Modeling undetected live type 1 wild poliovirus circulation after apparent interruption of transmission: Pakistan and Afghanistan.

Since 2013, wild poliovirus (WPV) transmission occurred only for type 1 (WPV1). Following several years of increasing reported incidence (2017-2019) and programmatic disruptions caused by COVID-19 (early 2020), Pakistan and Afghanistan performed a large number of supplementary immunization activities (late 2020-2021). This increased intensity of immunization, following widespread transmission, substantially decreased WPV1 cases and positive environmental samples during 2021. Modeling the potential for undetected circulation of WPV1 after apparent interruption can support regional and global decisions about certification of the eradication of indigenous WPV1 transmission. We apply a stochastic model to estimate the confidence about no circulation (CNC) of WPV1 in Pakistan and Afghanistan as a function of time since the last reported case and/or positive environmental sample. Exploration of different assumptions about surveillance quality suggests a range for CNC for WPV1 as a function of time since the last positive surveillance signal, and supports the potential use of a time with no evidence of transmission of less than 3 years as sufficient to assume die out in the context of good acute flaccid paralysis (AFP) surveillance. We show high expected CNC based on AFP surveillance data alone, even with imperfect surveillance and some use of inactivated poliovirus vaccine masking the ability of AFP surveillance to detect transmission. Ensuring high quality AFP and environmental surveillance may substantially shorten the time required to reach high CNC. The time required for high CNC depends on whether immunization activities maintain high population immunity and the quality of surveillance data.

Teachers' experiences using AAC devices to manage inappropriate behavior: A basic qualitative study

The problem of this basic qualitative study explored whether there is an underrepresentation of information surrounding strategies, systems, and programs special education teachers use to support students using augmentative alternative communication (AAC) and the impact said information has on student behaviors. The purpose of this basic qualitative study was to explore kindergarten through twelfth-grade self-contained special education teachers' successes and failures when using AAC to decrease inappropriate behaviors. In addition, the following research study utilized the technological, pedagogical, and content knowledge (TPACK) theoretical framework, which looked at processes, trainings, strategies, challenges, successes, and overall knowledge on specific AAC programs and devices teachers utilized through a TPACK lens. The basic qualitative study used semi-structured interviews to answer the research question: What strategies, programs, or practices are preschool through twelfth-grade teachers using when implementing AAC in the classroom to decrease inappropriate behaviors? The sample consisted of six self-contained special education teachers of varying grade levels. Participants selected represent two school districts in the Northwest region of the United States with a minimum of three years teaching experience utilizing AAC and managing student behavior. The overall goal was to obtain 10-12 participants;however, due to Covid-19 gaining consent from participants was difficult. Further research would suggest interviewing additional teachers within the parameters of the study to be able to reach saturation. The practical implications of the study provided self-contained special education teachers not using AAC devices a guide to follow when using AAC in self-contained classrooms. The guide shared teachers' successes and failures when using specific AAC programs or devices. The analysis discovered five themes regarding teachers' processes, strategies, challenges, training, and knowledge: low-tech before high tech, built-in reward systems, consistency of use, more access to training on high-tech AAC, and understanding individual students' levels of need. The findings indicated that teachers with consistent processes, strategies and a strong understanding of individual students needs had more success in reducing students' aberrant behaviors and increasing the students' ability to communicate appropriately. Recommendations for future studies include expanding the research question to additional regions of the United States. Additional research includes discovering district level processes, strategies, challenges, and training provided to teachers, support staff and families in support of AAC to improve student communication and access the classroom or community. (PsycInfo Database Record (c) 2023 APA, all rights reserved)

The impact of disruptions caused by the COVID-19 pandemic on global polio eradication.

In early 2020, the COVID-19 pandemic led to substantial disruptions in global activities. The disruptions also included intentional and unintentional reductions in health services, including immunization campaigns against the transmission of wild poliovirus (WPV) and persistent serotype 2 circulating vaccine-derived poliovirus (cVDPV2). Building on a recently updated global poliovirus transmission and Sabin-strain oral poliovirus vaccine (OPV) evolution model, we explored the implications of immunization disruption and restrictions of human interactions (i.e., population mixing) on the expected incidence of polio and on the resulting challenges faced by the Global Polio Eradication Initiative (GPEI). We demonstrate that with some resumption of activities in the fall of 2020 to respond to cVDPV2 outbreaks and full resumption on January 1, 2021 of all polio immunization activities to pre-COVID-19 levels, the GPEI could largely mitigate the impact of COVID-19 to the delays incurred. The relative importance of reduced mixing (leading to potentially decreased incidence) and reduced immunization (leading to potentially increased expected incidence) depends on the timing of the effects. Following resumption of immunization activities, the GPEI will likely face similar barriers to eradication of WPV and elimination of cVDPV2 as before COVID-19. The disruptions from the COVID-19 pandemic may further delay polio eradication due to indirect effects on vaccine and financial resources.

Serotype 2 oral poliovirus vaccine (OPV2) choices and the consequences of delaying outbreak response.

The Global Polio Eradication Initiative (GPEI) faces substantial challenges with managing outbreaks of serotype 2 circulating vaccine-derived polioviruses (cVDPV2s) in 2021. A full five years after the globally coordinated removal of serotype 2 oral poliovirus vaccine (OPV2) from trivalent oral poliovirus vaccine (tOPV) for use in national immunization programs, cVDPV2s did not die out. Since OPV2 cessation, responses to outbreaks caused by cVDPV2s mainly used serotype 2 monovalent OPV (mOPV2) from a stockpile. A novel vaccine developed from a genetically stabilized OPV2 strain (nOPV2) promises to potentially facilitate outbreak response with lower prospective risks, although its availability and properties in the field remain uncertain. Using an established global poliovirus transmission model and building on a related analysis that characterized the impacts of disruptions in GPEI activities caused by the COVID-19 pandemic, we explore the implications of trade-offs associated with delaying outbreak response to avoid using mOPV2 by waiting for nOPV2 availability (or equivalently, delayed responses waiting for national validation of meeting the criteria for nOPV2 initial use). Consistent with prior modeling, responding as quickly as possible with available mOPV2 promises to reduce the expected burden of disease in the outbreak population and to reduce the chances for the outbreak virus to spread to other areas. Delaying cVDPV2 outbreak response (e.g., modeled as no response January-June 2021) to wait for nOPV2 can considerably increase the total expected cases (e.g., by as many as 1,300 cVDPV2 cases in the African region during 2021-2023) and increases the likelihood of triggering the need to restart widescale preventive use of an OPV2-containing vaccine in national immunization programs that use OPV. Countries should respond to any cVDPV2 outbreaks quickly with rounds that achieve high coverage using any available OPV2, and plan to use nOPV2, if needed, once it becomes widely available based on evidence that it is as effective but safer in populations than mOPV2.

Polio eradication: Addressing the hurdles on the last mile.

1988, the World Health Assembly committed to eradicate poliomyelitis, a viral disease that can cause permanent paralysis. Today, only type 1 of the three wild poliovirus types remains circulating in limited geographic areas following widespread use of different poliovirus vaccines. While we are close to zero new cases of wild polio, it is a fragile situation, and there are many remaining and new hurdles to overcome. Here, experts discuss how to address them.

Safety, Tolerability, and Pharmacokinetics of Intravenous Doses of PF-07304814, a Phosphate Prodrug Protease Inhibitor for the Treatment of SARS-CoV-2, in Healthy Adult Participants.

Studies on targeted antivirals for treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the ongoing pandemic, are limited. PF-07304814 (lufotrelvir) is the phosphate prodrug of PF-00835231, a protease inhibitor targeting the 3C-like protease of SARS-CoV-2. This phase 1 study evaluated the safety, tolerability, and pharmacokinetics (PK) of single ascending intravenous doses of lufotrelvir (continuous 24-hour infusion of 50, 150, 500, or 700 mg) versus placebo in healthy volunteers (2 interleaving cohorts: 1, n = 8; 2, n = 7). Each dosing period was separated by a washout interval (≥5 days). Treatment-emergent adverse events, PK, and biomarker concentrations were estimated from plasma/urine samples. Lufotrelvir was administered to 15 volunteers (mean [SD] age 39.7 [11.8] years). No serious adverse events, discontinuations, or deaths were reported. Mean maximum observed concentration of PF-00835231 (active moiety; 97.0 ng/mL to 1288 ng/mL) were observed between median time to maximum concentration of 14 to 16 hours after the start of the lufotrelvir infusion. Near-maximum plasma concentrations of PF-00835231 were observed ≈6 hours after infusion start and sustained until infusion end. PF-00835231 plasma concentrations declined rapidly after infusion end (mean terminal half-life: 500 mg, 2.0 hours; 700 mg, 1.7 hours). Approximately 9%-11% of the dose was recovered in urine as PF-00835231 across doses. A continuous, single-dose, 24-hour infusion of lufotrelvir (50-700 mg) was rapidly converted to PF-00835231 (active moiety), with dose-proportional PK exposures and no significant safety concerns. A daily, 24-hour continuous infusion of 270 to 350 mg is expected to maintain PF-00835231 concentration at steady state/above effective antiviral concentrations. Further studies exploring lufotrelvir efficacy in patients with coronavirus disease 2019 are ongoing.

Health economic analyses of secondary vaccine effects: a systematic review and policy insights.

INTRODUCTION: Numerous analyses demonstrate substantial health-economic impacts of primary vaccine effects (preventing or mitigating clinical manifestations of the diseases they target), but vaccines may also be associated with secondary effects, previously known as nonspecific, heterologous, or off-target effects. AREAS COVERED: We define key concepts to distinguish primary and secondary vaccine effects for health economic analyses, summarized terminology used in different fields, and perform a systematic review of health economic analyses focused on secondary vaccine effects (SVEs). EXPERT OPINION: Health economists integrate evidence from multiple fields, which often use incomplete or inconsistent definitions. Like regulators and policy makers, health economists require high-quality evidence of specific effects. Consistent with the limited evidence on mechanisms of action for SVEs, the associated health economic literature remains highly limited, with 4 studies identified by our systematic review. The lack of specific and well-controlled evidence that supports quantification of specific SVEs limits the consideration of these effects in vaccine research, development, regulatory, and recommendation decisions and health economic analyses.

Updated Characterization of Poliovirus Transmission in Pakistan and Afghanistan and the Impacts of Different Outbreak Response Vaccine Options.

BACKGROUND: Pakistan and Afghanistan remain the only reservoirs of wild poliovirus transmission. Prior modeling suggested that before the coronavirus disease 2019 (COVID-19) pandemic, plans to stop the transmission of serotype 1 wild poliovirus (WPV1) and persistent serotype 2 circulating vaccine-derived poliovirus (cVDPV2) did not appear on track to succeed. METHODS: We updated an existing poliovirus transmission and Sabin-strain oral poliovirus vaccine (OPV) evolution model for Pakistan and Afghanistan to characterize the impacts of immunization disruptions and restrictions on human interactions (ie, population mixing) due to the COVID-19 pandemic. We also consider different options for responding to outbreaks and for preventive supplementary immunization activities (SIAs). RESULTS: The modeling suggests that with some resumption of activities in the fall of 2020 to respond to cVDPV2 outbreaks and full resumption on 1 January 2021 of all polio immunization activities to pre-COVID-19 levels, Pakistan and Afghanistan would remain off-track for stopping all transmission through 2023 without improvements in quality. CONCLUSIONS: Using trivalent OPV (tOPV) for SIAs instead of serotype 2 monovalent OPV offers substantial benefits for ending the transmission of both WPV1 and cVDPV2, because tOPV increases population immunity for both serotypes 1 and 2 while requiring fewer SIA rounds, when effectively delivered in transmission areas.

Updated Characterization of Outbreak Response Strategies for 2019-2029: Impacts of Using a Novel Type 2 Oral Poliovirus Vaccine Strain.

Delays in achieving the global eradication of wild poliovirus transmission continue to postpone subsequent cessation of all oral poliovirus vaccine (OPV) use. Countries must stop OPV use to end all cases of poliomyelitis, including vaccine-associated paralytic polio (VAPP) and cases caused by vaccine-derived polioviruses (VDPVs). The Global Polio Eradication Initiative (GPEI) coordinated global cessation of all type 2 OPV (OPV2) use in routine immunization in 2016 but did not successfully end the transmission of type 2 VDPVs (VDPV2s), and consequently continues to use type 2 OPV (OPV2) for outbreak response activities. Using an updated global poliovirus transmission and OPV evolution model, we characterize outbreak response options for 2019-2029 related to responding to VDPV2 outbreaks with a genetically stabilized novel OPV (nOPV2) strain or with the currently licensed monovalent OPV2 (mOPV2). Given uncertainties about the properties of nOPV2, we model different assumptions that appear consistent with the evidence on nOPV2 to date. Using nOPV2 to respond to detected cases may reduce the expected VDPV and VAPP cases and the risk of needing to restart OPV2 use in routine immunization compared to mOPV2 use for outbreak response. The actual properties, availability, and use of nOPV2 will determine its effects on type 2 poliovirus transmission in populations. Even with optimal nOPV2 performance, countries and the GPEI would still likely need to restart OPV2 use in routine immunization in OPV-using countries if operational improvements in outbreak response to stop the transmission of cVDPV2s are not implemented effectively.

A Health Economic Analysis for Oral Poliovirus Vaccine to Prevent COVID-19 in the United States.

COVID-19 led to a recent high-profile proposal to reintroduce oral poliovirus vaccine (OPV) in the United States (U.S.), initially in clinical trials, but potentially for widespread and repeated use. We explore logistical challenges related to U.S. OPV administration in 2020, review the literature related to nonspecific effects of OPV to induce innate immunity, and model the health and economic implications of the proposal. The costs of reintroducing a single OPV dose to 331 million Americans would exceed $4.4 billion. Giving a dose of bivalent OPV to the entire U.S. population would lead to an expected 40 identifiable cases of vaccine-associated paralytic polio, with young Americans at the highest risk. Reintroducing any OPV use in the U.S. poses a risk of restarting transmission of OPV-related viruses and could lead to new infections in immunocompromised individuals with B-cell related primary immunodeficiencies that could lead to later cases of paralysis. Due to the lack of a currently licensed OPV in the U.S., the decision to administer OPV to Americans for nonspecific immunological effects would require purchasing limited global OPV supplies that could impact polio eradication efforts. Health economic modeling suggests no role for reintroducing OPV into the U.S. with respect to responding to COVID-19. Countries that currently use OPV experience fundamentally different risks, costs, and benefits than the U.S. Successful global polio eradication will depend on sufficient OPV supplies, achieving and maintaining high OPV coverage in OPV-using countries, and effective global OPV cessation and containment in all countries, including the U.S.

Expected Implications of Globally Coordinated Cessation of Serotype 3 Oral Poliovirus Vaccine (OPV) Before Serotype 1 OPV.

Globally coordinated cessation of all three serotypes of oral poliovirus vaccine (OPV) represents a critical part of a successful polio endgame, which the Global Polio Eradication Initiative (GPEI) plans to conduct in phases, with serotype 2 OPV cessation completed in mid 2016. Although in 2016 the GPEI expected to globally coordinate cessation of the remaining OPV serotypes (1 and 3) by 2021, continuing transmission of serotype 1 wild polioviruses to date makes those plans obsolete. With increasing time since the last reported polio case caused by serotype 3 wild poliovirus (in November 2012) leading to high confidence about its successful global eradication, the Global Commission for the Certification of Poliomyelitis Eradication recently certified its eradication. Questions now arise about the optimal timing of serotype 3 OPV (OPV3) cessation. Using an integrated global model that characterizes the risks, costs, and benefits of global polio policy and risk management options, we explored the implications of different options for coordinated cessation of OPV3 prior to COVID-19. Globally coordinating cessation of OPV3 as soon as possible offers the opportunity to reduce cases of vaccine-associated paralytic polio globally. In addition, earlier cessation of OPV3 should reduce the risks of creating serotype 3 circulating vaccine-derived polioviruses after OPV3 cessation, which represents a significant threat to the polio endgame given current GPEI plans to reduce preventive OPV supplemental immunization activities starting in 2019.

Hypothetical emergence of poliovirus in 2020: part 1. Consequences of policy decisions to respond using nonpharmaceutical interventions.

OBJECTIVES: As efforts to control COVID-19 continue, we simulate hypothetical emergence of wild poliovirus assuming an immunologically naïve population. This differs from the current global experience with polio and serves as a model for responding to future pandemics. METHODS: Applying an established global model, we assume a fully susceptible global population to polioviruses, independently introduce a virus with properties of each of the three stable wild poliovirus serotypes, and explore the impact of strategies that range from doing nothing to seeking global containment and eradication. RESULTS: We show the dynamics of paralytic cases as the virus spreads globally. We demonstrate the difficulty of eradication unless aggressive efforts begin soon after initial disease detection. Different poliovirus serotypes lead to different trajectories and burdens of disease. In the absence of aggressive measures, the virus would become globally endemic in 2-10 years, and cumulative paralytic cases would exceed 4-40 million depending on serotype, with the burden of disease shifting to younger ages. CONCLUSIONS: The opportunity to eradicate emerging infections represents an important public policy choice. If the world first observed the emergence of wild poliovirus in 2020, adopting aggressive control strategies would have been required to prevent a devastating global pandemic.

An Updated Economic Analysis of the Global Polio Eradication Initiative.

Despite a strong global commitment, polio eradication efforts continue now more than 30 years after the 1988 World Health Assembly resolution that established the Global Polio Eradication Initiative (GPEI), and 20 years after the original target of the year 2000. Prior health economic analyses estimated incremental net benefits of the GPEI of 40-50 billion in 2008 U.S. dollars (US$2008, equivalent to 48-59 billion US$2019), assuming the achievement of polio eradication by 2012. Given the delays in achieving polio eradication and increased costs, we performed an updated economic analysis of the GPEI using an updated integrated global model, and considering the GPEI trajectory as of the beginning of 2020. Applying similar methods and assuming eradication achievement in 2023, we estimate incremental net benefits of the GPEI of 28 billion US$2019, which falls below the prior estimate. Delays in achieving polio eradication combined with the widescale introduction of relatively expensive inactivated poliovirus vaccine significantly increased the costs of the GPEI and make it less cost-effective, although the GPEI continues to yield expected incremental net benefits at the global level when considered over the time horizon of 1988-2029. The overall health and financial benefits of the GPEI will depend on whether and when the GPEI can achieve its goals, when eradication occurs, the valuation method applied, and the path dependence of the actions taken. Reduced expected incremental net benefits of the GPEI and the substantial economic impacts of the COVID-19 pandemic pose large financial risks for the GPEI.

Modeling and Managing Poliovirus Risks: We are Where we are .

This introduction for the third special issue on modeling poliovirus risks provides context for the current status of global polio eradication efforts and gives an overview of the individual papers included in the issue. Although risk analysis continues to support the Global Polio Eradication Initiative (GPEI), efforts to finish the job remained off track at the beginning of 2020 and prior to the COVID-19 pandemic, as discussed in the special issue. The disruptions associated with COVID-19 occurring now will inevitably change the polio eradication trajectory, and future studies will need to characterize the impacts of these disruptions on the polio endgame.