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Background: Severe fever with thrombocytopenia syndrome virus (SFTSV) is a viral pathogen causing significant clinical signs from mild fever with thrombocytopenia to severe hemorrhages. World Health Organization has paid special attention to the dramatic increase in human SFTS cases in China, Japan, and South Korea since the 2010s. The present study investigated the molecular evolution and genetic reassortment of SFTSVs using complete genomic sequences. Methods/Principal finding: We collected the complete genome sequences of SFTSVs globally isolated until 2019 (L segment, n = 307; M segment, n = 326; and S segment, n = 564) and evaluated the evolutionary profiles of SFTSVs based on phylogenetic and molecular selection pressure analyses. By employing a time-scaled Bayesian inference method, we found the geographical heterogeneity of dominant SFTSV genotypes in China, Japan, and South Korea around several centuries before and locally spread by tick-born spillover with infrequent long-distance transmission. Purifying selection predominated the molecular evolution of SFTSVs with limited gene reassortment and fixed substitution, but almost all three gene segments appeared to harbor at least one amino acid residue under positive selection. Specifically, the nonstructural protein and glycoprotein (Gn/Gc) genes were preferential selective targets, and the Gn region retained the highest number of positively selected residues. Conclusion/Significance: Here, the large-scale genomic analyses of SFTSVs improved prior knowledge of how this virus emerged and evolved in China, Japan, and South Korea. Our results highlight the importance of SFTSV surveillance in both human and non-human reservoirs at the molecular level to fight against fatal human infection with the virus. Author summary: SFTSV causes a high mortality disease in humans, especially in China, Japan, and South Korea. For a better understanding of the evolutionary characteristics of SFTSVs, our study performed phylogenetic and genetic reassortment analyses using the largely collected genomic information of SFTSVs. It appeared that dominant endemic SFTSVs in China, Japan, and South Korea likely diverged several centuries ago. Movement of vector (e.g., tick) or non-human mammalian reservoirs possibly played a key role in human SFTSV spillover and infrequently led to international spread among three countries. Purifying selection strongly limited the generation of novel variants through either molecular mutations or genetic reassortment. However, we observed a few amino acid sites under positive selection, especially in glycoproteins which might limitedly allow the generation of variants within a clade, in which molecular evolution might not be a major cause for the current emergence of SFTSVs but the ecological or epidemiological change possibly be a more plausible factor. However, we should still carefully monitor the evolutionary dynamics of SFTSV considering the potential of host adaptation in humans. [ABSTRACT FROM AUTHOR]

Zoonotic transmission of orthohantaviruses from rodent reservoirs to humans has been the cause of severe fatalities. Human infections are reported worldwide, but vaccines have been approved only in China and Korea. Orthohantavirus vaccine development has been pursued with no sense of urgency due to the relative paucity of cases in countries outside China and Korea. However, the orthohantaviruses continuously evolve in hosts and thus the current vaccine may not work as well against some variants. Therefore, a more effective vaccine should be prepared against the orthohantaviruses. In this review, we discuss the issues caused by the orthohantavirus vaccine. Given the pros and cons of the orthohantavirus vaccine, we suggest strategies for the development of better vaccines in terms of pandemic preparedness. [ABSTRACT FROM AUTHOR]