Sabin vaccine reversion in the field: a comprehensive analysis of Sabin-like poliovirus isolates in Nigeria
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 individual vaccination history. We confirmed observations from a recent vaccine trial that VP1 substitution rates are increased for Sabin-like isolates relative to the wild-type rate due to increased non-synonymous 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 evolution with the wild-type circulating VP1 molecular clock 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 type 1, 210 days for type 2, and 390 days for type 3. Phylogenetic relationships indicated transient local transmission of Sabin 3 and possibly Sabin 1 during periods of low wild polio incidence. Comparison of Sabin-like recombinants with known Nigerian VDPV recombinants shows that while recombination with non-Sabin enteroviruses is associated with cVDPV, the recombination rates are similar for Sabin-Sabin and Sabin-non-Sabin enterovirus recombination after accounting for time from dose to detection. Our study provides a comprehensive picture of the evolutionary dynamics of oral polio vaccine in the field.
IMPORTANCE The global polio eradication effort has completed its twenty-sixth 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 for vaccination programs of sustained high quality. One issue of critical importance is eliminating circulating vaccine-derived poliovirus (cVDPV) that have properties indistinguishable from wild poliovirus and can cause paralytic disease. cVDPV emerges due to the genetic instability of the Sabin viruses used in oral polio vaccine (OPV) in populations that have low immunity to poliovirus. However, the dynamics responsible are incompletely understood because it has historically been difficult to gather and interpret data about OPV evolution 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 polio intra-host dynamics to provide quantitative insight into polio vaccine evolution in the field.
FIG 10 Estimated number of days to VDPV emergence from the time of vaccine administration. Distributions show the probability of the time from initiation of the vaccine dose to the VDPV emergence threshold (10 VP1 substitutions for Sabin types 1 and 3, 6 VP1 substitutions for Sabin type 2) from the two-stage evolution model (Sabin-like to wild isolates) proposed in the text. For type 2, there is a significant probability that VDPV emergence will be reached in long-lived primary infections (30 to 60 days), and so VDPV type 2 genomes can appear within the duration of a single normal infection.