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Completing Polio Eradication: The Case for Antiviral Drugs

Tuesday, 14th of March 2017 Print

Completing Polio Eradication: The Case for Antiviral Drugs

J Infect Dis (2017) 215 (3): 333-334.

Excerpt below; full text with notes is at https://academic.oup.com/jid/article/215/3/333/2647465/Completing-Polio-Eradication-The-Case-for

Roland W. Sutter, John F. Modlin, Michel Zaffran; Completing Polio Eradication: The Case for Antiviral Drugs. J Infect Dis 2017; 215 (3): 333-334. doi: 10.1093/infdis/jiw547

After >2 decades of intensive efforts, the goal of eradicating poliovirus is nearing completion. Wild poliovirus type 2 has been certified as eradicated by the Global Commission for the Certification of Poliomyelitis Eradication, and wild poliovirus type 3 has not been detected anywhere in the world since 2012 [1]. However, wild poliovirus type 1 continues to circulate in parts of 3 countries (Afghanistan, Nigeria, and Pakistan).

The Global Polio Eradication Initiative (GPEI) (Rotary International, U.S. Centers for Disease Control and Prevention, Bill and Melinda Gates Foundation, United Nations Childrens Fund, and World Health Organization), is implementing its strategic plan [2], which addresses the following high-priority objectives: (1) poliovirus detection and interruption, (2) routine- immunization-systems strengthening and OPV withdrawal, (3) containment and certification, and (4) legacy planning (now referred to as “transition planning”).

The synchronized withdrawal of the Sabin type 2 strain from OPV has been implemented in April 2016 and validated by extensive internal and external monitoring processes [3]. Poliovirus type 2 is known to be present in vaccine manufacturing facilities and laboratories and may continue to replicate in individuals with primary immunodeficiency disorders (PIDs). Although the prevalence of poliovirus type 2 excretion appears to be low [4], exact data are lacking. Of concern, some individuals excreting the Sabin type 2 strain may excrete virus for many years [5–6].

The progress toward the endgame implementation allows the GPEI to focus on other unfinished business. Two large areas need further attention: (1) containment of poliovirus in laboratories and vaccine manufacturing facilities; and (2) identification and clearance of the remaining sources of poliovirus in communities (eg, excretors of poliovirus). The appropriate containment of poliovirus in laboratories and manufacturing sites is the cornerstone of securing eradication. To prevent reintroduction of poliovirus, the Global Action Plan [7] recommends reduction of the number of facilities to the minimum necessary to conduct critical functions of production, diagnosis, and research. Furthermore, the plan provides detailed guidance on risk mitigation in facilities that continue to work with poliovirus. The implementation of this plan is in progress.

At the same time, the GPEI cannot neglect the risks posed by immunodeficient individuals who excrete polioviruses, including vaccine-derived polioviruses with few or no phenotypic differences from wild-type polioviruses. This risk needs to be managed by (1) increasing the sensitivity of surveillance to capture nonparalyzed, poliovirus- infected patients with PIDs and (2) supporting the development of therapeutic options for clearing the excretion of poliovirus. The latter is a moral imperative because these individuals remain at risk for developing paralytic disease due to and dying of poliomyelitis [8]. In addition, the programmatic imperative requires that the reintroduction risks are mitigated.

The quest for finding effective therapeutic interventions started more than a decade ago. Such drugs have little commercial appeal but are needed for public health purposes. A first major milestone was the report by the National Research Council [9], followed by creation of a specific program led by the Taskforce for Child Health. A small private firm, ViroDefense, coordinated the development from the start, and a number of public health institutions, including the Centers for Disease Control, the Food and Drug Administration, and the National Institutes of Health, provided technical support. Funding from the Bill and Melinda Gates Foundation has also been critical.

Until now, no therapeutic intervention has been shown to shorten the period of poliovirus excretion. Collett et al, in an elegant investigation reported in this issue of The Journal of Infectious Diseases, provide a status report of the antiviral development efforts [10] and demonstrate that the capsid inhibitor pocapavir (1) is safe and well tolerated in different dosage regimens and (2) that it significantly reduces the period from monovalent type 1 OPV (mOPV1) challenge to cessation of virus excretion, but, conversely, (3) induces a high rate of drug resistance. The study further demonstrates the difficulties in quarantining volunteers: although this is necessary for precluding community transmission, it led to substantial transmission of resistant virus among study subjects confined to a dormitory.

Whether these data can be replicated in individuals with PIDs remains an open question, but efforts are under way to identify such individuals and offer them treatment under an investigational new drug protocol if they are shown to excrete poliovirus. Because of the high levels of resistance to pocapavir, the decision to treat now, rather than delaying treatment until combination drug therapy is available, must be based on individual case assessments. Regardless, the combination drug program needs to accelerate with a different class of antiviral agents (eg, a protease inhibitor). In addition, monoclonal antibodies are also in development and could be used separately or in combination with pocapavir.

Individuals who have PIDs and are excreting poliovirus could potentially transmit the virus back into communities. With the withdrawal of the Sabin type 2 strain from OPV, new birth cohorts are increasingly lacking mucosal immunity, increasing the likelihood of reestablishing endemic or epidemic spread following transmission. To mitigate these risks, the GPEI must have the therapeutic capability to clear prolonged or chronic infection among patients with PIDs. The study by Collett et al demonstrates the feasibility of achieving this and will help to ensure that the hard-fought progress by many cannot be undone inadvertently by a few.

Note

Potential conflicts of interest. J. F. M. was chair of the Steering Team for the Polio Antiviral Initiative at the Taskforce for Global Health 2008 and 2013 and continues to participate in meetings of the steering team as an observer. All authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

 

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