Jemma L. Geoghegan, Le Van Tan, Denise Kühnert, Rebecca A. Halpin, Xudong Lin, Ari Simenauer, Asmik Akopov, Suman R. Das, Timothy B. Stockwell, Susmita Shrivastava, Nghiem My Ngoc, Le Thi Tam Uyen, Nguyen Thi Kim Tuyen, Tran Tan Thanh, Vu Thi Ty Hang, Phan Tu Qui, Nguyen Thanh Hung, Truong Huu Khanh, Le Quoc Thinh, Le Nguyen Thanh Nhan, Hoang Minh Tu Van, Chau Viet, Ha Manh Tuan, Ho Lu Viet, Tran Tinh Hien, Nguyen Van Vinh Chau, Guy Thwaites, Bryan T. Grenfell, Tanja Stadler, David E. Wentworth, Edward C. Holmes, H. Rogier Van Doorn

Enterovirus A71 (EV-A71) is a major cause of hand, foot and mouth disease (HFMD) and is particularly prevalent in parts of Southeast Asia, affecting thousands of children and infants each year. Revealing the evolutionary and epidemiological dynamics of EV-A71 through time and space is central to understanding its outbreak potential. We generated the full genome sequences of 200 EV-A71 strains sampled from various locations in Viet Nam between 2011-2013, and used these sequence data to determine the evolutionary history and phylodynamics of EV-A71 in Viet Nam, providing estimates of the effective reproduction number (Re) of the infection through time. In addition, we described the phylogeography of EV-A71 throughout Southeast Asia, documenting patterns of viral gene flow. Accordingly, our analysis reveals that a rapid genogroup switch from C4 to B5 likely took place during 2012 in Viet Nam. We show that the Re of subgenogroup C4 decreased during the time-frame of sampling, while that of B5 increased and remained >1 at the end of 2013, corresponding to a rise in B5 prevalence. Our study reveals that the subgenogroup B5 virus that emerged into Viet Nam is closely related to variants that were responsible for large epidemics in Malaysia and Taiwan and therefore extends our knowledge regarding its associated endemic area. Subgenogroup B5 evidently has the potential to cause more widespread outbreaks across Southeast Asia. EV-A71 is one of many viruses that cause HFMD, a common syndrome that largely affects infants and children. HFMD usually causes only mild illness with no long-term consequences. Occasionally, however, severe infection may arise, especially in very young children, causing neurological complications and even death. EV-A71 is highly contagious and is associated with the most severe HFMD cases, with large and frequent epidemics of the virus recorded worldwide. Although major advances have been made in the development of a potential EV-A71 vaccine, there is no current prevention and little is known about the patterns and dynamics of EV-A71 spread. In this study we utilize full-length genome sequence data obtained from HFMD patients in Viet Nam, a geographical region where the disease has been endemic since 2003, to characterize the phylodynamics of this important emerging virus.