Elsevier

Antiviral Research

Volume 79, Issue 3, September 2008, Pages 179-187
Antiviral Research

Review
A case for developing antiviral drugs against polio

https://doi.org/10.1016/j.antiviral.2008.04.002Get rights and content

Abstract

Polio eradication is within sight. In bringing the world close to this ultimate goal, the Global Polio Eradication Initiative (GPEI) has relied exclusively on the live, attenuated oral poliovirus vaccine (OPV). However, as eradication nears, continued OPV use becomes less tenable due to the incidence of vaccine associated paralytic poliomyelitis (VAPP) in vaccine recipients and disease caused by circulating vaccine-derived polioviruses (cVDPVs) in contacts. Once wild poliovirus transmission has been interrupted globally, OPV use will stop. This will leave the inactivated poliovirus vaccine (IPV) as the only weapon to defend a polio-free world. Outbreaks caused by cVDPVs are expected post-OPV cessation, and accidental or deliberate releases of virus could also occur. There are serious doubts regarding the ability of IPV alone to control outbreaks. Here, we argue that antiviral drugs against poliovirus be added to the arsenal. Anti-poliovirus drugs could be used to treat the infected and protect the exposed, acting rapidly on their own to contain an outbreak and used as a complement to IPV. While there are no polio antiviral drugs today, the technological feasibility of developing such drugs and their probability of clinical success have been established by over three decades of drug development targeting the related rhinoviruses and non-polio enteroviruses (NPEVs). Because of this history, there are known compounds with anti-poliovirus activity in vitro that represent excellent starting points for polio drug development. Stakeholders must come to understand the potential public health benefits of polio drugs, the feasibility of their development, and the relatively modest costs involved. Given the timelines for eradication and those for drug development, the time for action is now.

Section snippets

Polio eradication

The Global Polio Eradication Initiative (GPEI), a partnership led by the World Health Organization (WHO), Rotary International, the US Centers for Disease Control and Prevention (CDC) and the United Nations International Children's Emergency Fund (UNICEF), is the largest, most expensive international public health project ever undertaken. Most would agree that the GPEI has been quite successful. When the program was launched in 1988, endemic wild poliovirus transmission occurred in more than

Current armament is not enough—new weapons needed

Developing strategies to respond to and control poliovirus outbreaks during the final stages of eradication and in a post-eradication era present significant challenges. First, there is the unpredictability of outbreaks. As VDPVs continue to circulate, there will be a high probability of outbreaks of paralytic disease in the first several years after OPV cessation, but their incidence and magnitude are unknown. Second, threats of accidental or deliberate release of wild type polioviruses and

Antiviral drugs and outbreak control

The idea of antiviral therapy for polio is not new. In the 1950s, shortly after the success of poliovirus propagation in cell culture, several inhibitors of in vitro polio replication were identified, some of which were evaluated in animals (Brown, 1952, Brown et al., 1953, Cochran et al., 1954, Francis et al., 1954, Knox et al., 1957, Barrbera-Oro and Melnick, 1961). In the 1960s, Hans Eggers was a vocal advocate of the concept of antiviral therapy for polio (Field and DeClercq, 2004).

How might a polio drug be used?

Currently, no poliovirus antiviral drug is available. However, if there were one, how might we use it? The above-listed general attributes of antiviral drugs portend multiple applications of a poliovirus drug in outbreak control both pre-eradication and post-eradication. Below, we discuss several possible situations in which an anti-polio drug might be used, including treatment, post-exposure prophylactic and prophylactic applications.

Development of polio antiviral drugs: excellent starting points

The technological feasibility of developing poliovirus drugs and the probability of clinical success have been clearly established by over three decades of drug development targeting the related rhinoviruses and NPEVs. These latter picornaviruses cause significant, widespread human disease for which there are no vaccines. Illnesses caused by rhinoviruses and NPEVs represented potentially lucrative commercial markets, and consequently have the attention of pharmaceutical companies.

True

Drug resistance

Development of resistance is to be anticipated for any antiviral drug that specifically targets a viral protein. Virus populations exist as quasispecies. Drug resistance is observed upon use of the drug on an otherwise drug susceptible virus population, during which minor pre-existing virus variants less susceptible to the drug are allowed to emerge as drug susceptible viruses are eliminated. In the case of positive strand RNA viruses, the error frequency giving rise to these variants in a

Development of polio antiviral drugs: who, how long and how much?

As outlined above, there are several strong starting points for development of anti-poliovirus drugs. Compounds that already show some anti-poliovirus activity could serve as scaffolds for the development of more potent and selective inhibitors when entered into a poliovirus-specific optimization program. While research programs should be initiated, there are also late stage preclinical and early stage clinical drug candidates specific for poliovirus that should be advanced (e.g., V-073 and

Closing comments

Polio eradication is within sight, but, like smallpox, the threat of polio will never go away. Protecting the estimated $7.3 billion, two-decade investment, and maintaining a polio-free world post-eradication, will depend on policies, defense strategies and emergency response capabilities available at the time of global eradication. These safeguards must defend against an accidental or deliberate re-introduction of the virus, and in the event of re-introduction, must be able to rapidly contain,

Conflict of interest statements

MSC is a principal in ViroDefense Inc. ViroDefense Inc, has been awarded a contract from the Task Force for Childhood Development and Survival to evaluate poliovirus antiviral candidate V-073, and is further participating in an NIAID program for provision of certain preclinical services. JN and JFM have no conflicts.

Acknowledgements

The authors wish to thank Walter Dowdle, Ellie Ehrenfeld, Sam Katz, and Dan Pevear, and others for their review of this manuscript, and their comments and suggestions.

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