GII.17 norovirus re-emerged in the 2020s as a result of dynamic and adaptive evolutionary processes.

Over the past two years, increased norovirus activity has been reported in multiple countries, accompanied by a rise in genotype GII.17 prevalence. Despite causing large outbreaks in Asia during 2014-2016, GII.17 has not historically been considered a predominant genotype. In this study, using 1471 archival and newly-identified GII.17 genomes, we investigated (i) global diversification patterns of this virus at the whole-genome level, (ii) in-depth mutational patterns within 511 viruses detected during a 10-year national survey in Germany, and (iii) intra-host viral diversity and adaptation processes that lead to the predominance of the GII.17 virus. The recent GII.17 norovirus exhibited extensive genetic diversity and multiple back-and-forth and recurrent mutations during the early phase of its epidemic; however, this diversity declined by 2024, suggesting that the virus had reached a phenotype efficient for human infection. Experimental data confirmed that mutations in the viral capsid enhanced binding to host factors associated with virus entry and resulted in antigenic changes compared to previously circulating clusters. Overall, this study demonstrated that the recent surge of GII.17 resulted from a dynamic, multifaceted process involving diverse adaptive strategies, ultimately enabling the virus to achieve sustained transmission within the human population.