The recent cVDPV outbreak in the Philippines has important implications for the global initiative to eradicate polio. First, it demonstrates that use of OPV with suboptimal coverage rates can lead to the emergence and spread of cVDPVs even in countries where indigenous wild polioviruses have already been eradicated. Second, it again shows that use of OPV at high rates of coverage can prevent further spread of cVDPVs. Third, it reaffirms the importance of maintaining sensitive acute flaccid paralysis and poliovirus surveillance in both polio-free and polio-endemic countries. Finally, it provides additional insights into the conditions permissive for cVDPV emergence and the biological and genetic properties of the emergent viruses.
The cVDPV outbreak in the Philippines differed in key respects from earlier outbreaks reported in Egypt (66
) and Haiti in Hispaniola (25
) and the subsequent outbreak in Madagascar (51
). In the other outbreak countries, OPV coverage rates were particularly low (<50%) in the affected communities and generally low nationwide. Moreover, nearly all of the case patients in the other outbreaks were unimmunized or incompletely immunized children (25
). By contrast, nationwide rates of routine coverage with three doses of OPV were reported to have been approximately 80% in the Philippines since the early 1990s (50
), and two of the case patients had received three doses of OPV and the third patient had received two doses (Table ). However, gaps in population immunity probably occurred after 1997, when the mass OPV campaigns in the form of national immunization days were last conducted in the Philippines. Subnational immunization days that covered the urban areas of Manila, Cebu, and Davao (Mindanao) followed in 1998 and 1999 but did not include the three provinces with cVDPV cases (Fig. ) (62
It is likely that gaps in OPV coverage developed most rapidly in the slum areas, such as those around metropolitan Manila, and these gaps were aggravated by a temporary shortage of OPV supply in 2000 to 2001. The widening immunity gap, coupled with very high population densities (especially around metropolitan Manila; Fig. ), poor hygiene or sanitation, and tropical conditions may have established local conditions favoring cVDPV emergence. Once poliovirus circulation starts, three prior OPV doses may not be enough to protect all children from poliomyelitis, particularly in high-risk communities (55
). However, overall population immunity appears to have been sufficiently high to restrict cVDPV transmission to a minimally branched chain, in contrast to the pattern of multichain transmission seen in Egypt and Hispaniola (25
). The important lesson from the Philippines outbreak is that cVDPVs can emerge even in countries with good rates of OPV coverage nationwide if immunity gaps develop in local areas at highest potential risk for poliovirus circulation.
The detection of the cVDPVs in the Philippines highlights the significant role of poliovirus surveillance in the final stages of global polio eradication. Immediately following the cVDPV outbreak in Hispaniola, intensive screening of cVDPVs was initiated by laboratories within the entire World Health Organization Global Polio Laboratory Network (8
). Vaccine-related poliovirus isolates are identified by genetic methods, such as probe hybridization (14
), and also characterized for evidence of antigenic divergence from the prototype OPV strains by antigenic tests, such as intratypic differentiation-ELISA (8
). The likelihood of antigenic divergence increases with the duration of replication of OPV strains in the human gut (41
), and all documented cVDPV isolates have been antigenic variants of the OPV strains (25
). Vaccine-related isolates having altered antigenic properties are candidate VDPVs and are characterized further by genomic sequencing. In addition, the World Health Organization is promptly notified of the virologic findings in order to accelerate active surveillance and to prepare for any necessary supplementary immunization campaigns, as described here for the Philippines (8
The Philippines cVDPV isolates, as with the other cVDPV isolates described so far (25
), have recombinant noncapsid sequences derived from other species C enteroviruses (6
). Since OPV contains all three serotypes of the Sabin strains, a recombinant poliovirus among heterogeneous strains readily emerges during virus replication in the gut of vaccinees. Nevertheless, recombination among the vaccine strains is known to occur frequently with serotypes 2 and 3 but rarely with type 1 (4
). On the other hand, circulating wild polioviruses with a block of sequence derived from Sabin 1 have been described (34
). It appears most likely that the donor of the noncapsid sequences to the Philippines type 1 cVDPV isolates was nonpolio enteroviruses, as the sensitive surveillance scheme for cases of acute flaccid paralysis maintained in the Philippines has not detected any indigenous or imported wild polioviruses since 1993. Although the apparent donor of the recombinant noncapsid sequences of cVDPVs has not been identified, growing evidences indicate frequent recombination between polioviruses and species C nonpolio enteroviruses (6
) as well as between serotypes within the same nonpolio enterovirus species (33
). Further epidemiological studies of species C nonpolio enteroviruses, especially in tropical areas, are needed to understand the conditions favorable for cVDPV recombination.
Although recombination with other enteroviruses appears to be an indicator of poliovirus circulation (25
), the possible role of recombination in the phenotypic reversion of OPV is less clear. Genetic determinants of attenuation and temperature sensitivity in Sabin 1 (but not in Sabin 2 and 3) are mapped in the 3Dpol
noncapsid region (5
), so that recombination may be an efficient mechanism to replace these mutations with consensus wild enterovirus sequences. However, the major determinants of attenuation in Sabin 1 map to the 5′-NTR and capsid regions, which were not replaced by recombination in either the Philippines or Hispaniola cVDPVs.
The partially attenuated and temperature-sensitive phenotypes of the most recently identified cVDPV isolate, Luzon-01-2c, from a healthy contact child, were unexpected in view of the close sequence relationship of the contact isolate to the other three Philippines cVDPV isolates that had biological properties similar to those of wild type 1 polioviruses. The temporal and phylogenetic relationships among the Philippines cVDPV isolates suggest that isolate Luzon-01-2c was derived from a more neurovirulent and less temperature sensitive progenitor, raising the possibility that reversion of the attenuated and temperature-sensitive phenotypes of Sabin 1 is not necessarily irreversible during cVDPV evolution. Although the Luzon-01-2c isolate has the same recombinant properties as the other cVDPV isolates, it does differ from the other three isolates at some specific nucleotide and amino acid substitutions (644, 667, and 720 in the 5′-NTR, VP1-224, 2A-101, 2A-129, 2B-75, and 2C-94). Further virologic, epidemiologic, and reverse genetic studies are needed to understand the role of mutation and recombination in poliovirus evolution and cVDPV emergence.