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1.  Genetic Characterization of the Hemagglutinin Genes of Wild-Type Measles Virus Circulating in China, 1993–2009 
PLoS ONE  2013;8(9):e73374.
Background
China experienced several large measles outbreaks in the past two decades, and a series of enhanced control measures were implemented to achieve the goal of measles elimination. Molecular epidemiologic surveillance of wild-type measles viruses (MeV) provides valuable information about the viral transmission patterns. Since 1993, virologic surveillnace has confirmed that a single endemic genotype H1 viruses have been predominantly circulating in China. A component of molecular surveillance is to monitor the genetic characteristics of the hemagglutinin (H) gene of MeV, the major target for virus neutralizing antibodies.
Principal Findings
Analysis of the sequences of the complete H gene from 56 representative wild-type MeV strains circulating in China during 1993–2009 showed that the H gene sequences were clustered into 2 groups, cluster 1 and cluster 2. Cluster1 strains were the most frequently detected cluster and had a widespread distribution in China after 2000. The predicted amino acid sequences of the H protein were relatively conserved at most of the functionally significant amino acid positions. However, most of the genotype H1 cluster1 viruses had an amino acid substitution (Ser240Asn), which removed a predicted N-linked glycosylation site. In addition, the substitution of Pro397Leu in the hemagglutinin noose epitope (HNE) was identified in 23 of 56 strains. The evolutionary rate of the H gene of the genotype H1 viruses was estimated to be approximately 0.76×10−3 substitutions per site per year, and the ratio of dN to dS (dN/dS) was <1 indicating the absence of selective pressure.
Conclusions
Although H genes of the genotype H1 strains were conserved and not subjected to selective pressure, several amino acid substitutions were observed in functionally important positions. Therefore the antigenic and genetic properties of H genes of wild-type MeVs should be monitored as part of routine molecular surveillance for measles in China.
doi:10.1371/journal.pone.0073374
PMCID: PMC3779233  PMID: 24073194
2.  Molecular epidemiology of measles viruses in China, 1995–2003 
Virology Journal  2007;4:14.
This report describes the genetic characterization of 297 wild-type measles viruses that were isolated in 24 provinces of China between 1995 and 2003. Phylogenetic analysis of the N gene sequences showed that all of the isolates belonged to genotype H1 except 3 isolates, which were genotype A. The nucleotide sequence and predicted amino acid homologies of the 294-genotype H1 strains were 94.7%–100% and 93.3%–100%, respectively. The genotype H1 isolates were divided into 2 clusters, which differed by approximately 2.9% at the nucleotide level. Viruses from both clusters were distributed throughout China with no apparent geographic restriction and multiple co-circulating lineages were present in many provinces. Even though other measles genotypes have been detected in countries that border China, this report shows that genotype H1 is widely distributed throughout the country and that China has a single, endemic genotype. This important baseline data will help to monitor the progress of measles control in China.
doi:10.1186/1743-422X-4-14
PMCID: PMC1802751  PMID: 17280609
3.  Measles Resurgence Associated with Continued Circulation of Genotype H1 Viruses in China, 2005 
Virology Journal  2009;6:135.
Measles morbidity and mortality decreased significantly after measles vaccine was introduced into China in 1965. From 1995 to 2004, average annual measles incidence decreased to 5.6 cases per 100,000 population following the establishment of a national two-dose regimen. Molecular characterization of wild-type measles viruses demonstrated that genotype H1 was endemic and widely distributed throughout the country in China during 1995-2004. A total of 124,865 cases and 55 deaths were reported from the National Notifiable Diseases Reporting System (NNDRS) in 2005, which represented a 69.05% increase compared with 2004. Over 16,000 serum samples obtained from 914 measles outbreaks and the measles IgM positive rate was 81%. 213 wild-type measles viruses were isolated from 18 of 31 provinces in China during 2005, and all of the isolates belonged to genotype H1. The ranges of the nucleotide sequence and predicted amino acid sequence homologies of the 213 genotype H1 strains were 93.4%-100% and 90.0%-100%, respectively. H1-associated cases and outbreaks caused the measles resurgence in China in 2005. H1 genotype has the most inner variation within genotype, it could be divided into 2 clusters, and cluster 1 viruses were predominant in China throughout 2005.
doi:10.1186/1743-422X-6-135
PMCID: PMC2759936  PMID: 19737391
4.  Genetic characterization of wild-type measles viruses isolated in China, 2006-2007 
Virology Journal  2010;7:105.
Molecular characterization of wild-type measles viruses in China during 1995-2004 demonstrated that genotype H1 was endemic and widely distributed throughout the country. H1-associated cases and outbreaks caused a resurgence of measles beginning in 2005. A total of 210,094 measles cases and 101 deaths were reported by National Notifiable Diseases Reporting System (NNDRS) and Chinese Measles Laboratory Network (LabNet) from 2006 to 2007, and the incidences of measles were 6.8/100,000 population and 7.2/100,000 population in 2006 and 2007, respectively. Five hundred and sixty-five wild-type measles viruses were isolated from 24 of 31 provinces in mainland China during 2006 and 2007, and all of the wild type virus isolates belonged to cluster 1 of genotype H1. These results indicated that H1-cluster 1 viruses were the predominant viruses circulating in China from 2006 to 2007. This study contributes to previous efforts to generate critical baseline data about circulating wild-type measles viruses in China that will allow molecular epidemiologic studies to help measure the progress made toward China's goal of measles elimination by 2012.
doi:10.1186/1743-422X-7-105
PMCID: PMC2887432  PMID: 20500809
5.  Evolutionary genetics of genotype H1 measles viruses in China from 1993 to 2012 
The Journal of General Virology  2014;95(Pt 9):1892-1899.
Virologic surveillance is a critical component of measles management. One of the criteria for verification of elimination of endemic measles is genetic analysis of wild-type viruses to demonstrate lack of an indigenous genotype. Measles is yet to be eliminated in China, and genotype H1 has been detected continuously since virologic surveillance was initiated in 1993. Virologic surveillance has been very active in China, providing a unique opportunity to conduct a detailed study of the evolution of a single, endemic genotype over a timespan of nearly two decades. Phylogenetic analysis performed on the 450 nt coding sequence for the C-terminal 150 amino acids of the nucleoprotein (N-450), fusion (F) gene and haemagglutinin (H) gene confirmed the continued circulation of genotype H1 viruses for 19 years. No evidence of selective pressure for the H protein was found. The substitution rates ranged from 0.75×10−3 substitutions site−1 year−1 for H to 1.65×10−3 substitutions site−1 year−1 for N-450. The time of most recent common ancestor (TMRCA) for genotype H1 was estimated as approximately 1985 (95 % highest probability density, 1979–1989). Finally, the overall diversity of measles sequences from China decreased from 2005 to 2012, coincident with a substantial decrease in measles cases. The results suggest that detailed evolutionary analyses should facilitate the documentation of eventual measles elimination in China. Moreover, the molecular approaches used in this study can be applied in other countries approaching measles elimination.
doi:10.1099/vir.0.066746-0
PMCID: PMC4135087  PMID: 24914068
6.  Molecular characterization of measles viruses that circulated in Cameroon between 2010 and 2011 
Virology Journal  2013;10:71.
Background
Measles virus (MeV) is monotypic, but genetic variation in the hemagglutinin H and nucleoprotein N genes can be analyzed by molecular epidemiologic techniques and used to study virus transmission patterns. The World Health Organization currently recognizes 8 clades (A-H) within which are 24 genotypes of MeV and one provisional genotype, d11. Genotype B3 is clearly the endemic genotype in most of African continent where it is widely distributed. We provide an update on the molecular characterization of wild-type MeVs that circulated in Cameroon between 2010 and 2011.
Findings
Viral RNA was extracted directly from samples obtained from clinically diagnosed measles patients using QIAamp viral RNA Mini Kit. Reverse transcription and PCR amplification of 634 nucleotides of the N gene was performed using the SuperScript™ III One-Step. Sequence analysis of 450 of the 634 nucleotides using Clustal X 2.0 program for multiple alignments and Mega version 5 for phylogenic analysis indicated that all the viruses belonged to genotype B3 with two distinct clusters. Twenty three (77%) belonged to subgroup B3.1 and the other 7 (23%) belonged to B3.3 a recently described subtype. Circulation of cluster 3 was detected in the Far-North Region (5/7) particularly along the Chad-Cameroon border in 2010 and later in Yaounde (2/7 in Biyem-assi Health District) the capital city of Cameroon in 2011.
Conclusion
This study highlights the endemic circulation in Cameroon of MeV B3 subtype 1, which probably has its source in the neighboring Nigeria, and the presence of the new subtype B3.3, suggesting a possible importation from Northern Africa where it was first described between 2008 and 2009.
doi:10.1186/1743-422X-10-71
PMCID: PMC3599851  PMID: 23497069
Measles virus; Genotype B3; Nucleoprotein N; Cameroon
7.  Genetic characterization of Measles Viruses in China, 2004 
Virology Journal  2008;5:120.
Genetic characterization of wild-type measles virus was studied using nucleotide sequencing of the C-terminal region of the N protein gene and phylogenetic analysis on 59 isolates from 16 provinces of China in 2004. The results showed that all of the isolates belonged to genotype H1. 51 isolates were belonged to cluster 1 and 8 isolates were cluster 2 and Viruses from both clusters were distributed throughout China without distinct geographic pattern. The nucleotide sequence and predicted amino acid homologies of the 59 H1 strains were 96.5%–100% and 95.7%–100%, respectively. The report showed that the transmission pattern of genotype H1 viruses in China in 2004 was consistent with ongoing endemic transmission of multiple lineages of a single, endemic genotype. Multiple transmission pathways leaded to multiple lineages within endemic genotype.
doi:10.1186/1743-422X-5-120
PMCID: PMC2600640  PMID: 18928575
8.  Molecular Epidemiology of Measles Virus before and after the 2003 Mass Vaccination Campaign for Measles/Rubella in Iran 
Background:
Molecular epidemiology of measles virus (MV) is important, not only to measure the success of measles vaccination programs but also to monitor the circulation and elimination of the virus worldwide. In this study, we compared MV obtained from patients before the 2003 mass vaccination MR campaign and viruses detected after 2003 until 2008 in Iran.
Methods:
The nucleoprotein (N) gene of 29 MV strains circulating in Iran between 2002 and 2008 were amplified by RT-PCR and subjected to sequence and phylogenetic analysis.
Results:
Molecular characterization of MV studied here revealed that although the outbreaks in Iran were associated with MV genotype D4, the isolated viruses clearly belonged to several different lineages. Maximum and minimum homology within the 29 Iranian strains in our study was100% and 94.9% within the carboxyl terminus of the N gene, respectively. Using ClustalX program, the alignment of Iranian MV sequences showed nine lineages.
Conclusion:
This study provides the usefulness of MV sequence analysis for the demonstration of local interruption of indigenous strain transmission as well as providing a valuable means for monitoring the elimination processes of MV control.
PMCID: PMC3481721  PMID: 23113053
Measles; Genotype; Mass campaign; Iran
9.  Genetic diversity of wild-type measles viruses: implications for global measles elimination programs. 
Emerging Infectious Diseases  1998;4(1):29-35.
Wild-type measles viruses have been divided into distinct genetic groups according to the nucleotide sequences of their hemagglutinin and nucleoprotein genes. Most genetic groups have worldwide distribution; however, at least two of the groups appear to have a more limited circulation. To monitor the transmission pathways of measles virus, we observed the geographic distribution of genetic groups, as well as changes in them in a particular region over time. We found evidence of interruption of indigenous transmission of measles in the United States after 1993 and identified the sources of imported virus associated with cases and outbreaks after 1993. The pattern of measles genetic groups provided a means to describe measles outbreaks and assess the extent of virus circulation in a given area. We expect that molecular epidemiologic studies will become a powerful tool for evaluating strategies to control, eliminate, and eventually eradicate measles.
PMCID: PMC2627654  PMID: 9452396
10.  Identification of different lineages of measles virus strains circulating in Uttar Pradesh, North India 
Virology Journal  2012;9:237.
Background
Genetic analysis of measles viruses associated with recent cases and outbreaks has proven to bridge information gaps in routine outbreak investigations and has made a substantial contribution to measles control efforts by helping to identify the transmission pathways of the virus.
Materials and methods
The present study describes the genetic characterization of wild type measles viruses from Uttar Pradesh, India isolated between January 2008 and January 2011. In the study, 526 suspected measles cases from 15 outbreaks were investigated. Blood samples were collected from suspected measles outbreaks and tested for the presence of measles specific IgM; throat swab and urine samples were collected for virus isolation and RT-PCR. Genotyping of circulating measles viruses in Uttar Pradesh was performed by sequencing a 450-bp region encompassing the nucleoprotein hypervariable region and phylogenetic analysis.
Results and conclusion
Based on serological results, all the outbreaks were confirmed as measles. Thirty eight strains were obtained. Genetic analysis of circulating measles strains (n = 38) in Uttar Pradesh from 235 cases of laboratory-confirmed cases from 526 suspected measles cases between 2008 and 2011 showed that all viruses responsible for outbreaks were within clade D and all were genotype D8.
Analysis of this region showed that it is highly divergent (up to 3.4% divergence in the nucleotide sequence and 4.1% divergence in the amino acid sequence between most distant strains). Considerable genetic heterogeneity was observed in the MV genotype D8 viruses in North India and underscores the need for continued surveillance and in particular increases in vaccination levels to decrease morbidity and mortality attributable to measles.
doi:10.1186/1743-422X-9-237
PMCID: PMC3544691  PMID: 23072489
India; Epidemiology; Outbreak; Measles virus; Genotype D8
11.  High Genetic Diversity of Measles Virus, World Health Organization European Region, 2005–2006 
Emerging Infectious Diseases  2008;14(1):107-114.
Importation of viruses from other continents caused prolonged circulation and large outbreaks in the WHO European Region.
During 2005–2006, nine measles virus (MV) genotypes were identified throughout the World Health Organization European Region. All major epidemics were associated with genotypes D4, D6, and B3. Other genotypes (B2, D5, D8, D9, G2, and H1) were only found in limited numbers of cases after importation from other continents. The genetic diversity of endemic D6 strains was low; genotypes C2 and D7, circulating in Europe until recent years, were no longer identified. The transmission chains of several indigenous MV strains may thus have been interrupted by enhanced vaccination. However, multiple importations from Africa and Asia and virus introduction into highly mobile and unvaccinated communities caused a massive spread of D4 and B3 strains throughout much of the region. Thus, despite the reduction of endemic MV circulation, importation of MV from other continents caused prolonged circulation and large outbreaks after their introduction into unvaccinated and highly mobile communities.
doi:10.3201/eid1401.070778
PMCID: PMC2600148  PMID: 18258089
measles virus; molecular epidemiology; WHO European Region; years 2005-2006; research
12.  Wild-Type Measles Viruses with Non-Standard Genome Lengths 
PLoS ONE  2014;9(4):e95470.
The length of the single stranded, negative sense RNA genome of measles virus (MeV) is highly conserved at 15,894 nucleotides (nt). MeVs can be grouped into 24 genotypes based on the highly variable 450 nucleotides coding for the carboxyl-terminus of the nucleocapsid protein (N-450). Here, we report the genomic sequences of 2 wild-type viral isolates of genotype D4 with genome lengths of 15,900 nt. Both genomes had a 7 nt insertion in the 3′ untranslated region (UTR) of the matrix (M) gene and a 1 nt deletion in the 5′ UTR of the fusion (F) gene. The net gain of 6 nt complies with the rule-of-six required for replication competency of the genomes of morbilliviruses. The insertions and deletion (indels) were confirmed in a patient sample that was the source of one of the viral isolates. The positions of the indels were identical in both viral isolates, even though epidemiological data and the 3 nt differences in N-450 between the two genomes suggested that the viruses represented separate chains of transmission. Identical indels were found in the M-F intergenic regions of 14 additional genotype D4 viral isolates that were imported into the US during 2007–2010. Viral isolates with and without indels produced plaques of similar size and replicated efficiently in A549/hSLAM and Vero/hSLAM cells. This is the first report of wild-type MeVs with genome lengths other than 15,894 nt and demonstrates that the length of the M-F UTR of wild-type MeVs is flexible.
doi:10.1371/journal.pone.0095470
PMCID: PMC3991672  PMID: 24748123
13.  Measles Outbreak in South Africa: Epidemiology of Laboratory-Confirmed Measles Cases and Assessment of Intervention, 2009–2011 
PLoS ONE  2013;8(2):e55682.
Background
Since 1995, measles vaccination at nine and 18 months has been routine in South Africa; however, coverage seldom reached >95%. We describe the epidemiology of laboratory-confirmed measles case-patients and assess the impact of the nationwide mass vaccination campaign during the 2009 to 2011 measles outbreak in South Africa.
Methods
Serum specimens collected from patients with suspected-measles were tested for measles-specific IgM antibodies using an enzyme-linked immunosorbent assay and genotypes of a subset were determined. To estimate the impact of the nationwide mass vaccination campaign, we compared incidence in the seven months pre- (1 September 2009–11 April 2010) and seven months post-vaccination campaign (24 May 2010–31 December 2010) periods in seven provinces of South Africa.
Results
A total of 18,431 laboratory-confirmed measles case-patients were reported from all nine provinces of South Africa (cumulative incidence 37 per 100,000 population). The highest cumulative incidence per 100,000 population was in children aged <1 year (603), distributed as follows: <6 months (302/100,000), 6 to 8 months (1083/100,000) and 9 to 11 months (724/100,000). Forty eight percent of case-patients were ≥5 years (cumulative incidence 54/100,000). Cumulative incidence decreased with increasing age to 2/100,000 in persons ≥40 years. A single strain of measles virus (genotype B3) circulated throughout the outbreak. Prior to the vaccination campaign, cumulative incidence in the targeted vs. non-targeted age group was 5.9-fold higher, decreasing to 1.7 fold following the campaign (P<0.001) and an estimated 1,380 laboratory-confirmed measles case-patients were prevented.
Conclusion
We observed a reduction in measles incidence following the nationwide mass vaccination campaign even though it was conducted approximately one year after the outbreak started. A booster dose at school entry may be of value given the high incidence in persons >5 years.
doi:10.1371/journal.pone.0055682
PMCID: PMC3577838  PMID: 23437059
14.  Implementation of a National Measles Elimination Program in Iran: Phylogenetic Analysis of Measles Virus Strains Isolated during 2010–2012 Outbreaks 
PLoS ONE  2014;9(4):e94846.
Measles virus (MV) causes small and large outbreaks in Iran. Molecular assays allow identifying and the sources of measles imported from neighboring countries. We carried out a phylogenetic analysis of measles virus circulating in Iran over the period 2010–2012. Specimens from suspected cases of measles were collected from different regions of Iran. Virus isolation was performed on urine and throat swabs. Partial nucleoprotein gene segments of MV were amplified by RT-PCR. PCR products of 173 samples were sequenced and analyzed. The median age of confirmed cases was 2 years. Among all confirmed cases, 32% had unknown vaccination status, 20% had been vaccinated, and 48% had not been vaccinated. Genotypes B3 and D8 (for the first time), H1 and D4 were detected mainly in unvaccinated toddlers and young children. Genotype B3 became predominant in 2012 and was closely related to African strains. H1 strains were also found in small and large outbreaks during 2012 but were not identical to Iranian H1-2009 strains. A majority of the Iranian D4 strains during 2010–2012 outbreaks were linked to the D4 strain identified in the Pakistan in 2007. We identified a single case in 2010 belonging to D8 genotype with 99.7% identity to Indian isolates. Although the vaccination program is currently good enough to prevent nationwide epidemics and successfully decreased measles incidence in Iran, the fraction of protected individuals in the population was not high enough to prevent continuous introduction of cases from abroad. Due to increasing number of susceptible individuals in some areas, sustained transmission of the newly introduced viral genotype remains possible.
doi:10.1371/journal.pone.0094846
PMCID: PMC3988093  PMID: 24736720
15.  New Measles Virus Genotype Associated with Outbreak, China 
Emerging Infectious Diseases  2010;16(6):943-947.
Better understanding of transmission patterns will enhance control and elimination programs.
To determine the origin of the virus associated with a measles outbreak in Menglian County, Yunnan Province, People’s Republic of China, in 2009, we conducted genetic analyses. Phylogenetic analyses based on nucleoprotein (N) and hemagglutinin (H) gene sequences showed that these Menglian viruses were not closely related to sequences of any World Health Organization (WHO) reference strains representing the 23 currently recognized genotypes. The minimum nucleotide divergence between the Menglian viruses and the most closely related reference strain, genotype D7, was 3.3% for the N gene and 3.0% for the H gene. A search of the databases of GenBank, WHO, and the Health Protection Agency Measles Nucleotide Surveillance showed that the Menglian viruses, together with the 2 older non-Menglian viruses, could be members of a new proposed measles genotype, d11. The new genotype designation will allow for better description of measles transmission patterns, especially in the Southeast Asian and Western Pacific regions.
doi:10.3201/eid1606.100089
PMCID: PMC3086224  PMID: 20507744
Measles virus; new genotype; phylogenetic analysis; viruses; research
16.  Spatiotemporal Analysis of Infant Measles Using Population Attributable Risk in Shandong Province, 1999–2008 
PLoS ONE  2013;8(11):e79334.
Background
Reduction of measles incidence and mortality has been encouraging in China. However, it remains an important public health concern among infants. This study aimed to examine the space–time distribution pattern of infant measles occurrence for the period of 1999–2008 in Shandong, China.
Methods and Findings
Measles cases among infants aged younger than 1 year were obtained from the national infectious diseases reporting information system. A spatiotemporal analysis using population attributable risk percent (PAR%) was used to distinguish between multiple geographic clusters of potential interest. The analysis detected 29 statistically significant space–time clusters with the most likely cluster in Zaozhuang City from 2006 to 2008. Of the 28 secondary clusters, 22 were found in 2008. The map of PAR%, relative risk (RR) and space–time cluster analysis indicated that the clusters were generally unchanged, and were found south-west and north-west of Shandong. The Lanshan District in Linyi had the highest PAR%, while highest RR was in the Yicheng District in Zaozhuang.
Conclusion
There were significant space-time clusters of infant measles in Shandong over the study period. PAR% is an effective way to analyze multiple clusters from their application like RR. Interrupting measles circulation and maintaining routine coverage over 95% may be the only effective strategy to achieve measles elimination.
doi:10.1371/journal.pone.0079334
PMCID: PMC3833981  PMID: 24260199
17.  Molecular evolution of measles viruses circulated in Taiwan 1992-2008 
Virology Journal  2009;6:219.
Genetic analyses of viral samples from 74 laboratory confirmed measles cases occurring in Taiwan during 1992-2008 identified six viral genotypes D3, D5, D9, G2, H1 and H2. The most frequently detected genotype, H1, was associated with outbreaks in 1994 and 2002, and was the likely indigenous genotype in 1992. In response to the outbreaks, two catch-up campaigns were launched and a routine second dose of measles, mumps, and rubella vaccine at entry to elementary school was introduced. The vaccination campaigns successfully reduced the number of measles cases in Taiwan, and many of the more recent cases can be traced to importations, primarily from other Asian countries. A number of measles genotypes which were associated with outbreaks in other Asian countries were detected among the more recent cases. The more recent genotype H1 viruses had sequences that were identical to those currently circulating in China or associated with international importation of virus.
doi:10.1186/1743-422X-6-219
PMCID: PMC2797522  PMID: 20003242
18.  Molecular epidemiology of measles virus in Italy, 2002–2007 
Virology Journal  2012;9:284.
Background
The European Regional Office of the World Health Organization (WHO/Europe) developed a strategic approach to halt the indigenous transmission of measles in its 53 Member States by 2015. In view of the goal of measles elimination, it is of great importance to assess the circulation of wild-type measles virus (MV). Genetic analysis is indispensable to understand the epidemiology of measles.
Methods
Urine and saliva samples were collected between May 2002 and December 2007, in order to find the origins and routes of wild type measles virus circulation. RT-PCR was performed on a total of 414 clinical samples of patients from different Italian regions. The results confirmed the genome presence in 199 samples, out of which 179 were sequenced. The sequences were genotyped by comparing the fragment coding for the carboxyl terminus of the nucleoprotein (450 nucleotides) with that one of the WHO reference strains.
Results
From the year 2002 to the year 2007 phylogenetic analysis of measles sequences showed a predominant circulation of the D7 genotype in the Italian territory for the years 2002–2004. This genotype was replaced by D4 and B3 genotypes in the biennium 2006–2007. During the same period C2, A, D5 and D8 genotypes were also detected.
Conclusions
Genetic characterization of wild-type MV provides a means to study the transmission pathways of the virus, and is an essential component of laboratory-based surveillance. Knowledge of currently circulating measles virus genotype in Italy will help in monitoring the success of the measles elimination programme and will contribute to evaluate the effectiveness of future vaccination campaigns.
doi:10.1186/1743-422X-9-284
PMCID: PMC3568056  PMID: 23173726
Measles outbreak; Molecular epidemiology; Genotype; Phylogenetic analysis
19.  Measles vaccine coverage estimates in an outbreak three years after the nation-wide campaign in China: implications for measles elimination, 2013 
Background
China is approaching measles elimination, but indigenous measles still circulates. County L in China has reported measles-containing vaccine (MCV) coverage rates >95% since 2000. Despite high reported coverage, a large measles outbreak occurred among young children in L County. We measured MCV coverage using 5 different methods during an investigation on this outbreak and compared our estimates with reported rates.
Methods
Reported coverage rates are determined by aggregating clinic-based data across the county: doses administered in each clinic divided by the number of children registered in each clinic. Our methods estimated coverage for the 2010–2012 birth cohort, and were (1) administrative method: doses administered in clinics divided by the birth cohort recorded in the Statistical Year Book, (2) house-to-house convenience-sample survey of children living near cases, (3) vaccination clinic records review, (4) determination of a convenience sample of measles outbreak cases’ vaccination statuses and using the field vaccine efficacy outbreak equation to estimate population coverage, and (5) a seroprevalence survey using a convenience sample of residual blood samples from hospitals.
Results
The measles outbreak totaled 215 cases, representing an incidence of 195.8 per million population. Our estimated MCV coverage rates were: (1) administrative method: 84.1%-87.0% for MCV1 and 80.3%-90.0% for MCV2, (2) in-house survey: 83.3% of 9–17 month children received MCV1, and 74.5% of 24–47 month children received MCV2, (3) clinic record review: 85.5% of 9–17 month children received MCV1, and 73.2% of 24–59 month children received MCV2, (4) field VE method: 83.6% of 9–47 month children received one or more MCV doses, and (5) serology: seropositive rates were <80% in the 12–17 and 18–23 month age cohorts.
Conclusions
Compared with reported coverage >95%, our 5 coverage assessments all showed substantially lower coverage. China should evaluate guidelines for reporting vaccination coverage and identify feasible improvements to the assessment methods.
doi:10.1186/s12879-015-0752-z
PMCID: PMC4307911  PMID: 25608672
Measles; Vaccination; Coverage; Estimation; Elimination; China
20.  Molecular Characterization of the Measles Virus Genotypes in JiLin Province, China 
PLoS ONE  2012;7(10):e46011.
Measles remains a severe global health threat, and nearly 30 million new cases are reported annually. Although many studies have analyzed measles viruses (MV) at the epidemiologic and phylogenetic levels, no study has yet to integrate these two types of data. To this end, we isolated 16 wild-type MV strains China's Jilin province. The MV genotype H1 was the most prevalent strain. After sequencing the nucleoprotein (N) genes of these strains, a maximum clade credibility tree was constructed by the Bayesian Markov Chain Monte Carlo method using 450 MV strains from GenBank with epidemiological information. The MV N gene evolution rate was 1.127E-3. Analysis of the time of the most recent common ancestor (TMRCA) for genotypes A/B/C/G/H revealed that genotypes D and B had the largest and smallest TMRCA (45.86 and 26.63, respectively). The highest level of genetic diversity for the MV N gene occurred around the year 2000. Here in this study, we uncovered the MV genotypes circulating in China's Jilin Province and estimated the epidemiologic and phylogenetic relationship for the six different genotypes of MV.
doi:10.1371/journal.pone.0046011
PMCID: PMC3466264  PMID: 23056226
21.  Cross-Sectional Surveys of Measles Antibodies in the Jiangsu Province of China from 2008 to 2010: The Effect of High Coverage with Two Doses of Measles Vaccine among Children 
PLoS ONE  2013;8(6):e66771.
Background
Changes in the epidemiological characteristics of measles since 2007 appeared in the Jiangsu province. Although the reported coverage with two doses of measles vaccine was greater than 95% in most regions of the province, measles incidence remained high across the whole province. Cross-sectional serological surveys of measles antibodies in the Jiangsu province of China were conducted from 2008 to 2010 to assess and track population immunity.
Methods
Measles-specific IgG levels were measured in serum samples using ELISA. GMTs and seroprevalence with 95% CIs were calculated by region, gender, and age. ANOVA and χ2 tests were used to test for statistically significant differences between groups for GMT levels and seroprevalence, respectively.
Results
Seroprevalence showed a significantly increasing trend annually (CMH χ2 = 40.32, p<0.0001). Although the seroprevalence among children aged 2–15 years was consistently over 95%, vaccine-induced measles antibodies may wane over time. Measles seropositivity in the Jiangsu province was 91.7% (95% CI: 90.1–93.2%) in 2010. Among adults aged 15 to 29-year-olds, the seropositivity rate was 88.4% (95% CI: 82.7–92.8%).
Conclusions
Vaccination strategies may need to be adjusted depending on the individual age and regions, particularly individuals between the ages of 8 months-14 years old and 20–29 years old. Additional SIAs are likely required to eliminate measles in China.
doi:10.1371/journal.pone.0066771
PMCID: PMC3692513  PMID: 23825562
22.  Epidemiology of two large measles virus outbreaks in Catalonia 
Measles cases in the European Region have been increasing in the last decade; this illustrates the challenge of what we are now encountering in the form of pediatric preventable diseases. In Catalonia, autochthonous measles was declared eliminated in the year 2000 as the result of high measles-mumps-rubella vaccine (MMR) coverage for first and second dose (15 mo and 4 y) since the mid-1990s. From then on, sporadic imported cases and small outbreaks appeared, until in 2006–2007 a large measles outbreak affecting mostly unvaccinated toddlers hit the Barcelona Health Region. Consequently, in January 2008, first dose administration of MMR was lowered from 15 to 12 mo of age. A new honeymoon period went by until the end of 2010, when several importations of cases triggered new sustained transmission of different wild measles virus genotypes, but this time striking young adults. The aim of this study is to show the effect of a change in MMR vaccination schedule policy, and the difference in age incidence and hospitalization rates of affected individuals between both outbreaks.
Epidemiologic data were obtained by case interviews and review of medical records. Samples for virological confirmation and genotyping of cases were collected as established in the Measles Elimination plan guidelines. Incidence rate (IR), rate ratio (RR) and their 95% CI and hospitalization rate (HR) by age group were determined. Statistic z was used for comparing proportions. Total number of confirmed cases was 305 in the 2010 outbreak and 381 in the 2006–2007 outbreak; mean age 20 y (SD 14.8 y; 3 mo to 51 y) vs. 15 mo (SD 13.1 y; 1 mo to 50 y). Highest proportion of cases was set in ≥ 25 y (47%) vs. 24.2% in 2006 (p < 0.001). Differences in IR for ≤ 15 mo (49/100,000 vs. 278.2/100,000; RR: 3,9; 95%CI 2,9–5.4) and in overall HR 29.8% vs. 15.7% were all statistically significant (p < 0.001).
The change of the month of age for the administration of the first MMR dose proved successful to protect infants. Yet, given the current epidemiological situation, continued awareness and efforts to reach young adult population, especially those at high risk of infection and transmission such as healthcare workers and travelers, are needed to stop the spread of the virus when importations occur.
doi:10.4161/hv.23265
PMCID: PMC3891728  PMID: 23303107
measles; outbreak; elimination; vaccination coverage; genotype
23.  Recurring Measles Epidemic in Vietnam 2005-2009: Implication for Strengthened Control Strategies 
Background: Measles remains a serious vaccine preventable cause of mortality in developing nations. Vietnam is aiming to achieve the level of immunity required to eliminate measles by maintaining a high coverage of routine first vaccinations in infants, routine second vaccinations at school entry and supplementary local campaigns in high-risk areas. Regular outbreaks of measles are reported, during 2005-2009.
Methods: National measles case-based surveillance data collected during 2005-June 2009 was analyzed to assess the epidemiological trend and risk factors associated with measles outbreak in Vietnam.
Results: Of the 36,282 measles suspected cases reported nationwide, only 7,086 cases were confirmed through laboratory examination. Although cyclical outbreaks occurred between 2005 and 2009, there was no definite trend in measles outbreaks during these periods. Overall, 2438 of measles confirmed cases were among children ≤5 years and 3068 cases were among people ≥16 years. The distribution with respect to gender skewed towards male (3667 cases) significant difference was not observed (P= 0.1693). Unsurprisingly, 4493 of the confirmed cases had no history of vaccination (X2 <0.01). The northern and highland regions were identified as the main endemic foci and the spatial distribution changed with time. The occurrence of cases, in a considerable proportion of vaccinated population, is not only a reflection of the high vaccination coverage in Vietnam but also portrays a possibility of less than 100% vaccine efficacy. More so, in order to prevent measles in adults, high-risk groups must be identified and catch-up for selected groups selected.
Conclusions: This study therefore reinforces the need for continued improvement of surveillance system and to probe into the possible role of changes in age-distribution of cases if the effective control of measles is to be achieved.
PMCID: PMC3039294  PMID: 21326852
Epidemiology; Measles; Outbreak; Vietnam
24.  The epidemiological characteristics of measles and difficulties of measles elimination in Hang Zhou, China 
Human Vaccines & Immunotherapeutics  2013;9(6):1296-1302.
Objective: Following the national proclaim of Measles Elimination 2012, plenty of activities for controlling the incidence had practiced in Hangzhou. However, the incidence did not decrease to low degree and remained perform as gap to the elimination target. The present study aimed to describe the epidemiological characteristics of measles, and proposed reasonable method to the target in Hangzhou. 
Method: Cases were collected by the National Notifiable Diseases Surveillance System (NNDSS) from 2004 to 2011. The descriptive epidemiology was employed to analyze characteristics of measles. 
Results: A total of 4712 confirmed cases were enrolled by the NNDSS with 7.87 per 100,000 people of incidence rate on average from 2004 to 2011. Individuals lived urban districts had higher risk of measles than counties. Infants aged <1 year observed the highest incidence rate with 239.35/100,000, and the age-specific incidence rate declined along with aged-group but reversed at adults. 52.20% of cases were floating cases and the measles vaccination was significantly different from the local cases (χ2=51.65,p <0.001). February to June was the epidemic period for measles incidence with 81.88% of cases reported in cluster. 
Conclusion: The descriptive characteristics of measles suggested that factors included infant and adult individual, floating population, and living urban area might be relate to the elimination target. More efforts were need to ensure susceptible population had accepted qualified measles vaccination. 
doi:10.4161/hv.24032
PMCID: PMC3901820  PMID: 23732896
measles; measles elimination; immunization strategy; descriptive epidemiology
25.  Measles Virus IgG Avidity Assay for Use in Classification of Measles Vaccine Failure in Measles Elimination Settings 
Clinical and Vaccine Immunology : CVI  2012;19(11):1810-1817.
In regions where endemic measles virus has been eliminated, diagnostic assays are needed to assist in correctly classifying measles cases irrespective of vaccination status. A measles IgG avidity assay was configured using a commercially available measles-specific IgG enzyme immunoassay by modifying the protocol to include three 5-min washes with diethylamine (60 mM; pH 10.25) following serum incubation; serum was serially diluted, and the results were expressed as the end titer avidity index. Receiver operating characteristic analysis was used for evaluation and validation and to establish low (≤30%) and high (≥70%) end titer avidity thresholds. Analysis of 319 serum specimens expected to contain either high- or low-avidity antibodies according to clinical and epidemiological data indicated that the assay is highly accurate, with an area under the curve of 0.998 (95% confidence interval [CI], 0.978 to 1.000), sensitivity of 91.9% (95% CI, 83.2% to 97.0%), and specificity of 98.4% (95% CI, 91.6% to 100%). The assay is rapid (<2 h) and precise (standard deviation [SD], 4% to 7%). In 18 samples from an elimination setting outbreak, the assay identified 2 acute measles cases with low-avidity results; both were IgM-positive samples. Additionally, 11 patients (15 samples) with modified measles who were found to have high-avidity IgG results were classified as secondary vaccine failures; one sample with an intermediate-avidity result was not interpretable. In elimination settings, measles IgG avidity assays can complement existing diagnostic tools in confirming unvaccinated acute cases and, in conjunction with adequate clinical and epidemiologic investigation, aid in the classification of vaccine failure cases.
doi:10.1128/CVI.00406-12
PMCID: PMC3491540  PMID: 22971778

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