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Between October 2001 and April 2002, five cases of acute flaccid paralysis (AFP) associated with type 2 vaccine-derived polioviruses (VDPVs) were reported in the southern province of the Republic of Madagascar. To determine viral factors that favor the emergence of these pathogenic VDPVs, we analyzed in detail their genomic and phenotypic characteristics and compared them with co-circulating enteroviruses. These VDPVs appeared to belong to two independent recombinant lineages with sequences from the type 2 strain of the oral poliovaccine (OPV) in the 5′-half of the genome and sequences derived from unidentified species C enteroviruses (HEV-C) in the 3′-half. VDPV strains showed characteristics similar to those of wild neurovirulent viruses including neurovirulence in poliovirus-receptor transgenic mice. We looked for other VDPVs and for circulating enteroviruses in 316 stools collected from healthy children living in the small area where most of the AFP cases occurred. We found vaccine PVs, two VDPVs similar to those found in AFP cases, some echoviruses, and above all, many serotypes of coxsackie A viruses belonging to HEV-C, with substantial genetic diversity. Several coxsackie viruses A17 and A13 carried nucleotide sequences closely related to the 2C and the 3Dpol coding regions of the VDPVs, respectively. There was also evidence of multiple genetic recombination events among the HEV-C resulting in numerous recombinant genotypes. This indicates that co-circulation of HEV-C and OPV strains is associated with evolution by recombination, resulting in unexpectedly extensive viral diversity in small human populations in some tropical regions. This probably contributed to the emergence of recombinant VDPVs. These findings give further insight into viral ecosystems and the evolutionary processes that shape viral biodiversity., Author Summary Following extensive vaccination campaigns using the attenuated oral polio vaccine, wild polioviruses remain endemic in only a few countries. Nevertheless, several poliomyelitis outbreaks associated with vaccine-derived polioviruses (VDPVs) were reported in different parts of the world in recent years, particularly in Madagascar in 2002. We analyzed the molecular characteristics of Madagascar VDPVs and compared them with those of co-circulating enteroviruses. These VDPVs appear to be recombinant viruses between vaccine polioviruses and human enteroviruses of species C (HEV-C) and to present phenotypic characteristics similar to those of wild polioviruses including pathogenicity. Similar VDPVs and other enteroviruses, including several HEV-C of different types, were found in the stools of healthy children living in neighboring villages to where most of the poliomyelitis cases occurred. Some HEV-Cs showed sequences closely related to those of VDPVs, indicating genetic recombination between these viruses and vaccine polioviruses. There was also evidence of multiple genetic recombination events among other HEV-C isolates resulting in numerous different genotypes. These findings indicate that co-circulation of HEV-C and vaccine polioviruses and their evolution by recombination results in unexpectedly extensive viral diversity, at least in some small human populations, probably contributing to the emergence of recombinant VDPVs. Results of this study give further insight into the world of viruses and their biodiversity.