The oral poliovirus vaccines (OPV) are one of most effective disease eradication tools in public health. However, the Sabin 2 vaccine strain can revert attenuation and cause outbreaks of circulating, vaccine-derived poliovirus (cVDPV2) that are clinically indistinguishable from wild poliovirus (WPV). Accurately assessing cVDP2 risk requires disentangling the complex interaction between epidemiology and evolutionary biology. Here, we developed a Sabin 2 reversion model that simulates the reversion of Sabin 2 to WPV based on the clinical differences in shedding duration and infectiousness between individuals vaccinated with Sabin 2 and those infected with wild poliovirus. Genetic reversion is informed by a canonical reversion pathway defined by three gatekeeper mutations (A481G, U2909C, and U398C) and the accumulation of genetic load from deleterious nonsynonymous mutations. Our model captures essential aspects of both phenotypic and molecular evolution and simulates transmission using a multiscale transmission model that consolidates the relationships among immunity, susceptibility, and transmission risk. We show that despite the rapid reversion of Sabin 2, cVDPV2 outbreaks can be controlled by maintaining high levels of population-level immunity and sanitation. Supplementary immunization activities must maintain high vaccine coverage to prevent future cVDPV2 outbreaks in the targeted intervention zone, but declining global immunity against Sabin 2 makes them increasingly risky to implement in poor sanitation regions regardless of historical immunization activity. A combined strategy of assessing and improving sanitation levels in conjunction with high coverage vaccination campaigns will limit future cVDPV2 emergence and spread.
