Uncovering the fitness of endemically circulating Zika virus strains

Zika virus (ZIKV) is an arbovirus that usually causes few symptoms and has circulated endemically in Asia for decades. However, a large outbreak in South America in 2015 uncovered the serious risk of congenital Zika syndrome in infants born from ZIKV infected mothers. It is unknown whether a lineage with distinct pre-existing fitness advantage emerged from Asia to cause the South American outbreak, and whether there is ongoing evolution that can result in future globally fit strains. Here we used 107 sequences from a single setting (Thailand) collected over an 18 year period (2006-2023). We used novel analytical tools to identify distinct lineages that have circulated in the population and estimated their relative epidemiological fitness. We found there have been six lineages circulating sequentially in the country, with regular emergence and replacement of lineages showing higher fitness than their predecessors. We identified 15 lineage-defining amino acid changes, including four well-documented fitness-enhancing mutations, and two UTR substitutions. The lineage that emerged in South America was evolutionarily linked to the highest-fitness lineage in Thailand, carrying seven of our lineage-defining substitutions acquired during endemic circulation there, and subsequently accumulating four additional changes. After the global pandemic, endemic ZIKV in Thailand continued to evolve, with newly emerged lineages showing novel mutations and increased fitness. Our findings have key implications for the monitoring of ZIKV and can help identify the pathway to increased transmissibility of this globally important pathogen.