Abstract
Ten outbreaks of poliomyelitis caused by pathogenic circulating vaccine-derived polioviruses (cVDPVs) have recently been reported in different regions of the world. Two of these outbreaks occurred in Madagascar. Most cVDPVs were recombinants of mutated poliovaccine strains and other unidentified enteroviruses of species C. We previously reported that a type 2 cVDPV isolated during an outbreak in Madagascar was co-circulating with coxsackieviruses A17 (CA17) and that sequences in the 3′ half of the cVDPV and CA17 genomes were related. The goal of this study was to investigate whether these CA17 isolates can act as recombination partners of poliovirus and subsequently to evaluate the major effects of recombination events on the phenotype of the recombinants. We first cloned the infectious cDNA of a Madagascar CA17 isolate. We then generated recombinant constructs combining the genetic material of this CA17 isolate with that of the type 2 vaccine strain and that of the type 2 cVDPV. Our results showed that poliovirus/CA17 recombinants are viable. The recombinant in which the 3′ half of the vaccine strain genome had been replaced by that of the CA17 genome yielded larger plaques and was less temperature sensitive than its parental strains. The virus in which the 3′ portion of the cVDPV genome was replaced by the 3′ half of the CA17 genome was almost as neurovirulent as the cVDPV in transgenic mice expressing the poliovirus cellular receptor gene. The co-circulation in children and genetic recombination of viruses, differing in their pathogenicity for humans and in certain other biological properties such as receptor usage, can lead to the generation of pathogenic recombinants, thus constituting an interesting model of viral evolution and emergence.
Highlights
The Sabin’s trivalent live-attenuated oral poliovirus vaccine (OPV) includes viral strains of three serotypes (Sabin 1, 2 and 3)
Partial genomic sequencing showed that the sequences of several serotype 17 and 13 coxsackie A viruses (CA17 and CA13) encoding viral proteins 2C and 3Dpol, respectively, were closely related to those of the circulating vaccine-derived polioviruses (cVDPVs) sequences. These results suggest that ancestors of these coxsackieviruses A17 (CA17) and CA13 strains were the donors of the human enteroviruses of species C (HEV-C) sequences present in the Madagascar cVDPVs; the nucleotide sequences showing the highest similarity between these coxsackie A viruses and cVDPVs remained significantly different (6–8%)
To confirm the relationship between CA17 isolates and the cVDPV MAD04 lineage, we sequenced the whole genome of one of the CA17 isolates (CA17.67591) that was found co-circulating with MAD04 [27] – EMBL Genbank accession number FM955278
Summary
The Sabin’s trivalent live-attenuated oral poliovirus vaccine (OPV) includes viral strains of three serotypes (Sabin 1, 2 and 3). These strains replicate in the digest tract following vaccination, inducing a strong local intestinal immune response that limits subsequent poliovirus (PV) replication and viral transmission in humans [1]. Low vaccine coverage over recent years has allowed occasional spread of wild PV strains from endemic countries to neighboring or distant countries where wild PV had disappeared [3]. Low vaccine coverage can lead to transmission of OPV strains to non-immunized people, allowing genetic drift and subsequent loss of their attenuation characteristics [4,5]. Ten outbreaks due to pathogenic circulating vaccine-derived polioviruses (cVDPVs) have recently been reported, two of which occurred in Madagascar in 2001–2002 and 2005 [3,6,7,8,9,10,11,12,13]
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