Spread of Vaccine-Derived Poliovirus from a Paralytic Case in an Immunodeficient Child: an Insight into the Natural Evolution of Oral Polio Vaccine

The Sabin oral poliovirus vaccine (OPV) readily undergoes changes in antigenic sites upon replication in humans. Here, a set of antigenically altered descendants of the three OPV serotypes (76 isolates) was characterized to determine the driving forces behind these changes and their biological implications. The amino acid residues of OPV derivatives that lie within or close to the known antigenic sites exhibited a marked tendency to be replaced by residues characteristic of homotypic wild polioviruses, and these changes may occur very early in OPV evolution. The specific amino acid alterations nicely correlated with serotype-specific changes in the reactivity of certain individual antigenic sites, as revealed by the recently devised monoclonal antibody-based enzyme-linked immunosorbent assay. In comparison to the original vaccine, small changes, if any, in the neutralizing capacity of human or rabbit sera were observed in highly diverged vaccine polioviruses of three serotypes, in spite of strong alterations of certain epitopes. We propose that the common antigenic alterations in evolving OPV strains largely reflect attempts to eliminate fitness-decreasing mutations acquired either during the original selection of the vaccine or already present in the parental strains. Variability of individual epitopes does not appear to be primarily caused by, or lead to, a significant immune evasion, enhancing only slightly, if at all, the capacity of OPV derivatives to overcome immunity in human populations. This study reveals some important patterns of poliovirus evolution and has obvious implications for the rational design of live viral vaccines.

Section: Resultsmentioning

confidence: 99%

Antigenic Evolution of Vaccine-Derived Polioviruses: Changes in Individual Epitopes and Relative Stability of the Overall Immunological Properties

Yakovenko

Cherkasova

Rezapkin

et al. 2006

“…The rates appear to be similar across the three poliovirus serotypes and for both circulating polioviruses and polioviruses associated with chronic infections. This very rapid rate of genomic evolution has facilitated high-resolution molecular epidemiologic studies, permitting the unambiguous identification of the sources of imported viruses (10, 41) and the resolution of separate lineages during outbreaks (39,43,74,75), during endemic transmission (23,52,90), during prolonged poliovirus replication in immunodeficient patients (9,31,53,89), and from environmental surveillance (23). However, the rapid accumulation of nucleotide substitutions, most of which are synonymous transitions, obscures deeper evolutionary relationships (46,70).…”

mentioning

confidence: 99%

Calibration of Multiple Poliovirus Molecular Clocks Covering an Extended Evolutionary Range

Jorba

Campagnoli

et al. 2008

165

168

We have calibrated five different molecular clocks for circulating poliovirus based upon the rates of fixation of total substitutions (K t ), synonymous substitutions (K s ), synonymous transitions (A s ), synonymous transversions (B s ), and nonsynonymous substitutions (K a ) into the P1/capsid region (2,643 nucleotides). Rates were determined over a 10-year period by analysis of sequences of 31 wild poliovirus type 1 isolates representing a well-defined phylogeny derived from a common imported ancestor. Similar rates were obtained by linear regression, the maximum likelihood/single-rate dated-tip method, and Bayesian inference. . Nonsynonymous substitutions at all P1/capsid sites, including the neutralizing antigenic sites, appeared to be constrained by purifying selection. Simulation of the evolution of third-codon positions suggested that saturation of synonymous transitions would be evident at 10 years and complete at ϳ65 years of independent transmission. Saturation of synonymous transversions was predicted to be minimal at 20 years and incomplete at 100 years. The rapid evolution of the K t , K s , and A s clocks can be used to estimate the dates of divergence of closely related viruses, whereas the slower B s and K a clocks may be used to explore deeper evolutionary relationships within and across poliovirus genotypes.Poliovirus is one of the most rapidly evolving viruses known (17,31,38,52,58). Estimates of the rates of total nucleotide substitution into poliovirus capsid regions average ϳ10 Ϫ2 substitutions per site per year (31, 39, 52-54, 89, 90). The rates appear to be similar across the three poliovirus serotypes and for both circulating polioviruses and polioviruses associated with chronic infections. This very rapid rate of genomic evolution has facilitated high-resolution molecular epidemiologic studies, permitting the unambiguous identification of the sources of imported viruses (10, 41) and the resolution of separate lineages during outbreaks (39,43,74,75), during endemic transmission (23,52,90), during prolonged poliovirus replication in immunodeficient patients (9,31,53,89), and from environmental surveillance (23). However, the rapid accumulation of nucleotide substitutions, most of which are synonymous transitions, obscures deeper evolutionary relationships (46,70).Underlying the rapid pace of poliovirus genomic evolution are the high rates of base misincorporation (in the range of 10 Ϫ5 to 10 Ϫ3 per base per replication) by the poliovirus RNAdependent RNA polymerase (2,15,19,81,82,84). These high mutation rates are attributable to the absence of 3Ј35Ј exonuclease proofreading mechanisms for the viral RNA polymerases (19), although other mechanisms may also be involved (17, 18). The strong transition bias of the poliovirus polymerase (2, 46) is reflected in the pattern of fixation nucleotide substitutions into poliovirus genomes.In this report, we have calibrated five different molecular clocks based upon the rates of fixation of total substitutions (K t ), synonymous substitutions (K s ),...

“…1), a feature which appears to be not infrequent among VDPV and which poses problems for precise evaluation of the viral "age." In some cases, such unevenness could be explained by intratypic recombination (8,28). This explanation seems to be especially realistic for PV2/Rus, whose history involved multiple recombination events apparently occurring between partners of different "ages."…”

Section: Vol 83 2009mentioning

confidence: 99%

“…Uncertainties of the causes of uneven accumulation of synonymous mutations notwithstanding, the extent of this accumulation in the VP1-coding region is widely used and has proved to be a relatively reliable measure of the VDPV "age." Assuming the rate of 3 ϫ 10 Ϫ2 synonymous substitutions per synonymous site per year (8), PV2/Bel and PV2/Rus were estimated to be ϳ1.6 and ϳ1.2 years "old," respectively. If PV2/Bel iVDPV could likely have replicated only within a single immunodeficient host, PV2/Rus, being isolated from a 6-month-old unvaccinated baby, had certainly passed through more than one person.…”

Section: Vol 83 2009mentioning

confidence: 99%

Evolution of the Sabin Vaccine into Pathogenic Derivatives without Appreciable Changes in Antigenic Properties: Need for Improvement of Current Poliovirus Surveillance

Yakovenko

Короткова

Ivanova

et al. 2009

The Sabin oral polio vaccine (OPV) may evolve into pathogenic viruses, causing sporadic cases and outbreaks of poliomyelitis. Such vaccine-derived polioviruses (VDPV) generally exhibit altered antigenicity. The current paradigm to distinguish VDPV from OPV and wild polioviruses is to characterize primarily those poliovirus isolates that demonstrate deviations from OPV in antigenic and genetic intratypic differentiation (ITD) tests. Here we report on two independent cases of poliomyelitis caused by VDPVs with "Sabin-like" properties in several ITD assays. The results suggest the existence of diverse pathways of OPV evolution and necessitate improvement of poliovirus surveillance, which currently potentially misses this class of VDPV.