Nationwide Molecular Epidemiology of Measles Virus in Japan Between 2008 and 2017

Abstract

Genotyping evidence that supports the interruption of endemic measles virus (MV) transmission is one of the essential criteria to be verified in achieving measles elimination. In Japan since 2014, MV genotype analyses have been performed for most of the measles cases in prefectural public health institutes nationwide. With this strong molecular epidemiological data, Japan was verified to have eliminated measles in March, 2015. However, even in the postelimination era, sporadic cases and small outbreaks of measles have been detected repeatedly in Japan. This study investigated the nationwide molecular epidemiology of MV between 2008 and 2017. The 891 strains in the total period between 2008 and 2017 belonged to seven genotypes (D5, D4, D9, H1, G3, B3, and D8) and 124 different MV sequence variants, based on the 450-nucleotide sequence region of the N gene (N450). The 311 MV strains in the postelimination era between 2015 and 2017 were classified into 1, 7, 8, and 32 different N450 sequence variants in D9, H1, B3, and D8 genotypes, respectively. Analysis of the detection period of the individual N450 sequence variants showed that the majority of MV strains were detected only for a short period. However, MV strains, MVs/Osaka.JPN/29.15/ [D8] and MVi/Hulu Langat.MYS/26.11/ [D8], which are named strains designated by World Health Organization (WHO), have been detected in many cases over 2 or 3 years between 2015 and 2017. The WHO-named strains have circulated worldwide, causing outbreaks in many countries. Epidemiological investigation revealed repeated importation of these WHO-named strains into Japan. To demonstrate the elimination status (interruption of endemic transmission) in situations with repeated importation of the same strains is challenging. Nevertheless, the detailed sequence analysis of individual MV strains and chronological analysis of these strains provided sufficient evidence to show that Japan has still maintained its measles elimination status in 2017.

Keywords: Japan; elimination; genotype; measles virus; molecular epidemiology.

FIGURE 1

Phylogenetic trees of the genotype D5, D4, and D9 MV strains. The phylogenetic trees were constructed using the maximum-likelihood method based on the N450 nucleotide sequence. Circles colored in gray indicate strains detected in Japan between 2008 and 2013. Circles colored in blue, green, orange, and red indicate strains detected in Japan in 2014, 2015, 2016, and 2017, respectively. Underlined MV strains are WHO reference strains. MV strains with brown characters are WHO-named strains. Others are overseas MV strains with the identical N450 sequences to one or another MV strains detected in Japan. The number (n) of each MV strain with an identical N450 sequence is shown, if the strain was detected from more than one case. (A) Genotype D5. (B) Genotypes D4 and D9.

FIGURE 2

Phylogenetic tree of the genotype G3 and H1 MV strains. The analysis and labeling methods of MV strains are described in the legend of Figure 1. Two lineages in H1 genotype (H1-gr.1 and H1-gr.2) tentatively proposed in this study are indicated.

FIGURE 3

Phylogenetic tree of the genotype B3 MV strains. The analysis and labeling methods of MV strains are described in the legend of Figure 1. Three lineages (B3-gr.1, B3-gr.2, and B3-gr.3) tentatively proposed in this study are indicated.

FIGURE 4

Phylogenetic tree of the genotype D8 MV strains. The analysis and labeling methods of MV strains are described in the legend of Figure 1. Five lineages (D8-gr.1a, D8-gr.1b, D8-gr.1c, D8-gr.2a, and D8-gr.2b) tentatively proposed in this study are indicated.

FIGURE 5

Time course of detection of MV strains by week. (A) The time course detection of all genotype strains detected between 2013 and 2017. The line graphs show the total number of reported measles cases. The colored horizontal bars show the genotype data of MV strains. The number of reported measles cases for each genotype is shown in the colored horizontal bars. (B) The time course detection of genotype D8 strains detected between 2014 and 2017. The line graphs show the total number of reported genotype D8 MV cases. The colored horizontal bars show the data of individual sequence variant D8 MV strains. The number of reported measles cases for each sequence variant D8 MV strain is shown in the colored horizontal bars.