title: Sabin Vaccine Reversion in the Field: a Comprehensive Analysis of Sabin-Like Poliovirus Isolates in Nigeria.
abstract: To assess the dynamics of genetic reversion of live poliovirus vaccine in humans, we studied molecular evolution in Sabin-like poliovirus isolates from Nigerian acute flaccid paralysis cases obtained from routine surveillance. We employed a novel modeling approach to infer substitution and recombination rates from whole-genome sequences and information about poliovirus infection dynamics and the individual vaccination history. We confirmed observations from a recent vaccine trial that VP1 substitution rates are increased for Sabin-like isolates relative to the rate for the wild type due to increased nonsynonymous substitution rates. We also inferred substitution rates for attenuating nucleotides and confirmed that reversion can occur in days to weeks after vaccination. We combine our observations for Sabin-like virus evolution with the molecular clock for VP1 of circulating wild-type strains to infer that the mean time from the initiating vaccine dose to the earliest detection of circulating vaccine-derived poliovirus (cVDPV) is 300 days for Sabin-like virus type 1, 210 days for Sabin-like virus type 2, and 390 days for Sabin-like virus type 3. Phylogenetic relationships indicated transient local transmission of Sabin-like virus type 3 and, possibly, Sabin-like virus type 1 during periods of low wild polio incidence. Comparison of Sabin-like virus recombinants with known Nigerian vaccine-derived poliovirus recombinants shows that while recombination with non-Sabin enteroviruses is associated with cVDPV, the recombination rates are similar for Sabin isolate-Sabin isolate and Sabin isolate-non-Sabin enterovirus recombination after accounting for the time from dosing to the time of detection. Our study provides a comprehensive picture of the evolutionary dynamics of the oral polio vaccine in the field.
  
  
  OBJECTIVE
  The global polio eradication effort has completed its 26th year. Despite success in eliminating wild poliovirus from most of the world, polio persists in populations where logistical, social, and political factors have not allowed vaccination programs of sustained high quality. One issue of critical importance is eliminating circulating vaccine-derived polioviruses (cVDPVs) that have properties indistinguishable from those of wild poliovirus and can cause paralytic disease. cVDPV emerges due to the genetic instability of the Sabin viruses used in the oral polio vaccine (OPV) in populations that have low levels of immunity to poliovirus. However, the dynamics responsible are incompletely understood because it has historically been difficult to gather and interpret data about evolution of the Sabin viruses used in OPV in regions where cVDPV has occurred. This study is the first to combine whole-genome sequencing of poliovirus isolates collected during routine surveillance with knowledge about the intrahost dynamics of poliovirus to provide quantitative insight into polio vaccine evolution in the field.
authors.affiliation: Institute for Disease Modeling, Intellectual Ventures Laboratory, Bellevue, Washington, USA mfamulare@intven.com.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0001-9275-7454
authors.initials: M
authors.lastname: Famulare
authors.affiliation: Institute for Disease Modeling, Intellectual Ventures Laboratory, Bellevue, Washington, USA.
authors.forename: Stewart
authors.initials: S
authors.lastname: Chang
authors.affiliation: Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Iber
authors.affiliation: Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Department of Virology, College of Medicine, University of Ibadan, Ibadan, Nigeria.
authors.forename: Johnson A
authors.initials: JA
authors.lastname: Adeniji
authors.affiliation: University of Maiduguri Teaching Hospital, Maiduguri, Nigeria.
authors.forename: David
authors.initials: D
authors.lastname: Bukbuk
authors.affiliation: Department of Medical Laboratory Science, College of Medical Sciences, University of Maiduguri, Maiduguri, Nigeria.
authors.forename: Marycelin
authors.initials: M
authors.lastname: Baba
authors.affiliation: Independent Researcher, Seattle Washington, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Behrend
authors.affiliation: Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Cara C
authors.initials: CC
authors.lastname: Burns
authors.affiliation: Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: M Steven
authors.initials: MS
authors.lastname: Oberste
mesh_terms: D036022:Capsid Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D019143:Evolution, Molecular; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D017720:Molecular Epidemiology; D059645:Mutation Rate; D009549:Nigeria / Q000453:epidemiology; D010802:Phylogeny; D017354:Point Mutation; D011051:Poliomyelitis / Q000453:epidemiology / Q000517:prevention & control* / Q000821:virology*; D017955:Poliovirus / Q000235:genetics* / Q000302:isolation & purification*; D011055:Poliovirus Vaccine, Oral / Q000008:administration & dosage / Q000009:adverse effects*; D012367:RNA, Viral / Q000235:genetics; D017385:Sequence Homology; D013997:Time Factors; D014774:Virulence
chemical_list: D036022:Capsid Proteins; D011055:Poliovirus Vaccine, Oral; D012367:RNA, Viral; C442540:VP1 protein, Poliovirus