Health Economic Analysis of Antiviral Drugs in the Global Polio Eradication Endgame.

BACKGROUND: Polio antiviral drugs (PAVDs) may provide a critical tool in the eradication endgame by stopping poliovirus infections in immunodeficient individuals who may not clear the virus without therapeutic intervention. Although prolonged/chronic poliovirus excreters are rare, they represent a source of poliovirus reintroduction into the general population. Prior studies that assumed the successful cessation of all oral poliovirus vaccine (OPV) use estimated the potential upper bound of the incremental net benefits (INBs) of resource investments in research and development of PAVDs. However, delays in polio eradication, OPV cessation, and the development of PAVDs necessitate an updated economic analysis to reevaluate the costs and benefits of further investments in PAVDs. METHODS: Using a global integrated model of polio transmission, immunity, vaccine dynamics, risks, and economics, we explore the risks of reintroduction of polio transmission due to immunodeficiency-related vaccine-derived poliovirus (iVDPV) excreters and reevaluate the upper bound of the INBs of PAVDs. RESULTS: Under the current conditions, for which the use of OPV will likely continue for the foreseeable future, even with successful eradication of type 1 wild poliovirus by the end of 2023 and continued use of Sabin OPV for outbreak response, we estimate an upper bound INB of 60 million US$2019. With >100 million US$2019 already invested in PAVD development and with the introduction of novel OPVs that are less likely to revert to neurovirulence, our analysis suggests the expected INBs of PAVDs would not offset their costs. CONCLUSIONS: While PAVDs could play an important role in the polio endgame, their expected economic benefits drop with ongoing OPV use and poliovirus transmissions. However, stakeholders may pursue the development of PAVDs as a desired product regardless of their economic benefits.HighlightsWhile polio antiviral drugs could play an important role in the polio endgame, their expected economic benefits continue to drop with delays in polio eradication and the continued use of oral poliovirus vaccines.The incremental net benefits of investments in polio antiviral drug development and screening for immunodeficiency-related circulating polioviruses are small.Limited global resources are better spent on increasing global population immunity to polioviruses to stop and prevent poliovirus transmission.

Case report: Clearance of longstanding, immune-deficiency-associated, vaccine-derived polio virus infection following remdesivir therapy for chronic SARS-CoV-2 infection.

The global polio eradication campaign has had remarkable success in reducing wild-type poliovirus infection, largely built upon the live attenuated Sabin oral poliovirus vaccine. Whilst rare, vaccine poliovirus strains may cause infection and subsequently revert to a neurovirulent type, termed vaccine-derived poliovirus (VDPV). Persistent, vaccine derived infection may occur in an immunocompromised host (iVDPV), where it is a recognised complication following receipt of the Sabin vaccine. This has significant implications for the global polio eradication campaign and there is currently no agreed global strategy to manage such patients.Here we describe a case of a 50-year-old man with common variable immune deficiency, persistently infected with a neurovirulent vaccine-derived type 2 poliovirus following vaccination in childhood. iVDPV infection had proven resistant to multiple prior attempts at treatment with human breast milk, ribavirin and oral administration of a normal human pooled immunoglobulin product. His iVDPV infection subsequently resolved after 12 days treatment with remdesivir, an adenosine analogue prodrug that is an inhibitor of viral RNA-dependent RNA polymerase, administered as treatment for a prolonged, moderate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. iVDPV from the patient, isolated prior to treatment, was subsequently demonstrated to be sensitive to remdesivir in vitro. Based on the observations made in this case, and the mechanistic rationale for use with iVDPV, there is strong justification for further clinical studies of remdesivir treatment as a potentially curative intervention in patients with iVDPV infection.

Translating Implementation Experiences and Lessons Learned From Polio Eradication Into a Global Health Course: Insights From an International Consortium.

Lessons learned from one global health program can inform responses to challenges faced by other programs. One way to disseminate these lessons is through courses. However, such courses are often delivered by and taught to people based in high-income countries and thus may not present a truly global perspective. The Synthesis and Translation of Research and Innovations from Polio Eradication (STRIPE) is a consortium of 8 institutions in Afghanistan, Bangladesh, the Democratic Republic of the Congo, Ethiopia, India, Indonesia, Nigeria, and the United States that seeks to carry out such a transfer of the lessons learned in polio eradication. This short report describes the collaborative process of developing content and curriculum for an international course, the learnings that emerged, the barriers we faced, and recommendations for future similar efforts. Various parts of our course were developed by teams of researchers from countries across South Asia and sub-Saharan Africa. We held a series of regional in-person team meetings hosted in different countries to improve rapport and provide a chance to work together in person. The course content reflects the diversity of team members' knowledge in a variety of contexts. Challenges to this effort included team coordination (e.g., scheduling across time zones); hierarchies across and between countries; and the coronavirus disease (COVID-19) pandemic. We recommend planning for these hierarchies ahead of time and ensuring significant in-person meeting time to make the most of international collaboration.

Clearance of Immunodeficiency-associated Vaccine-derived Poliovirus Infection With Pocapavir.

Pocapavir exhibits antiviral activity against both polio and nonpolio enteroviruses. There is limited experience of the use of this investigational drug in young children with enteroviral infection. We describe the successful clearance of prolonged immunodeficiency-associated vaccine-derived type 3 poliovirus infection by pocapavir in an infant with underlying X-linked agammaglobulinemia.

Updated modelling of the prevalence of immunodeficiency-associated long-term vaccine-derived poliovirus (iVDPV) excreters.

Conditions and evidence continue to evolve related to the prediction of the prevalence of immunodeficiency-associated long-term vaccine-derived poliovirus (iVDPV) excreters, which affect assumptions related to forecasting risks and evaluating potential risk management options. Multiple recent reviews provided information about individual iVDPV excreters, but inconsistencies among the reviews raise some challenges. This analysis revisits the available evidence related to iVDPV excreters and provides updated model estimates that can support future risk management decisions. The results suggest that the prevalence of iVDPV excreters remains highly uncertain and variable, but generally confirms the importance of managing the risks associated with iVDPV excreters throughout the polio endgame in the context of successful cessation of all oral poliovirus vaccine use.

Mechanism of Poliovirus Resistance to Host Phosphatidylinositol-4 Kinase III ß Inhibitor.

Phosphatidylinositol-4 kinase III ß (PI4KB) and oxysterol-binding protein (OSBP) family I have been identified as the major targets of anti-enterovirus drug candidates. Resistance mutations in poliovirus (PV) to these inhibitors have been identified in viral 3A protein, represented by a G5318A (3A-Ala70Thr) mutation, but the mechanism of viral resistance to host PI4KB/OSBP inhibitors remained unknown. In this study, we found that a G5318A mutation enhances the basal levels of phosphatidylinositol 4-phosphate (PI4P) and of the 3A protein and decreases the levels of the 3AB protein during PV replication. The 3A protein acted as a major effector responsible for the resistance to PI4KB inhibitor, but did not enhance the PI4KB activity in vitro in contrast to the 2C, 2BC, 3AB, and 3D proteins. The 3AB protein acted as the primary target of a G5318A mutation and also as an effector. We identified novel resistance mutations to a PI4KB inhibitor [C5151U (3A-T14M) and C5366U (3A-H86Y) mutations] and found that there is a positive correlation between the extent of the resistance phenotype and the levels of the 3A proteins. These results suggested that the 3A protein overproduced by enhanced processing of the 3AB protein with the resistance mutations overcomes the inhibitory effect of PI4KB inhibitor on PV replication independently of the hyperactivation of the PI4KB/OSBP pathway.

Identification and Analysis of Antiviral Compounds Against Poliovirus.

The Global Polio Eradication Initiative, launched in 1988, had as its goal the eradication of polio worldwide by the year 2000 through large-scale vaccinations campaigns with the live attenuated oral PV vaccine (OPV) (Griffiths et al., Biologicals 34:73-74, 2006). Despite substantial progress, polio remains endemic in several countries and new imported cases are reported on a regular basis ( http://www.polioeradication.org/casecount.asp ).It was recognized by the poliovirus research community that developing antivirals against poliovirus would be invaluable in the post-OPV era. Here, we describe three methods essential for the identification of selective inhibitors of poliovirus replication and for determining their mode of action by time-of-drug-addition studies as well as by the isolation of compound-resistant poliovirus variants.

Modeling the prevalence of immunodeficiency-associated long-term vaccine-derived poliovirus excretors and the potential benefits of antiviral drugs.

BACKGROUND: A small number of individuals with B-cell-related primary immunodeficiency diseases (PIDs) may exhibit long-term (prolonged or chronic) excretion of immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) following infection with oral poliovirus vaccine (OPV). These individuals pose a risk of live poliovirus reintroduction into the population after global wild poliovirus eradication and subsequent OPV cessation. Treatment with polio antiviral drugs may potentially stop excretion in some of these individuals and thus may reduce the future population risk. METHODS: We developed a discrete event simulation model to characterize the global prevalence of long-term iVDPV excretors based on the best available evidence. We explored the impact of different assumptions about the effectiveness of polio antiviral drugs and the fraction of long-term excretors identified and treated. RESULTS: Due to the rarity of long-term iVDPV excretion and limited data on the survival of PID patients in developing countries, uncertainty remains about the current and future prevalence of long-term iVDPV excretors. While the model suggests only approximately 30 current excretors globally and a rapid decrease after OPV cessation, most of these excrete asymptomatically and remain undetected. The possibility that one or more PID patients may continue to excrete iVDPVs for several years after OPV cessation represents a risk for reintroduction of live polioviruses after OPV cessation, particularly for middle-income countries. With the effectiveness of a single polio antiviral drug possibly as low as 40% and no system in place to identify and treat asymptomatic excretors, the impact of passive use of a single polio antiviral drug to treat identified excretors appears limited. Higher drug effectiveness and active efforts to identify long-term excretors will dramatically increase the benefits of polio antiviral drugs. CONCLUSIONS: Efforts to develop a second polio antiviral compound to increase polio antiviral effectiveness and/or to maximize the identification and treatment of affected individuals represent important risk management opportunities for the polio endgame. Better data on the survival of PID patients in developing countries and more longitudinal data on their exposure to and recovery from OPV infections would improve our understanding of the risks associated with iVDPV excretors and the benefits of further investments in polio antiviral drugs.

Dominant drug targets suppress the emergence of antiviral resistance.

The emergence of drug resistance can defeat the successful treatment of pathogens that display high mutation rates, as exemplified by RNA viruses. Here we detail a new paradigm in which a single compound directed against a 'dominant drug target' suppresses the emergence of naturally occurring drug-resistant variants in mice and cultured cells. All new drug-resistant viruses arise during intracellular replication and initially express their phenotypes in the presence of drug-susceptible genomes. For the targets of most anti-viral compounds, the presence of these drug-susceptible viral genomes does not prevent the selection of drug resistance. Here we show that, for an inhibitor of the function of oligomeric capsid proteins of poliovirus, the expression of drug-susceptible genomes causes chimeric oligomers to form, thus rendering the drug-susceptible genomes dominant. The use of dominant drug targets should suppress drug resistance whenever multiple genomes arise in the same cell and express products in a common milieu.

[Polio, late effects and post-polio].

Approximately 7,000 Danes are still living with sequelae after surviving an acute polio infection. Late effects of polio include deformities, arthrosis and overloaded muscles. In the long run polio patients are at risk of having a further decrease of muscle function and a wide variety of other symptoms, a condition called post-polio syndrome (PPS). Treatment of PPS is in general symptomatic. Recently it has been shown that treatment with intravenous immunoglobulin may have an effect on pain, tiredness and walking distance. Patients with prior polio have an increase in morbidity and mortality, and may be more sensitive to a variety of medicine.

H1PVAT is a novel and potent early-stage inhibitor of poliovirus replication that targets VP1.

A novel small molecule, H1PVAT, was identified as a potent and selective inhibitor of the in vitro replication of all three poliovirus serotypes, whereas no activity was observed against other enteroviruses. Time-of-drug-addition studies revealed that the compound interfered with an early stage of virus replication. Four independently-selected H1PVAT-resistant virus variants uniformly carried the single amino acid substitution I194F in the VP1 capsid protein. Poliovirus type 1 strain Sabin, reverse-engineered to contain this substitution, proved to be completely insensitive to the antiviral effect of H1PVAT and was cross-resistant to the capsid-binding inhibitors V-073 and pirodavir. The VP1 I194F mutant had a smaller plaque phenotype than wild-type virus, and the amino acid substitution rendered the virus more susceptible to heat inactivation. Both for the wild-type and VP1 I194F mutant virus, the presence of H1PVAT increased the temperature at which the virus was inactivated, providing evidence that the compound interacts with the viral capsid, and that capsid stabilization and antiviral activity are not necessarily correlated. Molecular modeling suggested that H1PVAT binds with high affinity in the pocket underneath the floor of the canyon that is involved in receptor binding. Introduction of the I194F substitution in the model of VP1 induced a slight concerted rearrangement of the core ß-barrel in this pocket, which disfavors binding of the compound. Taken together, the compound scaffold, to which H1PVAT belongs, may represent another promising class of poliovirus capsid-binding inhibitors next to V-073 and pirodavir. Potent antivirals against poliovirus will be essential in the poliovirus eradication end-game.

New small-molecule inhibitors effectively blocking picornavirus replication.

UNLABELLED: Few drugs targeting picornaviruses are available, making the discovery of antivirals a high priority. Here, we identified and characterized three compounds from a library of kinase inhibitors that block replication of poliovirus, coxsackievirus B3, and encephalomyocarditis virus. Using an in vitro translation-replication system, we showed that these drugs inhibit different stages of the poliovirus life cycle. A4(1) inhibited both the formation and functioning of the replication complexes, while E5(1) and E7(2) were most effective during the formation but not the functioning step. Neither of the compounds significantly inhibited VPg uridylylation. Poliovirus resistant to E7(2) had a G5318A mutation in the 3A protein. This mutation was previously found to confer resistance to enviroxime-like compounds, which target a phosphatidylinositol 4-kinase IIIß (PI4KIIIß)-dependent step in viral replication. Analysis of host protein recruitment showed that E7(2) reduced the amount of GBF1 on the replication complexes; however, the level of PI4KIIIß remained intact. E7(2) as well as another enviroxime-like compound, GW5074, interfered with viral polyprotein processing affecting both 3C- and 2A-dependent cleavages, and the resistant G5318A mutation partially rescued this defect. Moreover, E7(2) induced abnormal recruitment to membranes of the viral proteins; thus, enviroxime-like compounds likely severely compromise the interaction of the viral polyprotein with membranes. A4(1) demonstrated partial protection from paralysis in a murine model of poliomyelitis. Multiple attempts to isolate resistant mutants in the presence of A4(1) or E5(1) were unsuccessful, showing that effective broad-spectrum antivirals could be developed on the basis of these compounds. IMPORTANCE: Diverse picornaviruses can trigger multiple human maladies, yet currently, only hepatitis A virus and poliovirus can be controlled with vaccination. The development of antipicornavirus therapeutics is also facing significant difficulties because these viruses readily generate resistance to compounds targeting either viral or cellular factors. Here, we describe three novel compounds that effectively block replication of distantly related picornaviruses with minimal toxicity to cells. The compounds prevent viral RNA replication after the synthesis of the uridylylated VPg primer. Importantly, two of the inhibitors are strongly refractory to the emergence of resistant mutants, making them promising candidates for further broad-spectrum therapeutic development. Evaluation of one of the compounds in an in vivo model of poliomyelitis demonstrated partial protection from the onset of paralysis.

Bcgitis and vaccine-derived poliovirus infection in a patient with a novel deletion in RAG1 binding site.

A girl who developed severe BCGitis and vaccine-derived poliovirus infection was discovered to have a novel deletion of RAG1. A neonatal screening program for SCID would identify affected infants at birth, before live vaccines are administered.

Anti-poliovirus activity of protease inhibitor AG-7404, and assessment of in vitro activity in combination with antiviral capsid inhibitor compounds.

The National Research Council has recommended that at least one, preferably two, polio antiviral drugs be developed as a supplement to the tools currently available for control of polio outbreaks post-eradication. The primary application of such drugs is expected to be the resolution of chronic poliovirus excretion in persons with primary immunodeficiency disorders. We have assessed the in vitro activity of AG-7404 (also known as "compound 1"), an inhibitor of picornaviral 3C protease, against a large panel of programmatically important poliovirus strains and its activity in combination with two poliovirus capsid inhibitors, V-073 and BTA798. AG-7404 was active against all viruses in this panel, with EC50 values ranging from 0.080 to 0.674 µM. Similarly, BTA798 was active against all viruses in this panel, with EC50 values ranging from 0.003 to 0.591µM. By comparison, values for V-073 were 0.003-0.126 µM. BTA798 was active against V-073-resistant variants with an alanine to valine change in VP3 at position 24. However, BTA798 was inactive against the V-073-resistant strains with amino acid substitutions at VP1 amino acids 194 (equivalent to 192 in type 3) and 236. As expected from its different mechanism of action, AG-7404 was fully active against all V-073-resistant variants, with EC50 values ranging from 0.218 to 0.819 µM, compared to values of 0.202-0.407 µM for the V-073-susceptible parental strains. In vitro drug combination experiments demonstrated synergy between AG-7404 and either V-073 or BTA798, whereas the combination of the two capsid inhibitors acted additively.

Immune-mediated mechanisms in the pathogenesis of Hopkins syndrome.

Hopkins syndrome occurs after an acute asthma attack. An immune-mediated mechanism has been suggested. Immunoglobulin or methylprednisone pulse therapies comprise the most useful treatment. We describe a 3-year-old girl who developed severe weakness in her left arm, 7 days after an acute asthma attack. A complete blood count with autoimmune biomarkers, immunoglobulin profile, and virology study and magnetic resonance of the brain, spine, and brachial plexus produced normal results. In the cerebrospinal fluid, T lymphocytes comprised the predominant leukocyte population, and oligoclonal bands were positive. An electromyogram revealed a partial axonal lesion (normal motor nerve conduction velocity with low amplitude) of the axillary, musculocutaneus, and interosseous nerves of the left arm, with normal sensory nerve conduction and partial denervation. We began therapy with intravenous immunoglobulin for 5 consecutive days, repeated every 4 weeks for 2 months. Afterward, our patient recovered. This report contributes to understanding the role of immune-mediated mechanisms in the pathogenesis of this disease, and the importance of immunotherapy in its treatment.

Immunological and pathogenic properties of poliovirus variants selected for resistance to antiviral drug V-073.

BACKGROUND: The National Research Council has recommended development of polio antiviral drugs to assist in management of outbreaks and to mitigate adverse consequences of vaccination. V-073 is a small molecule poliovirus capsid inhibitor that is being developed for these purposes. Antiviral use raises the potential of treatment-emergent resistance. Understanding virological consequences of resistance is important. METHODS: Six independent laboratory-derived V-073-resistant poliovirus variants were characterized for their ability to be neutralized by conventional vaccine-induced immune sera, to elicit serum neutralizing antibodies upon CD-1 mouse immunization, and to replicate in and to cause paralysis of TgPVR21 mice. RESULTS: V-073-resistant variants were effectively neutralized by oral poliovirus vaccine and inactivated poliovirus vaccine human immune sera. All variants elicited virus neutralizing antibody titres in CD-1 mice that were comparable to drug-susceptible parental and Sabin vaccine strain viruses. Infection efficiency of TgPVR21 mice by variants was comparable to (1 of 6 variants) or considerably lower than (5 of 6 variants) parental viruses. Drug-resistant variants replicated to levels comparable to (1 of 6 variants) or substantially less than (5 of 6 variants) their drug-susceptible parental viruses and were on average 1.4 log(10) (range 0.3 to >2.8 log10) less neurovirulent. CONCLUSIONS: Laboratory-derived V-073-resistant variants exhibit clear attenuation of pathogenic properties while maintaining immunological features of drug-susceptible viruses.