Measles outbreak, Montenegro January–July 2018: Lessons learned

Abstract In 2017, the Regional Verification Commission for Measles and Rubella Elimination (RVC) of the World Health Organization confirmed that measles elimination was sustained in Montenegro, and the previous endemic transmission remained interrupted. However, the RVC was extremely concerned over the continuing low vaccination coverage reported for this country. In this study, we describe the most recent measles epidemic in Montenegro using the epidemiological data collected from January 1 to July 31, 2018. The outbreak is largely attributable to a dangerous accumulation of susceptible subjects across the country and represents a high‐risk factor for re‐establishing endemic transmission in the Balkan area. This study showed how a vaccine‐preventable communicable disease outbreak can have a dramatic impact and severe consequences on regional public health system performance in terms of the sanitary spending point of view. A detailed update is provided on the epidemiological situation in this Central European area, not available until now.

systems, increasing vaccination rates led to a reduction namely in measles morbidity and also mortality with a 75% reduction in number of measles deaths recorded in the period between 2000 and 2013, 6 with an estimated 15.6 million deaths prevented in this period. 7 In communities where vaccination coverage is lower than 95%, outbreaks can easily occur. 8 In 2010, all 53 countries in the World Health Organization (WHO) European Region (EUR) including Montenegro, reconfirmed eliminating measles and rubella and congenital rubella syndrome as a top political and public health priority 9 renewing their commitment to achieving those goals with 2015 being set as the new target date for the European regional goals of eliminating measles and rubella.
However, and as those efforts have failed, under the Global Vaccine Action Plan (GVAP), measles has been once again targeted for elimination in five WHO Regions by 2020. 10 WHO is the leading technical agency responsible for the coordination of immunization and surveillance activities supporting all countries to achieve this goal. 11 Before and few years following the introduction of mandatory measles immunization with measles-containing vaccine (MCV) in Montenegro in 1972 (as mono measles vaccine), measles cases were recorded annually with extensive outbreaks occurring almost every 2-3 years-  In total, 275 cases were epidemiologically processed as measleslike cases with the rate of discarded cases being 12.1.
At the same time, a total of 41 000 measles cases, including 37 deaths occurred in the first 6 months of 2018, in seven European countries highlighting measles as a European problem. 12 In total, and as of December 10, 2020, 89 148 measles cases have been registered in the European WHO region during 2018. 13 In this study, we describe the most recent measles epidemic in Montenegro using the epidemiological data collected from January 1 to July 31, 2018.

| METHODS
Mandatory notification of measles in Montenegro with comprehensive population coverage has been in place since the late sixties.
Nevertheless, and to improve case detection and increase the specificity of the surveillance system-mandatory reporting has also been imposed on microbiology laboratories along with microbiological investigation of every single case with clinical presentation of rash and fever ever since 2010.
Both clinicians and microbiologists are requested to report suspected, investigated, and confirmed measles cases immediately to the local epidemiology service as well as to the Institute for Public Health (IPH)-the institution responsible for coordinating and implementing surveillance and control measures on the national level. Regarding the immunization policies-mandatory measles vaccination with a single monovalent dose has been introduced in 1972 targeting all children in the second year of life. The monovalent vaccine has been later changed to combined measles-mumps (MM or in local language "Mo-Par") vaccine only to be replaced in 1995 with a combined measlesmumps-rubella (MMR) vaccine with an additional dose of the vaccine introduced in a prescribed schedule for children aged 12 years. Following a couple of years of implementation and based on the observed epidemiological data and age of the cases, the second dose has been shifted to preschool-age children (6-7 years) and is still currently given at that age-before the enrolment in primary schools. 14

| CASE DEFINITIONS AND DATA SOURCE
Classification of measles cases has been done according to the WHO definition and criteria. 15  To estimate the annual measles immunization coverage rates in Montenegro, the total number of immunized children (numerator) within one calendar year was divided by the total number of children who should have been immunized according to their age or year of birth by Montenegrin immunization schedule (denominator). The data on immunization coverage from immunization records of children were obtained as a part of routine surveillance of mandatory immunization in Montenegro. 14

| Statistical analysis
Parametric and nonparametric statistical tests have been applied including the Chi-square test, to evaluate possible differences of certain attributes between measles cases who have been hospitalized versus those who were not treated in hospitals. Logistic regression has been used to identify variables predicting hospitalization; only variables associated with the hospitalization statistically significant in the univariate analysis have been considered suitable for multivariate analysis. A p-value lower than 5% has been considered statistically significant. The analysis has been performed using STATA V.14.

| Ethical consideration
The study has been done in the framework of public health surveillance on communicable diseases in Montenegro. Sample and data collection was part of the standard patient and public health management of suspected measles cases and required oral informed patient consent. Access to identifiable patient data has been restricted and allowed only to IPH employees who have been directly involved in measles surveillance and diagnosis in accordance with the national legal framework.   A statistically significant difference between hospitalized and not hospitalized patients in terms of number of measles vaccines given has been probably due to low vaccination rates and small numbers rather than the number of doses themselves. At the same time, this finding can also be explained by the age of hospitalized patients that has been significantly lower respected than the nonhospitalized patients. Also, it is expected in the general population to have a higher compliance to vaccination programs in childhood than in older age. Cases were also observed among fully vaccinated which may be a consequence of the waning immunity over time or certain (more than expected) proportion of vaccinated children who failed to develop immunity from the first dose with the implication that the real vaccineinduced immunity is probably much lower than expected and significantly lower than the number of persons vaccinated.
Nevertheless, these findings should be further investigated.
The main circulating genotype reported in Montenegro was B3, pretty much the same as observed in other European countries at that time. 18,19 Interestingly, the majority of cases observed in this outbreak were in pediatric patients. This suggests that the adult population was adequately protected, probably as a result of both vaccination programs implemented in previous years and measles epidemics recorded in the Balkan area in past years, similarly to what has been observed also in other countries. 20 In particular, measles vaccination was introduced in the Socialist Federal Republic of Yugoslavia) in 1971 as monovalent vaccine administered at pediatric age in single dose, and mandatory mass measles vaccination started in 1972. In 1993, the monovalent vaccine was replaced by the two-dose MMR vaccine. 21,22 Moreover, live measles vaccine prepared from a further-attenuated Edmonston-Zagreb strain was also used for vaccination in Yugoslavia. 23 Before the introduction of measles immunization in 1971, large measles outbreaks in Yugoslavia were recorded every 1-3 years, mainly with cases reported among preschool children. In the postvaccination era, the measles incidence dropped dramatically, and only a small measles outbreak were reported, probably attesting to a good level of overall vaccination coverage in the general population at least until the beginning of the Yugoslav Wars fought from 1991 to 2001. 24 In the post-war period, a number of epidemiologically significant measles outbreaks have been described in the Balkan area especially in   By our experience and although the vaccination against measles is free of charge and mandatory, 29 in the last few years, there has been a trend of decline in immunization rates mainly for the first dose of MCV in Montenegro. The situation lead to a measles outbreak with a different age-specific distribution involved, mostly affecting younger, with statistically significant difference in age between hospitalized and nonhospitalized cases, as expected.
A decreased immunization has been most likely due to skepticism toward vaccination, fake news, and negative immunization messages shared on social media among inexpert people and probably mirroring the effect of an increased anti-vaccination movement in several European countries. 30

| CONCLUSIONS
Our study showed how a vaccine-preventable communicable disease outbreak can have a dramatic impact and severe consequences on