Kimberly M. Thompson

Expert Review on Poliovirus Immunity and Transmission

Successfully managing risks to achieve wild polioviruses (WPVs) eradication and address the complexities of oral poliovirus vaccine (OPV) cessation to stop all cases of paralytic poliomyelitis depends strongly on our collective understanding of poliovirus immunity and transmission. With increased shifting from OPV to inactivated poliovirus vaccine (IPV), numerous risk management choices motivate the need to understand the tradeoffs and uncertainties and to develop models to help inform decisions. The U.S. Centers for Disease Control and Prevention hosted a meeting of international experts in April 2010 to review the available literature relevant to poliovirus immunity and transmission. This expert review evaluates 66 OPV challenge studies and other evidence to support the development of quantitative models of poliovirus transmission and potential outbreaks. This review focuses on characterization of immunity as a function of exposure history in terms of susceptibility to excretion, duration of excretion, and concentration of excreted virus. We also discuss the evidence of waning of host immunity to poliovirus transmission, the relationship between the concentration of poliovirus excreted and infectiousness, the importance of different transmission routes, and the differences in transmissibility between OPV and WPV. We discuss the limitations of the available evidence for use in polio risk models, and conclude that despite the relatively large number of studies on immunity, very limited data exist to directly support quantification of model inputs related to transmission. Given the limitations in the evidence, we identify the need for expert input to derive quantitative model inputs from the existing data.

Characterizing Poliovirus Transmission and Evolution: Insights from Modeling Experiences with Wild and Vaccine‐Related Polioviruses

With national and global health policymakers facing numerous complex decisions related to achieving and maintaining polio eradication, we expanded our previously developed dynamic poliovirus transmission model using information from an expert literature review process and including additional immunity states and the evolution of oral poliovirus vaccine (OPV). The model explicitly considers serotype differences and distinguishes fecal-oral and oropharyngeal transmission. We evaluated the model by simulating diverse historical experiences with polioviruses, including one country that eliminated wild poliovirus using both OPV and inactivated poliovirus vaccine (IPV) (USA), three importation outbreaks of wild poliovirus (Albania, the Netherlands, Tajikistan), one situation in which no circulating vaccine-derived polioviruses (cVDPVs) emerge despite annual OPV use and cessation (Cuba), three cVDPV outbreaks (Haiti, Madura Island in Indonesia, northern Nigeria), one area of current endemic circulation of all three serotypes (northern Nigeria), and one area with recent endemic circulation and subsequent elimination of multiple serotypes (northern India). We find that when sufficient information about the conditions exists, the model can reproduce the general behavior of poliovirus transmission and outbreaks while maintaining consistency in the generic model inputs. The assumption of spatially homogeneous mixing remains a significant limitation that affects the performance of the differential equation-based model when significant heterogeneities in immunity and mixing may exist. Further studies on OPV virus evolution and improved understanding of the mechanisms of mixing and transmission may help to better characterize poliovirus transmission in populations. Broad application of the model promises to offer insights in the context of global and national policy and economic models.

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

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.

Review and Assessment of Poliovirus Immunity and Transmission: Synthesis of Knowledge Gaps and Identification of Research Needs

With the intensifying global efforts to eradicate wild polioviruses, policymakers face complex decisions related to achieving eradication and managing posteradication risks. These decisions and the expanding use of inactivated poliovirus vaccine (IPV) trigger renewed interest in poliovirus immunity, particularly the role of mucosal immunity in the transmission of polioviruses. Sustained high population immunity to poliovirus transmission represents a key prerequisite to eradication, but poliovirus immunity and transmission remain poorly understood despite decades of studies. In April 2010, the U.S. Centers for Disease Control and Prevention convened an international group of experts on poliovirus immunology and virology to review the literature relevant for modeling poliovirus transmission, develop a consensus about related uncertainties, and identify research needs. This article synthesizes the quantitative assessments and research needs identified during the process. Limitations in the evidence from oral poliovirus vaccine (OPV) challenge studies and other relevant data led to differences in expert assessments, indicating the need for additional data, particularly in several priority areas for research: (1) the ability of IPV-induced immunity to prevent or reduce excretion and affect transmission, (2) the impact of waning immunity on the probability and extent of poliovirus excretion, (3) the relationship between the concentration of poliovirus excreted and infectiousness to others in different settings, and (4) the relative role of fecal-oral versus oropharyngeal transmission. This assessment of current knowledge supports the immediate conduct of additional studies to address the gaps.

Modeling the Dynamics of Oral Poliovirus Vaccine Cessation

BACKGROUNDnOral poliovirus vaccine (OPV) results in an ongoing burden of poliomyelitis due to vaccine-associated paralytic poliomyelitis and circulating vaccine-derived polioviruses (cVDPVs). This motivates globally coordinated OPV cessation after wild poliovirus eradication.nnnMETHODSnWe modeled poliovirus transmission and OPV evolution to characterize the interaction between population immunity, OPV-related virus prevalence, and the emergence of cVDPVs after OPV cessation. We explored strategies to prevent and manage cVDPVs for countries that currently use OPV for immunization and characterized cVDPV emergence risks and OPV use for outbreak response.nnnRESULTSnContinued intense supplemental immunization activities until OPV cessation represent the best strategy to prevent cVDPV emergence after OPV cessation in areas with insufficient routine immunization coverage. Policy makers must actively manage population immunity before OPV cessation to prevent cVDPVs and aggressively respond if prevention fails. Sufficiently aggressive response with OPV to interrupt transmission of the cVDPV outbreak virus will lead to die-out of OPV-related viruses used for response in the outbreak population. Further analyses should consider the risk of exportation to other populations of the outbreak virus and any OPV used for outbreak response.nnnCONCLUSIONSnOPV cessation can successfully eliminate all circulating live polioviruses in a population. The polio end game requires active risk management.

Modeling Population Immunity to Support Efforts to End the Transmission of Live Polioviruses

Eradication of wild poliovirus (WPV) types 1 and 3, prevention and cessation of circulating vaccine-derived polioviruses, and achievement and maintenance of a world free of paralytic polio cases requires active risk management by focusing on population immunity and coordinated cessation of oral poliovirus vaccine (OPV). We suggest the need for a complementary and different conceptual approach to achieve eradication compared to the current case-based approach using surveillance for acute flaccid paralysis (AFP) to identify symptomatic poliovirus infections. Specifically, we describe a modeling approach to characterize overall population immunity to poliovirus transmission. The approach deals with the realities that exposure to live polioviruses (e.g., WPV, OPV) and/or vaccination with inactivated poliovirus vaccine provides protection from paralytic polio (i.e., disease), but does not eliminate the potential for reinfection or asymptomatic participation in poliovirus transmission, which may increase with time because of waning immunity. The AFP surveillance system provides evidence of symptomatic poliovirus infections detected, which indicate immunity gaps after outbreaks occur, and this system represents an appropriate focus for controlling disease outbreaks. We describe a conceptual dynamic model to characterize population immunity to poliovirus transmission that helps identify risks created by immunity gaps before outbreaks occur, which provides an opportunity for national and global policymakers to manage the risk of poliovirus and prevent outbreaks before they occur. We suggest that dynamically modeling risk represents an essential tool as the number of cases approaches zero.

Preeradication Vaccine Policy Options for Poliovirus Infection and Disease Control

With the circulation of wild poliovirus (WPV) types 1 and 3 continuing more than a decade after the original goal of eradicating all three types of WPVs by 2000, policymakers consider many immunization options as they strive to stop transmission in the remaining endemic and outbreak areas and prevent reintroductions of live polioviruses into nonendemic areas. While polio vaccination choices may appear simple, our analysis of current options shows remarkable complexity. We offer important context for current and future polio vaccine decisions and policy analyses by developing decision trees that clearly identify potential options currently used by countries as they evaluate national polio vaccine choices. Based on a comprehensive review of the literature we (1) identify the current vaccination options that national health leaders consider for polio vaccination, (2) characterize current practices and factors that appear to influence national and international choices, and (3) assess the evidence of vaccine effectiveness considering sources of variability between countries and uncertainties associated with limitations of the data. With low numbers of cases occurring globally, the management of polio risks might seem like a relatively low priority, but stopping live poliovirus circulation requires making proactive and intentional choices to manage population immunity in the remaining endemic areas and to prevent reestablishment in nonendemic areas. Our analysis shows remarkable variability in the current national polio vaccine product choices and schedules, with combination vaccine options containing inactivated poliovirus vaccine and different formulations of oral poliovirus vaccine making choices increasingly difficult for national health leaders.

Modeling Options to Manage Type 1 Wild Poliovirus Imported Into Israel in 2013

BACKGROUNDnAfter 25 years without poliomyelitis cases caused by circulating wild poliovirus (WPV) in Israel, sewage sampling detected WPV type 1 (WPV1) in April 2013, despite high vaccination coverage with only inactivated poliovirus vaccine (IPV) since 2005.nnnMETHODSnWe used a differential equation-based model to simulate the dynamics of poliovirus transmission and population immunity in Israel due to past exposure to WPV and use of oral poliovirus vaccine (OPV) in addition to IPV. We explored the influences of various immunization options to stop imported WPV1 circulation in Israel.nnnRESULTSnWe successfully modeled the potential for WPVs to circulate without detected cases in Israel. Maintaining a sequential IPV/OPV schedule instead of switching to an IPV-only schedule in 2005 would have kept population immunity high enough in Israel to prevent WPV1 circulation. The Israeli response to WPV1 detection prevented paralytic cases; a more rapid response might have interrupted transmission more quickly.nnnCONCLUSIONSnIPV-based protection alone might not provide sufficient population immunity to prevent poliovirus transmission after an importation. As countries transition to IPV in immunization schedules, they may need to actively manage population immunity and consider continued use of OPV, to avoid the potential circulation of imported live polioviruses before globally coordinated cessation of OPV use.

Modeling the Potential Role of Inactivated Poliovirus Vaccine to Manage the Risks of Oral Poliovirus Vaccine Cessation

BACKGROUNDnThe Global Polio Eradication Initiative plans to stop all oral poliovirus vaccine (OPV) after wild poliovirus eradication, starting with serotype 2. Stakeholders continue to discuss the role of using inactivated poliovirus vaccine (IPV) to manage the risks of circulating vaccine-derived polioviruses (cVDPVs) during the end game.nnnMETHODSnWe use a poliovirus transmission and OPV evolution model to explore the impact of various routine immunization policies involving IPV on population immunity dynamics and the probability and magnitude of cVDPV emergences following OPV cessation.nnnRESULTSnAdding a single IPV dose to an OPV-only routine immunization schedule at or just before OPV cessation produces very limited impact on the probability of cVDPV emergences and the number of expected polio cases in settings in which we expect cVDPVs in the absence of IPV use. The highest-cost option of switching to a 3-dose IPV schedule only marginally decreases cVDPV risks. Discontinuing supplemental immunization activities while introducing IPV prior to OPV cessation leads to an increase in cVDPV risks.nnnCONCLUSIONSnIntroducing a dose of IPV in countries currently using OPV only for routine immunization offers protection from paralysis to successfully vaccinated recipients, but it does little to protect high-risk populations from cVDPV risks.

The potential impact of expanding target age groups for polio immunization campaigns

BackgroundGlobal efforts to eradicate wild polioviruses (WPVs) continue to face challenges due to uninterrupted endemic WPV transmission in three countries and importation-related outbreaks into previously polio-free countries. We explore the potential role of including older children and adults in supplemental immunization activities (SIAs) to more rapidly increase population immunity and prevent or stop transmission.MethodsWe use a differential equation-based dynamic poliovirus transmission model to analyze the epidemiological impact and vaccine resource implications of expanding target age groups in SIAs. We explore the use of older age groups in SIAs for three situations: alternative responses to the 2010 outbreak in Tajikistan, retrospective examination of elimination in two high-risk states in northern India, and prospective and retrospective strategies to accelerate elimination in endemic northwestern Nigeria. Our model recognizes the ability of individuals with waned mucosal immunity (i.e., immunity from a historical live poliovirus infection) to become re-infected and contribute to transmission to a limited extent.ResultsSIAs involving expanded age groups reduce overall caseloads, decrease transmission, and generally lead to a small reduction in the time to achieve WPV elimination. Analysis of preventive expanded age group SIAs in Tajikistan or prior to type-specific surges in incidence in high-risk areas of India and Nigeria showed the greatest potential benefits of expanded age groups. Analysis of expanded age group SIAs in outbreak situations or to accelerate the interruption of endemic transmission showed relatively less benefit, largely due to the circulation of WPV reaching individuals sooner or more effectively than the SIAs. The India and Nigeria results depend strongly on how well SIAs involving expanded age groups reach relatively isolated subpopulations that sustain clusters of susceptible children, which we assume play a key role in persistent endemic WPV transmission in these areas.ConclusionsThis study suggests the need to carefully consider the epidemiological situation in the context of decisions to use expanded age group SIAs. Subpopulations of susceptible individuals may independently sustain transmission, which will reduce the overall benefits associated with using expanded age group SIAs to increase population immunity to a sufficiently high level to stop transmission and reduce the incidence of paralytic cases.