The Elimination of Indigenous Measles Transmission in England

SUPPLEMENT ARTICLE

The Elimination of Indigenous Measles Transmission in England and Wales Downloaded from https://academic.oup.com/jid/article/187/Supplement_1/S198/2043868 by guest on 02 October 2021 Mary E. Ramsay,1 Li Jin,2 Joanne White,1 Pam Litton,2 Bernard Cohen,2 and David Brown2 1Immunisation Division, Public Health Laboratory Service (PHLS) Communicable Disease Surveillance Centre, and 2Enteric, Respiratory and Neurological Virus Laboratory, PHLS Central Public Health Laboratory, London, United Kingdom

Following a school-based measles-rubella vaccination campaign in November 1994, enhanced surveillance of measles, including IgM antibody testing of oral fluid from clinically diagnosed case-patients, was introduced in England and Wales. Between 1995 and 2001, 665 cases of measles were confirmed, including 371 (56%) confirmed only by IgM detection in oral fluid. Two hundred thirty-nine cases (36%) were sporadic and 426 (64%) were associated with 61 clusters. Fifty-four (23%) of the 239 sporadic cases and 26 (43%) of the 61 clusters were associated with a probable or possible importation of infection from overseas, and a wide variety of genotypes were identified in each calendar year. The effective reproduction number for measles over the period was estimated to be below 0.7. These data suggest that most measles in the United Kingdom is acquired following limited transmission from an imported infection, and they confirm that measles elimination has been achieved and sustained over this period.

In 1968, the United Kingdom introduced measles vac- of the incidence of a specified disease in a defined ge- cine for children between the ages of 1 and 2 years, but ographical area,” but recent work suggests that the ab- throughout the 1970s and early 1980s, coverage re- sence of sustained transmission may be a more realistic mained below 80%. In 1988, the combined measles- definition [5]. mumps-rubella (MMR) vaccine was introduced in Before the 1994 mass vaccination campaign, measles place of measles vaccine for children 13–15 months of surveillance in England and Wales relied upon the no- age, and coverage improved to over 90%. Measles no- tification of clinically diagnosed cases to the Office of tifications declined to low levels, but in November 1994, National Statistics and upon reports of serologically all children aged 5–16 years in England and Wales were confirmed cases by laboratories to the Public Health offered combined measles-rubella vaccine in an attempt Laboratory Service (PHLS) Communicable Disease to prevent a predicted epidemic [1]. This approach rep- Surveillance Centre (CDSC). During 1991–1994, a resented the first mass vaccination campaign in an in- study confirmed measles infection in ∼40% of clinically dustrialized country, although similar approaches had diagnosed notified cases by the detection of measles been widely used in Latin America [2, 3]. By the end IgM in serum and demonstrated the sensitivity and of December 1994, 92% of school children had received specificity of an oral fluid assay [6]. After the vacci- measles-rubella vaccine [4]. The aim of the campaign nation campaign, surveillance was enhanced by follow- was to hasten the elimination of measles. Elimination has been previously defined as “the reduction to zero up all of notified cases with the offer of an IgM test on oral fluid [7]. Specimens from IgM-positive cases were also tested by reverse transcription–polymerase chain reaction (RT-PCR) for measles genome [8, 9]. Reprints or correspondence: Dr. Mary E. Ramsay, Immunisation Division, PHLS Communicable Disease Surveillance Centre, 61 Colindale Ave., London NW9 5EQ, This report summarizes the effect of the campaign on United Kingdom ([email protected]). the epidemiology and origin of confirmed measles since The Journal of Infectious Diseases 2003;187(Suppl 1):S198–207 1995 and demonstrates the interruption of sustained 2003 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2003/18710S-0031$15.00 indigenous transmission in the United Kingdom.

S198 • JID 2003:187 (Suppl 1) • Ramsay et al. MATERIALS AND METHODS the United Kingdom were defined as possibly imported. Spo- radic cases who had no travel history but who did have contact Measles is a notifiable disease in England and Wales. Practi- with a traveler with a rash illness were defined as import-related. tioners who diagnose measles are required by statute to report Clusters were defined on the basis of known contact between the case to the proper officer of the local authority (usually the cases or if attendance at the same event or the same institution Consultant in Communicable Disease Control [CCDC]). Sup- (e.g., hospital, university) occurred during the appropriate pe- plies of oral fluid testing kits have been distributed to the CCDC riod. Other confirmed cases were defined as possibly linked to in all health authorities. When a case is notified, a kit is sent a cluster if no definite history of contact was obtained but cases to the reporting doctor with a request for a sample of oral were linked geographically and in time. All cases in clusters in fluid. It is recommended that the sample be obtained within which the index case was a probable import or an import- 6 weeks of onset by the practice nurse, doctor, parent, or patient related case were classified as import-related; This classification Downloaded from https://academic.oup.com/jid/article/187/Supplement_1/S198/2043868 by guest on 02 October 2021 and be posted in a reply-paid box to the PHLS Enteric, Res- was not extended to contacts of possible import cases. piratory and Neurological Virus Laboratory (ERNVL) [7]. Re- PCR was used to amplify viral genome in oral fluid, whole sults are returned to the CCDC and general practitioner. For blood, or urine samples of IgM-positive cases. PCR products IgM-positive cases without a history of recent vaccination, a were sequenced as previously described [8, 9], and measles confirmatory serum sample is requested. For cases in preschool strains detected were classified according to World Health Or- children with a low positive IgM (test/negative ratio of below ganization (WHO) nomenclature for wild measles virus ge- 10.0), a second oral fluid sample is requested. Cases IgM pos- notypes [11]. A phylogenetic tree was constructed by analyzing itive by oral fluid testing but either IgM negative on serum the 450-nucleotide region of the H gene sequence [12], using sample testing or IgG and IgM negative on a second oral fluid the clustal method (Megalign program; DNASTAR). sample are excluded, as are cases with a low positive IgM for Each sporadic case and each cluster was designated a measles whom further investigation is not conducted. event. Genotypes associated with each measles event were an- Confirmed measles infections are reported by laboratories in alyzed by quarter of onset (taken from the onset date of the England and Wales (including ERNVL) to the CDSC, and the sporadic case or for the first case in the cluster). Clusters with reported information includes the method of confirmation. For more than one genotype identified were subsequently redefined all reports of measles since 1995 from laboratories other than as two events. ERNVL, an aliquot of serum was requested for further testing at ERNVL. Cases that were IgM positive at the source laboratory but negative at ERNVL were tested by a third IgM assay and RESULTS included if two assays were positive. Cases reported by laboratories with a high titer of measles IgG on a single serum An oral fluid sample was received for 19,060 (66%) cases pro- specimen or by detection of measles antigen in a clinical spec- visionally notified between 1995–2001 (table 1). The annual imen (such as nasopharyngeal aspirate) by immunofluoresc- number of notifications has declined each year, although the ence were excluded unless serum or oral fluid were also con- number of cases reported was higher in the first 2 quarters firmed to be IgM positive [10]. The case definition is therefore than in the second 2 quarters of each year. The proportion of a doctor-diagnosed case of measles that has been confirmed by notified cases that was investigated by oral fluid testing was the detection of measles IgM in oral fluid or serum or by the high throughout the period. The proportion found to be IgM detection of a 4-fold rise in measles IgG in serum. Cases with positive was low, at !10% in all quarters except for the final a history of a measles-containing vaccine in the 6 weeks before quarter of 1997. onset are excluded. A total of 576 cases confirmed IgM positive by oral fluid For all confirmed cases, additional details, including vacci- testing had onset dates in the study period, including 564 cases nation status (if not supplied on the request form), contact notified between 1995 and 2001 (table 1), 1 case notified in history, and history of travel, are requested from the general 2002, and 11 cases for which oral fluid was sent (usually by a practitioner. Missing vaccine histories for children !15 years hospital microbiologist) directly to ERNVL. One hundred of age are also checked on the computerized child health system eleven cases were excluded because of a recent history of vac- for the health authority. If the practitioner and the child health cination, and a further 33 cases were excluded because the initial system have no record of vaccination with measles, measles- sample result was thought to be a false positive. This included rubella, or MMR vaccine, the case is recorded as unvaccinated. 5 cases for whom a serum sample tested IgM negative and 29 Cases were defined as probably imported if the case-patient cases (including 24 in children !18 months of age) for whom was overseas for the full length of the incubation period (7–21 the IgM result was low positive (in 19, a second oral fluid days before onset). Cases among patients who had traveled sample was IgM and IgG negative; in 5, the result could not during this period but that also could have been acquired in be repeated on the initial sample; and in 4, a further sample

Elimination of Measles Transmission in England and Wales • JID 2003:187 (Suppl 1) • S199 Table 1. Investigation of notified measles cases by saliva test- At the end of follow-up, 285 (43%) of the 665 cases had ing in England and Wales, 1995–2001. been confirmed by detection of IgM in serum, 9 (1.4%) by No. tested by oral fluid sample detection of a 4-fold rise in antibody, and 371 (56%) only by IgM detection in у1 oral fluid specimens. One hundred thirty- Year, No. IgM IgM quarter notified Total (%) negative positive (%) one (35%) cases that were confirmed only by oral fluid testing 1995-1 2777 1781 (64) 1744 37 (2.1) were also positive for measles RNA by PCR, including 74 (61%) 1995-2 2018 1276 (63) 1265 11 (0.9) of 121 of those for which the sample was obtained within 2 1995-3 1524 929 (61) 913 16 (1.7) weeks of onset. 1995-4 1449 802 (55) 788 14 (1.7) Trends in the numbers of confirmed cases have not paralleled 1996-1 1963 1107 (56) 1088 19 (1.7) those among notified cases, and substantial increases in the Downloaded from https://academic.oup.com/jid/article/187/Supplement_1/S198/2043868 by guest on 02 October 2021 1996-2 1695 1034 (61) 993 41 (4.0) numbers of confirmed cases have not been reflected in an in- 1996-3 1125 738 (66) 718 20 (2.7) crease in the total number of notifications (e.g., 4th quarter 1996-4 1095 747 (68) 743 4 (0.5) 1997; table 1). The proportion of cases first tested by using oral 1997-1 1098 768 (70) 756 12 (1.6) fluid as opposed to serum was higher in children than in adults 1997-2 1140 693 (61) 680 13 (1.9) 1997-3 951 605 (64) 582 23 (3.8) (table 2). 1997-4 986 718 (73) 601 117 (16) Of the 665 confirmed cases, 239 (36%) were sporadic and 1998-1 1260 823 (65) 788 35 (4.3) 426 (64%) were associated with 61 clusters. An additional 69 1998-2 1100 759 (69) 748 11 (1.4) cases in which oral fluid specimens were obtained too late to 1998-3 820 489 (60) 483 6 (1.2) reliably detect IgM and 49 cases that occurred outside of the 1998-4 724 459 (63) 453 6 (1.3) study period were epidemiologically linked to these clusters. 1999-1 727 429 (59) 419 10 (2.3) Including these epidemiologically linked cases, most clusters 1999-2 650 432 (66) 424 8 (1.9) involved !5 cases (figure 1). On the basis of the distribution 1999-3 601 389 (65) 377 12 (3.1) of outbreak size during 1995–2001 [5], the estimated effective 1999-4 519 426 (82) 403 23 (5.4) reproduction number for measles in England and Wales was 2000-1 747 530 (71) 486 44 (8.3) 2000-2 691 502 (73) 472 30 (6.0) between 0.6 and 0.7. 1 2000-3 563 392 (70) 376 16 (4.0) There were 4 clusters that involved 25 cases; all occurred 2000-4 467 349 (75) 342 7 (2.0) in populations with low vaccine coverage. The largest outbreak 2001-1 741 598 (81) 592 6 (1.0) occurred between August 1997 and March 1998 in an unvac- 2001-2 572 456 (80) 450 6 (1.3) cinated community that follows the teachings of Rudolph 2001-3 466 347 (74) 340 7 (2.0) Steiner, an Austrian philosopher with a holistic view of human 2001-4 528 482 (91) 466 16 (3.3) life; this outbreak involved 142 confirmed cases in 4 different Total 28,997 19,060 (66) 18,490 570 (3.0) geographic locations and five schools [13]. Two further outbreaks occurred at the end of 1999 and early 2000 in poorly was not provided). Of the remaining 432 cases, 11 had already vaccinated religious communities in northwestern England and been confirmed by earlier serum testing. This left a total of 421 in London, with 41 and 43 cases, respectively [14]. The final infections first confirmed by testing oral fluid. cluster started in late 2001 with 5 cases in a nursery school in In addition to cases confirmed by testing oral fluid, a total inner London, a population where coverage of MMR vaccine of 186 infections with onset in the study period were reported has declined in recent years. During 2002, further cases were from laboratories in England and Wales. At the time of report, observed and an outbreak of ∼50 cases involving children in 65 were serum IgM positive, 21 had a 4-fold rise in serum the local community and at neighboring primary schools oc- measles IgG antibody, 17 had been confirmed by immunoflu- curred (see http://www.phls.org.uk/publications/cdr/archive02/ orescence in clinical samples, and 83 had a high single titer of News/news1302.html#measles). In two other large clusters that measles IgG in serum. One hundred cases were subsequently occurred in greater London (one of 18 and one of 22 cases), excluded; 50 were found to be IgM negative on serum testing, many of the case-patients did not have definite contact but 6 were IgM negative by oral fluid testing, and 44 that were not were classified as possibly linked because they occurred in ge- investigated further were excluded because of the use of a non- ographic and temporal proximity to each other. specific assay at the source laboratory (a single high IgG or Twenty-four clusters were associated with 11 case in an in- immunofluorescence). A further 158 infections were confirmed stitution: 10 were associated with a hospital, 6 with a university, as serum IgM positive from samples submitted directly to 3 with a nursery, and 5 with a school. Of the 5 clusters involving ERNVL, giving a total of 244 cases first confirmed by serology schools, 1 comprising 4 cases occurred in a primary school with onset between January 1995 and December 2001. after the index case was imported from Australia, 2 cases oc-

S200 • JID 2003:187 (Suppl 1) • Ramsay et al. Table 2. Confirmed measles cases by method of first confirmation, age group, sex, and vaccination status in England and Wales, 1995–2000.

Method of Population Average Total no. conﬁrmation, no. (%) Sex, no. (%) Age group, of cases estimate, annual years (% vaccinated) Oral ﬂuid Serum Male Female Unknown mid-1997 rate/100,000 !1 40 (1) 23 (58) 17 (43) 14 (35) 24 (60) 2 651,112 0.88 1–4 175 (18) 130 (74) 45 (26) 86 (49) 84 (48) 5 2,631,631 0.95 5–9 104 (6) 95 (91) 9 (8.7) 46 (44) 57 (55) 1 3,474,631 0.43 10–14 74 (2) 63 (85) 11 (15) 35 (47) 39 (53) 0 3,276,221 0.32 15–19 72 (9) 44 (61) 28 (39) 36 (50) 36 (50) 0 3,154,819 0.33 20–24 87 (9) 31 (36) 56 (64) 32 (37) 45 (52) 10 3,176,939 0.39 Downloaded from https://academic.oup.com/jid/article/187/Supplement_1/S198/2043868 by guest on 02 October 2021 25–29 49 (1) 16 (33) 33 (67) 23 (47) 24 (49) 2 3,971,894 0.18 30–34 24 (3) 9 (38) 15 (63) 13 (54) 10 (42) 1 4,317,916 0.08 у35 32 (0) 7 (22) 25 (78) 13 (41) 19 (59) 0 27,556,012 0.02 Unknown 8 (0) 3 5 4 4 0 Total 665 (49) 421 (63) 244 (37) 302 (45) 342 (51) 21 52,211,175 0.18

curred in residential schools for overseas students (with index Nepal, 2). Five importations were observed from the Western cases imported from Germany and Russia, respectively), and 2 Pacific Region (Indonesia, 1; Japan, 2; Malaysia, 2) and 3 from were in Steiner schools (one cluster involving five schools in the African Region (Ghana, Kenya, and South Africa, 1 each). 1997 and a further cluster in one school in 1999). The re- Another case-patient had traveled in both Africa and Europe maining 37 clusters were based mainly either in the community during the incubation period. A further 10 sporadic cases were or in a single family. possible imports (7 from Europe, 1 from the Western Pacific The average annual incidence of confirmed infection was Region [Australia], 1 from the Americas [United States], and 0.18/100,000 population and the incidence was !1/100,000 in 1 from an unspecified country). Of the 61 clusters, 26 (43%) each age group (table 2). The number of infected females involving 108 cases arose following a probable or possible im- slightly exceeded the number of males. Of 665 case-patients, ported case. A total of 13 clusters arose after probable imports 49 (7.4%) had received a measles-containing vaccine, but none (5 from the European Region [France, Germany, Ireland, Rus- of the confirmed cases had received two or more doses. Analysis sia, and Switzerland], 4 from the Eastern Mediterranean Region of cases by year of birth showed a difference between cases in [Pakistan, 3 cases; United Arab Emirates, 1], 1 from the South- the large Steiner outbreak compared with those in the general east Asian Region [India], 1 from the Americas [United States population (figure 2). Excluding the Steiner outbreak, very and Canada], and 2 from the Western Pacific Region [Australia small numbers of cases were observed in people born between and Thailand]). A further 13 clusters arose after possible im- 1979 and 1990—the population targeted for the measles-rubella ports (8 from the European Region). On the basis of the total campaign. Higher numbers of cases occurred in children and number of cases (n p 162 ) arising from these 80 known pos- adults born between 1971 and 1979, who would have been sible or probable imports in 1995–2001 [5], the estimated ef- eligible for single-antigen measles vaccine, but coverage with fective reproductive number for measles was 0.51. this vaccine was !70% in the 1970s. Cases were also observed In 5 sporadic cases and 1 cluster, contact with an imported in children born after 1991 who were scheduled to have MMR case was implicated (import related) (2 cases from Europe, 1 at between 13 and 15 months of age; a second dose of MMR from the Southeast Asian Region, and 2 in language schools at preschool age (3.5–4 years) was not introduced until October for overseas students from many countries). The single cluster 1996. of 4 cases was observed following a case with contact with a Importations. Fifty-four (23%) of the 239 sporadic cases US member of a Steiner community who had traveled through were associated with importation of infection from overseas. several countries. Forty-four sporadic cases were probable imports and originated Genotyping. Genotyping of viral RNA from 234 case-pa- from all WHO regions except the Americas. The highest num- tients (67 sporadic cases and 167 cases in 45 clusters) was ber of probable imported cases (n p 17 ) arose in the European performed: 13 distinct genotypes were identified. Measles ge- Region (Albania, 1 case; France, 2; Germany, 2; Greece, 1; Italy, notypes are defined on the basis of the H and N genes, and 1; Ireland, 3; Poland, 1; Spain, 2; Turkey, 4), but 8 cases arose these genes may contain up to 7% variability at the nucleotide in the Eastern Mediterranean (Pakistan, 7; Oman, 1) and 10 level [11]. According to the divergence based on the sequence arose in the Southeast Asian Region (Bangladesh, 3; India, 5; of the most variable region of the H gene (450 nt), the diver-

Elimination of Measles Transmission in England and Wales • JID 2003:187 (Suppl 1) • S201 Downloaded from https://academic.oup.com/jid/article/187/Supplement_1/S198/2043868 by guest on 02 October 2021

Figure 1. Distribution of cluster size for confirmed and epidemiologically linked measles cases—England and Wales, 1995–2001 gence between the UK genotypes shows up to 10%. Even within notype was D6; this genotype was associated with many events genotypes, considerable diversity (up to 2%) in strain sequences in 1996 and 1997 but has not been observed since mid-2000. was observed in sporadic UK cases. During 1999–2000, D8 became the commonest type, despite In 32 clusters, viral RNA from 11 case (range, 2–32) was only one identification of this type in 1995–1998. Genotype C2 genotyped. The same genotype was detected in all cases in 28 was not identified after mid-1998, and genotypes D4 and D5 clusters, and different genotypes were detected for 4 clusters. showed no clear trend with time. Two of these clusters occurred in universities. In one university The distribution of genotypes in cases with a probable or cluster, viral RNA from all 4 cases was genotyped, and the final possible association with importation was similar to those in case-patient, who had traveled to Greece and had onset 19 days cases without a recognized link (table 3). Genotype D4 was the after the third case, had a different genotype than the other 3 commonest imported strain and was associated mainly with patients. In the other university, viral RNA from all 5 cases was importation from the Indian subcontinent (table 4). Genotypes genotyped, and the first 2 case-patients had a different genotype C2, D2, D6, and D7 were only linked to importations from than the final 3 (no history of travel was obtained). Another Europe; however, C2 was detected in 1 case-patient who had cluster involved 22 cases in greater London, and genotyping also traveled in sub-Saharan Africa and D2 was detected in a was available for 11 of the case-patients. One of the early case- backpacker who had recently arrived in the United Kingdom, patients in this cluster had a history of possible importation but the countries previously visited by this person were not from Yugoslavia, and this case had the same genotype as 8 specified. Genotype D8 was associated with importations from other case-patients in the cluster. Two cases that occurred mid- the Indian subcontinent across the period but also arose from way through the cluster, with onset dates within 2 weeks of the Balkans and from Oman during 1998. In a similar manner, each other, shared a genotype that was distinct from the rest genotype D5 was associated with importation from the Far East of the cluster; 1 of these case-patients had recently arrived in across the period but from the Indian subcontinent in 2000 the United Kingdom, but the source country was not known. and from South America in 2001. Region of origin is less clear In the remaining cluster, the 2 cases occurred 3 weeks apart in for genotype G2, which was associated with a single importation a town in northwestern England. The first case had been ac- from the Far East in 1997 and with importation from several quired following contact with an Irish cousin, but the strain distinct regions during 2000. identified in the second case had a distinct genotype. These 4 clusters were therefore reclassified into eight events. DISCUSSION Analysis of the genotypes associated with each event showed a wide variety over the surveillance period (table 3). For each The advent of testing oral fluid has transformed the surveillance genotype, a period of at least 4 quarters occurred during which of measles in England and Wales. Despite a decline in the no identifications were made. In 20 of the 28 quarters, more numbers of notified cases, the proportion of cases tested re- than one genotype was identified in association with one or mains high, and the proportion confirmed is low. With the more measles events. Five genotypes (C2, D4, D5, D6, D8) current epidemiology of measles, clinical notifications of mea- were identified in more than 10 events. The commonest ge- sles do not reflect true trends in the incidence of measles in-

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Figure 2. Confirmed measles cases by year of birth—England and Wales, 1995–2001. Case-patients born before 1960 have been excluded. fection. The acceptability of noninvasive testing, particularly in dose of MMR vaccine. Coverage of first-dose MMR was 190% children, allows a unique surveillance system that combines the until 1998, and a second dose of MMR was introduced for sensitivity of a clinical diagnosis together with the specificity preschool children in October 1996. The routine second dose of laboratory investigation. will be expected to help prevent such cases in the future, but With a sensitivity of 92% and a specificity of at least 98%, a recent decline in first-dose MMR coverage to 84% (http:// the IgM test on oral fluid is adequate for surveillance, but false- www.phls.org.uk/publications/cdr/pages/immunisation.html# positive and -negative results may occur [6]. The sensitivity of COVER) will have left a larger proportion of younger cohorts oral fluid testing in this study is supported by the high pro- unprotected. So far, however, only one substantial outbreak has portion of cases in the Steiner outbreak that were confirmed been observed in this age group (http://www.phls.org.uk/ positive for IgM on oral fluid testing [13]. False-positive results publications/cdr/archive02/News/news1302.html#measles). are likely to be a greater problem when the incidence of true The low number of cases and the small number of large measles is low, a time when a low predictive value becomes an clusters observed suggests that herd immunity in England and issue for all diagnostic strategies [10]. By following the con- Wales is high. The largest cluster was observed in a community firmatory strategy, a high number of cases tested by oral fluid with low vaccine coverage but did not spread to involve the were also confirmed by serum IgM or RNA detection, sug- general community, confirming the high level of herd immunity gesting that false-positive results were uncommon. Most false- [13]. Other large clusters occurred in inner London, where positive test results on oral fluid were observed in infants and exposure to people who have traveled to and from endemic young children who had low levels of IgM in the initial oral countries is likely to be common. The finding of two distinct fluid sample. In most cases, a second sample of oral fluid was genotypes in one of these clusters suggests that the observation negative for both IgM and IgG, excluding true infection. False- of large clusters in such settings may be explained by multiple positive IgM results, however, may be a significant issue for importations rather than by sustained indigenous transmission. oral fluid testing and highlight the need to have a confirmatory Known importations form a large proportion of sporadic strategy. cases were responsible for several clusters. Importation was Given the highly sensitive methods of surveillance in England most commonly recognized from the Indian subcontinent and and Wales, the incidence of confirmed measles remains low. from Western Europe, probably reflecting the large volume of Cases are predominantly observed in unvaccinated children and travel to and from these regions. Many possible importations adults in age groups outside of that targeted in the school were recognized from short-term travel in Western Europe, but campaign in 1994. The success of the campaign is also reflected indigenous transmission could not be excluded. Short-term in the small number of clusters identified in schools. Small visitors to the United Kingdom from countries in Western Eu- numbers of cases have occurred in preschool age groups, and rope with high incidence of measles are probably common [5], some of these children have a documented history of a single and illness may only become recognized on return to their

Elimination of Measles Transmission in England and Wales • JID 2003:187 (Suppl 1) • S203 Table 3. Number of genotypes identiﬁed among measles events by quarter of onset in England and Wales, 1995–2001.

Genotype, no. identiﬁed Year, Total quarter AB2B3C2D2D3D4D5D6D7D8G2H no. 1995-1 0 0 0 0 0 0 2 (1) 0 1 0 0 0 0 3 (1) 1995-2 0 0 0 1 0 0 1 0 0 0 1 (1) 0 0 3 (1) 1995-3 0 0 0 0 0 0 0 1 (1) 0 0 0 0 0 1 (1) 1995-4 0 0 0 0 0 0 1 (1) 0 0 0 0 0 0 1 (1) 1996-1 0 0 0 1 (1) 0 0 3 (1) 0 1 (1) 0 0 0 0 5 (3) 1996-2 2 0 0 2 0 1 2 (1) 0 7 (2) 0 0 0 1 15 (3) 1996-3 0 0 0 2 0 0 0 0 4 0 0 0 0 6 (0) Downloaded from https://academic.oup.com/jid/article/187/Supplement_1/S198/2043868 by guest on 02 October 2021 1996-4 0 0 0 0 0 0 0 0 1 0 0 0 0 1 (0) 1997-1 0 0 0 1 0 0 1 (1) 0 1 0 0 0 0 3 (1) 1997-2 0 0 0 1 (1) 0 0 0 0 3 0 0 1 (1) 0 5 (2) 1997-3 0 0 0 0 0 0 0 1 (1) 2 0 0 0 0 3 (1) 1997-4 0 0 0 0 0 0 0 0 0 0 0 0 0 0 (0) 1998-1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 (0) 1998-2 0 0 0 2 (1) 0 0 1 (1) 0 0 0 0 0 0 3 (2) 1998-3 1 (1) 2 0 0 0 0 0 0 0 0 0 0 0 3 (1) 1998-4 0 0 0 0 0 0 1 (1) 0 2 (1) 0 0 0 0 3 (2) 1999-1 0 0 0 0 0 0 0 0 1 (1) 0 3 (1) 0 0 4 (2) 1999-2 0 0 0 0 0 1 0 0 0 0 5 (2) 0 0 6 (2) 1999-3 0 0 0 0 2 (2) 0 1 0 0 0 2 (1) 0 0 5 (3) 1999-4 0 0 0 0 0 0 0 0 1 0 0 0 0 1 (0) 2000-1 0 0 0 0 0 0 1 (1) 0 1 0 2 0 0 4 (1) 2000-2 1 0 0 0 2 (2) 0 4 (3) 0 4 0 2 (1) 0 0 13 (6) 2000-3 0 0 0 0 0 0 0 2 (1) 0 0 1 1 1 (1) 5 (2) 2000-4 0 0 0 0 0 0 0 0 0 0 0 4 (3) 0 4 (3) 2001-1 0 0 0 0 0 0 1 (1) 0 0 0 0 0 0 1 (1) 2001-2 0 0 0 0 1 0 4 0 0 1 (1) 0 0 0 6 (1) 2001-3 0 0 0 0 0 0 0 1 (1) 0 2 (1) 1 (1) 1 (1) 0 5 (4) 2001-4 0 0 1 0 0 0 0 6 (2) 0 0 0 0 0 7 (2) Total 4 (1) 2 (0) 1 (0) 10 (3) 5 (4) 2 (0) 23 (12) 11 (6) 29 (5) 3 (2) 17 (7) 7 (5) 2 (1) 116 (46)

NOTE. Data in parentheses represent the number that were imported or import related. home country. Because of the delay between onset and con- also positive for measles RNA, particularly if obtained in the firmation, case-patients could not always be contacted to obtain first 2 weeks after onset. The potentially important role for oral travel histories, and nonresidents of the United Kingdom may fluid testing in measles surveillance therefore includes both have returned to their country of origin. The number of ob- confirming the diagnosis and characterizing the virus strain on served infections linked to importation, therefore, is likely to a single noninvasive sample. underestimate the true number of cases to a greater extent than Identification of measles strains in the United Kingdom prior for indigenous cases. Despite this underascertainment, the to the 1994 campaign [9] confirmed that genotypes D6 and number of cases arising from known importations is consistent C2 were the predominant strains circulating, and these types with a low effective reproduction number and with elimination were probably shared with the rest of Europe [15–17]. Between of measles in England and Wales [5]. 1995 and 2001, the most common strain observed was genotype In addition to confirming the diagnosis by IgM detection, D6, and an increase in this genotype was associated with im- oral fluid specimens were useful for detecting measles virus portations from Europe in early 1996. This coincided with an genome by RT-PCR. The source of the viral RNA in oral fluid increase in measles incidence in Greece [18], and D6 strains is not clear, but most likely originates in the upper respiratory were reported as causing an outbreak in Germany in 1996 [16], tract. A high proportion of IgM-positive oral fluid samples were importations into Luxembourg from Italy, and importations

S204 • JID 2003:187 (Suppl 1) • Ramsay et al. Table 4. Measles genotypes linked to importation or import-related events in England and Wales.

No. of Genotype events Nature of link, implicated country(ies), and year(s) A 1 Recently arrived student from Russia, 1998 C2 3 University cluster; index case took day trip to France, 1996 Air steward traveling in Western Europe, 1997 Traveler arrived from Africa via Western Europe, 1998 D2 4 Community cluster; index case had recently arrived in the United Kingdom (country not speciﬁed), 1999 Recent contact with visitor from Spain, 1999

Recent contact with Irish relatives, 2000 Downloaded from https://academic.oup.com/jid/article/187/Supplement_1/S198/2043868 by guest on 02 October 2021 Recent travel to Ireland, 2000 D4 12 Recent travel to Pakistan, 1996, 1996, and 2000 Recent travel to India, 1995, 1997, 2000, and 2000 Recent arrival from Pakistan, 1998, 1998 Recent contact with relatives from Pakistan, 2000 Family cluster arising after holiday in United States, 1995 Hospital cluster; index case had visitors from Afghanistan, 2001 D5 6 Acquired in language school for overseas students, 1995 Recent arrival from Malaysia, 1997 Recent travel to Bangladesh, 2000 Hospital cluster; index case recently traveled to Thailand, 2001 University cluster; index case from South American community, 2001 Family cluster; index case recent travel to Argentina, 2001 D6 5 University cluster; student recently arrived from Greece, 1996 Student recently returned from Greece, 1996 Contact with infected sibling in Germany, 1996 Recent arrival from Poland, 1999 Recent travel to Ireland, 1999 D7 2 Family cluster after recent travel to France, 2001 Recent travel to Spain, 2001 D8 7 Community cluster; index case recently traveled to Pakistan, 1995 Recent missionary work in India, 1999 Community cluster following arrival from Yugoslavia, 1998 Recent work in refugee camps in Albania, 1998 Contact with case in Oman, 1998 Recent travel to Bangladesh, 2000 Contact with visitor from Pakistan, 2001 G2 5 Recent arrival from Indonesia, 1997 Community cluster; index case had visitors from South Africa, 2000 Hospital cluster; index case had recent travel to Mexico, 2000 Nurse exposed to rash on recent arrival from Australia, 2000 School cluster; index case recently traveled to Australia, 2000 H 1 Contact with US member of Steiner community, 2000

into the United States from several Western European countries were reported in 1996–1997 in Luxembourg and Denmark [15, [15, 19]. These observations confirm the conclusion that ge- 16], coinciding with most C2 identifications in England. The notype D6 was the predominant genotype in Western Europe. identification of genotype A from Russia and genotype D7 from In this survey, evidence of C2 strains being imported from Western Europe corresponds to the geographic distribution Western Europe was less compelling, but cases of C2 infection previously described [16, 20]. Genotype D4 was associated with

Elimination of Measles Transmission in England and Wales • JID 2003:187 (Suppl 1) • S205 several importations from the Indian subcontinent [19], and of MMR. The ability to maintain this level of measles control, since travel between this region and the United Kingdom is in the face of frequent importations from neighboring coun- common, it perhaps explains the frequent identification of this tries, will require continued high coverage with two doses of strain. The identification of genotype D8 in 1999–2000 is more measles-containing vaccines. The recent decline in first-dose interesting because importations from south Asia, the Middle MMR coverage, which is associated with unfounded concerns East, and the Balkans were associated with this genotype at that about vaccine safety [26], illustrates the difficulty with sustain- time. The same type was identified in Ethiopia in 1998–1999 ing a successful program in the absence of natural disease. The [21], and some importations may reflect the increase in measles continued threat of measles becoming reestablished in the observed during 1998 in both the African and Eastern Medi- United Kingdom can only be avoided by a global effort to terranean regions [18]. Although genotyping has been useful control measles. The acceptance of a measles elimination target Downloaded from https://academic.oup.com/jid/article/187/Supplement_1/S198/2043868 by guest on 02 October 2021 in describing measles diversity, we have not been able to at- in several WHO regions [14, 27], and most importantly in tribute all of the less common genotypes to importation from Europe [28], is therefore to be welcomed. specific regions. Genotype D2, previously described in South Africa [22], and genotypes G2 and D5, previously linked to the Acknowledgments Far East [19, 20, 23], were associated with possible importations from other regions. A lack of consistent findings over time will The authors gratefully acknowledge the help of all the pa- probably reflect the reimportation of strains from endemic areas tients as well as the Consultants in Communicable Disease into those populations that had interrupted measles transmis- Control, general practitioners, and their teams who participate sion, such the Americas. The wide diversity of genotypes, the in the oral fluid testing scheme. In addition, the role of hospital absence of each genotype for prolonged periods of time, and clinicians, microbiologists and their staff who report confirmed the finding of a similar distribution of genotypes in indigenous measles cases and refer specimens for confirmation is recog- and imported cases, however, supports the belief that most cases nized. We also thank David Little for estimating the effective in England and Wales arise from importation of infection. reproduction numbers and Carol Parker and Doreen Moffat In addition to the pattern of importation and the high pro- for data entry on the survey. portion of sporadic cases with distinct genotypes, the small cluster size observed is consistent with a low effective repro- References duction number and compatible with measles elimination [5, 1. Ramsay M, Gay N, Miller E, et al. The epidemiology of measles in 24]. It has been suggested that surveillance in the United King- England and Wales: rationale for the 1994 national vaccination cam- dom may underestimate cluster size because of failure to iden- paign. Commun Dis Rep CDR Rev 1994; 4:R141–6. tify links between cases [24]. The data presented here indicate 2. de Quadros C, Olive J, Hersh B, et al. Measles elimination in the Americas evolving strategies. JAMA 1996; 275:224–9. that we have had a low threshold for attributing links between 3. Anonymous. Role of mass campaigns in global measles control. Global cases on the basis of proximity in time and place. The obser- Programme for Vaccines of the World Health Organization. Lancet vation of two distinct genotypes in four clusters suggests that 1994; 344:174–5. 4. Salisbury DM, Horsley SD. Measles campaign. BMJ 1995; 310:1334. we may be overestimating outbreak size. The absence of links 5. De Serres G, Gay NJ, Farrington CP. Epidemiology of transmissible between sporadic cases is also supported by the diversity of diseases after elimination. Am J Epidemiol 2000; 151:1039–48. measles genotypes observed in each quarter. Even within ge- 6. Brown DW, Ramsay ME, Richards AF, Miller E. Salivary diagnosis of measles: a study of notified cases in the United Kingdom, 1991–3. BMJ notypes, considerable diversity was observed among strains de- 1994; 308:1015–7. tected in sporadic cases, suggesting that direct transmission 7. Ramsay M, Brugha R, Brown D. Surveillance of measles in England between such cases was not occurring. When travel to and from and Wales: implications of a national saliva testing programme. Bull measles-endemic countries (such as those in Western Europe World Health Organ 1997; 75:515–21. 8. Jin L, Richards A, Brown D. Development of a dual target-PCR for and the Indian subcontinent) is common, as it is in the United detection and characterization of measles virus in clinical specimens. Kingdom, then multiple importations will occur. With a sen- Molec Cell Probes 1996; 10:191–200. sitive surveillance system based on noninvasive testing, such as 9. Jin L, Brown DW, Ramsay ME, Rota PA, Bellini WJ. The diversity of measles virus in the United Kingdom, 1992–1995. J Gen Virol 1997; that described here, it is not surprising that large numbers of 78:1287–94. sporadic cases will be commonly observed. 10. Ramsay M, Cohen B, Brown D. Serum IgM testing is needed in all We believe that surveillance in England and Wales has clearly cases of suspected measles. BMJ 1996; 313:231. 11. Anonymous. Expanded Programme on Immunization (EPI). Stan- demonstrated the absence of sustained indigenous transmission dardization of the nomenclature for describing the genetic character- and therefore the elimination of measles. Interruption of trans- istics of wild-type measles viruses. Wkly Epidemiol Rec 1998; 73:265–9. mission has been achieved by high routine vaccination coverage 12. Jin L, Sun YJ, Ge L, Brown DW. Characterization of a new genotype of measles virus detected in China and England. Epidemiol Infect for MMR, a successful campaign using measles-rubella vaccine 1998; 121:691–7. in older children [4, 25], and the introduction of a second dose 13. Hanratty B, Holt T, Duffell E, et al. UK measles outbreak in non-

S206 • JID 2003:187 (Suppl 1) • Ramsay et al. immune anthroposophic communities: the implications for the elim- 22. Kreis S, Vardas E, Whistler T. Sequence analysis of the nucleocapsid ination of measles from Europe. Epidemiol Infect 2000; 125:377–83. gene of measles virus isolates from South Africa identifies a new ge- 14. Anonymous. Outbreaks of measles in communication with low vaccine notype. J Gen Virol 1997; 78:1581–7. coverage. Commun Dis Rep CDR Wkly 2000; 10:29. 23. de Swart RL, Wertheim-Van Dillen PM, van Binnendijk RS, Muller 15. Hanses F, van Binnendijk R, Ammerlaan W, et al. Genetic variability CP, Frenkel J, Osterhaus AD. Measles in a Dutch hospital introduced of measles viruses circulating in the Benelux. Arch Virol 2000; 145: by an immuno-compromised infant from Indonesia infected with a 541–51. new virus genotype. Lancet 2000; 355:201–2. 16. Santibanez S, Heider A, Gerike E, Agafonov A, Schreier E. Genotyping 24. Hinman AR, Orenstein WA, Papania MJ. Invited commentary: epi- of measles virus isolates from central Europe and Russia. J Med Virol 1999; 58:313–20. demiology of transmissible diseases after elimination. Am J Epidemiol 17. Rima BK, Earle JA, Baczko K, et al. Sequence divergence of measles 2000; 151:1049–52. virus haemagglutinin during natural evolution and adaptation to cell 25. Gay N, Ramsay M, Cohen B, et al. The epidemiology of measles in culture. J Gen Virol 1997; 78:97–106. England and Wales since the 1994 vaccination campaign. Commun 18. World Health Organization. WHO vaccine preventable diseases: mon- Dis Rep CDR Rev 1997; 7:R17–21. Downloaded from https://academic.oup.com/jid/article/187/Supplement_1/S198/2043868 by guest on 02 October 2021 itoring system. 2000 global summary. Geneva: WHO, 2000 (WHO/ 26. Chief Medical Officer. Measles, measles mumps rubella (MMR) vac- V&B/00.32). cine, Crohn’s disease, and autism. London: Department of Health, 1998 19. Bellini WJ, Rota PA. Genetic diversity of wild-type measles viruses: (PL/CMO/98/2). implications for global measles elimination programs. Emerg Infect Dis 27. Hersh BS, Tambini G, Nogueira AC, de Quadros CA. Review of regional 1998; 4:29–35. measles surveillance data in the Americas, 1996–99. Lancet 2000; 355: 20. Anonymous. Nomenclature for describing the genetic characteristics 1943–8. of wild-type measles viruses (update). Part I. Wkly Epidemiol Rec 2001; 76:242–7. 28. Ramsay M. A strategic framework for the elimination of measles in 21. Nigatu W, Jin L, Cohen B, et al. Measles virus strains circulating in the European Region. Copenhagen: Expanded Programme on Im- Ethopia in 1998–1999: molecular characterisation using oral fluid sam- munization in the European Region of WHO, 1999 (EUR/ICP/CMDS ples and identification of a new genotype. J Med Virol 2001; 65:373–80. 01 01 05).

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