Global Evolution and Phylodynamics of Coxsackievirus A4.

Coxsackievirus A4 (CVA4) is an enterovirus associated with diverse clinical syndromes, yet its global evolution and transmission dynamics remain poorly defined. This study aimed to characterize the molecular epidemiology, evolutionary history, and phylodynamic patterns of CVA4 at both local and global scales. In 2024, 34 CVA4 infections were identified during a localized herpangina outbreak in Beijing, primarily affecting children under 5 years of age, with a pronounced peak in July. High detection and isolation rates, together with temporal clustering in mid-2024, indicate a genuine short-term expansion rather than sporadic detection. Phylogenetic analysis of global VP1 sequences resolved six genotypes (A-F), with Beijing strains clustering within genotype E and subgenotype F2, reflecting ongoing worldwide circulation. Bayesian phylodynamic analysis estimated a VP1 evolutionary rate of 1.626 × 10-3 substitutions per site per year (95% highest probability density [HPD], 1.428-1.827 × 10-3) and dated the CVA4 time to the most recent common ancestor back to March 1917 (95% HPD, June 1908-April 1926). Demographic reconstruction revealed fluctuating genetic diversity, with notable expansions in 2013 and 2016, as well as a modest increase in 2023 preceding the outbreak. Phylogeographic analyses identified France and China as key seeding regions. Recombination in the P2 and P3 regions, including evidence of CVA2-related donors, highlights recombination as a major contributor to CVA4 diversity. These findings improve our understanding of CVA4 evolution and transmission and underscore the need for enhanced genomic surveillance.