Rubella Epidemics and Genotypic Distribution of the Rubella Virus in Shandong Province, China, in 1999–2010

PLOS ONE, Dec 2019

Background The rubella vaccine was introduced into the immunization program in 1995 in the Shandong province, China. A series of different rubella vaccination strategies were implemented at different stages of measles control in Shandong province. Methodology/Principal Findings The average reported incidence rate of rubella cases remained at a low level in Shandong province after 1999. However, rubella epidemics occurred repeatedly in 2001/2002, 2006, and 2008/2009. The age of the onset of rubella cases gradually increased during 1999–2010, which showed that most cases were found among the 10 years old in 1999 and among the 17 years old in 2010. Phylogenetic analysis was performed and a phylogenetic tree was constructed based on the World Health Organization standard sequence window for rubella virus isolates. All rubella viruses isolated in Shandong province were divided into 4 genotypes: 1E, 1F, 2A, and 2B. Genotype 1E viruses accounted for the majority (79%) of all these viruses. The similarity of nucleotide and amino acid sequences among genotype 1E viruses was 98.2–100% and 99.1–100%, respectively. All Shandong genotype 1E strains, differed from international genotype 1E strains, belonged to cluster 1 and interdigitated with the viruses from other provinces in mainland China. The effective number of infections indicated by a Bayesian skyline plot remained constant from 2001 to 2009. Conclusions/Significance The gradual shift of disease burden to an older age group occurred after a rubella-containing vaccine was introduced into the childhood immunization schedule in 1995 in Shandong province. Four genotypes, including 1E, 1F, 2A, and 2B, were found in Shandong province during 2000–2009. Genotype 1E, rather than genotype 1F, became the predominant genotype circulating in Shandong province from 2001. All Shandong genotype 1E viruses belong to the genotype 1E/cluster 1; they have constantly circulated, and co-evolved and co-circulated, with those from other provinces.

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Rubella Epidemics and Genotypic Distribution of the Rubella Virus in Shandong Province, China, in 1999–2010

in 1999-2010. PLoS ONE 7(7): e42013. doi:10.1371/journal.pone.0042013 Rubella Epidemics and Genotypic Distribution of the Rubella Virus in Shandong Province, China, in 1999-2010 Changyin Wang 0 Zhen Zhu 0 Qing Xu 0 Aiqiang Xu 0 Xueqiang Fang 0 Lizhi Song 0 Weixiu Li 0 Ping Xiong 0 Wenbo Xu 0 Dong-Yan Jin, University of Hong Kong, Hong Kong 0 1 Shandong Provincial Key Laboratory for Infectious Disease Control and Prevention, Shandong Center for Disease Control and Prevention , Jingshi Road, Jinan , People's Republic of China, 2 WHO WPRO Regional Reference Measles/Rubella laboratory, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention , Changbai Road, Changping District, Beijing , People's Republic of China Background: The rubella vaccine was introduced into the immunization program in 1995 in the Shandong province, China. A series of different rubella vaccination strategies were implemented at different stages of measles control in Shandong province. Methodology/Principal Findings: The average reported incidence rate of rubella cases remained at a low level in Shandong province after 1999. However, rubella epidemics occurred repeatedly in 2001/2002, 2006, and 2008/2009. The age of the onset of rubella cases gradually increased during 1999-2010, which showed that most cases were found among the 10 years old in 1999 and among the 17 years old in 2010. Phylogenetic analysis was performed and a phylogenetic tree was constructed based on the World Health Organization standard sequence window for rubella virus isolates. All rubella viruses isolated in Shandong province were divided into 4 genotypes: 1E, 1F, 2A, and 2B. Genotype 1E viruses accounted for the majority (79%) of all these viruses. The similarity of nucleotide and amino acid sequences among genotype 1E viruses was 98.2-100% and 99.1-100%, respectively. All Shandong genotype 1E strains, differed from international genotype 1E strains, belonged to cluster 1 and interdigitated with the viruses from other provinces in mainland China. The effective number of infections indicated by a Bayesian skyline plot remained constant from 2001 to 2009. Conclusions/Significance: The gradual shift of disease burden to an older age group occurred after a rubella-containing vaccine was introduced into the childhood immunization schedule in 1995 in Shandong province. Four genotypes, including 1E, 1F, 2A, and 2B, were found in Shandong province during 2000-2009. Genotype 1E, rather than genotype 1F, became the predominant genotype circulating in Shandong province from 2001. All Shandong genotype 1E viruses belong to the genotype 1E/cluster 1; they have constantly circulated, and co-evolved and co-circulated, with those from other provinces. - Funding: This work was supported by the Key Research Plan on Medicine from the Health Department of Shandong province in China (2009HD014), the National Natural Science Foundation of China (project no. 81101244), the National Infectious Diseases Surveillance Program (2012ZX10004201, 2008ZX10004-008, 2009ZX10004-201, and 2009ZX10004-202), and WHO Measles Regional Reference Laboratory funding (WPCHN1002802). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. The rubella virus is the etiological agent of a disease known as rubella (or German measles) [1]. The disease is generally benign, and infection is often asymptomatic. As rubella virus is a potent, infectious, and teratogenic agent, virus infection of non-immunized women during the early stages of pregnancy, particularly during the first 16 weeks, can result in miscarriage, fetal death, or an infant born with birth defects such as congenital rubella syndrome (CRS) [1,2,3]. In 2000, therefore, the World Health Organization (WHO) recommended the use of rubella-containing vaccine (RCV) in all countries with national childhood immunization schedules to prevent congenital rubella infection, including CRS [4]. The number of WHO Member States using RCV increased from 83 (43%) in 1996 to 130 (67%) in 2009. The number of rubella cases reported dramatically decreased from 670,894 in 2000 to 121,344 in 2009 [5]. RuV is a small, enveloped virus in the Rubivirus genus of the Togavirus family. The genome of RuV is a single-stranded, positive-sense RNA of approximate 10 kb. The genome encodes 2 open reading frames (ORFs), the 39-proximal ORF (structural protein ORF) encodes the virion proteins, the nucleocapsid protein (C), and the 2 envelope glycoproteins (E2 and E1) [3]. The 739-nt region (nt 87319469) within the E1 glycoprotein contains important functional domains including a hemagglutination inhibiting and neutralizing epitope, and antigenic sites [6], and has been designated as WHO standard sequence window for rubella phylo (...truncated)


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Changyin Wang, Zhen Zhu, Qing Xu, Aiqiang Xu, Xueqiang Fang, Lizhi Song, Weixiu Li, Ping Xiong, Wenbo Xu. Rubella Epidemics and Genotypic Distribution of the Rubella Virus in Shandong Province, China, in 1999–2010, PLOS ONE, 2012, Volume 7, Issue 7, DOI: 10.1371/journal.pone.0042013