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Ensuring Preparedness for Potential Poliomyelitis Outbreaks

Ensuring Preparedness for Potential Poliomyelitis Outbreaks Paralytic poliomyelitis was once endemic in the United States; however, because of high vaccination levels, the last case of wild disease occurred in 1979. Although worldwide polio eradication may be achieved in the near future, the presence of undervaccinated children in urban areas and among groups who refuse vaccination creates an outbreak risk, should importation of wild virus occur. In 1999, the Advisory Committee on Immunization Practices (ACIP) recommended that inactivated poliovirus vaccine (IPV) be used for routine immunization of the US population and that oral poliovirus vaccine (OPV) be reserved for “mass vaccination campaigns to control outbreaks of paralytic polio.” Subsequently, the sole US manufacturer of OPV withdrew from the market. In 2003, a joint National Vaccine Advisory Committee (NVAC)/ACIP working group was charged with reporting to its parent bodies concerning the need for a poliovirus vaccine stockpile. Based on that working group’s report, the NVAC and ACIP have concluded that stockpiles of both IPV and OPV should be maintained. In the event of an outbreak in which OPV continues not to be available, IPV should be used for control, and a stockpile of 8 million doses seems to be sufficient. Should IPV be manufactured only in combination with other vaccines, appropriate procurement actions should be taken to ensure that uncombined IPV continues to be stockpiled. Under circumstances of diminished population immunity, OPV may offer outbreak control advantages. The NVAC and ACIP recommend that the United States collaborate with international agencies to provide guaranteed and rapid access to at least 8 million doses of trivalent OPV or 8 million doses of each of the 3 types of monovalent OPV. The regulatory and practical obstacles to implementation of this recommendation will require assertive facilitation at high levels of the federal government and careful planning at the state and local levels.BACKGROUNDPoliovirus Infection and DiseaseLike other enteroviruses, polioviruses replicate in the gut and the pharynx and are transmitted by direct or indirect contact with stool and saliva.High rates of transmission occur within households in all settings. Under good hygienic conditions, community spread may depend on the oropharyngeal route, whereas the fecal route may enhance transmission in communities with poor sanitation.Less than 1% of individuals infected with poliovirus are paralyzed,which makes case-based surveillance for poliovirus infection insensitive. However, the virus can be detected in sewage, making environmental surveillance possible.Once a global disease, wild poliovirus was endemic in only 6 countries by 2003 as a result of the World Health Organization (WHO) Global Eradication Program.Risk of a Wild Poliovirus Outbreak in the United StatesThe last case of wild polio occurred in the United States in 1979and in the Western hemisphere in 1991.Data from the 2002 National Immunization Survey suggest that among 78 state and local grantees, the lowest 2-dose polio vaccination coverage was 93% (unpublished data, Centers for Disease Control and Prevention [CDC], 2002), and 86% to 100% of school-aged children had received at least 3 doses of poliovirus vaccine.The threshold of polio herd immunity is thought to be 60% to 80%.However, polio outbreaks have occurred in western Europe among poorly immunized populations living in an environment of high coverage.In Finland, 10 polio cases occurred despite 80% coverage when a wild virus was imported for which Finnish vaccine provided inadequate immunity.In the Netherlands, hundreds of cases occurred among poorly immunized members of a conservative religious sect despite data that suggest general population immunity greater than 90%.In 1979, outbreaks of poliomyelitis that occurred in Amish communities that refused immunizations in the United States and Canada were determined to have been imported from the previous epidemic in the Netherlands.In addition, the US measles resurgence suggests that pockets of urban underimmunization, combined with in-migration from countries with low immunization rates and active disease transmission, can provide opportunities for sustained epidemics of vaccine-preventable diseases.Thus, the risk of a naturally occurring US polio outbreak is low, but not zero.The risk of a polio bioterrorism attack is difficult to evaluate. Although poliovirus has been synthesized in a laboratory,synthesized or naturally occurring wild poliovirus does not seem to represent an ideal biologic weapon if directed against the United States or other developed nations because (1) viral communicability is low compared with other pathogens,(2) viral spread is impeded by the high levels of hygiene present in the United States and other developed nations,(3) 99% of infected individuals do not develop paralysis,and (4) polio immunization levels are currently high in the United States.Internationally, polio immunization levels may exceed those for other vaccines because of eradication efforts.In the current context, the need for a poliovirus vaccine stockpile would be based on prudent public health preparedness rather than on data that suggest the high likelihood of an impending outbreak or attack.Poliovirus VaccinesOral Poliovirus Vaccine.Oral poliovirus vaccine (OPV) is a live attenuated vaccine that replicates in the gut and pharynx. Infection induces humoral immunity (protecting against paralysis) and gut and pharyngeal immunity (protecting against wild virus replication and transmission). Even before immunity is established, replication of the vaccine virus in the gut/pharynx may interfere with wild virus replication.Transmission of the vaccine virus through stool and saliva provides secondary vaccination and boosting to contacts.Vaccine virus can revert to a neurovirulent formand rarely causes paralysis.Where coverage is low, vaccine-derived neurovirulent strains can circulate in the community.Because of ease of oral administration and low cost on the global market (pennies a dose), OPV is the vaccine of choice throughout the developing world and in many developed nations as well.In the United States, it was the primary vaccine from the early 1960s until 2000, when its use was discontinued because the risk of paralysis of vaccinees seemed to outweigh the risk of wild-type disease.Domestically and internationally, OPV has a long record of effective outbreak control.It can be administered either as a trivalent formulation (tOPV), including all 3 polio serotypes, or as 3 different monovalent formulations (mOPV) (serotypes 1, 2, and 3), each consisting of only 1 polio serotype. Monovalent OPV induces type-specific immunity more quickly than tOPV (generally 1 dose of mOPV provides type-specific protection equivalent to ≥2 doses of tOPV) but only protects against the single serotype present in the formulation, leaving the vaccinee potentially susceptible to the other 2 serotypes.Monovalent OPV is not licensed for use anywhere in the world, but in a posteradication environment, mOPV may become the vaccine of choice for outbreak control because of its high single-dose protection and inability to introduce the other 2 OPV types into circulation.Inactivated Poliovirus Vaccine.Inactivated poliovirus vaccine (IPV) is a killed vaccine that contains all 3 polio serotypes. It induces humoral and pharyngeal immunity equivalent to OPV but less gut immunity; thus, it may permit more wild virus transmission than OPV in certain settings.Inactivated poliovirus vaccine does not provide interference with wild virus replication in the gastrointestinal tract, and it is not transmitted to nonimmune contacts. However, for the same reason, it would not create the risks of reversion to neurovirulence or production of circulating vaccine-derived strains. Two or more doses are required to provide adequate protection.Although IPV was used to eliminate polio in 4 European nations and reduced disease by 96% within 5 years of introduction in the United States, IPV has not been used for outbreak control since the 1950s.Advisory Committee on Immunization Practices Position on OPV Use in OutbreaksOn June 17, 1999, the Advisory Committee on Immunization Practices (ACIP) recommended that as of January 1, 2000, all US children receive routine vaccinations as IPV because the risk of vaccine-associated paralysis with OPV seemed to exceed the risk of paralytic disease with wild virus.Nevertheless, because of the biologic advantages of OPV over IPV in outbreak control suggested in the literature and the extensive outbreak control experience with OPV compared with IPV, the ACIP recommended that OPV be used in “mass vaccination campaigns to control outbreaks of paralytic polio.”Status of the Poliovirus Vaccine StockpileInactivated poliovirus vaccine has been the sole poliovirus vaccine available in the United States since 2000, and a stockpile of 4 million doses of trivalent IPV already exists, with a goal of 8 million doses by 2005.Neither tOPV nor mOPV is available in the United States, and neither is a current stockpile of OPV. Hence, in the event of an outbreak of polio, the United States would not be able to adhere to the ACIP recommendation for the use of OPV in outbreak control.Joint National Vaccine Advisory Committee/ACIP Poliovirus Vaccine Stockpile Working GroupIn February 2003, a working group was formed consisting of members from the National Vaccine Advisory Committee and the ACIP and participants from academic medicine, local public health, the US Food and Drug Administration (FDA), nongovernmental organizations, and the CDC. It was charged with evaluating the polio vaccine stockpile situation and providing recommendations to ensure the adequacy of polio outbreak control preparedness. The working group decided that this question was best evaluated in 4 components: (1) the rationale for the selection of vaccine for the stockpile, (2) the characteristics of the stockpile, (3) manufacturing issues, and (4) implementation issues. These components were addressed by 4 subgroups. Input was solicited from, among others, the WHO and pharmaceutical firms that might manufacture OPV for the stockpile. Reports by the subgroups were edited and approved by the overall working group and form the basis of the overall report in the following sections.RATIONALE FOR A POLIOVIRUS VACCINE STOCKPILEThe United States currently maintains a very high overall level of immunity against poliomyelitis, but immunization rates have been low in the pastand underimmunization remains a concern, particularly among pre–school-aged children residing in disadvantaged communities. Susceptibility rates may be increasing among these populations because OPV viruses are no longer circulating. Should IPV immunization rates decline in the future for any reason, the degree of concern would increase. The inclusion of IPV in childhood combination vaccines may reduce the risk of declining polio immunization rates, but it may also make uncombined IPV unavailable for outbreak control.The immunity level required to prevent transmission of virulent polioviruses within a community is not known. Outbreaks of wild-type polioviruses have occurred with immunization levels of less than 60% in affected populations in the Netherlandsand more recently with vaccine-derived virulent polioviruses in Haiti, the Philippines, Egypt, and Madagascar.The theoretical advantages of OPV for outbreak control have not been subjected to a controlled trial and have been neither proved nor disproved by experience in a country or region that has controlled poliomyelitis. A recent decision analysis model developed during the activities of the working groupand a review by Caceres and Suttersuggest that use of mOPV vaccine would be the most advantageous strategy for outbreak control, especially since optimum control can be achieved with 1 dose. The model predicts that OPV would have a slight advantage over IPV for outbreak control. Because tOPV and IPV require at least 2 doses to achieve adequate protection, the number of doses seems more important than which vaccine is used.Outbreaks are not environments in which randomized vaccine trials are easily conducted, so the previous assessment is unlikely to change. Existing data do not demonstrate the need for a tOPV stockpile to supplement the already-existing IPV stockpile, but existing data also do not demonstrate that a tOPV stockpile would never be needed under any circumstance. Stockpiles are specifically developed for unlikely situations. In a context in which polio vaccination coverage has been low in the past and where the potential exists for the use of poliovirus as a weapon of bioterrorism, an inclusive and consensus approach to a poliovirus vaccine stockpile seems prudent, particularly where the safety of the nation is involved.Available data suggest that use of the current IPV stockpile would probably be sufficient to control outbreaks in the United States under current circumstances of high overall immunity. However, circumstances may change, and it would be prudent for the United States to create a mechanism to access the large stores of tOPV currently available on the international market. Should safe and effective mOPV become available to the United States through either a domestic or a global manufacturer, it should be the preferred formulation.CHARACTERISTICS OF THE POLIOVIRUS VACCINE STOCKPILEInactivated Poliovirus VaccineThe IPV stockpile currently has 4 million doses on hand, with a goal of 8 million doses, or enough to provide the US birth cohort with 2-dose protection, but the primary purpose of this stockpile is to overcome a temporary manufacturing shortage rather than to control an outbreak. Nevertheless, these quantities should be more than sufficient for outbreak control in the current context where OPV is not available. Should OPV become available for outbreak control, the IPV stockpile would be needed for rapid improvement of routine immunization levels outside the outbreak zone and for use within the outbreak zone among persons with conditions for whom OPV is contraindicated (eg, AIDS).Oral Poliovirus VaccineType.Monovalent OPV has advantages over tOPV in polio outbreak control and may eventually be the vaccine of choice in response to a polio outbreak. However, mOPV is not currently licensed anywhere in the world, and tOPV is the vaccine of choice for routine vaccination in most nations and the only vaccine used for outbreak control globally. The United States has extensive previous experience with the administration of tOPV. Therefore, at this time, the trivalent, rather than the monovalent, formulation is the only practical alternative for an OPV stockpile. In a posteradication environment, with global outbreak control relying on mOPV, this recommendation should be reexamined.Quantity of Doses.Given the existing high levels of vaccination, the stockpile need not provide doses for vaccination of the entire US population. For the worst plausible case scenario—an outbreak centered in an inadequately vaccinated urban population—8 million doses should be enough to provide control. We would optimally want sufficient supply for 2 doses for children younger than 5 years regardless of vaccination status; should this occur in a large city (ie, 125 000/y birth cohort), we estimate a maximum need of 1.25 million doses. Eight million doses would cover 6 large city outbreaks or 2 doses for 1 entire US birth cohort. A larger stockpile of doses would be appropriate if vaccination coverage in the US population declines. (Note: The WHO has an outbreak protocol under development. The number of doses may need to be reexamined on the basis of finalization and adaptation of the protocol to the US environment.) Because international health organizations may create OPV stockpiles of hundreds of millions of doses, access to such stockpiles would be more than adequate for any US outbreak. Rapid and unfettered US access to such international stockpiles would need to be guaranteed in the event of a domestic outbreak for this cooperative approach to fulfill the requirements of national security.Standards of Quality.Because OPV is not currently licensed in the United States, production would be outside the United States and not subject to usual FDA standards of quality control for licensed vaccines. However, vaccine in the stockpile should be produced by manufacturers approved by the United Nations Children’s Fund (UNICEF) for the production of OPV and should meet the standards required by the FDA for investigational new drugs (INDs) in the United States.MANUFACTURING ISSUES FOR A POLIOVIRUS VACCINE STOCKPILEInactivated Poliovirus VaccineThe IPV stockpile has encountered few manufacturing issues, because IPV is the only licensed US poliovirus vaccine and acquisition of additional vaccine for the creation of a stockpile is only a question of procurement and cost. These issues may become more complex if IPV is manufactured only as a combination product with other vaccines, in which case special procurement issues will need to be addressed to ensure an adequate supply of IPV for outbreak control.Oral Poliovirus VaccineBecause OPV is manufactured only outside the United States, a variety of complex issues arise. Of 4 pharmaceutical firms currently certified by the WHO for the manufacture of OPV internationally, the working group interviewed representatives of 2 firms.Production Capacity.Each company distributes OPV to more than 60 nations, supplies the world with 800 million doses of vaccine annually, and expects to continue production at this rate in the near future. Both companies expressed that they would be readily able to supply 8 million doses for the US stockpile and have adequate “surge capacity” to handle more production for US needs. They anticipate that this “surge capacity” will increase as the demand for OPV internationally diminishes with progress toward polio eradication. Charges for OPV were not disclosed by the companies, but they indicated that this information could be obtained from the WHO or UNICEF. If special US requirements were imposed, prices would be higher. Cold-chain (appropriate storage temperature), potency testing, and safety protocols are followed, as required by the WHO. One company currently supplies mOPV to 2 countries in bulk form and would be willing to supply it to the United States in this form; the other company was not interested in discussing mOPV.Regulatory Issues.Both companies are certified by WHO to manufacture tOPV, and each vaccine is licensed in the country in which each manufacturer is situated but not in the United States. Neither company would be interested in submitting a Biologics License Application for tOPV to the FDA for evaluation and eventual licensure or in submitting an IND application to the FDA to obtain permission for use of an unlicensed vaccine. However, if the CDC were to submit the IND, they would consider participating in the stockpile, although the formulation would need to be the same as for the WHO/UNICEF requirements. Both companies stated that although their production facilities and practices meet WHO standards, FDA standards are different and in certain areas are more stringent. It would require substantial outlays to upgrade their facilities and practices to meet the FDA periodic inspections, outlays that might well exceed the cost of the stockpiled vaccine, perhaps many-fold. In addition, it is unlikely that either company would be willing to invest money and time into performing clinical and toxicologic studies if the FDA were to require them.Both companies anticipate that labeling issues would be a dominant consideration in production. If the vaccine were labeled for WHO/UNICEF use, the vaccine could not be used in the United States; however, if produced with a US IND label, the product could not be rotated for use in other countries. Hence, creating a “bulge in the supply chain” would be administratively difficult, particularly given the relatively small number of doses needed by the US stockpile compared with international needs. A dedicated US stockpile of IND-labeled vaccine with periodic destruction of outdated lots seemed to be administratively simpler and less costly to the manufacturers than attempting to produce a “multiuse” product. The companies would store the vaccine in their respective home countries. Given a preformed stockpile of US-labeled product, speed of delivery would depend only on speed of transportation, in theory as short as overnight shipment. Neither company would invest in production of OPV for a US stockpile unless these regulatory issues were resolved and a contract was in place. Collaboration of the United States with the WHO and UNICEF may help overcome OPV manufacturing challenges.IMPLEMENTATION ISSUES FOR A POLIOVIRUS VACCINE STOCKPILEInactivated Poliovirus VaccineBecause IPV is the only vaccine in routine use in the United States, and an IPV stockpile already exists, IPV use in polio outbreak control would proceed in the same manner as with any other vaccine-preventable disease.Oral Poliovirus VaccineBecause OPV is not manufactured in the United States, the creation and use of an OPV stockpile raises issues not previously encountered in outbreak control. Presently, OPV could only be administered in the United States under an IND protocol accepted by the FDA. Because no OPV supply chain exists in the United States, the stockpile would necessarily be located outside the United States, requiring special transportation arrangements for speedy use. As an IND, OPV would need to be administered under a research protocol that involves informed consent for the potential adverse effects of OPV, including the risk of paralysis, which caused its removal from the US market. The advance of medical treatments and increasing prevalence of disease states associated with immune deficiency has created a larger population for whom OPV would be contraindicated. The logistics of such protocols and the potential liability for providers might well preclude participation by most health professionals in the private sector, who currently administer 50% to 75% of routine vaccinations in the United States.Each outbreak “study subject” would have to be offered the option of IPV. Public educational efforts would be needed to convince such subjects to expose themselves to the risk, however small, of vaccine paralysis when tOPV offers no advantage over IPV in personal protection against paralysis from wild disease.RECOMMENDATIONSIPV StockpileThe current projection of 8 million doses of IPV for the stockpile seems adequate. In the event of an outbreak in which OPV continues not to be available, IPV should be used for control. Given the lack of collateral spread of vaccine virus, high vaccination levels with 2 or more doses may need to be achieved among the previously unvaccinated. In the future, if IPV is manufactured only in combination with other vaccines, the CDC should take appropriate procurement actions to ensure that uncombined IPV continues to be licensed and available for outbreak response. Even if an OPV stockpile becomes available, an IPV stockpile will continue to be necessary in outbreak response to raise immunization levels outside the outbreak zone and to provide immunizations within the outbreak zone to those for whom OPV is contraindicated or unacceptable.OPV StockpileThe working group believes that prudent preparedness requires that the United States have access to and be able to use a stockpile of OPV effectively in the event of an outbreak. A quantity of 8 million doses of tOPV or 8 million doses of each of the 3 types of mOPV seems adequate.Overcoming Special OPV Stockpile ChallengesIn the absence of a domestic manufacturer of OPV products, building an OPV stockpile will likely require the use of an unlicensed vaccine manufactured outside the United States. The regulatory and public health issues inherent in stockpiling and using an unlicensed vaccine are substantial and make achieving this objective difficult. Assertive facilitation at high levels of the federal government and careful planning at the state and local levels will be required. For optimal public understanding, initial and periodic updated explanations by the US Public Health Service and the US Department of Health and Human Services of the rationale and circumstances under which OPV would be used in an outbreak will be needed.Regulatory Issues.Many of the requirements regarding the use of OPV in an outbreak could be eliminated if procedures existed for emergency US licensure of vaccines available in other nations. Creating procedures for such emergency US licensure should be investigated. In the meantime, the Office of the Secretary of the US Department of Health and Human Services, the CDC, and the FDA should work together to ensure that an appropriate IND protocol is developed and in place for creation of an OPV stockpile and effective use of OPV in case of an outbreak. To be prudent, this protocol should include tOPV and mOPV because, should mOPV become available, it may be preferable to tOPV. Because it is required from all recipients of an unlicensed vaccine, informed consent poses unique challenges, especially in an emergency setting. The consent must inform recipients that the Vaccine Injury Compensation Program will provide compensation for vaccine-related adverse events in all age groups resulting from the use of OPV under an IND and that a licensed alternative (IPV) is available. The working group recognizes that not all potential recipients will accept OPV and that some potential recipients will not accept any poliovirus vaccine.Collaboration With the WHO and Other International Partners.Rather than attempting to create a separate US stockpile of OPV, the CDC and the FDA should work with the WHO and other international partners to help finance, create, and maintain a global poliovirus vaccine stockpile that provides the United States with immediate and guaranteed access. This may involve acceptance by the FDA of certification of OPV by organizations (eg, UNICEF and the WHO) other than itself and will require legislation.Collaboration With State and Local Health Authorities.The CDC should work with state and local health departments to develop plans for polio outbreak response. An OPV response plan should be available and should include aggressive education and clear articulation on the public health and individual benefits and risks of using OPV. Experience with the use of the vaccinia vaccine and planning for potential bioterrorism events may provide useful insight into practical approaches to implement control measures in an outbreak of paralytic poliomyelitis. These should be explored, including novel approaches to rapidly obtain informed consent from potential vaccine recipients. Individuals, and their close contacts, at increased risk of adverse events with the use of OPV (eg, immunodeficient patients) must be quickly identified.SUMMARYBiological considerations, recent decision analysis results, and a long successful history of outbreak control suggest that OPV, particularly in the monovalent formulation, has advantages over IPV in the control of outbreaks of polio. Although an IPV stockpile already exists and can be accessed swiftly and easily for outbreak control in the United States, no stockpile of OPV currently exists. Regulatory issues in the creation of an OPV stockpile for the United States must be considered well in advance of any polio outbreak.Correspondence:Lorraine Alexander, RN, MPH, National Immunization Program, Centers for Disease Control and Prevention, 12 Corporate Blvd, MS E-61, Room 3407, Atlanta, GA 30329 (lalexander@cdc.gov).Accepted for Publication:June 15, 2004.Funding/Support:This study was supported and staffed by the US Department of Health and Human Services, Washington, DC.Acknowledgments:We thank Norman Baylor, MD (FDA), and Bruce Gellin, MD, MPH (National Vaccine Program Office), for their many contributions to the writing of this article; Pamela Jenkins, MD, PhD (Dartmouth Medical School), for her help in guiding the working group’s deliberations by modeling different polio outbreak scenarios; Victor Caceres, MD, MPH, and Margaret Watkins, BSN, MPH (Global Immunization Division, National Immunization Program, CDC), for their assistance to the working group in understanding the international aspects of polio vaccination and vaccine stockpiles; and other members of the National Immunization Program who provided essential assistance in various aspects of the composition of this article, including Jim Alexander, MD, Steve Cochi, MD, MPH, Rex Ellington, Demetria Gardner, John Glasser, PhD, Hamid Jafari, MBBS, Walter Orenstein, MD, Ismael Ortega, PhD, Jane Seward, MBBS, MPH, Roland Sutter, MD, MPHTM, and Eddie Wilder.National Vaccine Advisory Committee and Advisory Committee on Immunization Practices Joint Working GroupNational Vaccine Advisory CommitteeThe National Vaccine Advisory Committee (NVAC) (http://www.hhs.gov/nvpo/nvac) advises and makes recommendations to the director of the National Vaccine Program and the assistant secretary for health at the US Department of Health and Human Services on matters related to the prevention of infectious diseases through immunization and the prevention of adverse reactions to vaccines. The NVAC is composed of 15 members from public and private organizations who represent vaccine manufacturers, physicians, parents, and state and local health agencies. This report was approved by the NVAC at its February 4, 2004, meeting. Members of the NVAC are as follows: Georges Peter, MD (chairperson), Brown Medical School; Ann M. Arvin, MD, Stanford University School of Medicine; Jeffrey P. Davis, MD, Wisconsin Division of Health; Patricia Fast, MD, PhD, International AIDS Vaccine Initiative; Fernando Guerra, MD, MPH, San Antonio Metropolitan Health District; Charles M. Helms, MD, PhD, University of Iowa Hospital and Clinics; Alan R. Hinman, MD, Task Force for Child Survival and Development; Ruth Katz, JD, MPH, George Washington University School of Public Health and Health Services; Jerome O. Klein, MD, Boston University School of Medicine; Mary Beth Koslap-Petraco, MS, CPNP, Suffolk County Department of Health Services; William Schaffner, MD, Vanderbilt University School of Medicine; Patricia N. Whitley-Williams, MD, Robert Wood Johnson Medical School; and Donald E. Williamson, MD, Alabama Department of Public Health.Advisory Committee on Immunization PracticesThe ACIP (http://www.cdc.gov/nip/ACIP) consists of 15 experts in fields associated with immunization who have been selected by the secretary of the US Department of Health and Human Services to provide advice and guidance to the secretary, the assistant secretary for health, and the CDC on the most effective means to prevent vaccine-preventable diseases. This report was approved by the ACIP at its February 24, 2004, meeting. Members of the ACIP are as follows: Myron J. Levin, MD (chairperson), University of Colorado School of Medicine; Jon S. 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Ensuring Preparedness for Potential Poliomyelitis Outbreaks

JAMA Pediatrics , Volume 158 (12) – Dec 1, 2004

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Abstract

Paralytic poliomyelitis was once endemic in the United States; however, because of high vaccination levels, the last case of wild disease occurred in 1979. Although worldwide polio eradication may be achieved in the near future, the presence of undervaccinated children in urban areas and among groups who refuse vaccination creates an outbreak risk, should importation of wild virus occur. In 1999, the Advisory Committee on Immunization Practices (ACIP) recommended that inactivated poliovirus vaccine (IPV) be used for routine immunization of the US population and that oral poliovirus vaccine (OPV) be reserved for “mass vaccination campaigns to control outbreaks of paralytic polio.” Subsequently, the sole US manufacturer of OPV withdrew from the market. In 2003, a joint National Vaccine Advisory Committee (NVAC)/ACIP working group was charged with reporting to its parent bodies concerning the need for a poliovirus vaccine stockpile. Based on that working group’s report, the NVAC and ACIP have concluded that stockpiles of both IPV and OPV should be maintained. In the event of an outbreak in which OPV continues not to be available, IPV should be used for control, and a stockpile of 8 million doses seems to be sufficient. Should IPV be manufactured only in combination with other vaccines, appropriate procurement actions should be taken to ensure that uncombined IPV continues to be stockpiled. Under circumstances of diminished population immunity, OPV may offer outbreak control advantages. The NVAC and ACIP recommend that the United States collaborate with international agencies to provide guaranteed and rapid access to at least 8 million doses of trivalent OPV or 8 million doses of each of the 3 types of monovalent OPV. The regulatory and practical obstacles to implementation of this recommendation will require assertive facilitation at high levels of the federal government and careful planning at the state and local levels.BACKGROUNDPoliovirus Infection and DiseaseLike other enteroviruses, polioviruses replicate in the gut and the pharynx and are transmitted by direct or indirect contact with stool and saliva.High rates of transmission occur within households in all settings. Under good hygienic conditions, community spread may depend on the oropharyngeal route, whereas the fecal route may enhance transmission in communities with poor sanitation.Less than 1% of individuals infected with poliovirus are paralyzed,which makes case-based surveillance for poliovirus infection insensitive. However, the virus can be detected in sewage, making environmental surveillance possible.Once a global disease, wild poliovirus was endemic in only 6 countries by 2003 as a result of the World Health Organization (WHO) Global Eradication Program.Risk of a Wild Poliovirus Outbreak in the United StatesThe last case of wild polio occurred in the United States in 1979and in the Western hemisphere in 1991.Data from the 2002 National Immunization Survey suggest that among 78 state and local grantees, the lowest 2-dose polio vaccination coverage was 93% (unpublished data, Centers for Disease Control and Prevention [CDC], 2002), and 86% to 100% of school-aged children had received at least 3 doses of poliovirus vaccine.The threshold of polio herd immunity is thought to be 60% to 80%.However, polio outbreaks have occurred in western Europe among poorly immunized populations living in an environment of high coverage.In Finland, 10 polio cases occurred despite 80% coverage when a wild virus was imported for which Finnish vaccine provided inadequate immunity.In the Netherlands, hundreds of cases occurred among poorly immunized members of a conservative religious sect despite data that suggest general population immunity greater than 90%.In 1979, outbreaks of poliomyelitis that occurred in Amish communities that refused immunizations in the United States and Canada were determined to have been imported from the previous epidemic in the Netherlands.In addition, the US measles resurgence suggests that pockets of urban underimmunization, combined with in-migration from countries with low immunization rates and active disease transmission, can provide opportunities for sustained epidemics of vaccine-preventable diseases.Thus, the risk of a naturally occurring US polio outbreak is low, but not zero.The risk of a polio bioterrorism attack is difficult to evaluate. Although poliovirus has been synthesized in a laboratory,synthesized or naturally occurring wild poliovirus does not seem to represent an ideal biologic weapon if directed against the United States or other developed nations because (1) viral communicability is low compared with other pathogens,(2) viral spread is impeded by the high levels of hygiene present in the United States and other developed nations,(3) 99% of infected individuals do not develop paralysis,and (4) polio immunization levels are currently high in the United States.Internationally, polio immunization levels may exceed those for other vaccines because of eradication efforts.In the current context, the need for a poliovirus vaccine stockpile would be based on prudent public health preparedness rather than on data that suggest the high likelihood of an impending outbreak or attack.Poliovirus VaccinesOral Poliovirus Vaccine.Oral poliovirus vaccine (OPV) is a live attenuated vaccine that replicates in the gut and pharynx. Infection induces humoral immunity (protecting against paralysis) and gut and pharyngeal immunity (protecting against wild virus replication and transmission). Even before immunity is established, replication of the vaccine virus in the gut/pharynx may interfere with wild virus replication.Transmission of the vaccine virus through stool and saliva provides secondary vaccination and boosting to contacts.Vaccine virus can revert to a neurovirulent formand rarely causes paralysis.Where coverage is low, vaccine-derived neurovirulent strains can circulate in the community.Because of ease of oral administration and low cost on the global market (pennies a dose), OPV is the vaccine of choice throughout the developing world and in many developed nations as well.In the United States, it was the primary vaccine from the early 1960s until 2000, when its use was discontinued because the risk of paralysis of vaccinees seemed to outweigh the risk of wild-type disease.Domestically and internationally, OPV has a long record of effective outbreak control.It can be administered either as a trivalent formulation (tOPV), including all 3 polio serotypes, or as 3 different monovalent formulations (mOPV) (serotypes 1, 2, and 3), each consisting of only 1 polio serotype. Monovalent OPV induces type-specific immunity more quickly than tOPV (generally 1 dose of mOPV provides type-specific protection equivalent to ≥2 doses of tOPV) but only protects against the single serotype present in the formulation, leaving the vaccinee potentially susceptible to the other 2 serotypes.Monovalent OPV is not licensed for use anywhere in the world, but in a posteradication environment, mOPV may become the vaccine of choice for outbreak control because of its high single-dose protection and inability to introduce the other 2 OPV types into circulation.Inactivated Poliovirus Vaccine.Inactivated poliovirus vaccine (IPV) is a killed vaccine that contains all 3 polio serotypes. It induces humoral and pharyngeal immunity equivalent to OPV but less gut immunity; thus, it may permit more wild virus transmission than OPV in certain settings.Inactivated poliovirus vaccine does not provide interference with wild virus replication in the gastrointestinal tract, and it is not transmitted to nonimmune contacts. However, for the same reason, it would not create the risks of reversion to neurovirulence or production of circulating vaccine-derived strains. Two or more doses are required to provide adequate protection.Although IPV was used to eliminate polio in 4 European nations and reduced disease by 96% within 5 years of introduction in the United States, IPV has not been used for outbreak control since the 1950s.Advisory Committee on Immunization Practices Position on OPV Use in OutbreaksOn June 17, 1999, the Advisory Committee on Immunization Practices (ACIP) recommended that as of January 1, 2000, all US children receive routine vaccinations as IPV because the risk of vaccine-associated paralysis with OPV seemed to exceed the risk of paralytic disease with wild virus.Nevertheless, because of the biologic advantages of OPV over IPV in outbreak control suggested in the literature and the extensive outbreak control experience with OPV compared with IPV, the ACIP recommended that OPV be used in “mass vaccination campaigns to control outbreaks of paralytic polio.”Status of the Poliovirus Vaccine StockpileInactivated poliovirus vaccine has been the sole poliovirus vaccine available in the United States since 2000, and a stockpile of 4 million doses of trivalent IPV already exists, with a goal of 8 million doses by 2005.Neither tOPV nor mOPV is available in the United States, and neither is a current stockpile of OPV. Hence, in the event of an outbreak of polio, the United States would not be able to adhere to the ACIP recommendation for the use of OPV in outbreak control.Joint National Vaccine Advisory Committee/ACIP Poliovirus Vaccine Stockpile Working GroupIn February 2003, a working group was formed consisting of members from the National Vaccine Advisory Committee and the ACIP and participants from academic medicine, local public health, the US Food and Drug Administration (FDA), nongovernmental organizations, and the CDC. It was charged with evaluating the polio vaccine stockpile situation and providing recommendations to ensure the adequacy of polio outbreak control preparedness. The working group decided that this question was best evaluated in 4 components: (1) the rationale for the selection of vaccine for the stockpile, (2) the characteristics of the stockpile, (3) manufacturing issues, and (4) implementation issues. These components were addressed by 4 subgroups. Input was solicited from, among others, the WHO and pharmaceutical firms that might manufacture OPV for the stockpile. Reports by the subgroups were edited and approved by the overall working group and form the basis of the overall report in the following sections.RATIONALE FOR A POLIOVIRUS VACCINE STOCKPILEThe United States currently maintains a very high overall level of immunity against poliomyelitis, but immunization rates have been low in the pastand underimmunization remains a concern, particularly among pre–school-aged children residing in disadvantaged communities. Susceptibility rates may be increasing among these populations because OPV viruses are no longer circulating. Should IPV immunization rates decline in the future for any reason, the degree of concern would increase. The inclusion of IPV in childhood combination vaccines may reduce the risk of declining polio immunization rates, but it may also make uncombined IPV unavailable for outbreak control.The immunity level required to prevent transmission of virulent polioviruses within a community is not known. Outbreaks of wild-type polioviruses have occurred with immunization levels of less than 60% in affected populations in the Netherlandsand more recently with vaccine-derived virulent polioviruses in Haiti, the Philippines, Egypt, and Madagascar.The theoretical advantages of OPV for outbreak control have not been subjected to a controlled trial and have been neither proved nor disproved by experience in a country or region that has controlled poliomyelitis. A recent decision analysis model developed during the activities of the working groupand a review by Caceres and Suttersuggest that use of mOPV vaccine would be the most advantageous strategy for outbreak control, especially since optimum control can be achieved with 1 dose. The model predicts that OPV would have a slight advantage over IPV for outbreak control. Because tOPV and IPV require at least 2 doses to achieve adequate protection, the number of doses seems more important than which vaccine is used.Outbreaks are not environments in which randomized vaccine trials are easily conducted, so the previous assessment is unlikely to change. Existing data do not demonstrate the need for a tOPV stockpile to supplement the already-existing IPV stockpile, but existing data also do not demonstrate that a tOPV stockpile would never be needed under any circumstance. Stockpiles are specifically developed for unlikely situations. In a context in which polio vaccination coverage has been low in the past and where the potential exists for the use of poliovirus as a weapon of bioterrorism, an inclusive and consensus approach to a poliovirus vaccine stockpile seems prudent, particularly where the safety of the nation is involved.Available data suggest that use of the current IPV stockpile would probably be sufficient to control outbreaks in the United States under current circumstances of high overall immunity. However, circumstances may change, and it would be prudent for the United States to create a mechanism to access the large stores of tOPV currently available on the international market. Should safe and effective mOPV become available to the United States through either a domestic or a global manufacturer, it should be the preferred formulation.CHARACTERISTICS OF THE POLIOVIRUS VACCINE STOCKPILEInactivated Poliovirus VaccineThe IPV stockpile currently has 4 million doses on hand, with a goal of 8 million doses, or enough to provide the US birth cohort with 2-dose protection, but the primary purpose of this stockpile is to overcome a temporary manufacturing shortage rather than to control an outbreak. Nevertheless, these quantities should be more than sufficient for outbreak control in the current context where OPV is not available. Should OPV become available for outbreak control, the IPV stockpile would be needed for rapid improvement of routine immunization levels outside the outbreak zone and for use within the outbreak zone among persons with conditions for whom OPV is contraindicated (eg, AIDS).Oral Poliovirus VaccineType.Monovalent OPV has advantages over tOPV in polio outbreak control and may eventually be the vaccine of choice in response to a polio outbreak. However, mOPV is not currently licensed anywhere in the world, and tOPV is the vaccine of choice for routine vaccination in most nations and the only vaccine used for outbreak control globally. The United States has extensive previous experience with the administration of tOPV. Therefore, at this time, the trivalent, rather than the monovalent, formulation is the only practical alternative for an OPV stockpile. In a posteradication environment, with global outbreak control relying on mOPV, this recommendation should be reexamined.Quantity of Doses.Given the existing high levels of vaccination, the stockpile need not provide doses for vaccination of the entire US population. For the worst plausible case scenario—an outbreak centered in an inadequately vaccinated urban population—8 million doses should be enough to provide control. We would optimally want sufficient supply for 2 doses for children younger than 5 years regardless of vaccination status; should this occur in a large city (ie, 125 000/y birth cohort), we estimate a maximum need of 1.25 million doses. Eight million doses would cover 6 large city outbreaks or 2 doses for 1 entire US birth cohort. A larger stockpile of doses would be appropriate if vaccination coverage in the US population declines. (Note: The WHO has an outbreak protocol under development. The number of doses may need to be reexamined on the basis of finalization and adaptation of the protocol to the US environment.) Because international health organizations may create OPV stockpiles of hundreds of millions of doses, access to such stockpiles would be more than adequate for any US outbreak. Rapid and unfettered US access to such international stockpiles would need to be guaranteed in the event of a domestic outbreak for this cooperative approach to fulfill the requirements of national security.Standards of Quality.Because OPV is not currently licensed in the United States, production would be outside the United States and not subject to usual FDA standards of quality control for licensed vaccines. However, vaccine in the stockpile should be produced by manufacturers approved by the United Nations Children’s Fund (UNICEF) for the production of OPV and should meet the standards required by the FDA for investigational new drugs (INDs) in the United States.MANUFACTURING ISSUES FOR A POLIOVIRUS VACCINE STOCKPILEInactivated Poliovirus VaccineThe IPV stockpile has encountered few manufacturing issues, because IPV is the only licensed US poliovirus vaccine and acquisition of additional vaccine for the creation of a stockpile is only a question of procurement and cost. These issues may become more complex if IPV is manufactured only as a combination product with other vaccines, in which case special procurement issues will need to be addressed to ensure an adequate supply of IPV for outbreak control.Oral Poliovirus VaccineBecause OPV is manufactured only outside the United States, a variety of complex issues arise. Of 4 pharmaceutical firms currently certified by the WHO for the manufacture of OPV internationally, the working group interviewed representatives of 2 firms.Production Capacity.Each company distributes OPV to more than 60 nations, supplies the world with 800 million doses of vaccine annually, and expects to continue production at this rate in the near future. Both companies expressed that they would be readily able to supply 8 million doses for the US stockpile and have adequate “surge capacity” to handle more production for US needs. They anticipate that this “surge capacity” will increase as the demand for OPV internationally diminishes with progress toward polio eradication. Charges for OPV were not disclosed by the companies, but they indicated that this information could be obtained from the WHO or UNICEF. If special US requirements were imposed, prices would be higher. Cold-chain (appropriate storage temperature), potency testing, and safety protocols are followed, as required by the WHO. One company currently supplies mOPV to 2 countries in bulk form and would be willing to supply it to the United States in this form; the other company was not interested in discussing mOPV.Regulatory Issues.Both companies are certified by WHO to manufacture tOPV, and each vaccine is licensed in the country in which each manufacturer is situated but not in the United States. Neither company would be interested in submitting a Biologics License Application for tOPV to the FDA for evaluation and eventual licensure or in submitting an IND application to the FDA to obtain permission for use of an unlicensed vaccine. However, if the CDC were to submit the IND, they would consider participating in the stockpile, although the formulation would need to be the same as for the WHO/UNICEF requirements. Both companies stated that although their production facilities and practices meet WHO standards, FDA standards are different and in certain areas are more stringent. It would require substantial outlays to upgrade their facilities and practices to meet the FDA periodic inspections, outlays that might well exceed the cost of the stockpiled vaccine, perhaps many-fold. In addition, it is unlikely that either company would be willing to invest money and time into performing clinical and toxicologic studies if the FDA were to require them.Both companies anticipate that labeling issues would be a dominant consideration in production. If the vaccine were labeled for WHO/UNICEF use, the vaccine could not be used in the United States; however, if produced with a US IND label, the product could not be rotated for use in other countries. Hence, creating a “bulge in the supply chain” would be administratively difficult, particularly given the relatively small number of doses needed by the US stockpile compared with international needs. A dedicated US stockpile of IND-labeled vaccine with periodic destruction of outdated lots seemed to be administratively simpler and less costly to the manufacturers than attempting to produce a “multiuse” product. The companies would store the vaccine in their respective home countries. Given a preformed stockpile of US-labeled product, speed of delivery would depend only on speed of transportation, in theory as short as overnight shipment. Neither company would invest in production of OPV for a US stockpile unless these regulatory issues were resolved and a contract was in place. Collaboration of the United States with the WHO and UNICEF may help overcome OPV manufacturing challenges.IMPLEMENTATION ISSUES FOR A POLIOVIRUS VACCINE STOCKPILEInactivated Poliovirus VaccineBecause IPV is the only vaccine in routine use in the United States, and an IPV stockpile already exists, IPV use in polio outbreak control would proceed in the same manner as with any other vaccine-preventable disease.Oral Poliovirus VaccineBecause OPV is not manufactured in the United States, the creation and use of an OPV stockpile raises issues not previously encountered in outbreak control. Presently, OPV could only be administered in the United States under an IND protocol accepted by the FDA. Because no OPV supply chain exists in the United States, the stockpile would necessarily be located outside the United States, requiring special transportation arrangements for speedy use. As an IND, OPV would need to be administered under a research protocol that involves informed consent for the potential adverse effects of OPV, including the risk of paralysis, which caused its removal from the US market. The advance of medical treatments and increasing prevalence of disease states associated with immune deficiency has created a larger population for whom OPV would be contraindicated. The logistics of such protocols and the potential liability for providers might well preclude participation by most health professionals in the private sector, who currently administer 50% to 75% of routine vaccinations in the United States.Each outbreak “study subject” would have to be offered the option of IPV. Public educational efforts would be needed to convince such subjects to expose themselves to the risk, however small, of vaccine paralysis when tOPV offers no advantage over IPV in personal protection against paralysis from wild disease.RECOMMENDATIONSIPV StockpileThe current projection of 8 million doses of IPV for the stockpile seems adequate. In the event of an outbreak in which OPV continues not to be available, IPV should be used for control. Given the lack of collateral spread of vaccine virus, high vaccination levels with 2 or more doses may need to be achieved among the previously unvaccinated. In the future, if IPV is manufactured only in combination with other vaccines, the CDC should take appropriate procurement actions to ensure that uncombined IPV continues to be licensed and available for outbreak response. Even if an OPV stockpile becomes available, an IPV stockpile will continue to be necessary in outbreak response to raise immunization levels outside the outbreak zone and to provide immunizations within the outbreak zone to those for whom OPV is contraindicated or unacceptable.OPV StockpileThe working group believes that prudent preparedness requires that the United States have access to and be able to use a stockpile of OPV effectively in the event of an outbreak. A quantity of 8 million doses of tOPV or 8 million doses of each of the 3 types of mOPV seems adequate.Overcoming Special OPV Stockpile ChallengesIn the absence of a domestic manufacturer of OPV products, building an OPV stockpile will likely require the use of an unlicensed vaccine manufactured outside the United States. The regulatory and public health issues inherent in stockpiling and using an unlicensed vaccine are substantial and make achieving this objective difficult. Assertive facilitation at high levels of the federal government and careful planning at the state and local levels will be required. For optimal public understanding, initial and periodic updated explanations by the US Public Health Service and the US Department of Health and Human Services of the rationale and circumstances under which OPV would be used in an outbreak will be needed.Regulatory Issues.Many of the requirements regarding the use of OPV in an outbreak could be eliminated if procedures existed for emergency US licensure of vaccines available in other nations. Creating procedures for such emergency US licensure should be investigated. In the meantime, the Office of the Secretary of the US Department of Health and Human Services, the CDC, and the FDA should work together to ensure that an appropriate IND protocol is developed and in place for creation of an OPV stockpile and effective use of OPV in case of an outbreak. To be prudent, this protocol should include tOPV and mOPV because, should mOPV become available, it may be preferable to tOPV. Because it is required from all recipients of an unlicensed vaccine, informed consent poses unique challenges, especially in an emergency setting. The consent must inform recipients that the Vaccine Injury Compensation Program will provide compensation for vaccine-related adverse events in all age groups resulting from the use of OPV under an IND and that a licensed alternative (IPV) is available. The working group recognizes that not all potential recipients will accept OPV and that some potential recipients will not accept any poliovirus vaccine.Collaboration With the WHO and Other International Partners.Rather than attempting to create a separate US stockpile of OPV, the CDC and the FDA should work with the WHO and other international partners to help finance, create, and maintain a global poliovirus vaccine stockpile that provides the United States with immediate and guaranteed access. This may involve acceptance by the FDA of certification of OPV by organizations (eg, UNICEF and the WHO) other than itself and will require legislation.Collaboration With State and Local Health Authorities.The CDC should work with state and local health departments to develop plans for polio outbreak response. An OPV response plan should be available and should include aggressive education and clear articulation on the public health and individual benefits and risks of using OPV. Experience with the use of the vaccinia vaccine and planning for potential bioterrorism events may provide useful insight into practical approaches to implement control measures in an outbreak of paralytic poliomyelitis. These should be explored, including novel approaches to rapidly obtain informed consent from potential vaccine recipients. Individuals, and their close contacts, at increased risk of adverse events with the use of OPV (eg, immunodeficient patients) must be quickly identified.SUMMARYBiological considerations, recent decision analysis results, and a long successful history of outbreak control suggest that OPV, particularly in the monovalent formulation, has advantages over IPV in the control of outbreaks of polio. Although an IPV stockpile already exists and can be accessed swiftly and easily for outbreak control in the United States, no stockpile of OPV currently exists. Regulatory issues in the creation of an OPV stockpile for the United States must be considered well in advance of any polio outbreak.Correspondence:Lorraine Alexander, RN, MPH, National Immunization Program, Centers for Disease Control and Prevention, 12 Corporate Blvd, MS E-61, Room 3407, Atlanta, GA 30329 (lalexander@cdc.gov).Accepted for Publication:June 15, 2004.Funding/Support:This study was supported and staffed by the US Department of Health and Human Services, Washington, DC.Acknowledgments:We thank Norman Baylor, MD (FDA), and Bruce Gellin, MD, MPH (National Vaccine Program Office), for their many contributions to the writing of this article; Pamela Jenkins, MD, PhD (Dartmouth Medical School), for her help in guiding the working group’s deliberations by modeling different polio outbreak scenarios; Victor Caceres, MD, MPH, and Margaret Watkins, BSN, MPH (Global Immunization Division, National Immunization Program, CDC), for their assistance to the working group in understanding the international aspects of polio vaccination and vaccine stockpiles; and other members of the National Immunization Program who provided essential assistance in various aspects of the composition of this article, including Jim Alexander, MD, Steve Cochi, MD, MPH, Rex Ellington, Demetria Gardner, John Glasser, PhD, Hamid Jafari, MBBS, Walter Orenstein, MD, Ismael Ortega, PhD, Jane Seward, MBBS, MPH, Roland Sutter, MD, MPHTM, and Eddie Wilder.National Vaccine Advisory Committee and Advisory Committee on Immunization Practices Joint Working GroupNational Vaccine Advisory CommitteeThe National Vaccine Advisory Committee (NVAC) (http://www.hhs.gov/nvpo/nvac) advises and makes recommendations to the director of the National Vaccine Program and the assistant secretary for health at the US Department of Health and Human Services on matters related to the prevention of infectious diseases through immunization and the prevention of adverse reactions to vaccines. The NVAC is composed of 15 members from public and private organizations who represent vaccine manufacturers, physicians, parents, and state and local health agencies. This report was approved by the NVAC at its February 4, 2004, meeting. Members of the NVAC are as follows: Georges Peter, MD (chairperson), Brown Medical School; Ann M. Arvin, MD, Stanford University School of Medicine; Jeffrey P. Davis, MD, Wisconsin Division of Health; Patricia Fast, MD, PhD, International AIDS Vaccine Initiative; Fernando Guerra, MD, MPH, San Antonio Metropolitan Health District; Charles M. Helms, MD, PhD, University of Iowa Hospital and Clinics; Alan R. Hinman, MD, Task Force for Child Survival and Development; Ruth Katz, JD, MPH, George Washington University School of Public Health and Health Services; Jerome O. 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JAMA PediatricsAmerican Medical Association

Published: Dec 1, 2004

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