Evolution of Measles Elimination Strategies in the United States

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1 SUPPLEMENT ARTICLE Evolution of Measles Elimination Strategies in the United States Alan R. Hinman, 1 Walter A. Orenstein, 2 and Mark J. Papania 2 1 Task Force for Child Survival and Development, Decatur, and 2 National Immunization Program, Centers for Disease Control and Prevention, Atlanta, Georgia There have been 3 efforts to eliminate measles from the United States since the introduction of measles vaccine in To date, 10 major lessons have been learned from elimination efforts. First, elimination requires very high vaccination-coverage levels by age 2 years. Second, school immunization requirements ensure high coverage rates among schoolchildren. Third, a second dose of measles vaccine is needed to achieve satisfactory levels of immunity. Fourth, school immunization requirements can also ensure delivery of a second dose. Fifth, coverage assessment is crucial. Sixth, measles surveillance is critical for developing, evaluating, and refining elimination strategies. Seventh, surveillance requires laboratory backup to confirm a diagnosis. Eighth, tracking measles virus genotypes is critical to determining if an endemic strain is circulating. Ninth, once endemic transmission has been interrupted, internationally imported measles cases will continue and will cause small outbreaks. Tenth, collaborative efforts with other countries are essential to reduce imported measles cases. BACKGROUND After measles was introduced in the New World during European colonization, it spread in epidemic fashion in the Americas, with severe impact on native populations that had previously not been exposed. In what is now the United States, outbreaks were reported as early as Routine reporting of measles cases began in 1912 (figure 1). In the first decade of reporting, an average of 297,216 cases were reported each year, representing a mean reported measles incidence of 289/ 100,000. In the same period, an average of 5948 measles-related deaths were reported annually. The average annual number of reported measles cases increased to 530,217 (incidence, 310 cases/100,000) in the decade preceding licensure of measles vaccine ( ). Population-based surveys suggested that reported cases underestimated actual cases in the prevaccine period by 85% 90% [1]. By , the mean annual number of fatal measles virus infections had decreased to 440, despite more reported cases [2]. Reprints or correspondence: Dr. Alan R. Hinman, The Task Force for Child Survival and Development, 750 Commerce Dr., Suite 400, Decatur, GA (ahinman@ taskforce.org). The Journal of Infectious Diseases 2004; 189(Suppl 1):S17 22 This article is in the public domain, and no copyright is claimed /2004/18909S Measles case fatality decreased from 21 deaths/1000 reported cases in to!1 death/1000 in This improvement in survival of people infected with measles virus presumably resulted from improved nutrition and medical care, especially the availability of newly discovered antibiotics to treat many of the bacterial complications of measles. It is difficult to estimate whether measles-related deaths were as severely underreported as were measles cases. US MEASLES ELIMINATION EFFORTS First elimination goal: The introduction of measles vaccine in 1963 and its subsequent widespread use resulted in a dramatic decline in the number of reported cases, from the prevaccine annual average ( ) of 530,000 cases to 204,136 cases in 1966 (figure 1), a decline of 160%. The dramatic decline in measles incidence led to a call for eradication of measles from the United States in 1967 [3]. The characteristics of measles that supported the feasibility of eradication included its short period of infectiousness, predictable incubation period, high infectivity, characteristic clinical illness, lifelong immunity following infection, and absence of nonhuman reser- Evolution of US Measles Strategies JID 2004:189 (Suppl 1) S17

2 Figure 1. Reported measles cases and deaths, United States, voir. Sencer et al. [3] cited the 1930s report by Hedrich [4], which indicated that when a sufficient proportion of the population in Baltimore became immune (153%), epidemics did not develop. This suggested a threshold level of immunity that would protect against a measles epidemic. Sencer et al. [3] recognized that the proportion of children to be immunized to achieve eradication would be higher than suggested by Hedrich s data, but they believed that in the United States the immune threshold (would be) considerably less than 100% (p. 255). The program advocated had 4 strategies: routine immunization of infants, immunization of all susceptible children on entry to school or other place of congregation, surveillance, and epidemic control. Eradication was not specifically defined in the 1967 initiative. During , considerable effort and resources were devoted to measles eradication, and reported measles cases dropped at an even more rapid rate, to a low level of 22,231 in 1968, a decline of nearly 90% compared with 1966 and a total decrease of 195% compared with the prevaccine era. However, in 1969, major program emphasis shifted to implementation of rubella vaccination with the newly licensed vaccine (to prevent a recurrence of the devastating epidemic of that resulted in 120,000 infants born with congenital rubella syndrome). As federal funding for measles vaccination decreased and then ceased entirely in July 1969, reported measles cases increased, peaking at 75,290 cases in 1971 [5] (figure 2; data are shown on a logarithmic scale to highlight relative changes). Lessons learned: The most crucial factor in the failure to achieve eradication was the failure to reach and sustain universal infant immunization with measles vaccine [6]. Measles vaccine coverage among 1- to 4-year-old children did not exceed 63% for any year, according to the US Immunization Survey (figure 3). The cessation of federal funding for measles vaccination in July 1969 was cited as the primary reason for lack of complete routine infant immunization. Fewer than half of the states had school immunization requirements, which were considered necessary to achieve the second strategic objective of immunization of all susceptible children on school entry. Conrad et al. [6] ascribed the failure to achieve eradication of measles in the United States to incomplete implementation of the strategy rather than to a faulty strategy. They surmised that the immunity threshold needed to eradicate measles was 190% and concluded, no scientific reason has yet arisen to make us believe that eradication of measles was not possible. The reasons for measles eradication remain as important as ever (p. 2309). Programs: In the mid-1970s, program emphasis and incidence of measles varied considerably. Immunization coverage among 1- to 4-year-old children did not increase (figure 3). In 1974, a record low number of cases was reported (22,094); however, the incidence of measles rebounded, reaching a high of 57,345 cases in Unlike measles in the prevaccine era, which primarily affected preschool and young school-aged children, a substantial proportion of cases in the mid- to late 1970s occurred in middle or high school students. In 1977, 82% of reported cases occurred in people 5 19 years of age. Because the vaccination program had reduced the overall incidence of measles, many unimmunized children escaped measles and remained susceptible as they entered school. This allowed susceptibility to increase among school-aged children and shifted the majority of cases into the school-aged group (figure 4). In 1977, a nationwide childhood immunization initiative was announced, with objectives of raising immunization levels to 90% by October 1979 and of implementing a mechanism to maintain such levels thereafter. The effort focused on increasing federal and state governmental support for immunization, reviewing immunization records of schoolchildren and vaccinating those without documentation of measles vaccine or illness, increasing involvement of volunteers, and improving coordination of government activities. Measles elimination efforts: Initial success in the immunization initiative led to the announcement in Oc- Figure 2. Reported measles incidence, United States, Data are shown on a logarithmic scale to highlight relative changes. S18 JID 2004:189 (Suppl 1) Hinman et al.

3 Figure 3. Measles vaccine first-dose coverage, United States, NIS, National Immunization Survey; USIS, US Immunization Survey. tober 1978 of a further goal: elimination of indigenous measles from the United States by 1 October Elimination was to be indicated by the absence of measles cases, except for those that could be traced directly (within 2 generations) to a foreign source [7]. The measles elimination program had 3 major elements: achievement and maintenance of high immunization levels, strong and effective surveillance systems, and aggressive response to the occurrence of disease [8]. To ensure high immunization levels, major emphasis was placed on enactment and enforcement of school immunization requirements. In 1977 and 1978, the incidences of measles in states strictly enforcing school immunization requirements were 50% and 90% lower than elsewhere in the country. By 1981, all 50 states required measles immunization (or history of disease) before initial school entry, and in most states, the requirements extended throughout primary and secondary school and to licensed day care centers [9]. Since the school year, 95% of children entering school in the United States have had proof of measles immunization (figure 3). During this period, however, efforts to ensure that children received their measles vaccine at the recommended age (12 15 months) were less effective. Coverage remained!70% for 1- to 4-year-old children. Standard definitions of measles were developed and used nationwide. The clinical case definition of measles was generalized maculopapular rash of 3 days duration, fever ( 38.3 C, if measured), and cough or coryza or conjunctivitis. A suspected measles case was any rash illness with fever. A probable case met the clinical case definition but neither was linked to another probable or confirmed case nor had a positive serological test result. A confirmed case met the clinical case definition and was epidemiologically linked to another probable or confirmed case or was serologically confirmed (in which case it did not need to meet the clinical case definition). All suspected cases were to be reported to state health departments and investigated. Both probable and confirmed cases were to be reported by states to what is now the Centers for Disease Control and Prevention (CDC), but only confirmed cases were officially counted as reported measles cases. Substantial efforts were made to improve reporting, including active surveillance in some cities in which selected health care providers were contacted on a regular (weekly) basis to see whether they had seen any cases of measleslike illness [10]. In addition to the clinical classification of cases, an epidemiological classification system was developed. An imported case originated outside the state (or nation), the patient had rash onset within 18 days of entering the state, and the case could not be linked to local transmission. Imported cases were subcategorized as international or out-of-state importations. An importation spread case was one that could be linked directly to an imported case within 2 generations. An indigenous measles case could not be related to an imported case or had onset 12 generations after an imported case. Any case that could not be proven to be imported or importation spread within 2 generations was classified as an indigenous case. About 100 importations were anticipated annually with, on average, 4 importation spread cases for each importation, giving an annual total of 500 cases even after elimination was achieved. The third element of the strategy, vigorous response to cases, included immediate investigation, exclusion from school of children without adequate proof of immunity during an outbreak, and major efforts to provide vaccine to all vaccine-eligible persons in a wide area around the case. Application of the measles elimination strategies led to a further major reduction in reported incidence of measles to a record low level of 1497 cases in 1983, a 195% decline since 1977 levels. Measles incidence remained low in the mid-1980s, averaging 3700 cases/year (3 cases/100,000.) Nonetheless, the elimination target was not achieved. Lessons learned: By the late 1980s, data began to show that measles was occurring primarily in 2 groups: (1) preschool-aged children who had not been vaccinated against measles and (2) children and adolescents of school age, most of whom had received a single dose of measles vaccine (figure Figure 4. Measles cases by age group, United States, Evolution of US Measles Strategies JID 2004:189 (Suppl 1) S19

4 Figure 5. Reported measles cases and vaccination status by age, United States, ). A large proportion of preschool-aged children were not vaccinated against measles. Although school immunization requirements ensured high vaccination-coverage levels for all cohorts by school entry, coverage by age 2 years remained 70%. In 1986, the US immunization survey was stopped, and there was no national assessment of immunization coverage levels in preschool-aged children. Although school immunization requirements were extremely effective in reducing measles among schoolchildren, it became apparent that even very high coverage with a single dose of highly effective measles vaccine was not sufficient to prevent transmission in all settings. Studies in the United States and in other countries [11 13] indicated that levels of immunity must be 95% to ensure that transmission of measles cannot be sustained. The highest immunity levels are needed in schoolaged populations, in which high contact rates among students facilitate the spread of disease. In 1988, Orenstein et al. [14] noted, The high communicability of measles and the demonstration that measles transmission can be sustained among highly vaccinated populations in some instances suggest that more than one dose may be necessary to eliminate measles. The major problem with measles in highly vaccinated populations occurred among middle school, junior high school, senior high school, and college students. The quickest way to eliminate that problem would be a mass revaccination campaign of all such students. This was considered too expensive and logistically difficult to carry out. (p. 68). To address the problem of measles in the school-aged group, the Advisory Committee on Immunization Practices and the American Academy of Pediatrics recommended a second dose of measles vaccine for school-aged children in Starting in 1989, state immunization programs gradually incorporated second-dose recommendations into school immunization requirements. Measles resurgence: The problems with measles elimination in the United States in the 1980s were emphasized by a major resurgence of measles during , when 55,685 cases and 123 deaths were reported. This resurgence occurred in all countries in the Western Hemisphere, and hundreds of cases were imported into the United States from neighboring countries. In 1989, most outbreaks occurred in school-aged children, because implementation of the second-dose recommendations had not begun. The primary focus of the resurgence was unvaccinated preschool-aged children living in poor urban areas (figure 4). A 1991 analysis of the problem by the National Vaccine Advisory Committee [15] found that the principal cause was failure to provide vaccine on schedule to vulnerable children. The committee recommended improved availability of immunization, improved management of immunization services, improved capacity to measure childhood immunization status, implementation of a 2-dose measles vaccine strategy, and additional research needs. Many of these recommendations were implemented during 1992, and additional resources were provided to support state immunization services. Current elimination strategy. Following the measles resurgence of , increased focus on childhood vaccination led to a new childhood immunization initiative accompanied by a massive infusion of funds to support immunization. The initiative included a renewed call for elimination of measles, with a target date of The elimination of measles was also included as a goal of the US Public Health Service s Healthy People 2000 initiative. The strategy for the new measles elimination goal was based on lessons learned from the previous programs. Initially, the program s goal was defined (as in the previous elimination effort) as the absence of measles cases, except for those that could be traced directly within 2 generations to a foreign source. The 4 components of the current strategy to achieve and maintain elimination of endemic measles in the United States are to maximize population immunity through vaccination, to ensure adequate surveillance, to respond rapidly to outbreaks, and to work with other countries to achieve improved global measles control. The 2 key factors in the effort to maximize population immunity are to improve timely immunization of preschool-aged children and to deliver a second dose of measles vaccine to schoolchildren. Strategies to improve on-schedule immunization of preschoolaged children are broad-based and address all immunizations delivered to young children and all aspects of immunization programs. They include a new financing mechanism for vaccines (Vaccines for Children) to ensure that poor, uninsured, and underinsured children receive vaccines without charge in their medical home [16]. Programmatic links have been established with government programs, such as WIC, the special supplemental nutrition program for women, infants, and children, to ensure immunization of high-risk children [17]. S20 JID 2004:189 (Suppl 1) Hinman et al.

5 Monitoring of vaccination coverage among children aged months was initiated through the National Immunization Survey (NIS). This telephone-based survey provides rolling 12- month estimates for all US vaccination programs (states and major cities). Measures to help immunization providers improve coverage among their patients, including assessment of coverage at the provider level [18] and means of identifying children who are behind schedule and then contacting their parents [19], have resulted in improved vaccination coverage among preschool-aged children. There have been dramatic increases in immunization coverage. The NIS has documented an increase in coverage with measles-containing vaccine (measles or measles-mumps-rubella vaccines) among 19- to 35- month-old children to 90% since 1996 [20] (figure 3). To ensure immunization with 2 doses of measles-containing vaccine for schoolchildren, states gradually incorporated a requirement for a second dose of measles vaccine into school immunization requirements [21]. The Vaccines for Children (VFC) program expanded funding for a second dose of measles vaccine among schoolchildren. Initially the program allowed states to choose one grade cohort to be covered under VFC funding for a second dose of measles vaccines. Currently the VFC covers the cost of a second dose of measles vaccine for VFC-eligible children in all grades. In 1998, the Advisory Committee on Immunization Practices and American Academy of Pediatrics jointly recommended that states ensure second-dose coverage of children in all grades by The recommended schedule suggested that the second dose be delivered at entry to elementary schools, with an assessment at middle school entry to ensure that all students had received the second dose. As of the school year, only one state, Idaho, did not have a requirement for 2 doses of measles vaccine for schoolchildren. In 25 states, children in all grades from kindergarten through grade 12 are covered by a 2-dose requirement. On a population basis, 80% of US school-aged children are covered by a 2-dose school entry requirement [21]. To ensure adequate surveillance for measles and other vaccine-preventable diseases, additional federal funds were provided to states for staff for surveillance of vaccine-preventable diseases. The surveillance definitions for measles were also revised. The clinical case definition and definition of a suspected case of measles remained the same; however, a probable case was no longer classified as confirmed on the basis of epidemiological linkage to another probable case. Because the positive predictive value of the clinical case definition is very low when incidence is very low, a case must now be laboratoryconfirmed or have an epidemiological link to a laboratoryconfirmed case. This increases the importance of laboratory tests in confirming the diagnosis of measles. Molecular virology also began to play a major role in measles surveillance. Measles viruses can be classified into different genotypes on the basis of nucleotide sequencing [22, 23]. The measles virus that circulated in the resurgence of had a D3 genotype. The disappearance of this genotype from the United States and the lack of a consistently repeating pattern for any other genotype demonstrate that there is no endemic measles virus strain circulating in the United States [24, 25]. Genotype identification is also useful in distinguishing wildtype measles viruses from vaccine strains and for identifying the potential source regions for imported viruses when epidemiological data are incomplete. The epidemiological classification system has been modified. The imported case definition remains the same, but all cases not directly imported from another country are now considered indigenous. Indigenous cases are subclassified into 3 groups: importation-spread cases, which are epidemiologically linked to imported cases; imported virus cases, which have virological evidence of international importation; and unknown-source cases, which lack epidemiological or virological evidence of importation. These classifications are used to link cases to international importation and to determine whether the number and distribution of unknown-source cases are sufficient to suggest continuing endemic transmission of measles. Changes in the epidemiological status classification reflect a subtle change in the elimination goal. Rather than absence of indigenous measles cases (except those linked within 2 generations to an imported source) the current goal is absence of endemic measles [26]. The basis for this goal change is 3-fold. First, it is not possible to link every indigenous case to its imported source. Many imported cases are impossible to detect because the patients are in the United States only during their prodromal infectious period or leave after rash onset but before seeking medical care. Also, some cases are misclassified as confirmed measles cases as a result of false-positive laboratory tests. These cannot be linked to imported cases. The second reason for the goal change is that the genotypic information that demonstrates an imported source for the measles virus in some indigenous cases cannot determine the duration of indigenous transmission to meet the within 2 generations criterion. Finally, as described by DeSerres et al. [27], the duration of outbreak spread from imported cases follows a normal distribution. Even when population immunity is very high and most imported cases result in no spread or only 1 generation of spread, occasional outbreaks will extend beyond 2 generations of spread. These outbreaks do not indicate a reestablishment of endemic transmission. Surveillance indicators have been implemented to monitor the quality of measles surveillance, and studies have been conducted to measure the level of investigative effort of the surveillance system [28]. The factors that highlight the quality of the measles surveillance system are its ability to detect isolated Evolution of US Measles Strategies JID 2004:189 (Suppl 1) S21

6 cases and small outbreaks and the consistent detection of imported measles cases. State and local immunization programs respond rapidly to reported measles cases and outbreaks to identify and vaccinate people exposed to measles. In 2 states, Alaska and South Dakota, outbreaks among school-aged children and adolescents prompted rapid acceleration of the second-dose school requirement to cover all school grades in!6 months. The largest outbreak in the years had only 33 cases. The CDC has increased support for measles control in other countries. It has assisted in coordinated efforts with the Pan American Health Organization to drastically reduce measles cases in the Americas from 1250,000 cases in 1990 to!1000 cases in 2000 [29]. As a result, there are few importations from Latin America to the United States, in contrast to the situation before 1990, when Mexico was the leading source. The CDC National Immunization Program has a Global Measles Branch to address international measles issues. Resources have been allocated by the US Congress to assist with vaccine purchase and to provide technical support for international measles control. Importations of measles virus have decreased from 1300 cases in 1990 to!40 cases a year during Implementation of the current elimination strategy has led to a dramatic further decline in measles cases. Fewer than 150 cases were reported each year during , a 190% reduction from the previous record low seen in Subacute sclerosing panencephalitis, a late complication of measles, has virtually disappeared from this country. The incidence for the period was!1 case/1 million people. Other articles in this supplement document the recent history of measles in the United States and provide the rationale for asserting that we have finally achieved the target initially identified 30 years ago the elimination of measles as an endemic disease in this country. References 1. Langmuir AD. Medical importance of measles. Am J Dis Child 1962; 103: National Center for Health Statistics. Vital statistics system. Multiple cause-of-death files, Bethesda, MD: National Center for Health Statistics, Sencer DJ, Dull HB, Langmuir AD. Epidemiologic basis for eradication of measles in Public Health Rep 1967; 82: Hedrich AW. Monthly estimates of the child population susceptible to measles, , Baltimore, Maryland. Am J Hyg 1933; 17: Hinman AR, Brandling-Bennett AD, Nieburg PI. The opportunity and obligation to eliminate measles from the United States. JAMA 1979; 242: Conrad J, Wallace R, Witte JJ. The epidemiologic rationale for the failure to eradicate measles in the United States. Am J Public Health 1971; 61: Hinman AR, Bart KJ, Orenstein WA, et al. History of measles control efforts. In: Gruenberg EM, ed. Vaccinating against brain syndromes: the campaign against measles and rubella. New York: Oxford University Press, 1986: Hinman AR, Kirby CD, Eddins DL, et al. Elimination of indigenous measles from the United States. Rev Infect Dis 1983; 5: Hinman AR, Eddins DL, Kirby CD, et al. Progress in measles elimination. JAMA 1982; 247: Centers for Disease Control. Measles surveillance report 11, Bethesda, MD: US Public Health Service, Yorke JA, Nathanson N, Pianigiani G, Martin J. Seasonality and the requirements for perpetuation and eradication of viruses in populations. Am J Epidemiol 1979; 109: Hethcote H. Measles and rubella in the United States. Am J Epidemiol 1983; 117: Anderson RM, May RM. Directly transmitted infectious diseases: control by vaccination. Science 1982; 215: Orenstein WA, Markowitz LE, Hersh BS, Preblud SR, Hinman AR. The elusiveness of measles elimination: ten years and still counting. In: Proceedings of the 23rd Immunization Conference (San Diego, 5 9 June 1989). Atlanta, GA: Centers for Disease Control and Prevention, 1989: National Vaccine Advisory Committee. The measles epidemic: the problems, barriers, and recommendations. JAMA 1991; 266: Santoli JM, Rodewald LE, Maes EF, Battaglia MP, Coronado VG. Vaccines for Children program, United States, Pediatrics 1999; 104: e Birkhead GS, LeBaron CW, Parsons P, et al. The immunization of children enrolled in the special supplemental food program for women, infants, and children (WIC): the impact of different strategies. JAMA 1995; 274: LeBaron CW, Chaney M, Baughman AL, et al. Impact of measurement and feedback on vaccination coverage in public clinics, JAMA 1997; 277: Dini EF, Linkins RW, Sigafoos J. The impact of computer-generated messages on childhood immunization coverage. Am J Prev Med 2000; 18: Herrera GA, Smith P, Daniels D, et al. National, state, and urban area vaccination coverage levels among children aged months United States, MMWR CDC Surveill Summ 2000; 49: Kolasa M, Klemperer-Johnson S, Papania MJ. Progress toward implementation of a second-dose measles immunization requirement for all schoolchildren in the United States. J Infect Dis 2004; 189(Suppl 1): S World Health Organization. Nomenclature for describing the genetic characteristics of wild-type measles viruses (update). Part I. Wkly Epidemiol Rec 2001; 76: World Health Organization. Nomenclature for describing the genetic characteristics of wild-type measles viruses (update). Part II. Wkly Epidemiol Rec 2001; 76: Rota JS, Rota PA, Redd SB, Pattamadilok S, Bellini WJ. Genetic analysis of measles viruses isolated in the United States, J Infect Dis 1998; 177: Rota PA, Liffick SL, Rota JS, et al. Molecular epidemiology of measles viruses in the United States: Emerg Infect Dis 2002;8: Papania MJ, Orenstein WA. Defining and assessing measles elimination goals. J Infect Dis 2004; 189(Suppl 1):S DeSerres G, Gay NJ, Farrington CP. Epidemiology of transmissible diseases after elimination. Am J Epidemiol 2000; 151: Harpaz R, Papania MJ, McCauley MM, Redd SB. Has surveillance been adequate to detect endemic measles in the United States? J Infect Dis 2004; 189(Suppl 1):S de Quadros CA, Izurieta H, Venczel L, Carrasco P. Measles eradication in the Americas: progress to date. J Infect Dis 2004; 189(Suppl 1): S S22 JID 2004:189 (Suppl 1) Hinman et al.