Role of Sequencing the Measles Virus Hemagglutinin Gene and Hypervariable Region in the Measles Outbreak Investigations in Sweden During 2013–2014

Harvala, Heli; Wiman, Åsa; Wallensten, Anders; Zakikhany, Katherina; Englund, Hélène; Brytting, Maria

doi:10.1093/infdis/jiv434

Cited by 20 publications

(20 citation statements)

References 28 publications

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“…For the D8 samples analysed, the regions where higher variability is observed are located at the N-450, in the region of the P gene encoding the carboxyl terminus of the P protein, at the M/F NCR, along the F gene and in several regions of the L gene (black line in Fig 6 ). Comparison of this plot to that obtained for all complete genome sequences from non-A measles genotypes (given that A genotype sequences are mainly vaccine strains) available in GenBank (grey line in Fig 6 ) suggests that N-450 and M/F NCR are the most variable regions in the genome across all measles genotypes, in agreement with the observations from phylogenetic analyses (Figs 3 and 4 and S1 – S3 Figs) and previous studies [ 26 – 30 ].…”

Section: Resultssupporting

confidence: 88%

“…However, the phylogenetic resolution afforded by this region is closely followed by that obtained with the M/F NCR. The nucleotide variability observed at each genome position and substitution rates estimated for each of these sequences support the notion that the M/F NCR and the N-450 are the most variable regions across all genotypes ( Fig 6 ) [ 26 – 30 ]. Interestingly, we also find that the variability of specific regions of the genome differs between MeV D8 and B3 genotypes, with the whole of the N gene being more variable in the first and the H gene in the second, for example.…”

Section: Discussionsupporting

confidence: 61%

“…Additional information can be obtained from the sequencing of the N-450 region, which provides crucial information on global measles circulation and assists in the characterisation and tackling of countless outbreaks worldwide, for example by enabling clinicians and epidemiologists to identify and distinguish between cases resulting from simultaneous outbreaks of different MeV genotypes. However, in view of the decrease in the diversity of the circulating MeV as several regions of the WHO endeavour to eliminate measles, it is likely that the diversity of the N-450 sequences will also decrease [ 30 , 31 ]. In this context, additional tools for molecular characterisation would be required.…”

Section: Discussionmentioning

confidence: 99%

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Assessment of the Utility of Whole Genome Sequencing of Measles Virus in the Characterisation of Outbreaks

et al. 2015

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BackgroundMeasles is a highly infectious disease caused by measles virus (MeV). Despite the availability of a safe and cost-effective vaccine, measles is one of the world-leading causes of death in young children. Within Europe, there is a target for eliminating endemic measles in 2015, with molecular epidemiology required on 80% of cases for inclusion/exclusion of outbreak transmission chains. Currently, MeV is genotyped on the basis of a 450 nucleotide region of the nucleoprotein gene (N-450) and the hemagglutinin gene (H). However, this is not sufficiently informative for distinguishing endemic from imported MeV. We have developed an amplicon-based method for obtaining whole genome sequences (WGS) using NGS or Sanger methodologies from cell culture isolates or oral fluid specimens, and have sequenced over 60 samples, including 42 from the 2012 outbreak in the UK.ResultsOverall, NGS coverage was over 90% for approximately 71% of the samples tested. Analysis of 32 WGS excluding 3’ and 5’ termini (WGS-t) obtained from the outbreak indicates that the single nucleotide difference found between the two major groups of N-450 sequences detected during the outbreak is most likely a result of stochastic viral mutation during endemic transmission rather than of multiple importation events: earlier strains appear to have evolved into two distinct strain clusters in 2013, one containing strains with both outbreak-associated N-450 sequences. Additionally, phylogenetic analysis of each genomic region of MeV for the strains in this study suggests that the most information is acquired from the non-coding region located between the matrix and fusion protein genes (M/F NCR) and the N-450 genotyping sequence, an observation supported by entropy analysis across genotypes.ConclusionsWe suggest that both M/F NCR and WGS-t could be used to complement the information from classical epidemiology and N-450 sequencing to address specific questions in the context of measles elimination.

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Section: Resultssupporting

confidence: 88%

Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

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Assessment of the Utility of Whole Genome Sequencing of Measles Virus in the Characterisation of Outbreaks

et al. 2015

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“…A long M 3’UTR promotes M protein translation inducing efficient replication, and a long F 5’UTR discourages F protein translation, reducing the cytopathogenicity of the virus. The M-F NCR region is one of the most variable regions of the MeV genome [ 6 , 10 ] and has recently been proposed as a new target for MeV molecular characterization [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Measles virus genotype D4 strains with non-standard length M-F non-coding region circulated during the major outbreaks of 2011-2012 in Spain

et al. 2018

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In recent decades, vaccination has substantially reduced the number of measles cases to levels close to the elimination stage. However, major measles outbreaks occurred in Europe during 2010–2012, after the introduction of the D4-Enfield lineage. We have performed a molecular characterization of 75 measles virus genotype D4 strains from patients infected in Spain between 2004 and 2012 by sequencing the N-450 region and the M-F non-coding region (M-F NCR) in order to identify genetic features of these viruses. The analysis of the N-450 region confirmed that all samples obtained since 2008 belonged to variants or sets of identical sequences of the D4-Enfield lineage, including a new one named MVs/Madrid.ESP/46.10/. Analysis of the M-F NCR showed insertions and deletions associated with previously described, uncommon non-standard genome length measles viruses. This genetic feature was identified in the D4-Enfield lineage viruses, but not in the other D4 viruses that were circulating in Spain before 2008, suggesting that these non-standard length M-F NCR sequences are characteristic of the D4-Enfield lineage. The results of the phylogenetic analysis of Spanish M-F NCRs suggest higher resolution in discriminating strains than did the N-450 analysis. In addition, the results of the analysis of the M-F NCR on the MVs/Madrid.ESP/46.10/ sub-lineage seem to support the potential utility of this region as a tool for epidemiological surveillance complementary to the N-450 region, as previously suggested. Further investigation on this question, as well as the surveillance of new potentially emerging strains with non-standard length M-F NCR are strongly recommended as part of future strategies for measles elimination.

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“…This technique can elucidate the spatial and temporal transmission dynamics of microbes, as has been done in studies of avian influenza virus [8], human immunodeficiency virus [9], hepatitis C virus [10], and Salmonella typhimurium [11]. Although there have been many epidemiological reports about inter-country transmission of measles [12,13,14,15], systematic analysis of the global transmission dynamics of MV has been limited.…”

Section: Introductionmentioning

confidence: 99%

Global Transmission Dynamics of Measles in the Measles Elimination Era

Furuse

Oshitani

2017

Viruses

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Although there have been many epidemiological reports of the inter-country transmission of measles, systematic analysis of the global transmission dynamics of the measles virus (MV) is limited. In this study, we applied phylogeographic analysis to characterize the global transmission dynamics of the MV using large-scale genetic sequence data (obtained for 7456 sequences) from 115 countries between 1954 and 2015. These analyses reveal the spatial and temporal characteristics of global transmission of the virus, especially in Australia, China, India, Japan, the UK, and the USA in the period since 1990. The transmission is frequently observed, not only within the same region but also among distant and frequently visited areas. Frequencies of export from measles-endemic countries, such as China, India, and Japan are high but decreasing, while the frequencies from countries where measles is no longer endemic, such as Australia, the UK, and the USA, are low but slightly increasing. The world is heading toward measles eradication, but the disease is still transmitted regionally and globally. Our analysis reveals that countries wherein measles is endemic and those having eliminated the disease (apart from occasional outbreaks) both remain a source of global transmission in this measles elimination era. It is therefore crucial to maintain vigilance in efforts to monitor and eradicate measles globally.

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Role of Sequencing the Measles Virus Hemagglutinin Gene and Hypervariable Region in the Measles Outbreak Investigations in Sweden During 2013–2014

Cited by 20 publications

References 28 publications

Assessment of the Utility of Whole Genome Sequencing of Measles Virus in the Characterisation of Outbreaks

Assessment of the Utility of Whole Genome Sequencing of Measles Virus in the Characterisation of Outbreaks

Measles virus genotype D4 strains with non-standard length M-F non-coding region circulated during the major outbreaks of 2011-2012 in Spain

Global Transmission Dynamics of Measles in the Measles Elimination Era

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