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- Major Efforts for Disease Eradication OVERVIEW The eradication of smallpox is the only successful global eradication campaign thus far and is testament to the immeasurable public health benefits that can be achieved through eradication. There is optimism that several other viral diseases are candidates for global eradication in the near future given sufficient resources, effort, and international cooperation. These include, in their order of likely eradication, polio, measles, and ru- bella, all of which satisfy the necessary preconditions for eradication. How- ever, there were many factors that uniquely favored smallpox eradication, and each of these other diseases involves major challenges which must be overcome before eradication can be achieved. Major lessons learned from the global smallpox eradication program are that the necessary vaccination technology must be in hand and the practicality of eradication must be demonstrated in the field before eradica- tion can be considered. Lack of preparation invites costly failure and, more importantly, the loss of credibility for public health professionals who are . . . . . earing t ye ~n~t~at~ves. Data from the Americas show that measles transmission can be inter- rupted on entire continents; thus, eradication is technically feasible. Lack of sufficient political will is probably the greatest impediment to global measles eradication. Some of the lowest measles vaccine coverage rates occur in the richest countries. The industrialized world must be encouraged to increase vaccine coverage in order to reduce the likelihood of their becoming reser- 33

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34 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION voirs for the virus and to increase their funding to developing countries where measles takes its greatest toll. Measles results in approximately 900,000 deaths per year, half of which occur in Africa. Likewise, eradication of rubella by correct application of a measies- rubella or measles-mumps-rubella vaccine is feasible. However, a major challenge to congenital rubella syndrome (CRS) eradication are inapparent, or subclinical, infections which make diagnosis and surveillance very diffi- cult. CRS eradication efforts are also encumbered by a general lack of awareness of the disease. Polio has been regionally eradicated from the Americas (the last indig- enous case was in 1991) and is expected to be the next globally eradicated infectious viral disease. Once eradicated, knowing if, how, and when to stop immunization will be a major challenge. Cessation of immunization will require assurance that OPV-derived viruses are no longer circulating and that laboratory poliovirus stocks are adequately contained. SMALLPOX D.A. Henderson, M.D., M.P.H. Director, Center for Civilian Biodefense Studies The Johns Hopkins University, Baltimore, MO The eradication of smallpox removed, hopefully forever, one of the greatest of all the world's plagues. With a 30/O fatality rate, smallpox was in a class by itself as a global health problem. Eradication was an extraor- dinary, cooperative effort involving, under World Health Organization (WHO) leadership, countries throughout the world and perhaps as many as 150,000 field staff at various points during the campaign (Fenner et al., 1988~. It dramatically demonstrated the extraordinary cost-benefit ratios that might be achieved with eradication. The total investment in interna- tional assistance was just under $100 million; national investments were estimated to be perhaps $200 million. Yet, because vaccination and quar- antine measures are no longer necessary, savings of at least $1 billion annually are being realized. Lessons for Eradication of Other Diseases Poliomyelitis is generally considered to be the next candidate for eradi- cation, and a heroic effort is now being made to eradicate it. However, given the task yet to be done and the many current uncertainties, it would be presumptuous to forecast a reasonably certain date for polio eradication, its status now being roughly where we were with smallpox some five years

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MAJOR EFFORTS FOR DISEASE ERADICATION 35 before transmission was finally stopped. Thus, as the first lesson from the smallpox campaign, and before indulging in extended discussions about what might or might not be done post-eradication, it would be productive to ascertain whether, in the cold hard light of accumulating experience and available technology, there are reasonable prospects for the eradication of any other disease within the next ten to twenty years. So far, there have been seven campaigns intended to eradicate an infec- tious disease globally. The first four failed; only one smallpox succeeded; and two are still in progress. Despite the fact that there has been only one success in eradicating a disease, many experts speculate that a wide variety of diseases and conditions should be susceptible to eradication given suffi- cient resources, effort, and cooperation. However, this is precisely the wrong lesson to be learned from the smallpox campaign. There were many factors that uniquely favored smallpox eradication: . No other disease has features that made diagnosis and surveillance for infection so easy. Because every infected] person haci a characteristic rash, the presence or absence of the virus could be determined quickly in every geographic area. Most transmission was through droplets spread by face-to-face contact, making outbreak containment comparatively easy. It was one of the few diseases that both confers permanent immu- nity and has no carrier state or animal reservoir (two important precondi- tions for the eradication of disease see Chapter 11. The smallpox vaccine had many advantageous properties: it was heat-stable and inexpensive; it provided protection with only a single inocu- lation, it could be administered anytime from birth onward; and, using the new bifurcated needle, vaccination was simply accomplished. Given the fact that all countries were cleeply concerned about smallpox and were regularly vaccinating large numbers of their citizens, it was an eradication program that should have commanded the highest possible political commitment. However, expected voluntary contributions to the program were sparse at best, and inadequate funds seriously hampered the program throughout its first nine years of existence. A number of endemic countries had to be cajoled into undertaking any program at all. On several occasions, the program hung in the balance because of political and social problems and, despite the best efforts of technical staff, could well have suffered serious setbacks that delayed eradication, perhaps indefinitely. Not until seven years into the program were the staff confident that eradication could be achieved, and events as late as 12 months prior to the last case threatened a successful conclusion. Vaccine played an especially critical role in the success of the smallpox

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36 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION program. The smallpox vaccine had been known since 1798, but not until the end of the 19th century did large quantities become available as a result of growth of the virus on the flank of cows. Transporting it, however, was a problem. Thus, smallpox continued to spread largely unabated in most of the world, except in industrialized countries where sufficiently rapid trans- port and refrigeration were possible. Finally, in Indonesia in the 1930s, a vaccine that retained potency for periods of six months or more at 37C was perfected by air-drying over sulfuric acid. Although often heavily con- taminated, take rates of 80%+ were usual. By the end of the 1930s, Indone- sia was smallpox-free. A similar product was introduced into a number of French colonies with similarly dramatic results. In 1967, when the global smallpox campaign began, there were a num- ber of Latin American, east Asian, and African countries where smallpox transmission had been stopped. This was due in large part to the use of the air-dried vaccine or a new freeze-ctried product developed in the early 1950s. Thus, vaccine technology had advanced to the point where eradication was a feasible proposition. Had we been dependent on a vaccine no more heat-stable nor immunogenic than, for example, polio vaccine, the pros- pects for eradication would have been significantly diminished. Post-Eradication Strategies During the course of the eradication campaign, there was very little planning for post-eradication strategies and activities. Procedures were de- veloped for certifying large contiguous geographic areas as smallpox-free, but this was the extent of the effort. In major part, this reflected the belief that the margin for error in the program was small and that all available resources had to be directed toward the goal of interrupting smallpox transmission. Otherwise, there would be no post-eradication era. In fact, transmission continued for one year beyond the date anticipated, when smallpox invaded Somalia, spread throughout the country, and threatened the whole of the Middle East. Not until late 1975, when smallpox was confined to Ethiopia, and the interruption of transmission appeared to be only a matter of months away, were significant efforts made to define post- eradication needs. In December 1979, the Global Commission for the Certification of Smallpox Eradication, as part of its final report, made 19 recommendations for post-eradication actions (WHO, 1980~. The recommendations were subsequently approved by the 1980 World Health Assembly (WHA), after which a special committee, the Orthopoxvirus Committee, regularly met every four years up until recently. Some of the post-eradication actions taken in response to the recommendations are described below.

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MAJOR EFFORTS FOR DISEASE ERADICATION :Vaccine and Vaccination (Recommendations 1-6) 37 Most countries discontinued routine vaccination by 1982, and all coun- tries by 1984. By that time, countries had also stopped requiring travelers to show certificates of proof of recent smallpox vaccination. A few coun- tries continued to vaccinate their military, but that practice ceased by about 1990. Seed lot vials of smallpox vaccine were produced at the Rijks Institute (The Netherlands) and clistributed to several vaccine production centers for storage to assure that vaccinia virus would be available at several sites, should it ever be needed. Vaccine was also stored in rented cold storage lockers at two locations in Switzerland and regularly retitered to assure that it retained potency, which it did. But the costs of vaccine storage and periodic retitering were considerable, and WHO budgets were under great stress due in large part to the U.S. failure to pay its assessments to the organization. Thus, in 1990, nearly 13 years after the last known case, the committee recommended, perhaps prematurely, that the OHIO stockpile be reduced from 200 million doses to 500,000 doses, and that the balance of the vaccine be sent back to its respective donor countries. As of 1999, individual countries reported retaining as much as 80 million doses of vaccine, not at! of which has been properly stored or retitered. Suspect Cases of Smallpox (Recommendations 7, 8) As anticipated, rumors of possible smallpox cases continued to be re- ported to WHO. It was considerecl important that all rumors be thoroughly investigated so as to provide assurance to the international community that there were no further naturally occurring cases. The number of rumors decreased from 30 or so annually in the first two years to 10 per year by 1985, with a scattering of cases thereafter. About half were found to be chickenpox or measles, one-third were erroneous news reports, and the rest, a miscellaneous collection of skin diseases. Laboratory Retention of Specimens (Recommendations 9-15) A major concern following eradication was the possible reintroduction of smallpox virus from a laboratory. Limiting the number of laboratories that retained smallpox virus was considered an important step in mitigating the risk of this occurring. In 1975, a survey was undertaken to determine which laboratories might have retained smallpox isolates. All countries and 823 laboratories included in the WHO list of virus laboratories were con- tacted. Special contacts were made with those laboratories that had pub- lished papers over the preceding 25 years indicating that they had grown

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38 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION smallpox virus. A total of 75 laboratories, nearly two-thirds of which were in Europe and the Americas, reported having smallpox virus isolates in 1975. The comparatively small number of labs is explained by the fact that most virus labs did not process smallpox virus specimens: Clinical characteristics were sufficient for diagnosis, and {abora- tory confirmation was seldom required. Growth on chick chorioallantoic membrane (CAM) was necessary for diagnosis and, in many areas, suitable uncontaminated eggs were ex- tremely difficult to obtain. . Laboratory researchers preferred to work with other orthopox- viruses for which there were suitable animal models for infection. The need for many countries to develop their own laboratories was diminished because official WHO Collaborating Laboratories provicled laboratory services. Following a request by the WHA that the laboratories destroy their isolates or transfer them to one of the two TRIO Collaborating Laborato- ries, 57 of the 75 reported that they had done so by July 1977. No effort was made by TRIO to confirm these reports. It was recognized that {abora- tories customarily retain microbial isolates for later reference, and that such specimens were not always well-referenced. A search of all creep freezers in the relevant laboratories throughout the world was far beyond the re- sources of WHO. The objective of mitigation of risk of release of smallpox virus was as much as could be reasonably expected. In 1978, a laboratory-associated outbreak in Birmingham, England, prompted a number of countries to destroy or transfer isolates to TRIO laboratories. By 1980, only six laboratories reported holding the virus but they strenuously resisted parting with specimens. However, by 1983, WHO haci reduced this number to two. Both labs were regularly inspected by WHO consultants. In 1994, the TRIO Orthopoxvirus Committee, in a report to the Direc- tor General, recommended that the 1995 WHA pass a resolution calling for the destruction of all remaining stocks of smallpox virus in June 1995. By that time, representative strains of variola virus had been prepared as a cloned fragment library and sequenced. A five-year study of monkeypox demonstrated it to be a zoonotic virus which only occasionally infected humans and which was unable to sustain human-to-human transmission (lezek and Penner, 19881. No research was known to have been conducted using smallpox virus for at least the past 12 years. In fact, the virus was known to have been grown only at the Centers for Disease Control and Prevention (CDC) to produce material for sequencing and to validate diag-

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MAJOR EFFORTS FOR DISEASE ERADICATION 39 noetic tests. The WHO laboratory in Moscow ceased research in 1982 and, in a later written report, Dr. Sandakhchiev, Director of the Novosibirsk Laboratory to which the Moscow strains had been sent, asserted that they had undertaken no laboratory studies using variola virus until July 1996. At that time, the only stated reason for retaining the virus was a hypotheti- cal one perhaps some day, someone would wish to undertake some type of research that would require the intact variola virus. Weighing the risks associated with retaining it against a hypothetical scientific need, the com- mittee, supported by five major scientific societies that had been explicitly consulted, recommended its destruction. As concerns grew about the use of smallpox as a biological weapon, scientists from a number of nations argued that the virus should be retained for research purposes to develop an anti-viral drug or improved vaccine. It was generally recognized that to do so would be costly and, even if a product were produced, its effectiveness in humans could not be deter- mined. In 1999, WHA delegates voted to defer a final decision on the destruction of the virus until 2002. Additionally, the United States con- tracted for 40 million vaccine doses to be produced for use in an emergency. What Lessons Does the Smallpox Eradication Experience Pronde; . Disease eradication is extremely difficult even when, as in the case of smallpox, the disease is severe, a heat-stable, highly effective single-dose vaccine is available, and the epidemiological characteristics are as close to ideal as one might wish. The direct implications of a failed eradication program can be significant. For most diseases, the cost of eradication is far greater than that of control (see Chapter 1 for definitions of eradication and control). Unless eradication is achieved within a finite time, and control measures can be stopped or significantly decreased, the added costs of eradication will not be recouped. Moreover, experience has shown that failed eradication pro- grams in most areas, although resulting in better control while special measures are in place, gradually revert to a pre-eradication status as special funds and interest fade. For sometime after the declaration of eradication, the only likely sources for the reintroduction of smallpox virus were from victims ex- humed from the tundra or escape from the laboratory. In either case, it was felt that the outbreaks would be small and readily containable. Use of smallpox as a biological weapon was considered to be unlikely, but poten- tially catastrophic if outbreaks were to occur. The fact that the Soviet Union, during the 1980s, had engaged in a massive research and develop- ment program to produce smallpox virus as a biological weapon height- ened this concern. .

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40 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION Persuading most laboratories to destroy or transfer smallpox virus to WHO Collaborating Laboratories posed few problems. A few objected strongly, and cooperation was achieved only with clifficulty. In 1999, the WHA, passed unanimously a resolution which reads as follows: " 1 ) Strongly reaffirms the decision of previous Assemblies that the remaining stocks of variola virus should be destroyed; 2) Decides to authorize temporary reten- tion up to not later than 2002 and subject to annual review by the World Health Assembly of the existing stocks of variola virus..." It was evident during the smallpox program that a failed eradica- tion effort could have serious repercussions for other global initiatives. Financial support for smallpox eradication was problematic throughout its course, largely because of a failed WHO-sponsored global malaria eradica- tion program after the investment of more than $2 billion. Thus, the cred- ibility of expert public health advice was at a low ebb, and most countries did not want any involvement with another eradication fiasco. Sustaining interest and support among countries was extremely difficult, especially after a nil incidence was achieved. Each country was understandably anxious to transfer money and manpower to deal with other critical health problems as soon as possible. They were not enthusias- tic about sustaining two or more years of intensive surveillance to confirm that eradication had been achieved. This needs to be borne in mind for eradication campaigns that would need to be phased-in over a long period. . In brief, eradication is not a program to be undertaken lightly. To do so before the necessary technology is clearly in hand and before the practica- bility of eradication has been demonstrated in the field is an invitation for costly failure and, more importantly, a loss of professional public health and medical credibility. THE NEXT TARGET AFTER POLIO: GLOBAL ERADICATION OF MEASLES Stephen L. Cochi, ~ M.D., M.P.H., Peter M. Strebel, M.D., Mark Papania, William f. Bellini, Walter A. Orenstein, M.D. *Director, Vaccine-Preventable Disease Eradication Division National Immunization Program Centers for Disease Control and Prevention, Atlanta, GA Despite the availability of highly. effective measles vaccines, measles results in approximately 900,000 deaths each year, half of which occur in Africa. The complications of measles (such as bronchopneumonia, diar-

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MAJOR EFFORTS FOR DISEASE ERADICATION 41 rhea, and blindness) are most severe in malnourished young children, espe- cially those with vitamin A deficiency. Based on estimates by ~IO, each year measles accounts for 30% of all deaths clue to vaccine-preventable diseases and 7/0 of deaths due to all causes among children under five years of age. In 1995, an estimated $1.1 billion was spent worldwide on measles treatment. In 1997, the Dahiem Conference on Disease Eradication established three fundamental criteria to be met before a disease is considered eradi- cable: 1) humans must be critical to maintaining circulation of the organism, 2) sensitive and specific diagnostic tools must be available, and 3) an effective intervention must be available. Additionally, many experts have established a fourth criterion: demonstra- tion of interruption of transmission for a prolonged period in a large geo- graphic area. Measles meets all four criteria in several ways. Humans Critical for Transmission Humans are critical to the maintenance of measles virus transmission; humans are the only reservoir for measles virus, and virus survival in the environment is limited to several hours. The major cell receptor for measles virus, CD46, is found only in primate cells (and in transgenic laboratory animals). Measles infections have been documented in non-human primates, and epizootics of measles among monkeys can occur in captive colonies in research facilities. However, serological evidence of infection is uncommon among non-human primates in limited contact with humans. Mathematical models and measles epidemiology studies in island populations have esti- mated that sustained transmission of measles requires a threshold popula- tion of at least several hundred thousand. Non-human primate communi- ties do not have sufficient population size or inter-community mixing to . . . . sustain meas es virus transmission. Sensitive and Specific Diagnostic Tools The clinical diagnosis of measles may be useful when measles is com- mon but is unreliable when measles is rare. Thus, greater reliance on labo- ratory diagnosis based on serologic and salivary assays becomes increas- ingly important as fewer cases are reported. Capture ELISA tests for IgM on serum have been cleveloped at CDC and are considered the reference standard in the Americas. Using nucleoprotein antigen grown in

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42 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION baculoviruses, these tests have been >95/0 specific and at least 90/0 sensi- tive. Approximately 77/0 of confirmed measles cases are positive by 72 hours and 100% between 72 hours and 11 days following rash onset. Ninety percent are still positive at 28 days. Commercial kits with similar sensitivity and specificity are available and easier to perform than the CDC assay. In the United Kingdom, enzyme immunoassays are being used on oral fluid specimens. Thus, accurate diagnostic tests are available to meet this criterion for measles eradication. The serological tests are complemented by virus isolation (using B95A marmoset lymphocyte cells), primarily as a way of tracing chains of trans- mission. They can be used to determine whether isolated cases or new outbreaks represent indigenous transmission from an existing focus or spread from an international importation. Sequencing of the nucleoprotein gene has led to the delineation of at least 15 genotypes, many of which can be traced and appear to circulate in specific geographic areas. Effective Intervention Herd Immunity Threshold Levels of protection incluced by a single dose of vaccine are adequate to interrupt transmission. Mathematical modelers have extended this observa- tion and calculated an age-dependent herd immunity threshold which must be exceeded to interrupt transmission. The younger the average age at infection, the more contagious the disease and the higher the immunity level needed. While herd immunity is a mathematical concept and cannot be relied upon to be an absolute predictor as to whether transmission will or will not occur in a specific instance, it provides a target for measles eradica- tion programs. Based on calculations (Anderson and May, 1992; Hethcote, 1983), the herd immunity threshed in the United States and Europe is at least 93- 95/0. Levels needed in developing countries may be higher, particularly in urban areas, because the average age at infection may be lower. Generally, however, a target of approximately 95/0 population immunity seems rea- sonable. Failure to Prevent Transmission with a Single Dose Based on seroconversion and clinical effectiveness studies, a single dose of measles vaccine administered in the second year of life induces immunity in about 95/0 of vaccinees. In the developing world, persistent transmission of measles virus and high infant morbidity and mortality have led to the recommendation that infants be vaccinated at nine months of age, even

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MAJOR EFFORTS FOR DISEASE ERADICATION 43 though maternal antibody may interfere with seroconversion. Seroconver- sion rates at nine months of age average 85%. This reduction in serocon- version may seem slight, but a seroconversion rate of 85% leaves three times more infants susceptible (i.e., 15% of vaccinees) than does a rate of 95% (i.e., 5% of vaccinees). Thus, this policy sacrifices maximum sero- conversion in an attempt to protect infants at a younger age. A single close is clearly inadequate to reach a 95/O immunity level. However, if a second dose is given in the second year of life, immunity levels can be increased substantially; at 85% coverage for two independent doses, immunity levels reach 95 /O. Indeed, all countries attempting to elimi- nate measles transmission have used some form of two-dose strategy. Demonstration of Prolonged Interruption * In recent years, major successes in measles elimination the interrup- tion of indigenous measles transmission but with continued vaccination activities due to the threat of imported cases from large geographic areas suggest that global eradication is feasible. Because of its potential for eradication and because global eradication efforts would protect against measles importation, the United States has made measles a global health priority. It has been estimated that the United States would save $45 million or more annually if measles were eradicated and vaccination stopped. In 1990, the United States supported the World Summit for Children goal to vaccinate 90/O of the worId's infants with the six EPI (Expanded Program on Immunization) antigens (measles, mumps, rubella, diphtheria, pertussis, tetanus) by 2000. Also in 1990, the United States reaffirmed the World Health Assembly goals of measles morbidity and mortality reduc- tion of 90/O and 95%, respectively, compared with pre-vaccine era levels. In 1994, the United States supported the Pan American Health Organiza- tion (PAHO) initiative to eliminate measles from the Western Hemisphere by 2000. Similar elimination goals have been adopted by the European region (by 2007) and the eastern Mediterranean region (by 2010~. Four complementary strategies are being used to achieve either measles control or elimination: Vaccination (routine and/or supplemental) Vitamin A supplementation Case management Surveillance The difference between control and elimination strategies is the inten- sity with which vaccination and surveillance activities are implemented

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MAJOR EFFORTS FOR DISEASE ERADICATION 53 the ocular lens, growth retardation, bone lesions, and general derangement of organ development in the fetus. The virus also damages the vascular endothelium, which is probably the cause of encephalitis, central nervous system problems, and damage to the cochlea. Some defects may not become manifest until later in life. The greatest risk of CRS occurs in the first trimester. Studies in the United Kingdom and the United States show that infection during the first eight weeks of gestation results in 50-90/0 abnormal fetuses. If infection occurs during the next four to eight weeks, this figure drops to about 33.3/0. After about seventeen weeks, there is little evidence of damage. Clinical effects include central nervous system and vision problems, deaf- ness, congenital cardiac disease particularly PDA (patent ductus arterio- sus) and peripheral pulmonic stenosis and other nonspecific effects. Rubella epidemiology follows three general patterns: In developed countries, pre-vaccination peak age of infection is around school age. Prevalence of seronegative women is S-20%. In island populations, pre-vaccination peak age depends on how recently rubella had been introduced. Prevalence of seronegative women is 20-50%. . In developing countries, the peak age of infection is pre-school age, and the prevalence of seronegative women is sometimes less than 5/0. However, many countries and regions of large countries show much higher prevalence of seronegativity (Cutts et al., 19973. Diagnosis Accurate diagnosis of both acquired rubella and CRS has important implications for surveillance issues and documentation of eradication or control. The most sensitive diagnostic technique is reverse transcriptase PCR, which can be used to detect either acquired rubella or CRS by identi- fying the presence of the virus in nasopharyngeal swabs, blood, or urine. However, PCR is not well adapted to field use. IgM antibody testing is more suited to use in the field. The IgM antibody is generally present for one to two months in acquired rubella and six to twelve months in CRS and can be used to detect either acquired rubella or CRS. Avidity determina- tions on IgG antibody is another useful diagnostic tool but it can only be performed in sophisticated laboratories and it is not well suited to public health uses. Thus, the most sensitive diagnostic techniques are not suited to or available for field use, and diagnoses often rely on clinical criteria. The major clinical criteria of CRS are cataracts, glaucoma, retinopathy, heart disease, and central deafness. Minor criteria include purpura, hepatosplenomegaly, microcephaly, developmental delay, meningoencepha-

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54 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION litis, and radiolucent bone lesions. As with the criteria for rheumatic fever, the presence of two major criteria is a very likely diagnosis of CRS because there are not very many other congenital problems that cause the same set of signs. The presence of one major and one minor criterion also mean a likely CRS diagnosis. Cataracts are the simplest clinical finding to detect in the field. Cata- racts are present in an estimated 25-35% of all CRS cases, and in the developing world an estimated 25% of all cataracts are due to CRS. If cataracts can be clinically detected in infants, then a very rough estimate of the number of CRS cases in an area can be calculated by multiplying the number of infants with confirmed rubella by four. Prevention Efforts Prevention efforts in developed nations rely on the attenuated rubella vaccine, which was developed over 30 years ago. The seroconversion rate is routinely above 95/O, and the resistance to reinfection considerable. In one study (Best et al., 1987), 70% of seronegatives challenged with rubella virus developecl viremia, and 100% developed viral excretion; 0/O of seroposi- tive and vaccinated individuals developed viremia, and 5% of seropositive and vaccinated individuals developed viral excretion. Other studies suggest that naturally seropositive and vaccinated individuals show 95% protec- tion against rubella when clinical criteria are appliecl and nearly 100% protection when confirmed by laboratory diagnosis. Other data show that even though re-infection following either natural disease or vaccination is a true phenomenon, it does not appear to play a significant role in the epide- miology of this disease. The primary safety issue concerning the vaccine a topic relevant to eradication attempts is possible transmission of live virus to the fetus from either intentional or inadvertent vaccination during pregnancy, or more often, vaccination during inadvertent pregnancy. However, transmis- sion to the fetus rarely occurs, and no CRS defects have been observed in infants born to women vaccinated during early pregnancy (CDC, 1989; Enders, 1984; Tookey et al., 1991~. Thus, the safety margin for the rubella vaccine is wide, even though transmission to the fetus during pregnancy . . . . remains a contra lcatlon. The application of vaccination has been fairly complete throughout the Americas and in Scandinavia (Pebody et al., 2000~. The United States re- ported only 567 cases from 1994-1997, 85% of which were in unvacci- nated individuals 15 years of age or older (CDC, 1997~. Interestingly, 54% of these cases were Latino, reflecting the non-use of rubella vaccine in Latin America. Recently, however, the situation has begun to change. There seems to be interruption of indigenous transmission in Mexico due to the intro-

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MAJOR EFFORTS FOR DISEASE ERADICATION 55 Suction of the rubella vaccine there, and an increasing proportion of im- ported cases in the United States come from Europe, Japan, and elsewhere. According to WHO, the percentage of countries in the Americas using the vaccine has been approaching 50%, and by now that percentage has prob- ably reached 100%. Thus far, the best rubella control has been achieved in Scandinavia, where two doses of vaccine have been systematically administered since the early 1980s. In continental Europe, however, the disease has far from dis- appeared because of considerable resistance to the use of rubella and measles vaccines. For example, the United Kingdom's control efforts are in danger because of rumors linking measles vaccination to autism (DeStefano and Chen, 1999~. The situation in the rest of the world is mixed. Immunization rates are increasing in the eastern Mediterranean, Southeast Asia, and western Pa- cific regions. However, the worId's two most populous countries, India and China, do not use rubella vaccine routinely, nor do Africa and large parts of Asia. Currently, there are an estimated 100 CRS cases per 100,000 live births in countries where the rubella vaccine is not used, which amounts to ap- proximately 100,000 CRS cases per year worldwide (see Table 2-31. Al- though rubella mortality is not as high as that of measles, the large number of CRS cases signifies a large population of handicapped individuals. There does not appear to be any geographical variation in the virulence of rubella virus for the fetus. Recent situations in Vellore, India, and Kumasi, Ghana, exemplify the widespread nature of the disease. In Vellore, India, over 200 cases of CRS were detected over a four-year period in a hospital with 10,000 annual births, yielding a rate of about five per 1,000 live births. Because these cases were diagnosed on the basis of clinical criteria and not confirmed with laboratory assays, this figure may be an overestimate. Nevertheless, even if the true figure were only a portion of this, it would still be high. In Kumasi, Ghana, there was an epidemic 30,000 reported casesof rash disease in 1995 (Lawn et al., 2000~. Local investigators used IgM assays to detect 18 cases of CRS, suggesting a minimum incidence of 0.8 per 1,000 live births. Assuming that rubella immunity was 92.5%, the investigators estimated that 3,000 pregnant women were infected with rubella anal 700 babies born with CRS during the epidemic. Eradication of Rubella There are several reasons to be optimistic about the eradication of rubella and/or CRS. First, there is no animal reservoir (one of the precondi- tions for eradication, as discussed in Chapter 1~. Second, human reservoirs

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56 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION TABLE 2-3 Mean Estimated Incidence Rate of CRS per 100,000 Live Births and Number of Cases of CRS by WHO Region, 1996 (Cutts and Vynnycky, 1999) WHO Region Incidence rate of CRS per 100,000 live births Number of CRS cases Africa 104 22,471 Americas Island 1 71 Mainland 1 75 Total 15,994 Eastern Mediterranean 77 12,080 Southeast Asia 136 46,621 Western Pacific 173 12,634 Global Total 109,800 are transitory and probably not very important at the public health level. Even though congenitally infected infants do excrete the virus, they stop excreting it when they acquire cellular, particularly CD4-mediated, immu- nity. Although there are rare cases of encephalitis in which virus persists in the brain, there have been no reported cases of excretion. And, so far, there is no example of an immunosuppressed individual continuing to excrete. Third, the rubella vaccine is effective and available in combination with the measles vaccine. The latter is significant because a measles-rubella (MR) or a measles-mumps-rubella (MMR) vaccine would not increase administra- tion costs in places where these other vaccines are currently available. Thus, CRS eradication by correct application of measIes-rubelIa-con- taining vaccines is feasible. Nonetheless, potential eradication efforts face several challenges: Although the administration cost would be the same, adding the mumps andlor rubella components to the measles vaccine would increase the price of the vaccine to approximately 30 to 50 cents per dose. Vaccine supply needs to meet demand, which would require en- couraging manufacturers to increase production, and also would lead to . . price rec suction. Decreasing the circulation of rubella among children may leave women who grow up without contact with the virus more susceptible to infection, thereby increasing their risk of acquired rubella and paradoxi- cally increasing the number of CRS cases in parts of the world where, ordinarily, women grow up immune.

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MAJOR EFFORTS FOR DISEASE ERADICATION 57 Unlike measles where a rash is an almost uniform manifestation of infection, rubella infections can be completely subclinical or without a rash. Eradication strategies differ between the developed and developing world. In developed countries, the current strategyuniversal MMR at 12 to 18 months and again at 4 to 12 years, plus vaccination of adolescents and adults at any opportunityis successful and should continue. In devel- oping countries, rubella should be addecl to the measles vaccine, and uni- versal immunization with combination MR vaccines at 9 to 12 months of age should be increased. Also in order to avoid paradoxical increases in CRS in developing countries, repeated, mass vaccination campaigns should be directed at children between 1 and 14 years of age in order to interrupt circulation of the virus. Attempts to vaccinate older individuals may be complicated by the lack of health service infrastructure and experience, as well as increased risk of reactogenicity and contraindication for use in adult women. In conclusion, CRS can be readily controlled. It could even be eradi- cated or eliminated in adult women by the correct application of combina- tion MR vaccines. However, because of the challenges that inapparent infections create, neither eradication of the virus nor post-eradication dis- continuation of vaccination is foreseeable in the near future. POST-POLIO ERADICATION: ISSUES AND CHALLENGES Walter R. Dowdie, Ph.D. Public Health Consultant, Task Force for Child Survival and Development, Atlanta, GA In the late 1950s, Albert Sabin, Hilary Kaproski, and others concluded that routine immunization (with either inactivated polio vaccine [IPV] or oral live-attenuated polio vaccine [OPV]), which had proven so successful at interrupting poliovirus transmission in developed countries, would not be effective in high-risk developing countries where social and environmen- tal conditions favor continuous virus transmission. Instead, Sabin proposed mass OPV immunization, which has proven to be the most effective strat- egy for the control of poliomyelitis epidemics in the developing world Cabin, 19851. Global eradication is the natural outcome. Eradication Strategy The global polio eradication initiative, which is driven by both public and private partnerships and spearheaded by WHO, Rotary International,

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58 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION CDC, and the United Nations Children's Fund (UNICEF), relies on age- specific routine childhood immunizations supplemented with mass OPV immunization. National immunization days (NIDs) with OPV are con- ducted two or more times annually for all children under the age of five years. As nationwide polio cases decline, immunization strategies are in- creasingly targeted to virus reservoir and high-risk population areas through sub-national immunization days and house-to-house mop-up operations. Aggressive surveillance is key to a successful immunization strategy. All cases of acute flaccid paralysis (AFP) in the country should be reported and investigated, and stool specimens collected for testing in accredited TRIO laboratories within two weeks of onset, regardless of clinical diagnosis (Hull et al., 1994~. Polioviruses can then be isolated, identified, differenti- ated as to wild or recent vaccine in origin, and sequenced for genome characterization. Current Progress At the time of the 1988 World Health Assembly resolution (ALPHA, 1988), paralytic polio was endemic in 125 countries on five continents, with an estimated 350,000 cases annually. The last indigenous case in the Americas was in 1991, the Western Pacific Region in 1997, and the Euro- pean Region in 1998. Wild poliovirus type 2 has not been found anywhere in the world since mid-l999. In 2000, polio still occurred in 20 countries, with less than 3,000 cases identified worldwide. Slightly more than 250 cases were detected in India, the worId's major exporter of wild polioviruses, despite major advances in surveillance. Still, this was down nearly a factor of 10 from the number of cases reported in 1998. Much work remains to be done to mop up poliovi- rus types 1 and 3 in the Middle East and southeast Asia and Africa, espe- cially in areas of civil conflict and in countries with weak or non-existent health infrastructure. The goal of eradication by 2000 was not met, but the original goal of certifying the world as polio-free by 2005 may still be within reach. Post-Eradication Strategies A major reason for polio eradication is that, as with the eradication of smallpox, immunization would no longer be required. However, stopping OPV immunization is no simple matter. The resulting rapid increase in non- immune persons in much of the post-eradication developing world raises concerns that polio could re-emerge from independently circulating OPV- derived viruses, unrecognized natural poliovirus reservoirs, or unintentional or intentional laboratory transmission (Fine and Carneiro, 19983.

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MAJOR EFFORTS FOR DISEASE ERADICATION . 59 In 1997, a WHO technical consultative group recommended that OPV Immunization should stop and IPV immunization may stop when there is sufficient assurance that wild polioviruses have been eradicated, vaccine- derived polioviruses are no longer circulating, and the remaining stocks of wild polioviruses and infectious materials have been suitably contained in the laboratory (Wood et al., 2000~. Each of these three criteria is addressed below. Assurance of eradication' The world will be certified polio-free when the Global Commission for the Certification of Polio Eradication is satisfied that all six Regional Com- missions and their national committees have provided adequate data to document the absence of wild poliovirus transmission after at least three years of high-quality post-eradication surveillance (WHA, 1988~. Assurance of the absence of circulating OPV-derived wild virus Sabin OPV strains are genetically unstable and regain certain wild virus characteristics upon replication in the human gut. But high levels of immu- nity in adequately immunized populations limit opportunities for indepen- dent OPV virus circulation. However, inadequately immunized populations represent a considerable risk. Polio caused by independently circulating OPV-derived type 2 viruses is reported to have occurred in the past (CDC, 2001~. Recent cases of polio from the island of Hispaniola extend these finclings to OPV type 1 as well (CDC, 2000~. AcIding to the complexity of assuring absence of circulating OPV are the rare immuno-compromised individuals who may shed OPV-derived viruses for a prolonged period of time. Nearly a dozen such persons have been identified worldwide over the last 38 years (Wood et al., 2000~. Some have stopped spontaneously; others have shed vaccine-derived poliovirus for up to 10 years or more. Assurance that laboratory stocks and infectious materials are adequately contained Absolute containment cannot be assured. Questions of intentional or unintentional non-compliance will always remain. However, effective con- tainment is a realistic goal. To achieve effective containment, the reasons must be clear and compelling, the biosafety requirements appropriate, and the goals realistic. In theory, inadvertent transmission of viruses from the laboratory to the community may occur through contaminated clothing, liquid or air effluents, or improper disposal of infectious materials. No evidence exists

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60 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION for poliovirus transmission by these routes, but such possibilities are effec- tively addressed by the appropriate WHO standards for laboratory design and biosafety practices (WHO, 1999~. The major challenge presented by poliovirus is to prevent transmission to the community through an unrecog- nizect infectious laboratory worker. For such transmission to occur, four conditions must be met: (1) poliovirus materials must be present in the laboratory, (2) some operation must be performed with those materials that exposes the worker to the virus, (3) the worker must be susceptible to an infection that results in poliovirus shedding and the exposure of others, and (4) those exposer! in the community must be susceptible to infection. Block- ing transmission by eliminating the first three conditions is currently not possible. But the risks from each of the three conditions can be greatly reduced, collectively providing a high level of community protection and greatly reducing the chances of inadvertent transmission. Reducing the risks of the fourth condition requires alignment of biosafety recommenda- tions with post-eradication immunization policies adopted by the interna- . . Mona. . community. In December 1999, WHO published the WHO Global Action Plan for Laboratory Containment of Wild Polioviruses (WHO, 1999; ~WHO, 2000~. The first step in this wiclely reviewed plan requires that each nation survey all laboratories that may possess wild poliovirus infectious or potentially infectious materials, encourage the disposition of unneeded materials, and prepare a national inventory of all laboratories that retain such materials. By the end of the second year after detection of the last wild poliovirus, all laboratories that retain wild poliovirus infectious material will be re- quired to dispose of such materials or institute biosafety level 3 (high con- tainment). Laboratories with potentially infectious materials will be re- quired to implement biosafety procedures appropriate for the risks. Decisions about if, how, and when to stop immunization wit! directly affect the final containment requirements. If OPV immunization is stopped, the requirement will increase to maximum containment (BSL-43 for wild polio- viruses and high containment for all OPV-derived viruses. Post-Eradication OPV Options Three post-eradication immunization options may be considered: (1) continue OPV, (2) discontinue OPV after synchronized global immuniza- tion days (GIDs), or (3) replace OPV with routine IPV for an indefinite period of time. New OPV strains, even if scientifically possible, are a ques- tionable option because of length of time, costs for development, and prac- tical and ethical considerations that preclude complete field trials in a fully immunized population. Further, genetic stability and rare adverse events would not be known until the vaccine is in widespread use.

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MAJOR EFFORTS FOR DISEASE ERADICATION 61 Option 1, continuing mass OPV immunization, maintains the status quo and reduces concerns of re-emerging wild virus. The major disadvan- tage of this strategy is that vaccine-associated paralytic poliovirus (VAPP) continues in developing countries that have neither the health infrastructure nor the funds to convert to IPV. Paracloxically, continuing OPV to avoid the risk of independently circulating OPV-derived viruses is also an argu- ment for stopping it. Maintaining adequate vaccine coverage levels will not be easy in the absence of wild poliovirus, during a time of changing public perception of OPV risk/benefits, and in an era of decreased international funding. Option 2, stopping OPV after synchronized global immunization days, is based on the observations in Cuba and elsewhere that circulation of OPV strains ceases in a well-immunized population about three months after the last NID (PAHO, 1985~. The advantages of this option are the elimination of VAPP and vaccine costs. The disadvantages are the inequities of continu- ing IPV use in developed countries and absence of any protection in devel- oping countries where the risks of polio re-emergence are greatest. Finally, the unknowns inherent in this option necessitate establishing large OPV stockpiles and rapid response contingency plans, in themselves also un- knowns. Option 3, replacing OPV with IPV, is an attractive option on the sur- face. Virtually all polio risks are eliminated for the vaccine recipient, IPV can replace OPV on a systematic country-by-country basis, and, most im- portantly, it can strengthen routine expanded program of immunization (EPI) coverage through combination IPV/DPT (diphtheria-pertussis-teta- nus) vaccines. However, the effectiveness of IPV in preventing OPV-derived virus circulation in developing tropical countries is unknown. Finally, the global costs of IPV and demand on production capacity are not fully appre- ciated. Conclusion A world without polio brings with it unprecedented public health challenges and the urgent need for clarity of perspective on appropriate post-eradication actions. With continued high quality surveillance, over time, the absence of circulating wild virus can be assured. With the full commitment of all nations, effective laboratory containment is a realistic goal. However, the potential of OPV-derived polioviruses to establish and maintain circulation in inadequately immunized populations has impor- tant post-eradication implications. Decisions about if, how, and when to stop OPV immunization must be based on scientific evidence from contin- ued epidemiological and virological surveillance, poliovirus studies, labo- ratory containment progress, and further research on post-eradication op-

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62 CONSIDERATIONS FOR VIRAL DISEASE ERADICATION tions. Time is of the essence. OPV acceptance may wane in the absence of wild poliovirus circulation. Of particular urgency is research on the role of IPV and possible combinations of options leading to sound post-eradica- . tion strategies. REFERENCES Anderson RM and May RM. 1992. Infectious Diseases of Humans: Dynamics and Control. Oxford: University of Oxford Press. Best JM, Welch JM, Baker DA, and Banatvala JE. 1987. Maternal rubella at St Thomas' Hospital in 1978 and 1986: Support for augmenting the rubella vaccination programme. Lancet 2(8550):88-90. Centers for Disease Control and Prevention. 1989. Rubella vaccination during pregnancy- United States, 1971-1988. Morbidity and Mortality Weekly Report 38(17):289-293. Centers for Disease Control and Prevention.1997. Rubella and congenital rubella syndrome- United States, 1994-1997. Morbidity and Mortality Weekly Report 46(16):350-354. Centers for Disease Control and Prevention. 2000. Outbreak of poliomyelitis Dominican Republic and Haiti, 2000. Morbidity and Mortality Weekly Report 49:1094, 1103. Centers for Disease Control and Prevention. 2001. Circulation of a type 2 vaccine derived poliovirus, Egypt, 1982-1993. Morbidity and Mortality Weekly Report 50(3):41~2, 51. Cutts FT and Vynnycky E. 1999. Modelling the incidence of congenital rubella syndrome in developing countries. International Journal of Epidemiology 28(6):1176-1184. Cutts FT, Robertson SE, Diaz-Ortega JL, and Samuel R. 1997. Control of rubella and con- genital rubella syndrome (CRS) in developing countries, Part 1: Burden of disease from CRS. Bulletin of the World Health Organization 75(1):55-68. DeStefano F and Chen RT. 1999. Negative association between MMR and autism. Lancet 353(9169):1987-1988. Enders G. 1984. Accidental rubella vaccination in pregnancy. Deutsche medizinische Wochetzschrift 109(47) 1806-1809. Fenner F. Henderson DA, Arita I, Jezek Z. and Ladnyi ID. 1988. Smallpax and Its Eradica- tion. Geneva: World Health Organization. Fine P and Carneiro L. 1998. Transmissibility and persistence of oral polio vaccine viruses: Implications for the global poliomyelitis eradication initiative. America7' Journal of Epi- demiology 150(10):1001-1021. Hethcote HW. 1983. Measles and rubella in the United States. American Journal of Epidemi- ology 117(1):2-13. Hull HF, Ward NA, Hull BP, Milstien JB, and de Quadros C. 1994. Paralytic poliomyelitis seasoned strategies, disappearing disease. Lancet 343:1331-1337. Jezek Z and Fenner F. 1988. Human Monkeypax. Basel, Switzerland: S Karger. Lawn JE, Reef S. Baffoe-Bonnie B. Adadevoh S. Caul EO, and Griffin GE. 2000. Unseen blindness, unheard deafness, and unrecorded death and disability: Congenital rubella in Kumasi, Ghana. American Journal of Public Health 90(10):1555-1561. Murray JL and Lopez AD. 1996. The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. Geneva: World Health Organization. Pan American Health Organization (PAHO). 1985. Director announces campaign to eradi- cate poliomyelitis from the Americas by 1990. Bulletin of the Pan American Health Organization 19:213-215.

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MAJOR EFFORTS FOR DISEASE ERADICATION 63 Pebody RG, Edmunds WJ, Conyn-van Spaendonck M, Olin P. Berbers G. Rebiere I, Lecoeur H. Crovari P. Davidkin I, Gabutti G. Gerike E, Giordano C, Hesketh L, Plesner AM, Raux M, Rota MC, Salmaso S. Tischer A, Valle M, and Miller E. 2000. The seroepidemiology of rubella in western Europe. Epidemiology and Infection 125(2):347- 357. Sabin AB. 1985. Oral poliovirus vaccine: History of its development and use and current challenge to eliminate poliomyelitis from the world. Journal of Infectious Diseases 151 :420~36. Tookey PA, Jones G. Miller BH, and Peckham CS. 1991. Rubella vaccination in pregnancy. Communicable Disease Report (London England: Review) 1(8):R86-R88. Wood DJ, Sutter RW, and Dowdle WR. 2000. Stopping poliovirus vaccination after eradica- tion: Issues and challenges. Bulletin of the World Health Organization 78:347-357. World Health Assembly. 1988. Global Eradication of Poliomyelitis by the Year 2000. Geneva: World Health Organization. World Health Organization. 1980. The Global Eradication of Smallpax: Final Report of the Global Commission for the Certification of Smallpox Eradication. Geneva: World Health Organization. World Health Organization. 1999. Global Action Plan for Laboratory Containment of Wild Polioviruses. Geneva: World Health Organization. World Health Organization. 2000. Guidelines for Implementing the Pre-Eradication Phase of the Global Action Plan for Laboratory Containment of Wild Polioviruses. Geneva: World Health Organization.