrhea, pneumonia, encephalitis, and even death. In Taiwan, measles occurred epidemically with a 2-year cyclic fluctuation in the prevaccination era.1 To diminish the burden of this disease, the Taiwanese government has been making a great effort by the use of measles-containing vaccines over the past 3 decades. In Taiwan, the live attenuated measles vaccine (Schwarz strain) was first licensed for use in 1968 and a nationwide mass vaccination program with a two-dose schedule for children aged 9 months and 15 months was started in 1978. In January 1988, the immunization program was switched to a single dose of vaccine at 12 months of age, but was soon changed back to a two-dose schedule administered at 9 months and 15 months of age in May 1988, because of an outbreak of measles.2 This strategy was continuously employed until 1991. Since 1992, the second dose of measles vaccine at 15 months of age was substituted with a measles, mumps, and rubella (MMR) vaccine on account of the policy for the elimination of measles, congenital rubella syndrome, poliomyelitis, and neonatal tetanus. Furthermore, a catch-up campaign with one dose of MMR vaccination targeting school students aged 7e13 years was conducted from 1992 to 1994. Since 2001, giving the second dose of MMR vaccine when first attending primary school was started. Another catch-up campaign was carried out for children aged 8e13 years from 2001 to 2004 due to outbreaks.3 Since 2006, the first dose of measles vaccine was ceased, and a schedule of two doses of MMR vaccine was adopted: one at 12e15 months of age and the other at elementary school entry. However, the schedule for the first MMR vaccine was changed to 12 months of age in April 2009 in response to a reappearance of measles resulting from imported cases during the period of November 2008 to February 2009.4,5 The second dose of MMR vaccine was switched to be given to children aged 5e6 years before they entered primary school, in September 2012. According to data from the Taiwan Centers for Disease Control, the coverage rate for the first dose of measles vaccine reached 97.31% by 2012. However, domestic cases as well as imported cases of measles were still identified in low numbers every year in Taiwan. Seroepidemiologic data were very beneficial in understanding the epidemiology of infectious disease and determining the control strategy. Although seroprevalence for measles in Taiwan was previously well documented, the childhood serostatus was no longer well understood as measles became a sporadic
disease, especially in the past 3 years. Therefore, we carried out this survey to investigate the immunity status against measles in elementary school students in Northern Taiwan. The survey will be the pilot study of an ongoing nationwide study, and will be provided as the reference for a national immunization program.
Materials and methods Ethics statement The study proposal was reviewed and approved by the Institutional Review Board at Chang Gung Memorial Hospital, Taoyuan, Taiwan in 2012. Informed consents were obtained from all participants as well as their guardians. All informed consents were in the written form.
Study populations and selection of participants A cross-sectional survey of measles-specific immunoglobulin (Ig)G antibody in the population of elementary schoolchildren in New Taipei City was conducted from September 2012 to June 2013. New Taipei City comprises 29 administrative districts and is the second largest special municipality in Northern Taiwan. A total of 225,234 pupils resided in this city, which accounted for 16.5% of all primary school children in Taiwan in 2012. A multistage stratified method with probability proportional to size sampling was employed to obtain samples. The 29 administrative districts of New Taipei City were classified into five strata based on 14 variables, which included four demographic variables [population density (persons/km2), proportion of population aged > 65 years, < 15 years, and < 6 years], four socio-educational variables (number of physicians, nursing staff, low-income households, and nearpoor households/10,000 people), and six medical facilities’ variables (nursing staff/10,000 people, medical personnel/ 10,000 people, all staff in health centers/10,000 people, number of colleges or universities/10,000 people, proportion of agriculture population, and proportion of population with a college degree or above). From each stratum, elementary schools were selected as the primary sampling unit, and then classes were selected as the second sampling unit. One class was drawn from each grade in a sampled school, that is, a total of six classes were drawn from each sampled school. Students were selected at the final stage of the sampling scheme. Selected students were bled for the serologic tests of measles. All participants were manifestly healthy without acute illness as blood drawing. Past medical histories were obtained by a questionnaire from
Please cite this article in press as: Lin Y-C, et al., Seroepidemiology for measles among elementary school children in Northern Taiwan, Journal of Microbiology, Immunology and Infection (2014), http://dx.doi.org/10.1016/j.jmii.2014.08.015
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each participant and information on vaccination status was reliably obtained by vaccination records.
Determination of measles-specific antibodies Sera were stored at 20 C before measurements. Two different methods were employed to determine measlesspecific IgG: (1) chemiluminescence immunoassay (CLIA; Liaison, DiaSorin, Italy); and (2) enzyme immunoassay (EIA; NovaLisa, NovaTec, Dietzenbach, Germany). Sera were tested following the directions of the manufacturers. The results were interpreted based on the respective manufacturer’s instructions. For the Liaison method, the antibody titers were calculated in arbitrary unit (AU)/mL. Samples with an antibody titer of > 16.5 AU/mL were classified as positive, a titer between 13.5 AU/mL and 16.5 AU/mL was grouped as equivocal, and a titer of < 13.5 AU/mL was considered as negative. With respect to the NovaLisa assay, antibody titers were acquired using NovaTec Units (NTU). An NTU was defined as patient (mean) absorbance value 10/ cut-off value. The results were considered positive for titers > 11 NTU. Titers < 9 NTU and in the range of 9e11 NTU were negative and equivocal, respectively.
Statistical analysis Measles-specific antibody titers were presented as geometric mean titers (GMT). Differences in seropositive
Table 1
percentages between different groups and the two assays were tested by the Chi-square test. The unpaired t test was used to compare the statistic deviances between GMT levels in different grades. The trend of decreasing GMTs was assessed by a linear regression method. Data analyses were performed using SPSS software version 17.0 (SPSS Inc., Chicago, IL, USA). A p value < 0.05 was considered statistically significant.
Results Selected schools and the number of individuals in each stratum are shown in Table 1. In total, 856 schoolchildren from 14 schools were recruited and bled for the serologic tests of measles; 416 (48.5%) were male. From each school, the difference of seropositivity or sex distribution was not statistically apparent. There was a statistically significant difference in seropositivity among five strata by the NovaLisa method (p Z 0.03), but not by the Liaison assay (p Z 0.86). When measured by the Liaison method, a total of 704 (82.24%) samples were positive for measles-specific IgG, whereas 789 (92.17%) were seropositive when the NovaLisa assay was used (Table 1). A statistically significant difference was observed in the seropositive rate between the two assays (p < 0.001). Grade-specific measles seroprevalence and the change of GMTs are shown in Fig. 1. When tested by the Liaison assay, the seropositive rate was 94.96% for Grade 1 but
Seroprevalence among 856 primary school children in five strataa
School (administrative district)
1st stratum Zhong-Shan (Ban-Qiao) San-Zhong (San-Zhong) Zhong-Gang (Xin-Zhuang) Lu-Zhou (Lu-Zhou) Ji-Mei (San-Zhong) Ju-Guang (Ban-Qiao) 2nd stratum Cheng-Fu (San-Xia) Xin-Xing (Dan-Shui) 3rd stratum Jin-Mei (Jin-Shan) Jin-Long (Xi-Zhi) 4th stratum Gan-Yuan (Shu-Lin) Wu-Gu (Wu-Gu) 5th stratum Shi-Ding (Shi-Ding) Shuang-Xi (Shuang-Xi) Total
Schoolchildren, n
517 89 92 86 77 89 84 109 59 50 66 35 31 140 70 70 24 12 12 856
Sex (M/F)
0.99 0.82 0.96 0.83 1.2 1.23 1 0.85 0.64 1.17 0.61 0.67 0.55 0.94 1 0.89 2 5 1 0.95
Positive, n (%) Liaison (CLIA)
NovaLisa (EIA)
429 67 79 72 65 70 72 89 46 43 52 30 22 115 54 61 19 10 9 704
486 84 88 81 73 83 77 92 47 45 62 34 28 127 61 66 22 11 11 789
(82.98) (75.28) (85.87) (83.72) (84.42) (78.65) (90.48) (81.65) (77.97) (86.00) (78.79) (85.71) (70.97) (82.14) (77.14) (87.14) (79.17) (83.33) (75.00) (82.24)
(94.00) (94.38) (95.65) (94.19) (94.81) (93.26) (91.67) (84.40) (79.66) (90.00) (93.94) (97.14) (90.32) (90.71) (87.14) (94.29) (91.67) (91.67) (91.67) (92.17)
a The five strata were classified according to 14 variables (see text). CLIA Z chemiluminescent immunoassay; EIA Z enzyme immunoassay. b The p values for seropositivity among 14 schools were p Z 0.25 and p Z 0.07 by the Liaison and NovaLisa assays, respectively. c The p values for seropositivity among five strata were p Z 0.86 and p Z 0.03 by the Liaison and NovaLisa methods, respectively. d A p value < 0.001 for seropositive rate between the two assays.
Please cite this article in press as: Lin Y-C, et al., Seroepidemiology for measles among elementary school children in Northern Taiwan, Journal of Microbiology, Immunology and Infection (2014), http://dx.doi.org/10.1016/j.jmii.2014.08.015
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A
B
Figure 1. Grade-specific seropositivity and geometric mean titers of measles among 856 schoolchildren by (A) the Liaison assay and (B) the NovaLisa assay. The p values for declining seropositivity and geometric mean titers (GMTs) by both assays were all p < 0.001.
declined to 82.88% for Grade 2 (p Z 0.001). Thereafter, seroprevalence decreased gradually to a nadir of 70.63% for Grade 6. Similarly, seropositivity determined by the NovaLisa assay also had a declining tendency from 100% for Grade 1 to 81.12% for Grade 6 (p < 0.001). In addition, the number of schoolchildren with equivocal serostatus increased over time, either tested by the Liaison or the NovaLisa assay. Similar to seroprevalence, both assays also showed a decay of measles-specific IgG titers (both p for declining trend < 0.001) with the maximum drop between Grade 1 and Grade 2 (both p < 0.001). Among 856 participants, 24 had an unclear vaccination status, all but one of whom had received at least one dose of MMR vaccine, and were excluded when the association between seroprevalence and vaccination doses was further analyzed. A total of 798 (93.2%) received two doses of measles vaccine. Participants with two-dose vaccination had a significantly higher seropositive rate than those who
only received one dose of MMR vaccine (2 doses, 92.5% vs. 1 dose, 82.4 by NovaLisa, p Z 0.047; and 2 doses, 82.8% vs. 1 dose, 64.7 by Liaison, p Z 0.001). The comparisons of seropositivity between the two different methods according to vaccination doses are displayed in Table 2.
Discussion This study revealed an overall anti-measles IgG seropositive rate of 82.3e92.2% via two different serological tests in the population of elementary school students in New Taipei City in Taiwan. Even though both the Liaison and NovaLisa assays disclosed seropositive rates of measles > 90% for Grade 1, the rates for Grade 6 were only in the range of 70e80%. The difference in the seropositivity rates between the tests by Liaison CLIA and NovaLisa EIA was statistically
Please cite this article in press as: Lin Y-C, et al., Seroepidemiology for measles among elementary school children in Northern Taiwan, Journal of Microbiology, Immunology and Infection (2014), http://dx.doi.org/10.1016/j.jmii.2014.08.015
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Table 2 The comparisons of seropositivity between enzyme immunoassay (EIA) and chemiluminescent immunoassay (CLIA), according to measles, mumps, and rubella (MMR) vaccination status Vaccination doses
2 (n Z 798)
1 (n Z 34)
p
Positive, n (%)
738 (92.5)
28 (82.4)
0.032
662 (82.8)
22 (64.7)
0.007
EIA (NovaLisa) CLIA (Liaison)
significant. CLIAs have been reported to provide equal, even greater, sensitivity and specificity in serologically diagnosing a variety of infectious diseases when compared to traditional EIAs.6e11 Liaison measles IgG is a new semiqualitative, fully automated method for determination of measles-specific IgG, and the sensitivity and specificity provided by the manufacturer were 94.7% and 97.4%, respectively. To the best of our knowledge, almost all studies use conventional EIA to measure specific IgG for measles. In the literature to date, only two studies employed this new automated Liaison CLIA to determine measles IgM, in which diagnostic performances of Liaison measles IgM were excellent.7,8 It is hard to distinguish which method is more sensitive or specific, but the result of a seroprevalence of 82.24% revealed by the Liaison assay is lower than expected, considering that all participants in our study received a second dose of MMR vaccine just before or at elementary school entry. Further investigation to resolve this question is warranted. Although measles-specific IgG titers were at a high level for Grade 1, antibody titers declined rapidly at Grade 2 from 171.05 AU/mL to 102.55 AU/mL by the Liaison method and from 29.99 NTU to 24.5 NTU by the NovaLisa method, respectively. In agreement with our findings, other research observed a rapid drop of the antibody level within the 1st year of vaccination.12 Since a nationwide childhood immunization program was implemented in 1978, the incidence of measles has declined rapidly in Taiwan. From 2000 to 2013, the incidence of measles was low, varying from 0 people/year to < 3/1,000,000 people/year (Taiwan Center for Disease Control). As a result, participants in the present study had a low possibility of exposure to wild measles virus and got immunity mainly from vaccination. In our survey, we found a declining seropositivity among primary school students despite the fact that there was somewhat of a discrepancy in the seroprevalence examined by two measurements. The seropositive rate significantly declined to a nadir of 70e80% for Grade 6, whereas schoolchildren with antibody titers in the equivocal range increased gradually as their grade increased. These findings presumably reflected a waning vaccine-evoked immunity with increasing age. Without a natural booster of measles, a rapid decay of vaccine-induced antibody titers in the Taiwanese population was also reported in several studies.12e14. It appeared as though immunity obtained from natural infection provided longer lasting protection. In two previous measles seroepidemiological studies in Taiwan, the seroprevalence in the population born before 1978 was in the range of 95e100%.2,15 Another study in Taiwan reported that infection-induced immunity can even be
lifelong. According to the study, a high level of seropositive rate > 95% remained in people > 65 years old.12 A two-dose regime of MMR vaccination was generally considered appropriate and has been introduced into many countries to eliminate measles infection successfully.16e19 Our study also showed that individuals with two-dose vaccination had a significantly higher seropositive rate than those who only received one dose of MMR vaccine. However, the seropositive rate in Asian countries was substantially lower when compared to Western countries. In addition to a seropositive rate of 70e80% for Grade 6 students in our study, a study conducted in southern mainland China in 2008 revealed that 84.4% of the group aged 2e3 years old were seropositive, whereas the seropositivity decreased to 58.8% in the 15e29-year-old group, despite two dose vaccination coverage data being reported as high (> 90%) since 1986.20 In Korea, a survey revealed that the seropositive rate was 75.3% in the population aged 11e13 years old.21 A cohort study in Finland, however, found that the seropositive rate in vaccinees for MMR was 95% after the 20-year follow-up.22 Similarly, in a national serosurvey in the United States, the rate of measles seropositivity in the population overall was as high as 95.9% during 1999e2004.23 Race difference may play a role in this seroprevalent discrepancy and should be taken into consideration in making vaccination plans. Measles was thought to be a highly contagious disease with an estimated prevaccination reproductive number in the range of 4.78 to 8.0 in Taiwan.24 Hence, a seroprevalence of about 95% in the population was presumed to interrupt measles transmission.25 Although several studies delineated that clinically vaccinees with undetectable or low antibody titers may not necessarily be susceptible to symptomatic measles infection because immune memory and cellular immunity also had an influence against measles infection,26e28 this may be a challenge to prevent outbreaks of measles in the future, since immunity prevalence did not reach the requirement for Grade 6 students. This population is potentially at risk of infection with measles and then plays a role in transmitting the disease. A booster vaccination has been reported to be useful in decreasing the proportion of vaccinees with low antibody titers.29 A revaccination approach for schoolchildren of Grade 5 or 6 deserves further investigation but might not be a matter of great urgency, because the incidence of measles in Taiwan has been low in recent years. The present study had several limitations. First, although we employed a multilevel design using 14 variables to minimalize selecting bias, our participants may not accurately represent all schoolchildren nationwide. Second, serologic results can be confounded by previous measles infection. All participants were not on the list of reporting cases and we used questionnaires to obtain the past medical histories from all schoolchildren. Modified measles can be difficult to diagnose and the questionnaires are still not a thoroughly reliable method. Therefore, we cannot completely exclude the possibility of getting measles before, although the chance was very low. Furthermore, someone may question the results of seroprevalence because there was an inconsistency between the two assays. Indeed, we did not put much effort into analyzing which assay had a better diagnostic performance in this
Please cite this article in press as: Lin Y-C, et al., Seroepidemiology for measles among elementary school children in Northern Taiwan, Journal of Microbiology, Immunology and Infection (2014), http://dx.doi.org/10.1016/j.jmii.2014.08.015
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6 study. Nevertheless, the fact that there was a decay of seropositivity was convincing enough, because both of the assays disclosed the same tendency. In conclusion, the present survey demonstrated a seroepidemiologic profile for measles in elementary school students in Northern Taiwan. A low seroprevalence, around 70e80%, was apparent for schoolchildren above Grade 5 and two-dose vaccines had a higher seropositivity than onedose vaccines. Our findings may provide guidance for national medical authorities in determining a vaccination strategy to reach the goal of measles elimination and also point out that the seroepidemiologic status for measles should be monitored meticulously in the future.
Conflicts of interest All authors declare that they have no conflicts of interest associated with the materials discussed in the article.
Acknowledgments This study was supported in part by a grant from the Centers for Disease Control, Taiwan (DOH101-DC-1016). We would like to thank Ms. Kun-Ju Tsai, a member of the Public Health Department of New Taipei City Government, for her helpful support.
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