title: Phylodynamics of Enterovirus A71-Associated Hand, Foot, and Mouth Disease in Viet Nam.
abstract: 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 and 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, whereas 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 area of endemicity. Subgenogroup B5 evidently has the potential to cause more widespread outbreaks across Southeast Asia.
  
  
  OBJECTIVE
  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.
authors.affiliation: Marie Bashir Institute for Infectious Diseases and Biosecurity, Charles Perkins Centre, School of Biological Sciences and Sydney Medical School, The University of Sydney, Sydney, Australia jemma.geoghegan@sydney.edu.au tanlv@oucru.org.
authors.forename: Jemma L
authors.initials: JL
authors.lastname: Geoghegan
authors.affiliation: Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam jemma.geoghegan@sydney.edu.au tanlv@oucru.org.
authors.forename: Le Van
authors.initials: le V
authors.lastname: Tan
authors.affiliation: Department of Environmental Systems Science, ETH Zurich, Zurich, Switzerland Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Denise
authors.initials: D
authors.lastname: Kühnert
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Halpin
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland, USA.
authors.forename: Xudong
authors.initials: X
authors.lastname: Lin
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland, USA.
authors.forename: Ari
authors.initials: A
authors.lastname: Simenauer
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland, USA.
authors.forename: Asmik
authors.initials: A
authors.lastname: Akopov
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland, USA.
authors.forename: Suman R
authors.initials: SR
authors.lastname: Das
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland, USA.
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Stockwell
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland, USA.
authors.forename: Susmita
authors.initials: S
authors.lastname: Shrivastava
authors.affiliation: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Nghiem My
authors.initials: NM
authors.lastname: Ngoc
authors.affiliation: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Le Thi Tam
authors.initials: le TT
authors.lastname: Uyen
authors.affiliation: Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam.
authors.forename: Nguyen Thi Kim
authors.initials: NT
authors.lastname: Tuyen
authors.affiliation: Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam.
authors.forename: Tran Tan
authors.initials: TT
authors.lastname: Thanh
authors.affiliation: Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam.
authors.forename: Vu Thi Ty
authors.initials: VT
authors.lastname: Hang
authors.affiliation: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Phan Tu
authors.initials: PT
authors.lastname: Qui
authors.affiliation: Children's Hospital 1, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen Thanh
authors.initials: NT
authors.lastname: Hung
authors.affiliation: Children's Hospital 1, Ho Chi Minh City, Vietnam.
authors.forename: Truong Huu
authors.initials: TH
authors.lastname: Khanh
authors.affiliation: Children's Hospital 1, Ho Chi Minh City, Vietnam.
authors.forename: Le Quoc
authors.initials: le Q
authors.lastname: Thinh
authors.affiliation: Children's Hospital 1, Ho Chi Minh City, Vietnam.
authors.forename: Le Nguyen Thanh
authors.initials: le NT
authors.lastname: Nhan
authors.affiliation: Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Hoang Minh Tu
authors.initials: HM
authors.lastname: Van
authors.affiliation: Children's Hospital 2, Ho Chi Minh City, Vietnam.
authors.forename: Do Chau
authors.initials: do C
authors.lastname: Viet
authors.affiliation: Children's Hospital 2, Ho Chi Minh City, Vietnam.
authors.forename: Ha Manh
authors.initials: HM
authors.lastname: Tuan
authors.affiliation: Children's Hospital 2, Ho Chi Minh City, Vietnam.
authors.forename: Ho Lu
authors.initials: HL
authors.lastname: Viet
authors.affiliation: Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam.
authors.forename: Tran Tinh
authors.initials: TT
authors.lastname: Hien
authors.affiliation: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen Van Vinh
authors.initials: NV
authors.lastname: Chau
authors.affiliation: Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Guy
authors.initials: G
authors.lastname: Thwaites
authors.affiliation: Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, USA Fogarty International Center, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Grenfell
authors.affiliation: Swiss Institute of Bioinformatics, Lausanne, Switzerland Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Stadler
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Wentworth
authors.affiliation: Marie Bashir Institute for Infectious Diseases and Biosecurity, Charles Perkins Centre, School of Biological Sciences and Sydney Medical School, The University of Sydney, Sydney, Australia.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Holmes
authors.affiliation: Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: H Rogier
authors.initials: HR
authors.lastname: Van Doorn
mesh_terms: D001483:Base Sequence; D002648:Child; D004196:Disease Outbreaks; D029821:Enterovirus A, Human / Q000145:classification / Q000235:genetics*; D058872:Epidemics; D051456:Gene Flow / Q000235:genetics; D016679:Genome, Viral / Q000235:genetics*; D006232:Hand, Foot and Mouth Disease / Q000453:epidemiology* / Q000235:genetics* / Q000821:virology; D006801:Humans; D008969:Molecular Sequence Data; D058974:Phylogeography; D017423:Sequence Analysis, RNA; D014744:Vietnam / Q000453:epidemiology; D014779:Virus Replication / Q000502:physiology