Measles Sequencing: Lessons Learned from a Large-Scale Outbreak.

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.