Evolution of Surveillance of Measles, Mumps, and Rubella in England and Wales: Providing the Platform for Evidence-based Vaccination Policy

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1 Epidemiologic Reviews Copyright 2002 by the Johns Hopkins Bloomberg School of Public Health All rights reserved Vol. 24, No. 2 Printed in U.S.A. DOI: /epirev/mxf002 Evolution of Surveillance of Measles, Mumps, and Rubella in England and Wales: Providing the Platform for Evidence-based Vaccination Policy A. J. Vyse 1,2, N. J. Gay 1, J. M. White 1, M. E. Ramsay 1, D. W. G. Brown 2, B. J. Cohen 2, L. M. Hesketh 3, P. Morgan-Capner 3, and E. Miller 1 1 PHLS Communicable Disease Surveillance Centre, London, United Kingdom. 2 Enteric, Respiratory and Neurological Virus Laboratory, Central Public Health Laboratory, London, United Kingdom. 3 Seroepidemiology Unit, Preston Public Health Laboratory, Royal Preston Hospital, Preston, Lancashire, United Kingdom. Received for publication May 20, 2002; accepted for publication September 25, Abbreviations: COVER, Cover of Vaccination Evaluated Rapidly; IgG, immunoglobulin G; IgM, immunoglobulin M; MMR, measles-mumps-rubella. INTRODUCTION Vaccination is one of the most cost-effective measures for preventing morbidity and mortality that modern medicine has to offer (1). Measles, mumps, and rubella are three viral infections causing significant morbidity for which an effective vaccine is available. Otitis media (5 percent of cases), pneumonia or bronchitis (4 percent), and neurologic complications (1 percent), including subacute sclerosing panencephalitis, are associated with cases of measles (2), while mumps is recognized as a common cause of aseptic meningitis and can cause orchitis in adult males (3). Rubella infection in pregnancy, especially during the first trimester, can cause miscarriage or congenital rubella syndrome, which is characterized by a pattern of congenital abnormalities including nerve deafness, cataracts, cardiac abnormalities, and mental retardation (4, 5). Before vaccines became available, immunity to measles, mumps, and rubella was obtained through acquisition of the wild-type virus. In 1968, a monovalent measles vaccine was introduced for infants in England and Wales (6), and it was followed in 1970 by rubella vaccine for schoolgirls and susceptible women (7). Monovalent measles vaccine was replaced by the combined measles-mumps-rubella (MMR) vaccine in 1988, with the aim of eliminating all three diseases. Monovalent rubella vaccine remained available to susceptible adult women. For the first 3 years of the program, a catch-up dose was also offered to children at age 4 years (8). In 1994, a combined measles-rubella vaccine was offered to all schoolchildren aged 5 16 years in a national campaign lasting 6 weeks (9, 10). Since 1996, a two-dose schedule of MMR has been routinely offered to all children (11). This review describes how and why these decisions on vaccine policy for measles, mumps, and rubella have been made in England and Wales over the last three decades. It demonstrates how the national surveillance system for measles, mumps, and rubella has evolved and illustrates the way in which it is used in conjunction with mathematical models to inform national policy. The situation in England and Wales is used as an example because the surveillance methods employed there can serve as a model for other countries with an interest in controlling these infections, particularly given the commitment by the World Health Organization to eliminate global morbidity and mortality resulting from measles (12). SURVEILLANCE METHODS Four surveillance methods are used in England and Wales to monitor the impact of the MMR vaccination program. These methods provide data on vaccination coverage, clinical notifications, laboratory-confirmed cases, and antibody prevalence. Vaccination coverage Since the mid-1960s, data for estimating coverage in 2- year-old children in England and Wales have been collected annually by the Department of Health and the Welsh Office Reprint requests to A. J. Vyse, PHLS Communicable Disease Surveillance Centre, 61 Colindale Avenue, London NW9 5EQ, United Kingdom ( avyse@phls.org.uk). 125

2 126 Vyse et al. from health authorities. Estimates initially used the number of livebirths in each district health authority as the denominator, moving in 1988 to computerized child health registers holding vaccination details for all children resident in the district (Körner returns). These computerized records, which cover the entire population, have been used to generate more timely quarterly information on primary immunization coverage for England and Wales (and later Northern Ireland). The system was developed by the Communicable Disease Surveillance Centre and is termed the Cover of Vaccination Evaluated Rapidly (COVER) Program (13). Its purpose is twofold: first, to improve vaccination coverage through regular and accurate feedback to district immunization coordinators, thereby stimulating local interest in vaccination coverage and investigation of reasons for poor performance; and second, to enable changes in vaccination coverage to be detected quickly. The COVER Program calculates quarterly vaccine coverage data for sentinel antigens. These included initially measles vaccine and then subsequently MMR vaccine. Data are provided on children who reached their second or fifth birthday in the evaluation quarter that is, on coverage of the first dose of measles/mmr vaccine at age 14 months and coverage of the first and second doses at age 5 years. These data are requested from, and fed back to, district immunization coordinators, as well as published quarterly in the Communicable Disease Report. Clinical notifications Measles (since 1940), mumps (since 1988), and rubella (since 1988) are statutory notifiable infectious diseases, and clinicians are legally required to report any cases diagnosed to the appropriate officer of the local government authority. This is usually the responsibility of the consultant in communicable disease control for the area where the patient resides, who reports weekly to the Office for National Statistics. There are no formal case definitions; notifications are made on suspicion or diagnosis of clinical disease (14). Laboratory-confirmed cases When an infection is common, the positive predictive value of a clinical diagnosis is sufficiently high to base surveillance on notifications. However, as the infection becomes less common because of childhood vaccination, it is to be expected that an increasing proportion of notified cases will be due to other infections that have a similar clinical presentation. For example, cases of parvovirus B19, human herpes virus 6 (roseola infantum), human herpes virus 7, and group A streptococcus all involve symptoms of rash and fever and may be misdiagnosed as measles or rubella (15, 16). Laboratory confirmation by the detection of specific immunoglobulin M (IgM) in an appropriate clinical specimen can be used in association with notification to improve the accuracy of the data. Traditionally, the specimen of choice for such antibody testing has been serum. Saliva (oral fluid) is an alternative noninvasive type of clinical specimen that contains immunoglobulins and has considerable compliance advantages. Saliva is safe and easy to collect (17 20), which makes it attractive for surveillance. A pilot study designed to validate oral fluid diagnosis of measles demonstrated the high specificity of oral fluid IgM testing and showed that less than 40 percent of clinically diagnosed cases were confirmed by laboratory testing (21, 22). This demonstrated that reliance on notification alone was not sufficient to monitor progress towards elimination of measles and that identification of the true incidence of infection could only be achieved through laboratory investigation of suspected cases. Prior to 1994, surveillance of laboratory-confirmed cases of measles was based on cases investigated by public health and National Health Service laboratories and reported to the Public Health Laboratory Service Communicable Disease Surveillance Centre. Since November 1994, the Public Health Laboratory Service has enhanced surveillance of measles, mumps, and rubella by offering to test oral fluid specimens from all notified cases for virus-specific IgM. Samples collected between 1 and 6 weeks after the onset of symptoms are sent to the Enteric, Respiratory, and Neurological Virus Laboratory at the Public Health Laboratory Service Central Public Health Laboratory, where they are tested for specific antibody (22) to confirm the diagnosis (9, 23 25). Such laboratory confirmation is currently not obligatory, but every effort is made to facilitate this service (9). Between January 1995 and December 2001, 65.3 percent of measles notifications, 60.9 percent of mumps notifications, and 54.6 percent of rubella notifications had subsequent oral fluid samples collected and sent for laboratory confirmation, with the diagnosis being confirmed in 2.4 percent, 19.6 percent, and 12.7 percent, respectively ( Genotyping of measles, mumps, and rubella is an additional laboratory technique that is now being used to supplement surveillance data (26 29). Measles, mumps, and rubella virus genome can be extracted from suitable clinical specimens, including oral fluid (30), collected soon after the onset of symptoms in suspected cases. Specific regions are then amplified by reverse transcription polymerase chain reaction, and the amplicons are directly sequenced (26). In addition to assisting in laboratory confirmation, analysis of genomic variation (genotyping) allows investigation of transmission pathways and sources of infection (31). This is particularly useful for epidemiologically linking cases and investigating unusual cases, and genotyping was used to investigate and link outbreaks of measles that occurred within Rudolph Steiner communities in England in 1997 (32, 33). Genotyping is also a useful tool for obtaining information with which to document progress towards disease elimination (34). Antibody prevalence Since 1986, the prevalence of antibodies to measles, mumps, and rubella in the population has been monitored using anonymized residues of specimens submitted for microbiologic or biochemical testing to public health laboratories in England and Wales. Only age, sex, the collecting laboratory, and the date of collection are recorded (35, 36). An average of 7,000 serum samples have been collected each year since Samples from persons under age 25 years

3 Surveillance of Measles, Mumps, and Rubella 127 FIGURE 1. Annual measles notifications and vaccine coverage in England and Wales, MMR, measles-mumps-rubella; MR, measles-rubella. are collected as a priority, though every fifth year samples are collected across the complete age range. This collection is the best representation of the general population of England and Wales currently available. The first survey was conducted in 1986 before the introduction of MMR vaccine, and it established baseline seroprevalence using laboratory assays that detected specific immunoglobulin G (IgG). Until 1992, hemagglutination inhibition was used to detect measles-specific IgG, while mumps- and rubella-specific IgG was detected by radial hemolysis. Enzyme-linked immunosorbent assay is now used as the method of choice for all three infections (36). These data on the general population are supplemented by investigation of rubella susceptibility in antenatal women. Assessment of the risk of rubella infection in pregnancy by age and parity has been maintained since 1984 by six sentinel laboratories, which together screen approximately one sixth of the annual pregnancies in England and Wales (7, 37 41). Other sources of information The major sources of surveillance data described above may be supplemented with information obtained from death certificates sent to the Office for National Statistics, hospital admissions data, sentinel surveillance in general practices from the Royal College of General Practitioners Birmingham Research Unit (for mumps), and congenital rubella syndrome surveillance (for rubella). Epidemiology of measles, mumps, and rubella infection in England and Wales and vaccination policy When describing the epidemiology of measles, mumps, and rubella infection in England and Wales in conjunction with vaccination strategy and surveillance methods, distinct periods need to be considered. These account for the prevaccine era, when infection was endemic; the subsequent introduction of vaccine; and the later adjustments in vaccine policy. Measles Prevaccine era and Before measles vaccine was available, England and Wales experienced regular epidemics of measles, with hundreds of thousands of notifications each year (figure 1). In 1968, a single-antigen measles vaccine was introduced. Initially coverage was poor, but it slowly increased to a level of approximately 80 percent in 1988 (6). The introduction of vaccine had an immediate effect on the incidence of measles. The resulting decrease in notifications with the introduction of vaccine and increasing vaccine coverage over time is shown in figure In 1988, the MMR vaccine was introduced, and continued efforts were made to improve coverage (8). The combination of high vaccine coverage and an MMR catch-up program for children aged 2 4 years implemented at the time the vaccine was introduced had a large impact in reducing the transmission of measles, and little infection was documented in the early 1990s. However, serologic surveillance showed that while susceptibility had fallen in preschool-aged children, reflecting the increase in MMR vaccine coverage, susceptibility to measles among children aged 7 14 years had risen from 6 percent in 1986 to 9.2 percent in 1991 (figure 2). Analysis conducted in conjunction with mathematical models predicted that by the mid- 1990s, the increase in susceptibility among schoolchildren would be sufficient for an epidemic to occur. Susceptibility in these age groups was due to a combination of low coverage in the past, a small proportion of primary vaccine

4 128 Vyse et al. FIGURE 2. Proportion of serum samples negative for measles antibody in England and Wales in analyses using sera collected in , 1991, and failures, and decreased transmission of the virus in the early 1990s. This suggested that an unselective vaccination campaign targeting school-aged children was required if such an epidemic were to be prevented. Therefore, a national measles and rubella vaccine campaign for the United Kingdom was proposed. The program began in November All children aged 5 16 years were offered the combined measles-rubella vaccine. Of the 7.1 million eligible children in the United Kingdom, 92 percent were vaccinated during the campaign, which lasted approximately 6 weeks (6, 9, 10). To monitor the impact of this campaign on measles susceptibility in the target age groups, the Public Health Laboratory Service collected 4,496 serum samples in from children aged 2 16 years and screened them for measles-specific IgG by enzyme-linked immunosorbent assay. The minimum level of antibody thought to be required for clinical protection is miu/ml (42). The proportion of susceptible 5- to 16-year-olds fell from 8.4 percent in 1994 to 2.1 percent in 1995, confirming the success of the measles-rubella campaign. However, antibody levels among children aged 2 4 years, who were not included in the campaign, were similar in both 1994 and 1995, and 15.3 percent had antibody levels of less than 100 miu/ml. These data, when analyzed in conjunction with mathematical models, suggested that herd immunity in the population was now sufficient to prevent widespread transmission. However, small local outbreaks were expected to continue to occur as a result of limited spread from imported cases (9). The results of the national measles-rubella campaign in 1994 highlighted the need for administration of a routine second dose of MMR among preschool-aged children to provide an opportunity for immunizing poor responders (primary vaccine failures) or those who missed their first dose. This led to the introduction in 1996 of a second dose of MMR, offered to all children prior to entering school, as a measure for sustaining low levels of susceptibility (11) onwards. The results of enhanced surveillance using oral fluid IgM detection between January 1995 and December 2001 are shown in figure 3. In the period January 1995 December 2001, 64 percent (16,667/26,049) of provisionally notified cases of measles were screened for IgM, with antibody being detected in 2.5 percent (424/16,667). Therefore, notifications during this period grossly overestimated the true incidence of measles, since only a small proportion of cases were confirmed by laboratory tests of oral fluid (figure 3). The number of confirmed measles cases has remained low since the measles-rubella campaign, and most cases arise in unvaccinated preschool-aged children or young adults. However, relatively small local outbreaks of laboratoryconfirmed measles occurred in 1996, 1997, 1998, and 1999 (figure 3) as a result of limited secondary spread from imported cases. This is consistent with predictions from the modeling of vaccine coverage and serologic surveillance data. The largest outbreak began in July 1997 and affected unvaccinated children in several Rudolf Steiner communities, which do not participate in measles vaccination for philosophical reasons. The spread from one community to another was confirmed by genotyping. The majority of cases were in children under 15 years of age, and in only two confirmed cases had the child previously been vaccinated against measles (32). A similar situation occurred in late 1999 in Salford, northwestern England, affecting an orthodox Jewish community in which vaccination coverage was low (33). The complications of measles infection include pneumonia and subacute sclerosing panencephalitis. While these complications are rare, they are life-threatening. A steady decline in the number of cases of subacute sclerosing panencephalitis has been a direct result of the introduction of

5 Surveillance of Measles, Mumps, and Rubella 129 FIGURE 3. Numbers of notified and laboratory-confirmed cases of measles in England and Wales, January 1995 December measles vaccine (43), further illustrating the benefits of an effective vaccination program. Mumps Prevaccine era. Prior to 1988, mumps was not a notifiable disease, and surveillance utilized hospital admissions data, Royal College of General Practitioners data, and seroprevalence data. In the absence of an immunization program, epidemics of mumps occurred at 3-year intervals (44). Annual hospital admissions for mumps in England and Wales (often due to aseptic meningitis) averaged 1,300 over the period (23). In , a total of 8,716 serum samples from persons aged 1 65 years were screened for mumps-specific IgG (figure 4). The decreasing percentage negative by age reflects the acquisition of immunity through natural infection (figure 4). Despite the high number of cases of mumps meningitis, mortality and permanent sequelae were low. Therefore, mumps vaccination was FIGURE 4. Proportion of serum samples negative for mumps antibody in England and Wales in analyses using sera collected in and 1993.

6 130 Vyse et al. FIGURE 5. Numbers of notified and laboratory-confirmed cases of mumps in England and Wales, January 1995 December only considered a cost-effective intervention when the combined MMR vaccine became available (45, 46) Immunization against mumps was introduced in England and Wales in October 1988 as a component of the MMR vaccine and is offered routinely to all children aged months. In addition, MMR was offered at age 4 years in a 3-year catch-up program. Hospital admissions for mumps in England and Wales fell to 79 in the year leading up to March 1991, and notification data showed that the incidence of mumps reached very low levels shortly after the introduction of MMR. This was due to the high acceptance rates of vaccine in the target age groups (23). Initially, the Urabe strain of mumps virus was used in MMR vaccine. However, subsequent evidence demonstrated that cases of aseptic meningitis were associated with use of this strain (47). The absence of proven cases of meningitis associated with an alternative mumps strain, Jeryl Lynn, led to the decision in 1992 to replace the Urabe strain with Jeryl Lynn in MMR vaccine used in the United Kingdom (48). The effect of mumps vaccination on susceptibility was shown by the screening of 3,535 serum samples, collected in 1993 from persons aged 1 24 years, for mumps-specific IgG. The percentage of people susceptible to mumps in comparison with the percentage susceptible before the introduction of vaccine ( ) is shown in figure 4. The immunity of children aged 2 6 years in 1993 can be almost entirely attributed to MMR vaccination. In addition, the proportion of those aged 9 12 years who were antibodynegative for mumps was higher in 1993 than in ; this was probably due to reduced exposure to natural infection in this age group following high acceptance of MMR vaccine. On the basis of these serologic surveillance data, the proportion of children aged years with no detectable mumps antibody was expected to peak at 19 percent in 1997 (23). A mumps component was not included with measles and rubella in the 1994 measles-rubella campaign. This was because there was no suitable mumps component available at the time, which prevented manufacturers from producing sufficient quantities of a vaccine that included a mumps component in addition to measles and rubella onwards. Mathematical models suggested the need for a critical level of approximately percent immunity within the population of England and Wales if mumps were to be eliminated (23). This was not achievable with the vaccine coverage seen for MMR in England and Wales using a one-dose schedule. Many individuals not protected would remain susceptible into adult life, when the risk of complications from mumps infection is greatest. Therefore, early delivery of a second dose of mumps vaccine was desirable. This was effected in 1996 by introducing a routine second dose of MMR for preschool children (11). Evidence demonstrating the necessity of a second dose of mumps vaccine began to become available after November 1994, when the Public Health Laboratory Service enhanced its surveillance of mumps by offering a diagnostic oral fluid test (to detect mumps-specific IgM) for all cases of mumps reported to the Office for National Statistics (23, 49). Data on notified cases and laboratory-confirmed cases for January 1995 December 2001 are shown in figure 5. During this period, 60 percent (6,771/11,234) of notified mumps cases were screened for IgM, with antibody being detected in 16 percent (1,104/6,771), increasing from 2.8 percent (27/962) in 1995 to 38.3 percent (582/1,518) in The outbreaks seen occurred predominantly in secondary-school-aged children (aged years) from 1997 to These children were too old to have received MMR when it was introduced in 1988 and are therefore unlikely to have received mumps vaccine. This is consistent with the modeling predictions based on vaccine coverage and serologic surveillance data. The occurrence of mumps in unvaccinated cohorts has also been experienced in other developed countries (50, 51).

7 Surveillance of Measles, Mumps, and Rubella 131 FIGURE 6. Number of laboratory-confirmed mumps cases in England and Wales between 1995 and 1999, by measles-mumps-rubella (MMR) vaccination history and year of birth, among persons born after Further evidence of the effectiveness of a second dose of vaccine is provided by a retrospective analysis of MMR vaccination history and year of birth in laboratory-confirmed mumps cases with onset dates between 1995 and 1999 (figure 6). This analysis highlighted that the majority of persons who had acquired a mumps infection during this period were born before 1988 and had received either no vaccine or a single dose of mumps vaccine (413/645; 64 percent). The majority of those with an unknown mumps vaccination history (225/645; 34.9 percent) had been born prior to the introduction of mumps vaccine in England and Wales. These persons may be considered highly unlikely to have received two doses of a mumps-containing vaccine, but they could have received a single dose via catch-up immunization. Only 1.1 percent (7/645) of cases had received a second dose of vaccine. These data therefore confirm that a second dose of mumps vaccine is necessary in order for a vaccination policy to effectively prevent this disease within the population. Rubella Rubella immunization programs are primarily designed to prevent maternal rubella infections and subsequent congenital rubella syndrome. The two basic approaches to rubella vaccination focus on minimizing the two factors determining the incidence of maternal infection in pregnancy: the proportion of pregnant women susceptible and the risk of infection to which susceptible women are exposed. A selective approach aims to reduce the proportion of pregnant women who are susceptible to rubella infection by targeting prepubertal girls and nonimmune women for vaccination. A universal strategy is designed to interrupt transmission of rubella, thus minimizing the possibility of susceptible pregnant women being exposed. Prevaccination era and Prior to 1970, rubella vaccine was not available in the United Kingdom, and immunity was acquired through natural infection. When rubella vaccine was introduced in the United Kingdom in 1970, a selective approach was adopted in which prepubertal girls and nonimmune women (either before or after pregnancy) were given one dose of monovalent rubella vaccine. This strategy was chosen primarily because of concerns about the duration of vaccine-induced immunity and because measles vaccine coverage at that time was low (only 50 percent), suggesting that a universal approach for rubella vaccination would not be successful (7). School-based vaccination for girls aged years achieved coverage of percent between 1970 and Implementation of postpartum vaccination for women found to be susceptible during antenatal screening was not monitored routinely, but it varied widely, from 5 percent to more than 80 percent in one study (37). The effect of these programs gradually accumulated and reduced the susceptibility of women of childbearing age. The first large-scale seroprevalence study showed that only 3.2 percent (47/ 1,452) of females aged years lacked detectable rubella antibody, a figure 49 percent lower than that for males of the same age (181/2,874; 6.3 percent) (35). Antenatal tests confirmed that by 1985, only 3.3 percent of nulliparous women and 1.5 percent of parous women were antibodynegative; these numbers fell further to 2.3 percent and 0.9 percent, respectively, by However, women who remained susceptible continued to be at risk of infection during pregnancy. In , follow-up of 3,062 women identified as susceptible at the beginning of pregnancy revealed that 34 (1.1 percent) were infected during the course of their pregnancy. The risk of infection was more than twofold higher in parous women than in nulliparous

8 132 Vyse et al. women, indicating that pregnant women risked being infected by their own children (7). The impact of the selective program on the incidence of rubella infection in pregnancy can be measured by reports on congenital rubella syndrome (since 1970), termination of pregnancy related to rubella infection (since 1971), and laboratory-confirmed rubella infection during pregnancy (since 1975). All showed significant downward trends; the numbers fell from an average of 42 congenital rubella syndrome cases, 801 terminations, and seven infections during pregnancy annually in to 22 births, 73 terminations, and six infections during pregnancy in (7, 40) In October 1988, when coverage and monitoring of coverage had improved and adequate surveillance had been set up, the selective rubella vaccination policy was augmented by universal vaccination of young children with rubella vaccine as part of the MMR vaccine. This was designed to eliminate circulating rubella. With such a universal program, high vaccination coverage of children of both sexes in the second year of life, together with supplementary catch-up vaccination for older cohorts when the vaccine is introduced, is imperative. With low coverage there is a danger of increasing the age of infection and hence the number of congenital rubella syndrome cases, because an increase in the proportion of women susceptible may outweigh the decrease in their risk of infection (52, 53). Initially there was a gradual decline in the number of cases of rubella between 1989 and A resurgence of rubella infection was seen in 1993 because of an epidemic that mainly affected young adult males, even though in 1991 the highest susceptibility was seen among children aged 8 10 years. These children were too old to have received MMR vaccine during the initial catch-up program for preschoolaged children (38, 39). Between 1989 and 1994, an average of six births associated with congenital rubella syndrome and 13 terminations were reported annually in the United Kingdom. The majority of mothers of children with reported congenital rubella syndrome were immigrants from countries without rubella vaccination programs (40, 41). A pilot study of notified cases of rubella in England and Wales from was carried out to investigate the accuracy of rubella surveillance based on clinical reports and to validate an oral fluid test. Only 29 percent (52/178) of notified cases were confirmed by the detection of IgM in serum. The sensitivity and specificity of the oral fluid IgM test were shown to be 90 percent and 99 percent, respectively, supporting the inclusion of rubella in the Public Health Laboratory Service enhanced surveillance program, which began in 1994 (24). In November 1994, combined measles-rubella vaccine was offered to all children aged 5 16 years in a national vaccination campaign. The prime motivation for the campaign was to prevent a measles epidemic, but it also provided an opportunity to improve rubella control in schoolchildren by reducing their level of susceptibility, particularly in the 20 percent of susceptible males aged years who had not been offered rubella vaccine previously (40). Without the measles-rubella campaign, these cohorts were expected to have fueled increasing numbers of outbreaks in universities over the next 10 years. Preventing such outbreaks would bring the nation closer to achieving rubella elimination (40). The age-specific prevalence of rubella-specific IgG before and after the measles-rubella campaign was assessed using 3,596 serum samples obtained from children aged 5 16 years in 1994 and 1995 (40). The proportion of susceptible 5- to 10-year-olds fell from 17.5 percent in 1994 to 3.0 percent in Among 11- to 16-year-olds, the proportion without antibody fell from 6.2 percent to 1.0 percent in girls and from 24.5 percent to 6.9 percent in boys. The lower susceptibility in girls in this age group reflects immunity derived from the selective vaccination policy that was previously in place onwards. Data on notified cases of rubella that were reported and laboratory-confirmed between January 1995 and December 2001 are shown in figure 7. During 1996, an outbreak occurred that particularly affected young adult males at universities and in the military in England and Wales who had never been offered vaccine (figures 7 and 8). This reflected the proportion of susceptible men aged years, which increased from 13 percent to 16 percent after the introduction of MMR vaccine, and highlighted the fact that the epidemiology of rubella is changing as vaccination policy has been adapted to offer maximum protection to women of childbearing age (40). There have been no large outbreaks of rubella in England and Wales since 1996 as the measles-rubella campaign cohorts have reached adulthood. Between January 1995 and December 2001, 53.7 percent (13,822/25,746) of patients with notified cases of rubella were screened for IgM in the oral fluid surveillance program, with antibody being detected in 13.6 percent (1,885/13,822). The proportion of notified cases confirmed by the detection of rubella-specific IgM in oral fluid rose from 5 percent in November and December 1994 to more than 40 percent in the first 6 months of Since November 1994, more than 90 percent of cases confirmed by the detection of IgM in oral fluid were in males over age 17 years (figure 7). This, coupled with the absence of any rubella epidemics in England and Wales since 1996 (figure 7), reflects the effectiveness of the 1994 measles-rubella campaign (40). Following the increase in the incidence of rubella seen in the spring of 1996, there were 12 cases of congenital rubella syndrome during the year among women born in the United Kingdom rather than among female immigrants (41). If congenital rubella syndrome is to be eliminated, this highlights the continuing need to thoroughly serologically investigate all pregnant women for rubella antibody and to offer postpartum vaccination when appropriate. Rubella is now emerging as an imported infection in England and Wales, with most cases arising as a result of immigration or travel overseas (54, 55). Therefore, continued surveillance of rubella and congenital rubella syndrome is required, with catch-up rubella immunization being considered for recent immigrants from countries with no immunization program (54, 56). Figure 9 shows antenatal susceptibility between 1985 and 1998 according to parity. The risk of infection among susceptible pregnant women has been higher in nulliparous

9 Surveillance of Measles, Mumps, and Rubella 133 FIGURE 7. Numbers of notified and laboratory-confirmed cases of rubella in England and Wales, January 1995 December women than in parous women, in contrast to the situation before MMR vaccine was introduced, and this is consistent with the change in the age group in which transmission is concentrated. Rubella susceptibility has always been higher among Asian women of childbearing age in comparison with non-asian women, particularly among nulliparous Asian women from countries where rubella vaccination is not available. Between 1990 and 1995, 7.4 percent of nulliparous Asian women were susceptible to rubella. However, this figure declined to a mean of 4.4 percent between 1996 and 1998, highlighting the increased attention being given to this group (40). The purpose of administering a second dose of rubella vaccine was to minimize the proportion of young susceptible children who would be vulnerable to some secondary transmission and therefore increase susceptible pregnant women s exposure to risk of infection, even though this proportion would not be large enough to sustain endemic rubella transmission (40). The routine second dose of MMR is offered at school entry and was implemented in 1996 (11). FIGURE 8. Percentage of the population of England and Wales that was susceptible to rubella (i.e., without antibodies to rubella) between 1996 and 1998, by age group and sex.

10 134 Vyse et al. FIGURE 9. CONCLUSIONS Overall susceptibility of women of childbearing age to rubella in England and Wales between 1985 and 1998, by parity. Introducing a new vaccination program affects the epidemiology of the infection targeted and reduces the risk of infection in unvaccinated persons. With such an intervention comes an obligation to monitor the impact of vaccination through effective surveillance that draws accurate data from a variety of sources and perspectives. When analyzed in conjunction with mathematical modeling techniques, such surveillance data can also be used to predict the extent to which a disease will be controlled and indicate how current strategies may need to be adjusted. This approach has been effected since 1986 in England and Wales to control measles, mumps, and rubella infection and was fundamental to the decision to introduce MMR vaccine in October 1988, the measles-rubella campaign in November 1994, and a routine two-dose strategy for MMR in For vaccination programs to be effective, it is essential that suitably high vaccine coverage be reached and maintained. Low coverage will increase the average age of infection and can lead to adverse outcomes, as illustrated in the case of rubella, where insufficient coverage results in an increase in congenital rubella syndrome. Suitably high coverage was achieved for the MMR vaccine in the early 1990s, but coverage subsequently dropped to less than 90 percent (57). The fall in MMR vaccine coverage reflects the adverse publicity the vaccine has received in the media because of alleged links between the vaccine and autism and Crohn s disease (58). MMR vaccine coverage is beginning to recover (59), though continuing adverse publicity and anxiety about vaccine safety make significant improvements in vaccine coverage in the near future unlikely (60). Therefore, it remains important that public confidence in the use of MMR vaccine as an effective preventive measure against measles, mumps, and rubella be restored. In addition to surveillance methods designed to help us understand the changing epidemiology of vaccine-preventable diseases, it is equally important to create enhanced surveillance techniques for the monitoring of vaccine safety when developing vaccination strategies (61). This combination will ensure that policymakers and parents alike will be able to confidently make the necessary informed decisions about vaccination needed to control and eliminate disease. As vaccination strategies for measles, mumps, and rubella have been implemented in England and Wales, the integrated surveillance work has highlighted the value of including a second dose of vaccine in the schedule, which is now routinely done for MMR. It has been shown that as the vaccination program takes effect and the incidence of disease declines, continued effective surveillance of measles, mumps, and rubella is impossible without suitable microbiologic support. Once widespread vaccination is in place, only a relatively small proportion of notified cases are confirmed by laboratory testing, indicating that a surveillance system which relies solely on clinical diagnosis lacks the necessary precision for effective disease control. Use of a safely and easily collected type of clinical sample (such as oral fluid) with high compliance properties for laboratory confirmation provides a further advantage (62). The combination of surveillance techniques developed in England and Wales illustrates how surveillance can be used to provide the necessary insights into the epidemiology of measles, mumps, and rubella needed to make informed decisions on national vaccine policy. The current low number of confirmed cases of these diseases is a testament to the success of vaccination. While these surveillance methods are only being applied in England and Wales at present, they serve as a model for other industrialized countries with a commitment to controlling these infections. While it may not

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