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International Journal of Environmental Research and Public Health logoLink to International Journal of Environmental Research and Public Health
. 2022 Mar 31;19(7):4140. doi: 10.3390/ijerph19074140

Measles Vaccination and Outbreaks in Croatia from 2001 to 2019; A Comparative Study to Other European Countries

Ines Drenjančević 1,2,*, Senka Samardžić 3,*, Ana Stupin 1,2, Katalin Borocz 4, Peter Nemeth 4, Timea Berki 4
Editor: Paul B Tchounwou
PMCID: PMC8998383  PMID: 35409823

Abstract

Due to the current burden of COVID-19 on public health institutions, increased migration and seasonal touristic traveling, there is an increased risk of epidemic outbreaks of measles, mumps and rubella (MMR). The aim of the present study was to analyze the epidemiological data on MMR immunization coverage and the number of measles cases in 2001–2019 in Croatia and a number of European countries. Results revealed a decreasing trend in vaccination in 2001–2019 throughout Europe. However, Croatia and Hungary still have the highest primary and revaccination coverage, compared to other analyzed countries. The highest number of measles cases was in 2017 in Romania. There was no significant correlation between the percentage of primary vaccination and the number of measles cases (r = −0.0528, p = 0.672), but there was a significant negative correlation between the percentage of revaccination and the number of measles cases (r = −0.445, p < 0.0001). In conclusion, the results of the present study emphasize the necessity to perform a full protocol of vaccination to reach appropriate protection from potential epidemic outbreaks. Furthermore, in the light of present migrations, documenting the migrants’ flow and facilitating vaccination as needed is of utmost importance to prevent future epidemics.

Keywords: measles-rubella-mumps vaccination, Europe, Croatia

1. Introduction

Throughout the world, vaccination with safe, effective, and affordable vaccines for measles, mumps and rubella (MMR) is freely available. The measles vaccination was introduced into the compulsory vaccination program in the Republic of Croatia in 1969. The first vaccination effort vaccinated all children one to six years old. Vaccination against rubella (1975) and mumps (1976) soon followed [1]. MMR vaccination began in 1976. Since the beginning of vaccination against MMR, a vaccine of domestic production (Immunology Institute) has been used. The measles vaccine strain, Edmonston–Zagreb, as well as the rubella vaccine strain, RA 27/3, were produced on human diploid cell culture, while the mumps virus vaccine strain was produced on chicken fibroblast cell culture [2,3]. The use of vaccines against these diseases has led to their almost complete eradication in Croatia, with sporadic cases. The Croatian law prescribes the required minimum coverage for measles vaccination of 95%. In Croatia, outbreaks of measles occurred in 2015 and 2018. In 2018, an outbreak in the southern-Adriatic part of the country was a consequence of the infection of an adult returning from Kosovo, with 15 epidemiologically-linked cases [4]. The median age of infected persons was 33 years, while one case was an 8-month-old infant. Two of these cases had received two doses of a measles-containing vaccine, one person had taken one dose and three were unvaccinated, while for nine cases, vaccination status was unknown [4]. In regard to neighboring countries, in 2017, there was a small outbreak of measles in Hungary, in close proximity of Osijek-Baranja County, which was not spread wider over the state border due to good epidemiological measures [5]. Measles outbreaks in 2018–2019 in the Croatian cities of Zagreb, Slavonski Brod, Split and Dubrovnik demonstrated possibly suboptimal vaccination coverage in certain cluster(s) of the population [5]. Despite the proximity of Slavonski Brod (tens of kilometers) and frequent commutation between counties, Osijek-Baranja County was not affected.

In the light of flaming waves of the COVID-19 pandemic, other contagious diseases somehow were put aside, partly due to successful vaccination programs, particularly in European countries. In the period between the end of 2019 and the spring of 2022, the COVID-19 pandemic significantly influenced interpersonal contacts, which also have different impacts on measles, mumps and rubella vaccination efforts and burden across the world. For example, Brazil reported a reduction in the number of MMR vaccine doses [6], while interestingly, Japan reported de-creased estimated annual burdens in 2020 for measles (98%), mumps (47%) and rubella (94%) compared with those in 2019 due to social distances in COVID-19 pandemic [7]. However, due to the current burden of COVID-19 on public health institutions, one may expect a decrease in vaccination coverage and potential new outbreaks in near future. We hypothesized that there is a relationship between vaccination coverage and the number of measles cases. The present study aimed to analyze the epidemiological data on population immunization and reflect the number of measles cases in the 2001–2019 period for Croatia and countries of the European region.

2. Materials and Methods

Data collection was performed using European Centre for Disease Prevention and Control (ECDC) reports [8,9,10] and World Health Organization (WHO) statistics from 2001 to 2019 [11]. For Croatia, data from National Institute of Public Health and Ministry of Health was used (Croatian Health Service Yearbook for years 2001 to 2019 [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30]).

Statistical analysis: Differences in percentage of vaccination (% vaccination) in observed period among regions/countries were analyzed using Two-way ANOVA, with appropriate post hoc test for multiple comparisons (Sidak’s or Tukey’s multiple comparisons test). Correlation between number of cases per year and vaccination coverage was assessed using Spearman’s correlation. p < 0.05 was considered statistically significant. GraphPad v6.0 (GraphPad Software, San Diego, CA, USA) and SigmaPlot, version 11.2 (Systat Software, Inc., Chicago, IL, USA) were used for statistical analysis.

3. Results

3.1. MMR Primary Vaccination and Revaccination in Croatia and Osijek-Baranja County 2001–2019

Table 1 presents data on the primary MMR vaccination in Croatia and particularly, Osijek-Baranja County (OBC). There was no significant difference in the percentage of primary vaccination between Croatia and OBC each year from 2001 to 2018. However, there was a significantly higher percentage of primary vaccination in Croatia compared to OBC only in 2019 (p < 0.05).

Table 1.

Measles-containing vaccine primary vaccination in Osijek-Baranja County and Croatia from 2001 to 2019.

Osijek-Baranja County
Primary Vaccination		 Croatia
Primary Vaccination
Year Scheduled Vaccinated % Scheduled Vaccinated %
2001 3312 3137 94.7 44,989 42,091 93.6
2002 3217 3001 93.3 44,467 42,110 94.7
2003 3019 2858 94.7 41,388 39,103 94.5
2004 2914 2755 94.5 40,985 39,230 95.7
2005 2849 2673 93.8 39,783 37,710 94.8
2006 3128 2984 95.4 41,721 39,797 95.4
2007 3032 2890 95.3 41,437 39,807 96.1
2008 2964 2826 95.3 41,714 39,855 95.5
2009 3030 2758 91.0 42,599 40,484 95.0
2010 3188 2934 92.0 44,659 42,855 96.0
2011 2992 2812 94.0 43,830 42,092 96.0
2012 2902 2682 92.4 41,606 39,446 94.8
2013 2928 2730 93.2 40,885 38,369 93.8
2014 2783 2605 93.6 39,862 37,342 93.7
2015 2300 2092 91.0 38,882 36,088 92.8
2016 2547 2197 86.3 37,306 33,440 89.6
2017 2520 2191 86.9 38,700 34,430 89.0
2018 2579 2314 89.7 39,651 36,970 93.2
2019 2259 1922 85.1 38,156 35,491 93.0
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Source for data: Croatian Health Service Yearbooks 2001–2019 [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30].

Table 2 presents the data on revaccination in Croatia and OBC. In Croatia, the percentage of revaccination compared to primary vaccination significantly increased in 2016 and 2017, with no significant change in other years between 2001 and 2019 (2016, p < 0.05; in 2017, p < 0.05). In OBC, the percentage of revaccination compared to primary vaccination significantly increased in 2009, 2010, 2016, 2017 and 2019 (p < 0.05), with no significant change in other years between 2001 and 2019.

Table 2.

Measles–rubella–mumps revaccination in Osijek-Baranja County and Croatia in years 2001 to 2019.

Osijek-Baranja County
1. Revaccination		 Croatia
1. Revaccination
Year Scheduled Vaccinated % Scheduled Vaccinated %
2001 7971 7902 99.1 101,917 99,395 97.5
2002 7550 7483 99.1 93,404 91,423 97.9
2003 7353 7310 99.4 92,221 90,555 98.2
2004 7429 7369 99.2 86,686 84,837 97.9
2005 3375 3335 98.8 46,153 45,157 97.8
2006 3480 3436 98.7 44,419 43,618 98.2
2007 2993 2942 98.3 42,884 42,086 98.1
2008 3085 3062 99.3 40,733 39,871 97.9
2009 2796 2774 99.2 39,599 38,821 98.0
2010 2785 2759 99.1 39,417 38,547 97.8
2011 2853 2803 98.2 40,410 39,540 97.8
2012 3009 2873 95.5 41,714 40,441 96.9
2013 2841 2787 98.1 41,280 40,098 97.1
2014 2770 2710 97.8 41,454 40,125 96.8
2015 2767 2661 96.2 41,434 39,699 95.8
2016 4111 3965 96.4 43,397 41,647 96.0
2017 2364 2221 94.0 39,630 37,703 95.1
2018 2556 2441 95.5 38,367 36,328 94.7
2019 2046 1921 93.9 36,674 34,745 94.7
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Source for data: Croatian Health Service Yearbooks 2001–2019 [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30].

3.2. MMR Primary Vaccination and Revaccination in Croatia and Neighboring Countries in Years 2001–2019

Table 3 presents differences in MMR primary vaccination among Croatia and neighboring countries. There was no significant difference in the percentage of primary vaccination between Croatia and neighboring countries from 2001 until 2015. Afterward, Croatia, Slovenia and Serbia generally had the best primary vaccination success, while Bosnia and Herzegovina (BiH) and North Macedonia had the lowest; e.g., in 2016, the percentage of primary vaccination in BiH was significantly lower compared to Croatia (2016, p < 0.05) and Slovenia (2016, p < 0.05), while in 2017 and 2018, the percentage of primary vaccination in BiH was significantly lower compared to Croatia (p < 0.05), Slovenia (p < 0.05), and Serbia (p < 0.05). Additionally, in 2018, North Macedonia had significantly lower percentage (75%) of primary vaccination compared to Croatia (2018, p < 0.05), Serbia (2018, p < 0.05), and Slovenia (2018, p < 0.05). Montenegro and the years 2013 and 2019 had to be excluded from the analysis due to missing data.

Table 3.

Measles-containing vaccine first dose (%) in Croatia and neighboring countries in the years 2001 to 2019.

Year BA HR MK ME RS SI
2001 92 94 92 * 91 94
2002 89 95 98 * 92 93
2003 84 95 96 * 87 94
2004 88 96 96 * 89 94
2005 90 96 96 * 96 94
2006 90 95 94 90 88 96
2007 96 96 96 90 95 96
2008 84 96 98 89 92 96
2009 93 95 96 86 95 95
2010 92 96 98 90 95 95
2011 89 96 97 91 93 96
2012 94 95 96 90 87 95
2013 * 94 96 88 92 94
2014 89 94 93 76 86 94
2015 83 93 89 64 87 94
2016 68 90 82 47 82 92
2017 69 89 83 58 86 93
2018 68 93 75 42 93 93
2019 * 93 * * 87 94
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* data not available; BA—Bosnia and Herzegovina; HR—Croatia; ME—Montenegro; MK—North Macedonia; RS—Serbia; SI—Slovenia. Source for data: World Health Organization (WHO) statistics from 2001 to 2019 [11].

Table 4 presents the data on MMR revaccination among Croatia and neighboring countries. In 2001 and 2002, there was a significantly lower percentage of revaccination in Serbia compared to Croatia (p < 0.05). There was no significant difference in the percentage of revaccination among Croatia and neighboring countries in 2003–2005 and 2007–2017. In 2006, the percentage of revaccination in BiH was significantly lower compared to Croatia (p < 0.05), North Macedonia (in 2006, p < 0.05) and Serbia (in 2006, p < 0.05). In 2018, the percentage of revaccination in BiH was significantly lower compared to Croatia (2018 p < 0.05) North Macedonia (2018, p < 0.05) and Serbia (2018, p < 0.05). Montenegro and Slovenia and the years 2009, 2013 and 2019 had to be excluded from analysis due to missing data.

Table 4.

Measles-containing revaccination (%) in Croatia and neighboring countries in the years 2001 to 2019.

Year BA HR MK ME RS SI
2001 86 98 94 * 74 98
2002 90 98 95 * 75 *
2003 85 98 97 * 96 *
2004 88 98 95 * 96 *
2005 90 98 95 * 98 *
2006 61 98 96 * 90 99
2007 95 98 95 95 96 98
2008 92 98 95 96 97 99
2009 88 * 97 97 87 98
2010 91 98 99 * 91 96
2011 88 98 98 97 90 96
2012 94 97 96 97 90 96
2013 * 97 96 97 82 95
2014 92 97 96 95 91 94
2015 88 96 93 94 87 96
2016 78 96 93 86 90 93
2017 80 95 97 83 91 94
2018 68 95 94 86 90 94
2019 * 95 * * 91 94
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* data not available; BA—Bosnia and Herzegovina; HR—Croatia; ME—Montenegro; MK—North Macedonia; RS—Serbia; SI—Slovenia; Source for data: World Health Organization (WHO) statistics from 2001 to 2019 [11].

3.3. MMR Primary Vaccination and Revaccination in European Countries 2001–2019

Data for Table 5 and Table 6 cover Austria, Hungary, Croatia, Czech Republic, Denmark, Germany, Italy, Poland, France, Belgium and Ukraine.

Table 5.

Measles-containing vaccine 1st dose (%) in European countries from 2001 to 2019.

Year AT HU HR CZ DK DE IT PL FR BE UA
2001 79 99 94 * 94 91 77 97 85 82 *
2002 78 99 95 * 99 91 81 98 86 82 *
2003 79 99 95 99 96 92 84 97 87 82 *
2004 74 99 96 97 96 92 86 97 88 82 *
2005 75 99 96 97 95 93 87 98 87 88 *
2006 80 99 95 * 90 94 88 99 89 92 *
2007 79 99 96 98 89 95 90 98 90 92 *
2008 83 99 96 97 * 95 90 98 89 93 *
2009 76 99 95 * 84 96 90 98 70 95 *
2010 * 99 96 * 85 96 91 98 89 95 *
2011 * 99 96 * 87 96 90 98 91 95 *
2012 * 99 95 * 90 97 90 98 90 96 *
2013 * 99 94 * 89 97 90 98 91 96 79
2014 96 99 94 99 90 97 87 97 91 96 56
2015 * 99 93 * 91 97 85 96 90 96 56
2016 95 99 90 98 94 97 87 96 90 96 42
2017 96 99 89 97 97 97 92 94 90 96 86
2018 94 99 93 96 95 97 93 93 * 96 *
2019 * 99 93 92 96 97 94 * * 96 *
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* data not available; AT—Austria; HU—Hungary; HR—Croatia; CZ—Czech Republic; DK—Denmark; DE—Germany; IT—Italy; PL-Poland; FR—France; BE—Belgium; UA—Ukraine; Source for data: World Health Organization (WHO) statistics from 2001 to 2019 [11].

Table 6.

Measles-containing revaccination (%) in selected European countries from 2001 to 2019.

Year AT HU HR CZ DK DE IT PL FR BE UA
2001 34 99 98 97 87 * * 96 * * *
2002 39 99 98 98 92 27 * 97 * * *
2003 46 99 98 97 88 53 * 97 * * *
2004 47 99 98 97 88 51 * 96 * * *
2005 91 99 98 97 91 66 * 90 * * *
2006 61 99 98 98 91 77 * 99 * 78 *
2007 56 100 98 98 88 83 * 98 * 78 *
2008 62 100 98 98 * 88 * 97 * 81 *
2009 64 99 * 98 85 89 * 95 * 83 *
2010 * 100 98 98 85 90 * 94 61 83 *
2011 * 100 98 98 86 92 * 95 67 83 *
2012 * 99 97 99 87 92 * 95 72 85 *
2013 * 99 97 99 86 92 84 93 75 85 54
2014 87 100 97 96 84 93 83 95 77 85 57
2015 * 99 96 99 80 93 83 94 79 85 57
2016 89 99 96 93 85 93 82 93 80 85 31
2017 84 99 95 90 88 93 86 93 80 85 84
2018 84 99 95 84 90 93 89 92 83 85 *
2019 * 99 95 * 90 93 88 * * 85 *
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* data not available; AT—Austria; HU—Hungary; HR—Croatia; CZ—Czech Republic; DK—Denmark; DE—Germany; IT—Italy; PL—Poland; FR—France; BE—Belgium; UA—Ukraine; Source for data: World Health Organization (WHO) statistics from 2001 to 2019 [11].

Table 5 presents data on MMR primary vaccination in European countries. Austria and the Czech Republic and the years 2008, 2013, 2018 and 2019 had to be excluded for analysis because of partly missing data. In 2001, the percentage of primary vaccination in Italy was significantly lower compared to Hungary (p < 0.05), Croatia (p < 0.05), Denmark (p < 0.05) and Poland (p < 0.05). Furthermore, in 2001, Belgium had a significantly lower percentage of primary vaccination compared to Hungary (p < 0.05). In 2002, the percentage of primary vaccination in Italy was significantly lower compared to Hungary (p < 0.05), Denmark (p < 0.05) and Poland (p < 0.05). Moreover, in 2002, Belgium had a significantly lower percentage of primary vaccination compared to Hungary (p < 0.05), Denmark, (p < 0.05) and Poland (p < 0.05). In 2003 and 2004, Belgium had a significantly lower percentage of primary vaccination compared to Hungary (p < 0.05). In 2009, the percentage of primary vaccination in France was significantly lower compared to Hungary (p < 0.05), Croatia (p < 0.05), Germany (p < 0.05), Italy (p < 0.05), Poland (p < 0.05) and Belgium (p < 0.05). There was no significant difference in the percentage of primary vaccination between EU countries from 2005 until 2007 and from 2010 until 2017. According to available data, differences in the percentage of primary vaccination between Ukraine and other European countries were analyzed for the period between 2013 and 2017. In 2014, 2015 and 2016, Ukraine had a significantly lower percentage of primary vaccination compared to Hungary (p < 0.05), Croatia (p < 0.05), Denmark (p < 0.05), Germany (p < 0.05), Italy (p < 0.05), Poland (p < 0.05), France (p < 0.05) and Belgium (p < 0.05). There was no significant difference in the percentage of primary vaccination between Ukraine and Italy in 2013, and 2017, Austria and the Czech Republic were excluded from the analysis because of partly missing data.

Table 6 presents data on MMR revaccination in EU countries. Austria, Italy, France and Belgium and the years 2001, 2008, 2009 and 2019 had to be excluded from analysis due to missing data. In 2002, the percentage of revaccination in Germany was significantly lower compared to Hungary (2002, p < 0.05), Croatia (2002, p < 0.05), Czech Republic (2002, p < 0.05), Denmark (2002, p < 0.05) and Poland (2002, p < 0.05). In 2003 and 2004, the percentage of revaccination in Germany was significantly lower compared to Hungary (2003, p < 0.05; 2004, p < 0.05), Croatia (2003, p < 0.05; 2004, p < 0.05), the Czech Republic (2003, p < 0.05; 2004, p < 0.05) and Poland (2003, p < 0.05; 2004, p < 0.05.) There was no significant difference in percentage of revaccination between EU countries from 2005 until 2007 and from 2010 until 2018. Again, according to available data, differences in the percentage of revaccination between Ukraine and other European countries were analyzed for the period between 2013 and 2017. In 2013, 2014, 2015 and 2016, Ukraine had a significantly lower percentage of revaccination compared to Hungary—a particularly low percentage revaccination in 2016, only 31% (p < 0.05)—Croatia (p < 0.05), Czech Republic (p < 0.05), Denmark (p < 0.05), Germany (p < 0.05), Italy (p < 0.05), Poland (p < 0.05), France (p < 0.05) and Belgium (p < 0.05). There was no significant difference in the percentage of revaccination between Ukraine and other EU countries in 2017. Austria was excluded from analysis because of partly missing data.

Table 7 presents the number of measles cases in European countries, from 2001 to 2019. In 2006, 2018 and 2019, Ukraine had a significantly higher number of measles cases compared to all other European countries listed in Table 7. There was no significant difference in the number of measles cases among European countries in the periods between 2002 and 2005, 2007 and 2009, 2011 and 2017.

Table 7.

Number and rate per 1,000,000 measles cases in selected European countries in 2001–2019.

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
N R N R N R N R N R N R N R N R N R N R
AL 18 5.9 16 5.2 8 2.6 7 2.3 6 2 68 22.2 22 7.2 0 0 0 0 10 3.3
AT 0 0 0 0 44 5.5 16 2 9 1.1 21 2.6 20 2.4 427 50.9 47 5.6 48 5.7
BE 83 24.8 0 0 44 4.3 61 5.9 25 2.4 15 1.4 58 5.5 98 9.4 33 3.1 40 3.8
BA 0 0 28 6.4 18 4.1 28 6.4 23 5.3 17 3.9 166 37.9 8 1.8 22 5 45 10.3
BG 8 1 0 0 0 0 0 0 3 0.4 1 0.1 1 0.1 1 0.1 2249 298.8 2205 2945.3
HR 8 18 6 1.4 19 4..3 54 12.2 2 0.4 1 0.2 0 0 50 11 2 0.4 7 1.5
CZ 6 0.6 4 0.4 30 29 17 1.7 0 0 6 0.6 2 0.2 2 0.2 5 0.5 0 0
FR 0 0 5185 84.5 0 0 4448 71.5 22 0.4 45 0.7 40 0.7 604 9.8 1544 24.8 5019 80.3
DE 6033 73.6 4665 56.9 778 9.5 122 1.5 778 9.5 2307 27.9 571 6.9 917 11.1 574 6.9 780 9.6
GR 12 1.1 5 0.5 8 0.8 1 0.1 116 10.9 512 46 2 0.2 1 0.1 2 0.2 149 13.3
HU 20 2 0 0 0 0 0 0 2 0.2 1 0.1 0 0 0 0 1 0.1 0 0
IT 799 13.9 18,312 318.7 10,939 190.7 676 11.8 218 3.8 595 10.2 420 7.2 1619 27.5 173 2.9 861 14.6
ME 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5 8
PL 133 3.5 34 0.9 48 1.3 11 0.3 14 0.4 120 3.1 43 1.1 100 2.6 109 2.9 10 0.3
PT 21 2.1 7 0.7 7 0.7 1 0.1 7 0.7 0 0 0 0 1 0.1 3 0.3 5 0.5
MK 27 13.3 19 9.4 18 8.9 9 4.4 5 2.5 3 1.5 1 0.5 27 13.3 5 2.5 217 107
RO 10 0.5 14 0.6 9 0.4 117 5.4 5647 254.9 3196 147.8 352 16.3 14 0.7 8 0.4 187 8.8
RS 35 4.7 63 8.4 15 2 11 1.5 2 0.3 2 0.3 201 26.8 2 0.3 1 0.1 20 2.7
SK 0 0 0 0 1 0.2 2 0.4 0 0 0 0 0 0 0 0 0 0 0 0
SI 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3 1.5
UA 16,970 350.2 7587 156.6 411 8.5 146 3 2392 49.4 42,724 * 881.7 1005 20.7 48 1 0 0 39 0.8
UK 73 1.2 327 5.5 469 7.8 202 3.4 78 1.3 773 12.9 1004 16.7 1406 23 1166 19 397 6.5
2011 2012 2013 2014 2015 2016 2017 2018 2019
N R N R N R N R N R N R N R N R N R
AL 28 9.9 9 3.2 0 0 0 0 0 0 17 6 12 4.2 1469 518.8 488 172.3
AT 99 12 19 2.3 75 8.9 112 13.3 309 36 27 3.1 95 10.8 77 8.7 151 17
BE 555 51 43 3.9 38 3.4 70 6.3 46 4.1 78 6.9 367 32.3 117 10.3 496 43.3
BA 10 2.3 22 5 0 0 3000 849.6 1677 474.9 133 37.7 18 5.1 62 17.6 1404 397.6
BG 157 21 1 0.1 16 2.2 0 0 0 0 1 0.1 165 23.2 13 1.8 1235 176.4
HR 12 2.8 2 0.5 1 0.2 14 3.3 219 51.8 4 1 7 1.7 23 5.6 52 12.8
CZ 17 1.6 22 2.1 14 1.3 222 21.1 9 0.9 7 0.7 146 13.8 207 19.5 590 55.4
FR 15,206 234 859 13.2 272 4.2 267 4.1 364 5.5 79 1.2 518 7.8 2919 43.6 2636 39.3
DE 1609 20 167 2 1772 21.7 446 5.4 2646 30.4 326 4 929 11.3 543 6.6 514 6.2
GR 40 4 3 0.3 3 0.3 1 0.1 1 0.1 0 0 967 89.8 2293 213.5 45 4.2
HU 5 0.5 2 0.2 1 0.1 0 0 0 0 0 0 36 3.7 14 1.4 23 2.4
IT 5181 85 682 11.2 2216 36.4 1676 28.1 256 4.2 861 14.2 5399 89.1 2686 44.4 1620 26.8
ME 5 8 0 0 0 0 0 0 0 0 0 0 0 0 200 319.9 0 0
PL 38 1 61 1.6 86 2.2 110 2.9 48 1.3 133 3.5 63 1.7 340 9 1423 37.5
PT 2 0.2 7 0.7 1 0.1 0 0 0 0 0 0 34 3.3 171 16.6 10 1
MK 701 346.6 7 3.5 4 2 116 57.4 1 0.5 0 0 19 9.4 64 31.6 1337 661
RO 4015 187 3843 179.5 1074 50.3 53 2.6 7 0.4 2435 123.1 9076 462 6398 327.6 1706 87.9
RS 370 51.5 0 0 1 0.1 37 5.1 383 53.3 11 1.5 721 100.3 5076 706.3 22 3.1
SK 2 0.4 1 0.2 0 0 0 0 0 0 0 0 6 1.1 565 103.8 319 58.5
SI 22 11 2 1 1 0.5 52 25.3 18 8.7 1 0.5 8 3.9 9 4.4 48 23.1
UA 1333 29.2 12,746 279.5 0 0 0 0 105 2.3 102 2.2 4782 1049 53,219 * 1167.1 57,282 * 1256.2
UK 1083 17 1902 30.4 1900 30.7 133 2.1 92 1.4 571 8.7 280 4.3 953 14.4 882 13.2
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N—number of measles cases; AL—Albania; AT—Austria; BE—Belgium; BA—Bosnia and Herzegovina; BG—Bulgaria; HR—Croatia; CZ—Czech Republic; FR—France; DE—Germany; GR—Greece; HU—Hungary; IT—Italy; ME—Montenegro; PL—Poland; PT—Portugal; MK—North Macedonia; RO—Romania; RS—Serbia; SK—Slovakia; SI—Slovenia; UA—Ukraine; UK—United Kingdom of Great Britain and Northern Ireland; * p < 0.005 2006, 2018 and 2019 Ukraine vs. all other countries; Source for data: World Health Organization Regional Office for Europe [31].

Analysis of the association between the percentage of primary vaccination and number of measles cases, just as between the percentage of revaccination and the number of measles cases between 2001 and 2019 included available data from the following countries: Austria, Hungary, Croatia, Czech Republic, Denmark, Germany, Italy, Poland, France, Belgium, Ukraine, Bosnia and Herzegovina, North Macedonia, Montenegro and Serbia. There was no significant correlation between the percentage of primary vaccination and the number of measles cases (r = −0.0671 p = 0.298) but there was a significant moderate negative correlation between the percentage of revaccination and the number of measles cases (r = −0.357 p < 0.0001).

4. Discussion

After the introduction of the measles vaccination, the number of affected patients decreased significantly. Before 1968 (when compulsory vaccination against measles was introduced in Croatia), the average annual number of patients in Croatia was around 15,000, while in the last ten years, this number has stayed below 20, with the exception of 2015, when we had an epidemic with 206 patients, and in 2018, with the measles epidemic in Dubrovnik-Neretva County [4]. Interestingly, our results show that in Croatia, the percentage of revaccination compared to primary vaccination significantly increased in 2016 and 2017. Analysis of neighboring countries of Croatia revealed that Croatia, Slovenia, and Serbia generally had the best primary vaccination success, while Bosnia and Herzegovina (BiH) and North Macedonia had the lowest primary vaccination percentage and BiH also had the lowest percentage of revaccination compared to neighboring countries (Table 3 and Table 4). Interestingly, in the first decade of the 21st century, Italy, Belgium and France had the lowest MMR primo-vaccination coverage of analyzed European countries. There was no significant difference in the percentage of primary vaccination between EU countries from 2005 until 2007 and from 2010 until 2017. However, in the period 2013–2017, Ukraine had the lowest primary vaccination and revaccination coverage compared to other European countries (e.g., in 2016 Ukraine had 47% primary vaccination and 31% revaccination). The highest percentages of coverage are seen in Hungary and Croatia (Table 5 and Table 6). This is in agreement with the notification rate per million population for measles. In Croatia from November 2020–October 2021 [8] and February 2021–January 2022, there were zero cases, and in Slovenia, Hungary, Slovakia, Czech Republic, Bulgaria, Greece, and Portugal, there were no cases of measles. Other EU countries reported 0.001–0.099 cases [9]. In contrast, in the period February 2020–January 2021, only Croatia, Hungary and Slovakia reported a notification rate per million of zero, while the majority of other EU countries had from 0.001–0.999 [10]. This could be attributed to suboptimal vaccine coverage in Europe, which led to a major resurgence of measles in recent years [32]. Several reasons may underline that situation, including increasing trends of vaccine hesitancy or refusal due to perception of measles risk and burden, mistrust in experts, concerns about vaccine safety, effectiveness, and accessibility [32]. Furthermore, migrations and consequences of wars or economical migrations from the countries with disturbed health care systems also influence vaccination coverage of the population. Importantly, one may hypothesize that the decrease in vaccination in the EU and neighboring countries increases the risk of an epidemic surge in the near future.

The biggest problem is the continuous decline in vaccination coverage of preschool children, which is below the minimum 95% and can lead to an epidemic [33]. Recently, in the study conducted in the frame of the CABCOS3 project, it was reported that the Hungarian serum samples and Croatian serum samples were largely overlapping in seropositivity ratios, which might be attributed to the intrinsic biological dynamics of vaccination-based humoral immunity to measles. Individuals 34–43 years old had the lowest seropositivity ratios (78%) [34]. A prospective study conducted in Prague, Czechia, on a total of 2782 participants aged 19–89 years, analyzed the level of measles-specific antibodies in serum samples and showed that the seropositivity rate in naturally immunized participants (before 54 years) was significantly higher than in fully vaccinated persons aged 19–48 (98.0% (95% CI: 96.5–99.0%) vs. 93.7% (95% CI: 92.4–94.9%)). Lower seropositivity persistence (86.6%) was found in a cohort of those born in 1971–1975, vaccinated mostly with one dose, compared to naturally immunized persons or compared to participants fully vaccinated with two doses [35]. Furthermore, in 2019, 59 measles cases were reported between 1 January and 11 March in Austria; 47 of them fulfilled the cluster case definition. Forty out of 47 patients (85.1%) were unvaccinated, while the age distribution of cases suggested measles immunity gaps in adults [36]. In Zagreb, Croatia, in the period from December 2014 to April 2015, 122 measles cases were notified, 93% of which were unvaccinated persons, age younger or equal to four years, and older than 20 [37]. The outbreak was successfully resolved, and Croatia has an excellent measles elimination profile [38]. Interestingly, in Korea, 2019, there were 26 measles case-patients, aged 18–28 years. Twenty-five of them had previously received the MMR vaccine (12/26, 46% (two doses); 13/26, 50% (one dose)), and 16 (62%) had positive results of measles IgG prior to measles diagnosis [39]. Altogether, these are important information in the light of the previously mentioned outbreak among adults in Dubrovnik-Neretva County [4], suggesting that the lack of previous immunization, together with a decrease in seropositivity, present a risk for future epidemic outbreaks.

It has been shown that several factors may influence the parental decision to choose MMR vaccination, such as confidence in experts and vaccine, measles severity, responsibility toward child and community health and peer judgment [32]. Through educational activities foreseen within CABCOS, our goal is to increase public awareness of the importance of vaccination and increase the share of vaccinated children. Trends of a decrease in immunization coverage are followed in other countries in the region. For example, in the years 2018 to 2020, in Kosovo, >90% (N = 430) of children 12–24 months old had fully completed immunization personal plans. There were delays in immunizations, from 1 to 3 months, mainly due to the COVID-19 pandemic, lack of time for parents to take the child for vaccination or the child being sick at the scheduled time of vaccination. The difference between non-vaccination and full vaccination was only related to the age of children (p < 0.001) [40].

In contrast to the situation in Croatia (Table 3 and Table 4), in Serbia, over the period 2000–2017, there was a significant decline in coverage of primary vaccination against measles, mumps, rubella (MMR) (p ≤ 0.01). In the same period, coverage of all subsequent revaccinations significantly decreased, e.g., in the second dose against MMR before enrolment in elementary school (p < 0.05) [41]. In Western Europe, the situation with vaccination coverage varies. 2018–2019 data in the UK, London area, showed that the coverage of children with dose two of MMR vaccine at their fifth birthday has been consistently low (76.3%) [42]. Results of the present study showed that Germany (Table 5 and Table 6) had also significantly lower primary vaccination and revaccination percentages compared to other countries in 2003 and 2004. Importantly, there was no significant difference in the percentage of revaccination between EU countries from 2005 until 2007 and from 2010 until 2018. It is not clear what was the cause of differences in immunization coverage in the period 2007 until 2010.

A recent systematic review (PROSPERO CRD42019157473; 1 January 2000 to 22 May 2020) identified studies on vaccine-preventable disease outbreaks involving migrants residing in the EU/EEA and Switzerland (including measles, mumps and rubella). 47 different vaccine-preventable disease outbreaks in 13 countries were reported in 45 studies. 40% of outbreaks (mostly varicella and measles) occurred in shelters or temporary refugee camps. Measles were the most reported outbreaks involving migrants (n = 24; 6496 cases) and 11 of them were associated with migrants from eastern European countries. There were only three reported rubella outbreaks (487 cases) and two reported mumps outbreaks (293 cases) [43]. As a study in 2017 demonstrated, the most important factor that prevented the resurgence of measles was vaccine coverage rates, regardless of the economic status of the country or the number of incoming travelers or migrants. In 2017, the incidence of measles was the highest in Romania (46.1/100,000), which has the lowest coverage rate (75%), followed by Ukraine (10.8/100,000) and Greece (8.7/100,000). Overall vaccination coverage with two doses in these countries was less than 84% [44]. Data from a 2017 survey on national immunization strategies to provide vaccinations for migrants show that Portugal, Italy, Croatia and Slovenia offer migrant children and adolescents all vaccinations included in the National Immunization Plan, and Greece and Malta provide only certain vaccinations, including those against measles–mumps–rubella and diphtheria–tetanus–pertussis and poliomyelitis. Portugal, Malta, Italy and Croatia also offer vaccination to adults. Vaccinations are delivered in holding centers and/or community health services in all countries. No country delivers vaccinations at the entry site to the country [45]. Thus, the finding of the present study, that there is a significant moderate negative correlation between the percentage of revaccination and the number of measles cases, provides additional support for the importance of the completion of vaccination protocols, since this correlation was not found in primo-vaccination.

5. Conclusions

In conclusion, the present study demonstrates that there is a negative correlation between the second vaccination (revaccination) and the number of measles cases, which emphasizes the necessity to perform a full protocol of vaccination to reach appropriate protection from potential epidemic outbreaks. Thus, it is important to have a strategy to document migrants’ flow and facilitate vaccination as needed; this is of utmost importance to prevent future epidemics. Additionally, follow-ups on seropositivity upon vaccination in the adult population should be monitored to highlight potential regions or sub-population at greater risk to be points of epidemic outbreaks.

Author Contributions

Conceptualization I.D. and S.S.; formal analysis I.D. and A.S.; investigation I.D., S.S., K.B., P.N. and T.B.; data curation I.D. and S.S.; writing—original draft preparation I.D. and S.S.; writing—review and editing I.D.; visualization S.S. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the project HUHR-1901-311-0032 with the title: CABCOS3 (Hungary-Croatia Cross-border Co-operation INTERREG-IPA EU funded grant).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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References

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