Oral poliovirus vaccine evolution and insights relevant to modeling the risks of circulating vaccine-derived polioviruses (cVDPVs)

Abstract

The live, attenuated oral poliovirus vaccine (OPV) provides a powerful tool for controlling and stopping the transmission of wild polioviruses (WPVs), although the risks of vaccine-associated paralytic polio (VAPP) and circulating vaccine-derived poliovirus (cVDPV) outbreaks exist as long as OPV remains in use. Understanding the dynamics of cVDPV emergence and outbreaks as a function of population immunity and other risk factors may help to improve risk management and the development of strategies to respond to possible outbreaks. We performed a comprehensive review of the literature related to the process of OPV evolution and information available from actual experiences with cVDPV outbreaks. Only a relatively small fraction of poliovirus infections cause symptoms, which makes direct observation of the trajectory of OPV evolution within a population impractical and leads to significant uncertainty. Despite a large global surveillance system, the existing genetic sequence data largely provide information about transmitted virulent polioviruses that caused acute flaccid paralysis, and essentially no data track the changes that occur in OPV sequences as the viruses transmit largely asymptomatically through real populations with suboptimal immunity. We updated estimates of cVDPV risks based on actual experiences and identified the many limitations in the existing data on poliovirus transmission and immunity and OPV virus evolution that complicate modeling. Modelers should explore the space of potential model formulations and inputs consistent with the available evidence and future studies should seek to improve our understanding of the OPV virus evolution process to provide better information for policymakers working to manage cVDPV risks.

Figure 1:

Annual numbers of circulating vaccine-derived poliovirus (cVDPV) and ambiguous vaccine-derived poliovirus (aVDPV) events, by serotype.

Figure 2:. Two alternative formulations of the OPV evolution process. *

a) Based on reversion of a small number of key attenuating mutations b) Based on a more gradual reversion process approximated by VP1 divergen Acronyms: Cumul. # = cumulative number of; OPV = oral poliovirus vaccine; VDPV = vaccine-derived poliovirus; VP1 = viral protein 1 region; WPV = wild poliovirus * Both formulations assume exponentially distributed times between reversion events based on different values. Panel a assumes hypothetical average times of 14, 35, and 60 days until attenuating mutations 1, 2, and 3, respectively. Panel b assumes 10 nucleotide changes per year based on the approximate molecular clock⁽⁴³⁾ and 900 total nucleotides in the VP1 region, with divergence truncated at 1% as a potential (although uncertain) point beyond which the virus is no longer attenuated and further divergence has only random effect on neurovirulence and transmissibility (i.e., any virus with 10 or more mutations receives a value “more than 1%” on the y-axis). In both panels, the” population average” represents the average of 100 realizations at each point in time.

Figure 3:

Hypothetical relationship between reversion of the virus and paralysis-to-infection ratio (PIR), showing differences between serotypes in PIR due to different starting points (virus age 0, reflecting oral poliovirus vaccine) and end points (oldest virus age, reflecting fully-reverted poliovirus with assumed PIR equal to wild poliovirus) and in the speed of the reversion process.