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. IMPORTANCEThe 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. O ver the last 50 years, mass vaccination campaigns with oral polio vaccine (OPV) have been a key fa...

The Evolutionary Pathway to Virulence of an RNA Virus

“…First, three substitution events occurred almost invariantly in all lineages deriving from OPV2. These substitutions include the known A481G and U2909C attenuation reversions, as well as an additional reversion at U398C in the 5’ UTR (Famulare et al, 2015; Macadam et al, 1991; Muzychenko et al, 1991). In all lineages with enough resolution (i.e.…”

“…To date, limited analyses of localized cVDPVs (Burns et al, 2013; Endegue-Zanga et al, 2015; Famulare et al, 2015; Hovi et al, 2013; Tao et al, 2013) have been undertaken, and many aspects of the evolutionary and epidemiological dynamics of cVDPVs remain unclear (Duintjer Tebbens et al, 2013). Understanding the evolutionary path(s) that leads from the attenuated and non-hazardous form of the virus into a circulating and pathogenic virus is central to the global poliovirus eradication efforts, for prediction of future epidemics, to understand the risks of current strategies and for designing new and safer vaccines.…”

Emergency Services of Viral RNAs: Repair and Remodeling

“…Nucleotide A 481 contributes to the attenuation phenotype of this vaccine virus, but it readily reverted to G in organisms of vaccinees, which is the event expected to disrupt the tertiary interaction. However, the potential for formation a stable C 398 -G 481 pair was regained in most isolates due to the reversion at position 398 as well (234,311,322) (Fig. 4B).…”

“…As noted above, the Sabin strain of this serotype has a destabilizing mutation at position 480 (A to G) contributing to its attenuated phenotype, but this destabilization is not usually conserved in vaccinees and their contacts. The strengthening of this base pairing might be accomplished not only by the reversion (G 480 A) but also by a compensating pseudoreversion (U 525 C) (311,322), which also resulted in a similar increase in virulence (323) and in restoration of the in vitro translation efficiency (311). Structural modeling suggested that G 481 of the predecessor of the Sabin-2 strain, strain P712, could potentially participate in a long-range interaction with C 398 , supporting the generation of a tertiary structure element (311) (Fig.…”

ΦX174 Attenuation by Whole Genome Codon Deoptimization

“…on Earth wild poliovirus and the emergent vaccine-derived polioviruses (cVDPVs) continues to cause concern over the resurgence of poliomyelitis (52)(53)(54)(55) . A synthetic poliovirus was assembled in 2002 (56) , codon deoptimized in 2006 (57,58) , codon pair deoptimized in 2008 (59) , and dinucleotide deoptimized in 2009 (11) .…”