Abstract
The attenuated Sabin strains contained in the oral poliomyelitis vaccine are genetically unstable, and their circulation in poorly immunized populations can lead to the emergence of pathogenic circulating vaccine-derived polioviruses (cVDPVs). The recombinant nature of most cVDPV genomes and the preferential presence of genomic sequences from certain cocirculating non-polio enteroviruses of species C (EV-Cs) raise questions about the permissiveness of genetic exchanges between EV-Cs and the phenotypic impact of such exchanges. We investigated whether functional constraints limited genetic exchanges between Sabin strains and other EV-Cs. We bypassed the natural recombination events by constructing 29 genomes containing a Sabin 2 capsid-encoding sequence and other sequences from Sabin 2 or from non-polio EV-Cs. Most genomes were functional. All recombinant viruses replicated similarly in vitro, but recombination modulated plaque size and temperature sensitivity. All viruses with a 5′UTR from Sabin 2 were attenuated in mice, whereas almost all viruses with a non-polio 5′UTR caused disease. These data highlight the striking conservation of functional compatibility between different genetic domains of cocirculating EV-Cs. This aspect is only one of the requirements for the generation of recombinant cVDPVs in natural conditions, but it may facilitate the generation of viable intertypic recombinants with diverse phenotypic features, including pathogenicity.
Highlights
The attenuated Sabin strains contained in the oral poliomyelitis vaccine are genetically unstable, and their circulation in poorly immunized populations can lead to the emergence of pathogenic circulating vaccine-derived polioviruses
We selected a panel of representative non-polio enteroviruses of species C (EV-Cs) isolated in Madagascar in 2001–2002 from healthy children living in the area in which the poliomyelitis outbreak occurred: three CV-A13 (67001, 68095 and 68145), two CV-A17 (67610 and 68154), one CV-A11 (66122) and one EV-C99
We constructed a set of chimeric Sabin 2/non-polio EV-C genomes with a Sabin 2 capsid-encoding sequence in common; the other sequences were from Sabin 2 or from non-polio EV-Cs (Fig. 1)
Summary
The attenuated Sabin strains contained in the oral poliomyelitis vaccine are genetically unstable, and their circulation in poorly immunized populations can lead to the emergence of pathogenic circulating vaccine-derived polioviruses (cVDPVs). All viruses with a 5′UTR from Sabin 2 were attenuated in mice, whereas almost all viruses with a non-polio 5′UTR caused disease These data highlight the striking conservation of functional compatibility between different genetic domains of cocirculating EV-Cs. These data highlight the striking conservation of functional compatibility between different genetic domains of cocirculating EV-Cs This aspect is only one of the requirements for the generation of recombinant cVDPVs in natural conditions, but it may facilitate the generation of viable intertypic recombinants with diverse phenotypic features, including pathogenicity. EVs are small non-enveloped viruses containing a single-stranded RNA genome of positive polarity of approximately 7.5 kb in length This genome consists of two untranslated regions (5′UTR and 3′UTR) flanking a single large open reading frame. Most of the determinants of vaccine strain attenuation, impairing replication in the nervous system, are located in the 5′UTR and the region encoding the capsid proteins[5] Many of these determinants confer a temperature-sensitive (ts) phenotype on the strains[6]. The Sabin strains can replicate to high titers only in the digestive tract, conferring strong systemic and intestinal immunity, limiting subsequent PV replication and viral www.nature.com/scientificreports/
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