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Vaccine 29 (2011) 9141– 9147

Contents lists available at SciVerse ScienceDirect

Vaccine

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hort communication

ubella revisited: Where are we on the road to disease elimination in Centralurope?

ytautas Usonisa,∗, Ioana Ancab, Francis Andréc, Roman Chlibekd, Milan Cizmane,nga Ivaskevicienea, Atanas Mangarovf, Zsófia Mésznerg, Penka Perenovskah, Marko Pokorne,oman Prymulad,i, Darko Richter j, Nuran Salmank, Pavol Simurka l, Eda Tammm, Goran Tesovic n,

ngrid Urbancíkováo

Vilnius University Clinic of Children’s Diseases, Faculty of Medicine, Vilnius University, Vilnius, LithuaniaUniversity of Medicine and Pharmacy – Department of Pediatrics ‘Prof. Dr. Alfred Rusescu’ Institute for Mother and Child Care, Bucharest, RomaniaChaussée de Huy, 136, 1325 Chaumont-Gistoux, BelgiumFaculty of Military Health Sciences, University of Defense, Hradec Kralove, Czech RepublicDepartment of Infectious Diseases, University Medical Centre, Ljubljana, SloveniaInfectious Diseases Hospital, Sofia, BulgariaNational Institute of Child Health, Budapest, HungaryPediatric Clinic the University Hospital ‘Aleksandrovska’, Sofia, BulgariaUniversity Hospital Hradec Kralove, Czech RepublicDepartment of Pediatrics, University Hospital Center, Zagreb, CroatiaInfectious Disease and Clinical Microbiology, Institute of Child Health, Istanbul University, Istanbul, TurkeyPediatric Clinic, University Hospital, Trencin, SlovakiaChildren’s Clinic of Tartu University Hospital, EstoniaDepartment for Pediatric Infectious Diseases, University Hospital for Infectious Diseases, University of Zagreb, School of Medicine, Zagreb, CroatiaDepartment of Pediatric Infectious Diseases, Children’s Faculty Hospital, Kosice, Slovakia

r t i c l e i n f o

rticle history:eceived 27 January 2011eceived in revised form 7 September 2011ccepted 23 September 2011vailable online 3 October 2011

eywords:ubellaongenital rubella syndromeMR vaccination

entral Europe

a b s t r a c t

Rubella is a contagious viral disease with few complications except when contracted by pregnant women.Rubella infection in pregnancy can result in miscarriage, stillbirth or an infant born with congenital rubellasyndrome (CRS) which comprises deafness, heart disease, cataracts and other permanent congenitalmanifestations. Clinical diagnosis of rubella is difficult due to overlapping symptoms with many otherdiseases and confirmation of rubella is not possible without laboratory testing.

Effective vaccination programmes are critical to the elimination of rubella and prevention of CRS.Such programmes have been successful in several countries in Europe and around the world. However,rubella outbreaks still occur due to suboptimal vaccine coverage and in the past 10 years rubella has beenreported in Central European countries such as Romania and Poland. Over the past decade the eliminationof rubella and prevention of congenital rubella infection in Europe has been a high priority for the WHOEuropean Regional Office. In 2010 the WHO regional committee for Europe renewed its commitment tothe elimination of rubella and prevention of CRS with a new target of 2015.

This paper examines the current situation for rubella and CRS in Central Europe and describes the

different rubella vaccination programmes in the region. The Central European Vaccination Advisory Group(CEVAG) recommends that two doses of measles, mumps and rubella vaccine, MMR, should be given to allchildren. The first dose should be given between 12 and 15 months of age. The second dose can be givenbetween the ages of 21 months and 13 years with the exact age of administration of the second dosedepending on the situation specific to each country. All suspected rubella cases should be laboratory-confirmed and monitoring systems to detect and investigate cases of CRS should be strengthened.

∗ Corresponding author at: Vilnius University Centre of Paediatrics, Vilnius University CTel.: +370 5 2492414; fax: +370 5 2720368.

E-mail address: vytautas.usonis@mf.vu.lt (V. Usonis).

264-410X/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.oi:10.1016/j.vaccine.2011.09.104

© 2011 Elsevier Ltd. All rights reserved.

hildren’s Hospital, Santariskiu-7, LT-08406, Vilnius-21, Lithuania.

9 cine 29

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. Introduction

Rubella is of high public health importance due to the effect itas on the growth and development of an embryo or foetus whenregnant women are infected. Typically a mild childhood disease,ubella infection during early pregnancy may cause miscarriage,oetal death or birth of an infant with congenital rubella syndromeCRS), which comprises deafness, heart disease, cataracts and otherermanent congenital manifestations [1].

A highly effective attenuated live rubella vaccine was devel-ped over thirty years ago [2,3]. Although elimination of rubelland prevention of CRS can be achieved through effective vaccina-ion programmes as seen in the USA, Sweden and Finland, casesf rubella continue to be reported across the world [4–6]. In 2009

total of 121,344 rubella (clinical, epidemiological or laboratoryonfirmed) cases were reported from 167 countries [7,8].

The elimination of rubella and prevention of congenital rubellanfection in Europe has been a high priority for the WHO Euro-ean Regional Office for the past 10 years. In 2002 a strategic planas developed and implemented for the prevention of congeni-

al rubella infection with the target of <1 case of CRS per 100,000ive births by 2010 [9]. Three years later the strategy was revisedo include rubella elimination by 2010, defined as <1 indigenousase per 1,000,000 [10]. In September 2010 the WHO regionalommittee for Europe renewed its commitment to the elimina-ion of rubella and prevention of CRS with the new target of 201511].

The Central European Vaccination Advisory Group (CEVAG) con-ists of regional experts from eleven Central European countries:ulgaria, Croatia, the Czech Republic, Estonia, Hungary, Lithuania,oland, Romania, Slovakia, Slovenia and Turkey. The aim of CEVAGs to encourage the efficient and safe use of vaccines to prevent,ontrol and if possible eliminate infectious diseases in the region,y raising awareness of immunisation and through the compilationnd distribution of appropriate information. This report examineshe situation in 2009 in CEVAG countries and the progress towardslimination of rubella and CRS.

. Clinical features and diagnosis of rubella and CRS

Rubella-infected children generally have few symptoms; adultsay experience fever, headache, malaise and runny nose over a

eriod of 1–5 days that are associated with viraemia, before theppearance of a maculopapular rash. Rubella infection is oftensymptomatic; 20–50% of infections have minimal or no clinicalymptoms depending on the age at primary infection [3]. Followingxposure, the incubation period before onset of symptoms is usu-lly 14–18 days (with a range of 12–23 days). The most infectioustage is when the rash breaks out; however, the infected individuals potentially contagious for more than 2 weeks as the virus may behed over periods that range from 7 days before the rash to 14 daysfter its appearance. Infants with congenital infection shed virus forven longer periods, with large quantities of virus being detectedhrough nasopharyngeal secretions and urine for up to 1 year orven longer [12,13].

CRS may occur when a susceptible woman is infected withubella virus at any stage of her pregnancy, although infectionn early pregnancy (during the first 11 weeks) carries the greaterisk of CRS. Up to 85% of infants born to women who are infectedith rubella during the first 12 weeks of pregnancy develop CRS

3]. Rubella infection during the first trimester may also lead ton approximately 50% increase in spontaneous abortions or still-

irths [14]. Infection before the ninth week of pregnancy leadso congenital cataracts and heart disease, while infection betweenhe eleventh and seventeenth weeks may give rise to other singlenomalies and isolated sensorineural hearing defects [13,14].

(2011) 9141– 9147

Signs and symptoms of CRS may be recognisable at birth; how-ever, some manifestations of CRS may not be detected for monthsor years. Cases of CRS may go unrecognised due to late onset ofsymptoms in infants and children.

2.1. Diagnosis of rubella and CRS

Rubella is one of the many diseases causing maculopapularrash with fever, and so clinical diagnosis is unreliable. Due tooverlapping symptoms, differential diagnosis of rubella from otherdiseases such as measles, dengue, parvovirus B19, human herpesvirus 6, Coxsackie, Echo, Ross River, Chikungunya, entero and ade-noviruses, and Streptococcus group A (beta haemolytic) remainsdifficult in young children. Laboratory testing is essential for con-firmation of rubella infection [12,13,15].

In order to identify CRS cases in infants, it is important to inves-tigate rash illness in pregnant women. This is the most practical incountries where women attend antenatal clinics during the first 16weeks of pregnancy [12]. Women with a history of rubella vacci-nation should also be tested since vaccination failures can occur invaccinees [3].

3. Rubella vaccination – a success story in some countries

Changes in the epidemiology of rubella and CRS were noted afterthe introduction of effective vaccination programmes. Highly effec-tive programmes have been implemented in a number of countriesincluding the USA, Sweden and Finland, eliminating indigenousdisease [4–6].

Endemic rubella was eliminated in the USA in 2004 [4]. Vacci-nation against rubella began in the USA in 1969 at a time when40,000–60,000 rubella cases were reported each year. Over thefollowing decades rubella and CRS incidence have declined dra-matically and reported cases have decreased by 99.8% to only ninecases reported in 2004 [4]. Between 2001 and 2004 only five casesof CRS were reported.

In Sweden no cases of CRS have been reported since 1985[5]. Rubella vaccination was initiated in Sweden in 1973–1974for schoolgirls, susceptible women after pregnancy and women atspecial risk. This prevention strategy did not result in a substan-tial reduction in the general circulation of rubella [5]. Ten yearslater the measles, mumps and rubella vaccine (MMR) was intro-duced for boys and girls aged 18 months and 12 years. A markedreduction of the total number of rubella cases was seen within 4years of MMR introduction. The percentage of susceptible pregnantSwedish women has declined gradually over the years from 12% in1975 and 2.8% in 1987 to around 2% in 1994 [5]. Before the vac-cination era, severe hearing impairment attributed to congenitalrubella occurred in approximately 19% of Swedish children. After1980 there were no cases of hearing impairment detected at theage of 4 years that were associated with rubella during pregnancy.

Similarly for Finland, the last case of CRS was reported in 1986and the circulation of indigenous rubella virus in Finland stopped inthe late 1990s [6]. During the pre-vaccination era the yearly inci-dence of notified rubella cases in Finland ranged from 33 to 249per 100,000. Rubella vaccination in Finland began in 1975 using asingle component rubella vaccine, switching to the MMR vaccinein 1982. With a consistent vaccine coverage of >95% for MMR since1987 there has been a noticeable reduction in rubella cases and acessation of indigenous transmission [6].

4. What is the current situation of rubella and CRS in

Central Europe?

The MMR vaccine has been introduced with varying schedules inall European countries but cases of rubella continue to be reported.

V. Usonis et al. / Vaccine 29 (2011) 9141– 9147 9143

Table 1Epidemiology of rubella and CRS in CEVAG countries for 2009 [16,22].

Country Rubella CRS

Number of cases (crudeincidence per 100,000)a

Number oflaboratory-confirmed cases

Vaccination status of cases (doses) Number ofcases reported

0 1 ≥2 Unspecified Unknown

Bulgaria 44 (0.61) 0 (0%) 563 samples tested,none positiveb

10 23 2 0 9 0

Croatia 0 (0.00) – 0 0 0 0 0 0Czech Republic 6 (0.1) (0%) 2 0 4 0 0 0Estonia 1 (0.08) 1 (100%) 1 0 0 0 0 0Hungary 0 (0.00) – 0 0 0 0 0 0Lithuaniac 0 (0.00) – 0 0 0 0 0 0Poland 7586 (19.71) 7 (0.1%) 3757 2827 113 0 889 1Romania 603 (2.71) 78 (13%) 0 0 0 0 603 2Slovakia 0 (0.00)d – 0 0 0 0 0 0Slovenia 0 (0.00) – 0 0 0 0 0 0Turkey 97 (0.13) (0%) 33 30 3 3 28 1

a Crude incidence calculated using estimated individual country population figures [36].

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d Analysis of epidemiologic situation in Slovakia – year 2009. Public Health Autho

n 2009 a total of 8951 rubella cases (2.1/100,000) were reportedrom 28 European countries – a 58% decrease from the previousear with a total of 21,475 cases (5.0/100,000) [16]. Most of thencidence data refer to clinically-confirmed cases of rubella withomparatively few cases that are laboratory-confirmed.

From the data reported in 2009 across Europe, Poland and Roma-ia stand out for their high disease incidence, contributing 85%nd 7% of the total number of cases. In Poland 7586 rubella cases20/100,000) were reported in 2009; a marked reduction from3,146 cases reported in 2008 [16,17]. The incidence of reportedubella cases in Romania at the last large rubella outbreak in 2003as 531 cases/100,000 but has since declined to about 3/100,000

n 2009 [16,18].Other countries represented in CEVAG reported <1/100,000

ubella cases in 2009 (Table 1). Since 2000 the number of reportedubella cases has steadily decreased to very low levels for Estonia,ungary and Lithuania, while for Croatia, Slovakia and Slovenia theumber of rubella cases has remained very low during this period19]. In Turkey, rubella cases have only been reported since 2005ut during this period there has been a decline in the number ofeported cases from 2245 (3.1/100,000 inhabitants) to 97 in 200919,20]. For the past 3 years 8/11 CEVAG countries have consistentlyeported <1 rubella case per 100,000 [16,21].

As can be expected, countries without effective rubella vacci-ation programmes have higher rates of CRS (0.6–2.2 children per000 live births) compared with those with effective programmes14]. Between 2000 and 2009 the majority of Central Europeanountries reported no cases of CRS; however, cases were reportedor 2009 in Romania (2), Poland (1) and Turkey (1) (Table 1) [22].or the majority of CEVAG countries, no cases of CRS were reportedn 2009.

.1. Rubella surveillance systems

In order to monitor progress towards rubella elimination, robustnd sensitive surveillance systems are crucial [13]. Rubella surveil-ance across Europe is complicated by the different methods used toollect rubella data in each country which requires standardisationcross the region [20]. In Central Europe the majority of CEVAGountries have established mandatory, case-based reporting of

ubella and CRS (Table 3). Croatia and Turkey only have rubellaurveillance. As the incidence of measles and rubella declines it ismportant that countries ensure their surveillance systems remainensitive to the detection of sporadic cases. Where the annual

f the Slovak Republic.

incidence of rubella is <1/100,000 such as in most CEVAG countries,all cases should be either laboratory-confirmed or epidemio-logically linked to a laboratory-confirmed case [13]. However,laboratory confirmation of reported rubella cases in Central Europeis not adequate. Only 1.6% of all European cases reported in 2009were laboratory-confirmed and 1.1% were epidemiologically linked[16]. For the two countries reporting the highest incidence ofrubella in 2009, <1% of cases reported in Poland (7 of 7586) and13% Romanian cases (78 of 603) were laboratory-confirmed. Forthe remaining CEVAG countries, laboratory confirmation of rubellacases was poor in 2009 (Table 1). None of the 97 cases reportedin Turkey in 2009 were laboratory-confirmed; however, in 2008all 139 Turkish cases were laboratory-confirmed, indicating diffi-culties in sustaining effective surveillance procedures [21]. Of thecases reported in 2009 (Table 1), 87% of Polish cases, 75% of Bul-garian cases and 65% of Turkish cases were either unvaccinatedor received only one dose of rubella-containing vaccine. The sin-gle rubella case from Estonia concerned an individual who wasunvaccinated. Four of six individuals with rubella from the CzechRepublic had reportedly received ≥2 doses; the reason for thesevaccine failures is unclear.

5. Vaccination against rubella

Effective vaccination programmes are critical to the elimina-tion of rubella and resulting prevention of CRS. Rubella-containingvaccines are well tolerated and are an effective tool for disease pre-vention [2,23]. The rubella vaccine is usually given as a combinedmeasles–mumps–rubella (MMR) but can be administered as a sin-gle vaccine or in combination with the measles vaccine, or with themeasles, mumps and varicella vaccine (MMRV). Combination vac-cines decrease the number of injections children receive, have thepotential to improve vaccination coverage for several diseases andincrease the level of compliance [24,25].

In the past 10 years the use of rubella-containing vaccines inWHO/Europe member states has increased from 75% (38/51) in2001 to 100% (53/53) in 2009 [7,20]. In 2009 all European countriesincluded a rubella-containing vaccine in their national immuni-sation schedule; predominantly MMR with a two-dose regimen,although some countries use the monovalent rubella vaccine or

MMRV (Table 2) [7]. The majority of European countries recom-mend the first dose of MMR to be administered between 12 and15 months of age; however, the recommended age for the sec-ond dose varies widely between countries. Most CEVAG countries

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Table 2MMR vaccination schedules in CEVAG countries [26,37].

Country Vaccine(s) in use Year of introduction ofchildhood rubella vaccination

Age at firstdose

Age at seconddose

Interval between1st and 2nd dose

Catch-upprogrammes

Vaccine coverageat dose (%)a

Vaccine coverage at firstand second dose (%)a

One dose Two dose

Bulgaria MMR 1992 2001 13 months 12 years ∼11 years None 96 93Croatiab MMR 1975 catch-up for

14-year-old girlsstarting 1976

1994 for all 12–18 months 6 years ∼5 years None 97.6 (2008) 98 (2008)c

Czech Republic MMR/MMRV – 1986 15 months 21–25 months ∼6–10 months None 97d 3 years of age: 98.3d

Estonia MMR 1992 1994 12 months 13 years ∼12 years None 1 year of age: 872 years of age: 95.1(2010)

91.2 (2010)

Hungary MMR 1991 1999 15 months 11 years ∼10 years None >99.5 99Lithuania MMR – 1992 15–16 months 6–7 years ∼5–6 years At 12 years of age if

previous doses at6–7 years weremissed

97e 6 years of age: 72.77 years of age: 94.2e

Poland MMR 1989 for 13-yearold girls 2003 MMRfor children aged13–15 months

20051st and 2nd dose:MMR

13–14 months 10 years ∼9 years At 11 years of agefor girls notcovered byimmunisationpreviously

98 95

Romania 1st and 2nd dose:MMR catch-updose: R

2004+Monovalent rubellavaccine for girls 14years (since 2003)

20051st and 2nd dose:MMR

12–15 months 6–7 years ∼6 years Monovalent rubellavaccination isgiven to girls at 14years of age

12 months of age:85.118 months of age:95f

93.4% (2010)f

Slovakia MMR 1985 1992 14 months 10 years ∼9 years None 99 11 years of age: 99.2(2010)g

Slovenia MMR – 1990 12–18 months 5–6 years ∼4–5 years None 95 98.2–96.4 (2008–2010)h

Turkey MMR – 2007 12 months 6 years ∼5 years None 97 88

a Year of estimate is 2009 unless otherwise indicated in parentheses.b EUVAC. Childhood Vaccination Schedule Croatia. http://www.euvac.net/graphics/euvac/vaccination/croatia.html. Accessed December 2010.c Croatian Health Service Yearbook 2008. Zagreb: Croatian Institute for Public Health http://www.hzjz.hr/publikacije/hzs ljetopis/Ljetopis Yearbook HR 2009.pdf.d Ref. [38].e Lithuanian Centre for Communicable Diseases and AIDS. www.ulac.lt.f Ref. [39].g Slovakia, Institute of Public Health. http://www.uvzsr.sk/.h Slovenia, Institute of Public Health. http://www.ivz.si/spremljanje precepljenosti.

V. Usonis et al. / Vaccine 29 (2011) 9141– 9147 9145

Table 3Rubella and CRS surveillance in CEVAG countries.

Country Surveillanceof rubella

Surveillanceof CRS

Is reportingmandatory?

Type of datarecorded

Class classification used

Clinically-confirmed Laboratory-confirmed Epidemiologically linked to alaboratory-confirmed case

Bulgaria Yes Yes Yes Case-based andaggregate

Yes Yes Yes

Croatia Yes No Yes Case-based Yes Yes YesCzech Republic Yes Yes Yes Case-based Yes Yes YesEstonia Yes Yes Yes Case-based Yes Yes YesHungary Yes Yes Yes Case-based – Yes –Lithuania Yes Yes Yes Case-based and

aggregateYes Yes Yes

Romania Yes Yes Yes Case-based Yes Yes Yes

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Slovenia Yes Yes Yes Both

Turkey Yes No Yes –

ecommend the second dose to be administered to children aged–7 years or 10–13 years whereas in the Czech Republic the sec-nd dose is given before 2 years of age (Table 2) [26]. In Centralurope the interval between the first and second dose rangesrom 6 to 10 months in the Czech Republic to 12 years in EstoniaTable 2).

Very high vaccine coverage (>95%) for each birth cohort is essen-ial to control rubella infection and to limit CRS. In Central Europeaccine coverage of the first dose is very high (>95%; Table 2). This islso reflected in high coverage for the second vaccine dose (>90%).he WHO specified that in order to reach the target of rubella elim-nation in the European region by 2015 very high coverage of ateast one dose of rubella-containing vaccine must be achieved and,

ore importantly, sustained [11].The strategy associated with rubella vaccine introduction varies

cross Central Europe (Table 2) and will influence the prevailingpidemiology and susceptibility profile in each of these countries13,20]. For a number of countries, such as Lithuania, the initialtrategy was to vaccinate all children starting at 12 months of age;owever, not enough time has passed to cover all women of child-earing age. Such situations require supplemental immunisationctivities to prevent accumulation of susceptible people in the gen-ral population [20]. This also applies to countries who revised theirmmunisation strategy, for example Poland, from initially targeting3-year-old girls to vaccinating all children starting at 12 months ofge. Catch-up programmes have been implemented in 10/32 Euro-ean countries, including Lithuania, Poland, Romania and Turkey,

n order to reach susceptible individuals who have been missed inoutine immunisation (Table 2) [26].

Seroprevalence studies are useful in identifying susceptible pop-lation groups that may require additional prevention strategiesnd should be carried out periodically. A seroprevalence studyrom 1996–2003 found that only 4/16 participating European coun-ries met the WHO target of <5% susceptibility among women ofhild-bearing age (protective immunity defined as antibody titre10 IU/ml) [27]. In 2002 in Poland a study of women aged 15–30ears showed that 10.5% did not have protective antibody titresdefined as >15 IU/ml) despite introduction of vaccination of 13-ear-old girls in 1989 [28]. In Turkey rubella seropositivity inomen of child-bearing age and pregnant women is reported to

ange from 55% (in Mersin) [29], to 78% (Afyonkarahisar) [30] andp to 96.1% (Kocaeli region) [31]. A recent Croatian study evaluatedhe seroprevalence of rubella antibodies in 295 children 5.5 yearsfter primary vaccination with MMR and before a booster vaccina-

ion at entry into the first grade of elementary school. A positiveubella-specific IgG (ELISA) level (>15 IU/ml) was found in 91.5% ofhildren while borderline levels (8–15 IU/ml) were seen in 4.8% andegative samples (<8 IU/ml) were seen for 3.7% of children [32].

Yes Yes YesYes Yes YesYes Yes Yes

An additional population identified as an important target groupfor immunisation includes rubella-susceptible women travelling toEurope from regions with no effective vaccination programmes andhigher incidence of rubella [20]. Efforts should be made to vaccinatepeople visiting relatives and friends in foreign countries. Vaccina-tion programmes for immigrant women and adolescent girls areimportant as they may have contracted rubella in a high-incidencecountry without a rubella immunisation programme. Given theconstant movement of people it is essential to achieve rubella con-trol throughout Europe in order to avoid disease transmission fromcountries with high rubella incidence to countries with low inci-dence or where the disease has been eliminated [33].

6. Discussion

The progress towards elimination of rubella in Europe has beensubstantial over the past 10 years and elimination is not far away. Asrubella control becomes more effective and countries approach thepoint of elimination, it will be necessary for surveillance systems todetect and assist in the investigation and laboratory confirmationof all clinical cases [34].

For Central European countries with few or no reported rubellacases, greater efforts are needed to ensure suspected cases arelaboratory-confirmed. It is vital that immunisation does not losepriority in the absence of disease. Rubella surveillance may be ham-pered by loss of disease awareness. Although the reported numberof cases is low for the majority of CEVAG countries, it is possible thatasymptomatic transmission may be more common than suggested.Cases of CRS may go under-recognised due to the asymptomaticnature of rubella infection in mothers, late onset of CRS symptomsin infants and children, and weaknesses in surveillance systems[35]. Physicians should remain vigilant and consider rubella infec-tion in susceptible individuals, particularly women of child-bearingage presenting with febrile rash and characteristic symptoms.

For Central Europe to reach the target of rubella elimination andprevention of CRS by 2015, very high vaccine coverage levels needto be maintained and catch-up campaigns continued to addresssusceptible groups, in particular women of child-bearing age. Keyareas needing improvement are strengthening surveillance sys-tems to report sporadic rubella infections, monitoring CRS, andaccurate diagnosis of rubella and CRS through laboratory confirma-tion of suspected cases. These activities are crucial in monitoringthe progress of rubella elimination and prevention of CRS in Europe.

6.1. CEVAG guidance statement

CEVAG recommends that two doses of rubella-containing vac-cine should be given to all children. The first dose should be

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iven between 12 and 15 months of age. The second dose cane given between the ages of 21 months and 13 years withhe exact age of administration of the second dose dependingn the situation specific to each country. Individual countrieshould decide on how best to implement this recommendationased on their circumstances but the second dose is prefer-ble earlier in life rather than later to avoid the build-up of

sizeable pool of susceptible individuals. All suspected rubellaases should be laboratory-confirmed. Monitoring systems toetect and investigate cases including those of CRS should betrengthened.

cknowledgements

Preparation of this report was supported by an educational grantrom GlaxoSmithKline (GSK) and Pfizer. Editorial assistance wasrovided by Dr Rebecca Milton of Wells Healthcare, funded withupport from GSK and Pfizer. All authors were actively involved inhe selection and review of all content and had full editorial controluring the writing of the manuscript.

Conflict of interest statement: VU has been the principalnvestigator in clinical studies supported by GSK, Novartis, and

yeth-Lederle Vaccines. He has also been a scientific consultant toventis Pasteur, Baxter, GSK, Merck, and Wyeth-Lederle Vaccinesnd has received sponsorship from these companies to attend sci-ntific meetings. IA has been the principal investigator in clinicaltudies supported by GSK. She has also been a scientific consultanto GSK, Wyeth and Nestle and has received sponsorship from theseompanies to attend scientific meetings. RC has been the princi-al investigator in clinical studies supported by GSK and Novartis.e has also been a scientific consultant to Baxter, GSK, Novar-

is, Aventis Pasteur and Pfizer and received sponsorship from GSKnd Aventis Pasteur to attend scientific meetings. MC is a mem-er of GSK advisory boards on vaccines and has received honorariaor lectures on vaccine use from GSK, Pfizer and Merck Sharp &ohme (MSD). II has been a scientific consultant to Baxter, GSK,erck and Wyeth-Lederle Vaccines and has received sponsor-

hip from these companies to attend scientific meetings. AM haseen a scientific consultant to Wyeth, GSK, Aventis Pasteur andolvay Pharma and has received sponsorship from these compa-ies to attend scientific meetings. ZM is a consultant to Wyeth,SK, MSD, Sanofi Pasteur, Novartis and Baxter on immunisation

ssues and has also received travel grants. PP was a consultant forSK in 2009. MP has received lecture fees from GSK Slovenia andas received sponsorship from GSK and PharmaSwiss Slovenia tottend scientific meetings. RP is a member of advisory boards forSK, MSD, Wyeth, Baxter and Aventis Pasteur and has received

esearch grants and honoraria from GSK, Wyeth, Baxter, Aventisasteur and Novartis. DR has received honoraria for lectures onaccines and respiratory drugs from GSK Croatia, MSD Idea Inc.roatia and PharmaSwiss Croatia. PS has received consulting feesnd lecture fees from GSK, Wyeth and MSD. ET has received spon-orship from GSK and PharmaSwiss to attend scientific meetings.T has received sponsorship from GSK, MSD and Wyeth to attendcientific meetings. IU has been a scientific consultant to GSK andfizer and has received lecture fees from GSK, Pfizer, MSD, Novartisnd MSD. She has received sponsorship from GSK, Pfizer and Sanofiasteur to attend scientific meetings. FA and NS have no competingnterests.

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