Summary

WHEN THE GLOBAL POLIO ERADICATION CAMPAIGN was launched in 1988, poliovirus caused more than 350,000 cases of paralytic disease annually in more than 125 countries. By 2003, only 784 cases of poliomyelitis were reported in a total of six countries (Aylward et al. 2005). This tremendous public health achievement—accomplished through the cooperation of international organizations, individual governments, private organizations and hundreds of thousands of volunteers—has vastly reduced the public health burden once imposed by paralytic polio. The final steps in the eradication of polio, however, pose a challenge.

The tool that has been crucial to the eradication effort can itself become a persistent source of poliovirus in the community. The oral polio vaccine, originally developed by Albert Sabin, contains weakened versions of each of the three strains of poliovirus. It is relatively inexpensive to produce and can be given by mouth. The vaccine viruses grow in the recipient’s intestines, causing a symptomless infection in the immunocompetent host that stimulates highly protective, enduring immunity to disease. The vaccine viruses can also spread to people who are in contact with the recipient, increasing the coverage of an immunization campaign. This last characteristic, however, now represents a serious problem. As the vaccine strains spread from person to person, they can mutate and reacquire the ability to cause paralytic disease. If the percentage of the population that is immunized is not kept very high, the vaccine-derived paralytic polioviruses can circulate among the unimmunized population and may cause new



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Exploring the Role of Antiviral Drugs in the Eradication of Polio: Workshop Report Summary WHEN THE GLOBAL POLIO ERADICATION CAMPAIGN was launched in 1988, poliovirus caused more than 350,000 cases of paralytic disease annually in more than 125 countries. By 2003, only 784 cases of poliomyelitis were reported in a total of six countries (Aylward et al. 2005). This tremendous public health achievement—accomplished through the cooperation of international organizations, individual governments, private organizations and hundreds of thousands of volunteers—has vastly reduced the public health burden once imposed by paralytic polio. The final steps in the eradication of polio, however, pose a challenge. The tool that has been crucial to the eradication effort can itself become a persistent source of poliovirus in the community. The oral polio vaccine, originally developed by Albert Sabin, contains weakened versions of each of the three strains of poliovirus. It is relatively inexpensive to produce and can be given by mouth. The vaccine viruses grow in the recipient’s intestines, causing a symptomless infection in the immunocompetent host that stimulates highly protective, enduring immunity to disease. The vaccine viruses can also spread to people who are in contact with the recipient, increasing the coverage of an immunization campaign. This last characteristic, however, now represents a serious problem. As the vaccine strains spread from person to person, they can mutate and reacquire the ability to cause paralytic disease. If the percentage of the population that is immunized is not kept very high, the vaccine-derived paralytic polioviruses can circulate among the unimmunized population and may cause new

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Exploring the Role of Antiviral Drugs in the Eradication of Polio: Workshop Report outbreaks of paralytic disease. The ability of viruses derived from the oral vaccine to persist in the population poses a substantial challenge to the final stages of eradication. Another problem is that oral polio vaccination of individuals with immune deficiencies can result in persistent infections, if not disease, in which the vaccine recipient can shed highly neurovirulent virus over extended periods of time. Attempts to cure these individuals have so far been unsuccessful. The known number of persistently infected individuals is exceedingly small, but the actual number of such shedders globally cannot be assessed at the present time. As long as oral polio vaccine continues to be administered routinely, the spread of vaccine-derived poliovirus is not a problem. Once wild poliovirus is eradicated, an achievement that is anticipated by the global polio eradication campaign authorities in the next few years, the current plan is to discontinue universal administration of oral polio vaccine. Aside from the difficulty of maintaining financial and political support for vaccinating against a virus that seems to have disappeared and is no longer causing disease, the oral vaccine itself causes paralytic disease in a very small number of recipients—about 1-2 per million. At some point, the continued administration of the oral vaccine may pose a greater risk than does the wild virus. As the time approaches when wild poliovirus is expected to be eradicated, a strategy is needed to deal with the ramifications of discontinuing universal vaccination with the oral polio vaccine. At the request of the Centers for Disease Control and Prevention and the World Health Organization, a committee was established by the National Research Council to organize a workshop to evaluate whether an antiviral drug against poliovirus would be helpful in the final stages of the global polio eradication campaign. The committee was not asked to evaluate the plan to discontinue universal vaccination with oral polio vaccine or other aspects of the post-eradication plans developed by the agencies. Rather, the committee was asked only to address the following issues: The feasibility and appropriateness of using a polio antiviral drug in the post-eradication era The properties a polio antiviral compound would need in order to meet the goals of the eradication program The most promising targets for polio antiviral drug development A comparison of different approaches to polio antiviral drug development, including an assessment of the required scientific expertise, infrastructural needs, risks, obstacles, and relative costs

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Exploring the Role of Antiviral Drugs in the Eradication of Polio: Workshop Report This report is based on discussions at the workshop, which was held in Washington, DC, on November 1-2, 2005. The workshop was attended by 30 people in addition to the seven committee members. The full statement of task, committee members’ biographies, workshop agenda, and participant list are included as Appendixes A-C. In the event that universal vaccination with oral polio vaccine is discontinued, the committee concludes that it would be extremely useful and possibly essential to develop another tool to control outbreaks of poliomyelitis in an increasingly immunologically susceptible world. The availability of an antiviral drug would provide the public health community much-needed flexibility in reacting to post-oral vaccine outbreaks. The models that have been developed to evaluate the likelihood of post-eradication outbreaks suggest that outbreaks are very likely in the first few years after cessation of universal vaccination but that the risk will then rapidly decline. Discussions at the two-day workshop were not in sufficient depth to allow the committee to evaluate the quality of these models. The committee notes, however, that there is considerable uncertainty about some of the parameters used in the models. Interrupting the final chains of transmission may prove more difficult than these models suggest. The committee concludes that it is not currently possible to predict exactly how the eradication of wild polioviruses and the residual problem of vaccine-derived polioviruses will play out. Among possible scenarios, it is possible that vaccine-derived strains will persist and continue to cause outbreaks longer than currently projected. Under such circumstances, continuing to respond to outbreaks with live polio vaccines may become undesirable. Using inactivated polio vaccines may be preferred, but may not be sufficient. The immunity provided by the inactivated vaccine prevents paralytic disease by blocking spread of the virus from the intestinal tract to the central nervous system, but does not protect against intestinal poliovirus infection and, ergo, viral replication. Therefore it is ill-suited to preventing the spread of poliovirus infections, especially in countries where water supplies are unhygienic and vaccination is carried out by periodic campaigns rather than as part of routine medical care. A drug that prevents infection and spread during the time the inactivated vaccine is being administered might be required for use in concert with the inactivated vaccine to contain outbreaks. The committee concludes that it would be appropriate to use an antiviral drug to protect vaccine recipients from poliovirus infection and to limit spread until immunity can be assured. Such a drug would have to be extremely safe, especially for children, as well as stable and easy to use. It

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Exploring the Role of Antiviral Drugs in the Eradication of Polio: Workshop Report would have to be active against all poliovirus types and possibly against non-polio enteroviruses. The success of an antiviral drug strategy will also depend on cost, timely distribution and compliance. Therefore an antiviral program will require not only the development of the antiviral drug itself, but also detailed plans for how it will be deployed and how compliance with the recommended usage will be ensured. There are reasons for optimism: the poliovirus has been well characterized biologically and presents a number of vulnerable targets for antiviral drugs, and promising lead molecules have already been identified for two of these targets. The committee recommends that the development of these compounds be explored further. Indeed, the committee identified several additional promising targets for potential polio antiviral drugs and there are, in fact, others that were brought to the committee’s attention subsequent to the workshop. Since workshop discussions were not sufficiently comprehensive to justify recommending a particular molecule for development, the report describes some of the advantages and disadvantages of each of the targets discussed at the workshop. The committee recommends that a secondary research effort be continued into targets not chosen for immediate development in order to ensure that there are additional compounds entering the development pipeline. Continued basic research into poliovirus will be necessary to support the development effort. The committee recommends the formation of a multidisciplinary steering group to oversee the development of polio antiviral drugs. Proving the safety and efficacy of a novel polio antiviral drug will require a well-conceived and well-conducted development and testing strategy, including studies using animal models and large clinical safety trials. The choice of the best targets, the formulation of a credible development plan and the early solicitation of advice from regulatory authorities should be undertaken by the steering group, since detailed justification of the plan will be extremely important to attract the investment needed. The development of one or more antiviral drugs against poliovirus, although expensive, serves as an insurance policy that provides an additional means of reacting to repeated outbreaks due to continued circulation of vaccine-derived strains, should they occur. Furthermore, the existence of such antiviral drugs, in combination with stockpiled vaccine, would provide the ability to respond to a future accidental or intentional reintroduction of poliovirus. The consequences of a laboratory accident or a bioterrorist attack with poliovirus will grow increasingly severe after universal vaccination has ceased. Experience with the development of drugs against other viruses

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Exploring the Role of Antiviral Drugs in the Eradication of Polio: Workshop Report suggests that it will take at least several years to develop effective polio antiviral drugs and therefore that it would be unwise to wait until the above scenarios play out. If the need for such a drug arises, it will be too late to initiate the drug development program. The committee recognizes that marshalling the resources to develop antiviral drugs against polio will be challenging. Drug development requires a large, long-term investment with an unsure outcome. However, the public health burden of paralytic polio that has been lifted as a result of the eradication effort is enormous and the recommended investment in drug development can be seen as the capstone to past investments in polio eradication. The committee concludes that it is important to ensure that past investment in the eradication effort be protected and therefore that it would be prudent to develop at least one, but preferably two, polio antiviral drugs as a supplement to the tools currently available for the control of poliomyelitis outbreaks in the post-eradication era.

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