AT THE REQUEST OF THE Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO), 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 (OPV) 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
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
Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 7
Exploring the Role of Antiviral Drugs in the Eradication of Polio: Workshop Report 1 An Overview of the Polio Eradication Challenge AT THE REQUEST OF THE Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO), 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 (OPV) 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 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
OCR for page 7
Exploring the Role of Antiviral Drugs in the Eradication of Polio: Workshop Report of task, committee members’ biographies, workshop agenda, and participant list are included as Appendixes A-C. The situation facing public health authorities who are responsible for the polio eradication effort is very complex and much effort has gone into developing current plans. The two-day workshop held by this committee was not designed to evaluate those plans and the description that follows should not be construed either as endorsement or criticism. Instead, this section is provided to acquaint the reader with the assumptions that the committee used in coming to its recommendations regarding the development of antiviral drugs against polio. The successful campaign to eradicate smallpox stands as one of history’s greatest public health achievements. It has served as an inspiration for the huge commitment needed to eradicate other infectious diseases. Lessons learned from the smallpox campaign have informed the choice of diseases to target and the strategy behind later eradication campaigns. In 1988, the WHO identified poliomyelitis as a disease that merited global eradication and met the basic biological conditions for potentially successful eradication (Fenner et al. 1988): The microbial agent infects only humans. Humans are the only reservoir for the microbial agent. The infection induces life-long immunity. There is a tool or intervention that effectively interrupts the chain of transmission of the infectious agent from one individual to another. OPV has been highly successful in interrupting the transmission of wild poliovirus through most of the eradication campaign; but as the final stages approach, the final condition is proving problematic. OPV, which contains live, attenuated versions of all three poliovirus types, does induce enduring immunity, but can itself transmit polioviruses to nonimmune people and, rarely, (1-2 per million recipients) causes paralytic disease. As long as OPV is used, new chains of transmission can be initiated among susceptible people. Interruption of these final challenging chains of transmission may require a different approach. 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 6 countries (Aylward et al. 2005). The tremendous success of this program occurred in spite of the fact that polio has proven in
OCR for page 7
Exploring the Role of Antiviral Drugs in the Eradication of Polio: Workshop Report several ways more difficult to eradicate than smallpox. In contrast with the characteristic rash of smallpox, the vast majority of poliovirus infections are subclinical; surveillance is therefore more difficult, as is defining the extent of spread. Smallpox spreads by face-to-face contact, but poliovirus is transmitted by fecal-oral transmission and can survive in local water supplies for weeks. Furthermore, OPV must be kept refrigerated and administered repeatedly in contrast with the single inoculation needed with the highly stable smallpox vaccine. In spite of these challenges, the strategy of populationwide National Immunization Days (NIDs) held a month or two apart and repeated at various intervals has succeeded in reducing the burden of poliomyelitis to the point where eradication appears attainable. Despite the earlier setbacks in 2004-2005, transmission of wild poliovirus had been interrupted in all but a few countries (esp. Nigeria, Somalia, Ethiopia, Yemen, Indonesia, and India) by the end of 2005. The setbacks were the consequence of cessation of vaccination in northern Nigeria; type 1 virus spread to a dozen countries, some of which had been polio-free for as long as 10 years (WHO 2005). Thus, the final steps in eradicating polio pose a challenge that was not faced in the smallpox campaign. OPV, which has been so successful in interrupting the transmission of wild poliovirus, can initiate new chains of transmission. Vaccine-derived polioviruses (VDPVs) can evolve in two ways. In areas where vaccine coverage rates are low and an OPV recipient may come into contact with many susceptible people, infection of a susceptible contact with excreted OPV may initiate a continuing chain of transmission of the virus (which is then called a circulating-vaccine derived poliovirus or cVDPV) among other susceptible people (Kew et al. 2004). Less common, but of major importance, is the prolonged excretion of VDPV by patients who have B-cell immune deficiencies (such as agamma-globulinemia, common variable immunodeficiency, and severe combined immunodeficiency), whose chronically excreted virus is labeled iVDPV (Kew et al. 1998). Although some of these immunodeficient patients develop vaccine-associated paralytic polio (VAPP), others may excrete iVDPV for years while remaining totally asymptomatic (MacLennan et al. 2004; Martin et al. 2004). As the vaccine-derived viruses replicate, either by circulation through susceptible people in the population or in immunocompromised people, they accumulate mutations and can reacquire the ability to infect the central nervous system (CNS) and cause paralytic disease. Reversion to highly neurovirulent phenotypes is particularly pronounced in OPV-derived strains that have recombined with non-polio
OCR for page 7
Exploring the Role of Antiviral Drugs in the Eradication of Polio: Workshop Report TABLE 1 Recent Outbreaks of Paralytic Polio Caused by cVDPVs (Sutter 2005) Country Year Number of Known Cases Indonesia 2005 31 Madagascar 2002, 2005 5, 2 China 2004 2 Cambodia* 2003 3 Philippines 2001 3 Hispaniola 2000 21 Egypt 1988-1993 32 *Arita et al. 2005. enteroviruses, specifically C-cluster coxsackie viruses (Kew et al. 2005, 2004). Transmission and neurovirulence phenotypes of these circulating viruses (cVDPVs) are indistinguishable from wild polioviruses. In the context of a fully immunized population, the presence of VDPVs is not a threat, but if rates of immunization decline, these strains can initiate new chains of transmission of virulent poliovirus. There have been several outbreaks of paralytic polio caused by such VDPV strains in insufficiently immunized populations (Table 1). The ability of OPV-derived viruses to persist in the population poses a substantial challenge to the final stages of eradication. However, continuing the use of OPV indefinitely, which could prevent the spread of cVDPV, is problematic. OPV administration must be maintained at nearly universal levels to prevent outbreaks of VDPV, as the examples in Table 1 demonstrate. It will be difficult to maintain financial and political support for repeated campaigns against a virus that is no longer seen to be causing disease. Also, OPV itself, as mentioned previously, causes paralytic disease in a very small number of the children to whom it is administered, so at some point after the eradication of wild poliovirus the continued administration of OPV may be seen to pose a greater risk than does the wild virus. The final stages of polio eradication therefore pose a dilemma. On the one hand, if OPV use can be discontinued, the source of live polioviruses for vaccine-derived outbreaks is eliminated, as is the risk of VAPP. On the other hand, OPV cessation results in a cohort of children and probably some young adults who will be vulnerable to infection by any remaining wild polioviruses or by cVDPV. In wealthy countries, the response to this
OCR for page 7
Exploring the Role of Antiviral Drugs in the Eradication of Polio: Workshop Report dilemma has been to cease administration of OPV and to administer instead an inactivated poliovirus vaccine (IPV). The immunity provided by IPV does not protect against intestinal poliovirus infection, but it does block spread of the virus from the intestinal tract to the central nervous system and thus prevents paralytic disease (Kew et al. 1998). Therefore, a cVDPV will not cause paralytic disease in a population protected by IPV. Polioviruses may, however, be able to circulate in such a population. This characteristic means that an IPV-based immunization strategy may not be effective in interrupting the spread of polioviruses in poor countries that do not provide immunization on a routine basis in infancy and do not have reliably clean water supplies. Furthermore, IPV, which must be injected, is currently more expensive and difficult to administer than OPV. An additional disadvantage of using IPV is that it is prepared from highly virulent poliovirus strains, whose continued production would grow increasingly risky as immunization levels declined. However, continued research may lead to new IPV candidates with novel effective and inexpensive delivery methods. If it is desirable to find a way to stop having to administer OPV universally and indefinitely, and universal administration of IPV is not a suitable alternative at the present time, how are the final challenges of polio eradication to be overcome? 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 OPV. The desirability of simultaneously ending the use of OPV worldwide is clear; the risk of spread of cVDPVs from areas still using the vaccine to those that have stopped is otherwise too high. Even with simultaneous cessation, it is recognized that cVDPVs will almost certainly emerge (Kew et al. 2005). The risk of initiating a new chain of transmission is expected to decline rapidly as the last round of children to receive OPV stop shedding the virus. At the same time, the proportion of the population susceptible to infection will begin to grow as soon as OPV use ends. There are approximately 350,000 births in the world every day, and over 130 million births annually. By 4 years after the cessation of OPV use, the proportion of the population lacking any immunity to poliovirus will approach 15-20% in many developing countries. Notably, the 0-4 year-old age group makes up from approximately 6% of the population in developed countries to almost 20% in some poor countries (Census Bureau 2005). The current strategy calls for intensive surveillance so that any emergence of cVDPV is detected rapidly. The use of monovalent OPV (mOPV, containing only the poliovirus type implicated in the outbreak) has proved
OCR for page 7
Exploring the Role of Antiviral Drugs in the Eradication of Polio: Workshop Report effective in extinguishing outbreaks in the past and therefore is the expected strategy for containing outbreaks in the post-OPV era (CDC 2005a). However, recent responses to cVDPV outbreaks have occurred in a well-immunized surrounding population, and this would continue to be true in the first years after OPV use has ceased. Models suggest that massive local intervention with mOPV would be capable of ending an outbreak without leaving enough susceptible people to sustain new chains of transmission (Duintjer Tebbens et al. 2005). Workshop discussions were not detailed enough to allow the committee to rigorously evaluate the models on which current eradication plans are based, but the committee believes that there are still too many unknowns to predict with certainty how the post-eradication scenario will unfold. The recent discovery of an iVDPV in five unvaccinated Amish children in Minnesota, 6 years after the discontinuation of OPV use in the United States and in the face of nearly universal vaccination with IPV in the surrounding population, suggests that the last chains of transmission of vaccine strains will be difficult to detect and terminate (CDC 2005b).