International Journal of Infectious Diseases 38 (2015) 1618

Contents lists available at ScienceDirect

International Journal of Infectious Diseases

j o urn a l hom e pa ge : ww w . e l s e v i e r . c om/ l o ca t e / i j i d

Short communications

Investigating the immunizing effect of the rubella epidemic in Japan,

2012-14 (Menyelidiki efek imunisasi epidemi rubella di Jepang, 2012-14)
Hiroshi Nishiura a,b,*, Ryo Kinoshita a,b, Yuichiro Miyamatsu a,b, Kenji Mizumoto c
a
Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 1130033, Japan
b
CREST, Japan Science and Technology Agency, Honcho 4-1-8, Kawaguchi, Saitama, 332-0012 Japan
c
Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 1538902, Japan

ARTICLE INFO ABSTRACT

Article history: Objectives: A rubella epidemic occurred in Japan from 2012-14, involving more than 15,000 cases. The present study aimed
Received 5 June 2015 to estimate the immunizing effect of the epidemic, analyzing seroepidemiological data that were collected over time and age.
Received in revised form 5 July 2015
Accepted 7 July 2015
Methods: Annual nationwide cross-sectional surveys were conducted from July to September, collecting serum from at least
Corresponding Editor: Eskild Petersen, 5,400 individuals. The proportions seropositive were estimated before (2012), during (2013) and after (2014) the epidemic.
Aarhus, Denmark

Results: While the cases were mainly seen among men aged from 30-49 years, no significant increase was observed in the
Keywords: rubella proportion seropositive in the corresponding age group. Even after the epidemic, age-standardized proportion seropositive of
wabah the total population remained 79.3% (95% confidence interval (CI): 75.2, 83.4) and that among males was as small as 76.7%
studi seroepidemiologic (95% CI: 73.8, 79.6).
vaksinasi Conclusions: Susceptible pockets remain in Japan, exposing the country to risk of additional rubella epidemics.
Jepang
rubella 2015 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open
epidemic access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
seroepidemiologic studies nc-nd/4.0/).
vaccination
Japan

1. Introduction
From 2012-14, Japan experienced a large-scale rubella epi-demic,
involving more than 15,000 cases along with 43 notified congenital rubella
syndrome (CRS) cases.1 A peculiar feature of the epidemic has been seen in
the age-distribution of cases: the highest incidence was observed among those
aged from 30-39 years, followed by those aged from 40-49 years.25 As
another remarkable observation, nearly 80% of cases were males. 2 These
features are associated with routine immunization schedules in the past. From
1977-94, only females at junior high school were targeted for rubella
vaccination aiming to prevent CRS at an individual level, but subsequently,
the country shifted the policy to target both males and females aged 12-90
months from 1995. A certain fraction of adult males aged from 20-49 years in
the present day has remained susceptible.
* Corresponding author. Graduate School of Medicine, The University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, Tokyo 1130033, Japan. Tel.: +81 3 5841 3688;
fax: +81 3 5841 3637.
E-mail address: nishiurah@m.u-tokyo.ac.jp (H. Nishiura).
As a consequence of the epidemic with immunizing effect, it is expected
that some susceptible hosts have acquired immunity for two different reasons,
i.e., natural infection and vaccination. Moreover, the immunity level among
those who were immune before the epidemic is likely to have been elevated,
due to a booster effect by exposure to infected individuals or by
revaccination. The present study is aimed to estimate the immunizing effect
of the epidemic, analyzing seroepidemiological data that were collected over
time and age, thereby to assess if the susceptible fraction has been
substantially lowered in Japan.
2. Materials and Methods
The seroepidemiological data were obtained from the National
Epidemiological Surveillance of Vaccine-Preventable Diseases (NESVPD)
after being approved by the Institutional Review Board. 6 Every year from
July to September, the cross-sectional serological survey is conducted and its
area is non-randomly selected. More than 5,400 participants ranging from all
age groups were manually recruited at regional levels, mostly among those
who visited a prefectural medical facility or public health center for some
other purpose. The timing of surveys from 2012-14 corresponds to

http://dx.doi.org/10.1016/j.ijid.2015.07.006
1201-9712/ 2015 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
 H. Nishiura et al. / International Journal of Infectious Diseases 38 (2015) 1618 17

before, during and after the rubella epidemic. The immunity against rubella
has been assessed by hemagglutination inhibition (HI) assay. From 2012-14,
serological testing covered a total of 2,225, 2,586 and 2,882 males and 2,869,
2,938 and 2,861 females, respectively.
From combinations of the three years of cross-sectional serological
surveys, distributions of HI titer by sex were obtained in all ages. Gender-
specific analysis was conducted because the epidemic from 2012-14 was
clustered among adult males and past vaccination histories greatly differed by
gender. Since the survey
does not follow a cohort design, the ratio of the titer at an individual level
cannot be measured, and thus, seropositive was defined as those with HI titer
32 times or greater ( 32), following the convention in Japan (corresponding to
enzyme-linked immu-nosorbent assay at 7.3 IU/ml or greater).
Seroprevalence data were compared against herd immunity level, as
calculated from 1-1/R0, where R0 is the basic reproduction number (i.e. the
average number of secondary cases generated by a single primary case in a
fully susceptible population) assumed at 6.1.7 Subsequently, the
seroprevalence in two years p1 and p2 was determined, and

Figure 1. Proportion seropositive against rubella before, during and after the epidemic in Japan, 2012-14
Panels A, C and E. Age-dependent proportion seropositive against rubella before (2012), during (2013) and after (2014) the epidemic in Japan. The sample proportion positive is shown. Horizontal
grey line indicates the herd immunity threshold of 83.6%, as calculated from 1-1/(basic reproduction number), implies from above major epidemic is expected to be prevented. The basic reproduction
number of rubella is assumed at 6.1.7 Panels B, D and F. Age-specific difference in proportions seropositive between 2012 and 2014 as well as 2013 and 2014. The horizontal solid line represents 0%
difference. Whiskers extend to the upper and lower 95% confidence intervals as calculated from the binomial distribution.

Gambar 1. Proporsi seropositif terhadap rubella sebelum, selama dan setelah epidemi di Jepang, 2012-14

Panel A, C dan E. Umur tergantung proporsi seropositif terhadap rubella sebelum (2012), selama (2013) dan setelah
(2014) epidemi di Jepang. Proporsi sampel positif ditunjukkan. garis abu-abu horizontal menunjukkan ambang
kekebalan kawanan 83,6%, yang dihitung dari 1-1 / (jumlah reproduksi dasar), menyiratkan dari atas epidemi besar
diharapkan akan dicegah. Jumlah reproduksi dasar rubella diasumsikan di 6.1.7 B Panel, D dan F. Age-spesifik
perbedaan proporsi seropositif antara tahun 2012 dan 2014 serta 2013 dan 2014. Garis padat horizontal mewakili 0%
perbedaan. Kumis meluas ke 95% interval kepercayaan atas dan bawah yang dihitung dari distribusi binomial.
18 H. Nishiura et al. / International Journal of Infectious Diseases 38 (2015) 1618
the elevation of the proportion seropositive was assessed by the difference p2-
p1. The 95% confidence intervals (CI) were calculated as practiced
elsewhere.8
3. Results
Figures 1A, 1C and 1E compare the proportion seropositive over time and
age for the total population and also by gender. From visual assessment,
three-year data were almost synchronized through age. Comparing
seroprevalence data against herd immu-nity level, the sample proportions
positive among males were frequently below the threshold, especially among
10s-40s. An evident fraction below the threshold was seen even after the
epidemic (2014) among males aged from 35-49 years. Calculating the age-
standardized proportion seropositive in 2014, the immune fraction of the total
population remained 79.3% (95% confidence interval (CI): 75.2, 83.4). The
estimate of seropositive males appeared to be 76.7% (95% CI: 73.8, 79.6),
which was well below the herd immunity threshold. The estimate of females
was 79.3% (95% CI: 75.2, 83.4).
Figures 1B, 1D and 1F show the change in the estimated proportions
acquiring immunity towards rubella by sex, compar-ing 2014 data against
before (2012) and during (2013) the epidemic. While an increase in the
sample difference was seen among males aged from 30-39 years, the increase
was not statistically significant. Moreover, no significant increase was
observed across all age groups for both males and females. There were even
significant decreases in seroprevalence when compar-ing 2012 and 2014
among 40-49 years old for both genders, presumably caused by decay in
antibody titer or spatial sampling bias.
4. Discussion
The present study assessed the proportions seropositive against rubella in
Japan, comparing estimates before, during, and after the epidemic and aiming
to estimate the immunizing effect of the epidemic. Three notable findings
were obtained. First, while the cases were mainly seen among men aged from
30-49 years old, no significant increase was observed in the proportion
seropositive. Second, for several male birth cohorts, the seroprevalence was
well below the herd immunity threshold level. Third, the age-standardized
proportion seropositive was calculated, and that for males was as small as
76.7%. Not only mens but also womens seroprevalence was below our
reference value of the threshold.
All three findings warn that there are susceptible pockets left, especially in
unimmunized birth cohorts of adult men, which accounted for 80% of cases
during the epidemic 2012-14. Susceptible cohorts could continue to fuel
future rubella epidemics in Japan. An important limitation of our study is that
our definition of seropositive (HI 32 ) rested on a convention in Japan based
on small number of samples and the actual immune fraction could potentially
be greater than we calculated. Nevertheless, our estimate is consistent with
the occurrence of the major epidemic from 2012-14, and moreover, our
finding of the absence of increase in seropositive fraction is seen with all
other cut-off levels
including HI 8 (results not shown). Limited herd immunity levels among
adult men are likely attributable to (i) missed chance of vaccination and (ii)
waning immunity. It must be noted that males aged from 10-19 years
followed the new protocol of vaccination, but their seropositive fraction was
below herd immunity threshold, and moreover, the seroprevalence decreased
over three years, perhaps reflecting the loss of vaccine-induced immunity. To
fill up the unvaccinated cohorts, the above mentioned findings call for strong
supplementary vaccination, not only among women at child-bearing age, but
also towards previously unvaccinated men aged from 10s-40s. Otherwise, the
finding of the absence of increase in seroprevalence indicates that Japan will
continue to be prone to further epidemics. Moreover, if it is certain that
immunity in the substantial fraction of previously vaccinated adults has been
waned, it would be necessary to plan a catch-up vaccination program.
Continued monitoring of suscepti-ble age groups by seroepidemiological
survey would be essential, as they permit estimating the epidemic size and
designing the most efficient vaccination strategy.9,10
Acknowledgments
HN received funding support from Public Health Research Foundation,
Daiwa Securities Health Foundation, the Japan Society for the Promotion of
Science (JSPS) KAKENHI Grant Number 26670308, Japan Agency for
Medical Research and Development, the Japan Science and Technology
Agency (JST) CREST program and RISTEX program for Science of Science,
Technology and Innovation Policy. The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the
manuscript.
Conflict of interest: The authors declare no conflicts of interest.
References
1. Ujiie M, Nabae K, Shobayashi T. Rubella outbreak in Japan. Lancet 2014;383: 14601.
2. Minakami H, Kubo T, Unno N. Causes of a nationwide rubella outbreak in Japan, 2012
2013. J Infect 2014;68:99101.
3. Anonymous. Nationwide rubella epidemic Japan, 2013. Morb Mortal Wkly Rep
2013;62:45262.
4. Sugishita Y, Takahashi T, Hori N, Abo M. Ongoing rubella outbreak among adults in
Tokyo, Japan, June 2012 to April 2013. Western Pac Surveill Response J 2013;4:3741.
5. Sugishita Y, Shimatani N, Katow S, Takahashi T, Hori N. Epidemiological characteristics
of rubella and congenital rubella syndrome in the 20122013 epidemics in Tokyo. Japan
2015;68:15965.
6. Ministry of Health, Labour, and Welfare (MHLW) Committee of NESVPD in National
Institute of Infectious Diseases. 20122014. Procedure for the National Epidemiological
Surveillance of Vaccine-Preventable Diseases (in Japanese).
7. Kanaan MN, Farrington CP. Matrix models for childhood infections: a Bayesian approach
with applications to rubella and mumps. Epidemiol Infect 2005;133: 100921.
8. Mizumoto K, yamamoto T, Nishiura H. Age-dependent estimates of the epide-miological
impact of pandemic influenza (H1N1-2009) in Japan. Comput Math Methods Med
2013;2013:637064.
9. Nishiura H, Chowell G, Castillo-Chavez C. Did modeling overestimate the transmission
potential of pandemic (H1N1-2009)? Sample size estimation for post-epidemic
seroepidemiological studies. PLoS One 2011;6:e17908.
10. Nabae K, Satoh H, Nishiura H, Tanaka-Taya K, Okabe N, Oishi K, et al. Estimating the
risk of parvovirus B19 infection in blood donors and pregnant women in Japan. PLoS One
2014;9:e92519.
ABSTRAK.
Tujuan: Sebuah epidemi rubella terjadi di Jepang 2012-14, yang melibatkan lebih dari 15.000 kasus.
Penelitian ini bertujuan untuk memperkirakan efek imunisasi epidemi, menganalisis data
seroepidemiological yang dikumpulkan dari waktu ke waktu dan usia.

Metode: Survei cross-sectional Tahunan nasional dilakukan dari Juli hingga September,
mengumpulkan serum dari setidaknya 5.400 orang. Proporsi seropositif diperkirakan sebelumnya
(2012), selama (2013) dan setelah (2014) epidemi.

Hasil: Sementara kasus terutama terlihat di antara laki-laki berusia 30-49 tahun, tidak ada peningkatan
yang signifikan diamati dalam seropositif proporsi pada kelompok usia yang sesuai. Bahkan setelah
epidemi, standarisasi-umur proporsi seropositif dari total penduduk tetap 79,3% (95% confidence
interval (CI): 75.2, 83.4) dan bahwa di antara laki-laki kecil seperti 76,7% (95% CI: 73,8, 79,6).

Kesimpulan: kantong Rentan tetap tinggal di Jepang, memperlihatkan negara untuk risiko epidemi
rubella tambahan.

2015 Penulis. Diterbitkan oleh Elsevier Ltd atas nama Masyarakat Internasional untuk Penyakit
Infeksi. Ini adalah sebuah artikel akses terbuka di bawah CC BY-NC-ND lisensi
(http://creativecommons.org/licenses/by-

1. Perkenalan

Dari 2012-14, Jepang mengalami rubella skala besar epi-akademis, yang melibatkan lebih

dari 15.000 kasus bersama dengan 43 diberitahu sindrom rubella bawaan (CRS) cases.1

Sebuah fitur khas epidemi telah terlihat di usia-distribusi kasus : insiden tertinggi diamati

antara mereka yang berusia 30-39 tahun, diikuti oleh mereka yang berusia 40-49 years.2-5

Sebagai pengamatan lain yang luar biasa, hampir 80% dari kasus yang males.2 fitur ini

berkaitan dengan jadwal imunisasi rutin di masa lalu. Dari 1977-1994, hanya perempuan di

SMP yang ditargetkan untuk vaksinasi rubella bertujuan untuk mencegah CRS pada tingkat

individu, tetapi kemudian, negara bergeser kebijakan untuk menargetkan baik laki-laki dan

perempuan berusia 12-90 bulan dari tahun 1995. Sebuah fraksi tertentu dewasa laki-laki

berusia 20-49 tahun pada hari ini tetap rentan.

Sebagai konsekuensi dari epidemi dengan imunisasi efek, diharapkan bahwa beberapa host

rentan telah memperoleh kekebalan karena dua alasan yang berbeda, yaitu, infeksi alami dan

vaksinasi. Selain itu, tingkat imunitas di antara mereka yang kekebalan sebelum epidemi
mungkin telah meningkat, karena efek penguat dengan paparan individu yang terinfeksi atau

dengan vaksinasi ulang. Penelitian ini bertujuan untuk mengestimasi dampak imunisasi

epidemi, menganalisis data seroepidemiological yang dikumpulkan dari waktu ke waktu dan

usia, sehingga untuk menilai apakah fraksi rentan telah secara substansial menurunkan di

Jepang.

2. Bahan dan Metode

Data seroepidemiological diperoleh dari National Surveilans Epidemiologi Vaksin-Dicegah Penyakit

(NESVPD) setelah disetujui oleh Institutional Review Board.6 Setiap tahun dari Juli hingga

September, survei serologis cross-sectional dilakukan dan daerah adalah non-acak terpilih. Lebih dari

5.400 peserta mulai dari semua kelompok umur secara manual direkrut di tingkat regional, sebagian

besar di antara mereka yang mengunjungi fasilitas medis Prefektur atau pusat kesehatan masyarakat

untuk tujuan lain. Waktu survei 2012-14 sesuai dengan sebelum, selama dan setelah epidemi

rubella. Kekebalan terhadap rubella telah dinilai oleh inhibisi hemaglutinasi (HI) assay. Dari

2012-14, pengujian serologis tertutup total 2.225, 2.586 dan 2.882 laki-laki dan 2.869, 2.938

dan 2.861 perempuan, masing-masing.

Dari kombinasi dari tiga tahun survey serologis cross-sectional, distribusi HI titer

berdasarkan jenis kelamin diperoleh di segala usia. analisis gender tertentu dilakukan karena

epidemi 2012-14 itu berkerumun di antara laki-laki dewasa dan sejarah masa lalu vaksinasi

sangat berbeda dengan gender. Sejak survei elevasi seropositif proporsi dinilai dengan perbedaan

p2-p1. Interval kepercayaan 95% (CI) dihitung sebagai elsewhere.8 dipraktekkan

3. Hasil

Angka 1A, 1C dan 1E membandingkan seropositif proporsi dari waktu ke waktu dan usia untuk total

populasi dan juga berdasarkan jenis kelamin. Dari penilaian visual, data yang tiga tahun hampir

disinkronisasi melalui usia. Membandingkan data prevalensi terhadap kawanan tingkat immu-nity,

proporsi sampel positif antara laki-laki yang sering di bawah ambang batas, terutama di kalangan 10s-

40s. Fraksi jelas di bawah ambang batas terlihat bahkan setelah epidemi (2014) antara laki-laki

berusia 35-49 tahun. Menghitung usia-standar proporsi seropositif pada tahun 2014, fraksi kekebalan

dari total penduduk tetap 79,3% (95% confidence interval (CI): 75.2, 83.4). Perkiraan laki-laki

seropositif tampaknya 76,7% (95% CI: 73,8, 79,6), yang jauh di bawah ambang batas kekebalan

kawanan. Perkiraan perempuan adalah 79,3% (95% CI: 75,2, 83,4).

Angka 1B, 1D dan 1F menunjukkan perubahan estimasi proporsi memperoleh kekebalan terhadap

rubella berdasarkan jenis kelamin, compar-ing 2014 data terhadap sebelum (2012) dan selama (2013)

epidemi. Sementara peningkatan perbedaan sampel terlihat di antara laki-laki berusia 30-39 tahun,

kenaikan itu tidak signifikan secara statistik. Selain itu, tidak ada peningkatan yang signifikan diamati

di semua kelompok umur untuk pria dan wanita. Bahkan ada penurunan yang signifikan dalam

prevalensi ketika compar-ing 2012 dan 2014 antara tua untuk kedua jenis kelamin, mungkin

disebabkan oleh kerusakan pada titer antibodi atau bias sampling spasial 40-49 tahun.

4. Diskusi

Penelitian ini menilai proporsi seropositif terhadap rubella di Jepang, membandingkan

perkiraan sebelum, selama, dan setelah epidemi dan bertujuan untuk memperkirakan efek

imunisasi epidemi. Tiga temuan penting diperoleh. Pertama, sedangkan kasus terutama

terlihat di antara laki-laki berusia tua 30-49 tahun, tidak ada peningkatan yang signifikan

diamati dalam seropositif proporsi. Kedua, selama beberapa kelompok kelahiran laki-laki,

seroprevalence itu jauh di bawah tingkat kawanan ambang kekebalan. Ketiga, usia-standar
proporsi seropositif dihitung, dan untuk laki-laki kecil seperti 76,7%. Tidak hanya pria, tetapi

juga prevalensi perempuan di bawah nilai referensi kami ambang batas.

Ketiga temuan memperingatkan bahwa ada kantong-kantong rentan kiri, terutama di

kelompok kelahiran diimunisasi pria dewasa, yang menyumbang 80% dari kasus selama

wabah 2012-14. kohort rentan bisa terus bahan bakar epidemi rubella masa depan di Jepang.

Sebuah batasan penting dari penelitian kami adalah bahwa definisi kita tentang seropositif

(HI 32) beristirahat di sebuah konvensi di Jepang berdasarkan sejumlah kecil sampel dan

fraksi kekebalan tubuh yang sebenarnya berpotensi menjadi lebih besar dari yang kita

dihitung. Namun demikian, perkiraan kami konsisten dengan terjadinya epidemi utama 2012-

14, dan terlebih lagi, temuan kami dari tidak adanya peningkatan fraksi seropositif terlihat

dengan semua tingkat cut-off lainnya.

tidak mengikuti desain kohort, rasio titer pada tingkat individu tidak dapat diukur, dan

dengan demikian, seropositif didefinisikan sebagai orang-orang dengan HI titer 32 kali atau

lebih besar (32), mengikuti konvensi di Jepang (sesuai dengan enzim-linked immu-nosorbent

assay 7,3 IU / ml atau lebih). Data prevalensi dibandingkan terhadap tingkat kekebalan

kawanan, karena dihitung dari 1-1 / R0, di mana R0 adalah jumlah reproduksi dasar (yaitu

rata-rata jumlah kasus sekunder yang dihasilkan oleh kasus primer tunggal dalam populasi

sepenuhnya rentan) diasumsikan di 6.1.7 Selanjutnya, prevalensi dalam dua tahun p1 dan p2

ditentukan, dan termasuk HI 8 (hasil tidak ditunjukkan). tingkat kekebalan kawanan terbatas

antara laki-laki dewasa cenderung berasal dari (i) kehilangan kesempatan vaksinasi dan (ii)

memudarnya imunitas. Harus dicatat bahwa laki-laki berusia 10-19 tahun mengikuti protokol

baru vaksinasi, tetapi sebagian kecil seropositif mereka adalah di bawah ambang batas

kekebalan kawanan, dan terlebih lagi, seroprevalence menurun selama tiga tahun, mungkin
mencerminkan hilangnya kekebalan yang disebabkan oleh vaksin. Untuk mengisi kohort

yang tidak divaksinasi, temuan yang disebutkan di atas panggilan untuk vaksinasi tambahan

yang kuat, tidak hanya di kalangan wanita di usia subur, tetapi juga terhadap manusia

sebelumnya tidak divaksinasi berusia 10-an-40-an. Jika tidak, temuan adanya peningkatan

prevalensi menunjukkan bahwa Jepang akan terus menjadi rentan terhadap epidemi lebih

lanjut. Selain itu, jika dapat dipastikan bahwa kekebalan pada fraksi besar orang dewasa yang

sebelumnya divaksinasi telah memudar, itu akan diperlukan untuk merencanakan program

vaksinasi catch-up. pemantauan lanjutan dari kelompok usia suscepti-ble oleh survei

seroepidemiological akan menjadi penting, karena mereka mengizinkan memperkirakan

ukuran epidemi dan merancang vaksinasi strategy paling efisien