Measles Sequencing: Lessons Learned from a Large-Scale Outbreak

Abstract

Between 2018 and 2019, Israel experienced one of its largest measles outbreaks in recent decades, with over 4300 reported cases and more than 100 documented importation events. Despite high national vaccination coverage, the prolonged nature of the outbreak posed a risk to the country's measles elimination status. Traditional epidemiological investigations and genotyping based on the N450 region lacked sufficient resolution to differentiate between sustained local transmission and multiple independent introductions. To address this, we performed whole-genome sequencing on 123 measles virus samples representing both imported and locally acquired cases from diverse geographic regions. Phylogenetic analysis revealed multiple, distinct transmission chains, several of which could be linked to separate importation events. The MF non-coding region (MF-NCR) not only showed the highest genetic variability, but also contained many of the phylogenetic cluster-defining mutations, though informative changes were found throughout the whole genome. These findings demonstrate the value of whole-genome sequencing in resolving complex transmission dynamics and highlight the importance of integrating genomic epidemiology into routine measles surveillance. Such integration can enhance outbreak investigations and better inform public health responses to protect elimination status.

Keywords: measles virus; molecular epidemiology; outbreak; phylogenetics; whole-genome sequencing.

Figure 1

Phylogenetic tree highlighting transmission chains across geographic locations. Phylogenetic tree of 123 whole-genome MeV sequences from the 2018–2019 outbreak in Israel. Nodes are colored by geographic location, representing the district health office associated with each sequenced patient sample, as shown in the accompanying map. Circle sizes on the map reflect the number of sequences obtained from each location. The reference sequence (KT732261.1) is labeled as “REF”. Dashed boxes (A–D) and corresponding insets (A–D) highlight clusters representing distinct transmission chains occurring within single or multiple geographic locations. Sample collection date or—when unavailable—the date of receipt in the laboratory for MeV testing is indicated within each inset. Divergence scales vary across insets; the number of mutations is indicated by numbers along the branches.

Figure 2

Phylogenetic tree highlighting importation-linked transmission. The phylogenetic tree in Figure 1, annotated according to country of importation linked to each sequenced patient sample or a local transmission. The reference sequence (KT732261.1) is labeled as “REF”. Dashed boxes (A–D) and corresponding insets (A–D) highlight clusters representing distinct transmission chains originating from sequenced patient samples linked to an importation. Sample collection date or—when unavailable—the date of receipt in the laboratory for MeV testing, as well as the DHO of the patient, is indicated within each inset. Divergence scales vary across insets; the number of mutations is indicated by numbers along the branches.

Figure 3

Genome-Wide Nucleotide Variability. Shannon entropy plot illustrating nucleotide variability at each position along the MeV genome, based on all sequenced data. Genomic regions are annotated along the x-axis, with the average entropy for each gene or non-coding region indicated in parentheses.

Figure 4

Genomic distribution of informative mutations in MeV phylogeny. The main branch of the phylogenetic trees shown in Figure 1 and Figure 2, annotated to indicate the MeV gene or genomic region in which key cluster-defining mutations occurred. Each gene or region is color-coded, with the specific mutation and its genomic position indicated.