Phylodynamics and Molecular Evolution of Hepatitis A Virus During the Years 1957-2021 in Japan

Hepatitis A virus (HAV) remains a significant public health concern despite the availability of effective vaccines, particularly in regions experiencing epidemiological transitions. Recent HAV cases in Japan have increasingly occurred among defined risk groups rather than through large food-borne outbreaks. This study analyzed the phylodynamic patterns and molecular evolution of capsid protein sequences of HAV circulating in Japan between 1957 and 2021. Phylogenetic analysis showed that genotype IA predominates in Japan forming five well-supported clusters, including two lineages that persisted for more than two decades, indicating long-term endemic co-circulation. Bayesian evolutionary analysis suggested that genotype IA diversification in Japan began in the early 20th century, and Bayesian Skygrid plot demonstrated substantial temporal fluctuations in effective viral population size, with notable peaks corresponding to documented outbreaks around 2010 and 2017, the latter associated with internationally transmitted men who have sex with men-related strains. Selection pressure analyses indicated strong purifying selection with limited evidence of adaptive evolution. HAV transmission dynamics in Japan are shaped by both endemic multi-lineage persistence and episodic introductions of international strains rather than viral genetic adaptation. Continuous genomic surveillance integrated with epidemiological data is essential for anticipating future outbreaks in low-endemicity area.