Invasive meningococcal disease in South-Eastern European countries: Do we need to revise vaccination strategies?

Figures & data

Table 1. IMD case definition and type of surveillance across the included countries.

Country	Case definition	Surveillance
Croatia	EU	Compulsory (nationwide)
Czech Republic	EU	Compulsory (nationwide), active surveillance Case-based and laboratory-based
Greece	EU	Compulsory (nationwide)
Hungary	EU + WHO	Passive (nationwide and case-based)
Poland	EU/PL	Compulsory (nationwide)
Romania	EU	Passive (nationwide and case-based)
Serbia	EU	Passive (nationwide and case-based)
Slovenia	EU	Compulsory (nationwide)
Ukraine	EU	Passive (case-based)

EU, European Union Case definition²⁷: Clinical criteria: Any person with at least one of the following symptoms: meningeal signs; hemorrhagic rash; septic shock; septic arthritis. Laboratory Criteria: At least one of the following four: isolation of Neisseria meningitidis from a normally sterile site, or from purpuric skin lesions; detection of Neisseria meningitidis nucleic acid from a normally sterile site, or from purpuric skin lesions; detection of Neisseria meningitidis antigen in cerebrospinal fluid (CSF); detection of Gram-negative stained diplococcus in CSF. Epidemiological criteria: An epidemiological link by human-to-human transmission. Case Classification: A) Possible case, any person meeting the clinical criteria; B) Probable case, any person meeting the clinical criteria with an epidemiological link; B) Confirmed case, any person meeting the laboratory criteria.

PL, Poland. Case definition the same as for EU, but with exclusion of possible cases.

WHO, World Health Organization. WHO suggested invasive meningococcal outbreak case definition²⁸: Suspected case, any person with sudden onset of fever (>38.5°C rectal or 38.0°C axillary), neck stiffness, OR other meningeal signs (including bulging fontanel in infants). Probable case, any suspected case with macroscopic aspect of CSF turbid, cloudy or purulent, or a CSF leukocyte count > 10 cells/mm3, or bacteria identified by Gram stain in CSF, or positive Neisseria meningitidis antigen detection (e.g., by latex agglutination testing). In infants, CSF leucocyte count > 100 cells/mm3, or CSF leucocyte count 10–100 cells/mm3 and either an elevated protein (>100 mg/dl), or decreased glucose (<40 mg/dl) level). Confirmed case, any suspected case that is laboratory confirmed by culture or polymerase chain reaction (PCR) detection of Neisseria meningitidis in the CSF or blood. Excluded case, suspected case where laboratory test shows another pathogen.

WHO suggested IMD surveillance case definition²⁸: Suspected IMD case, no standard case definition. Probable IMD case, any person with clinical diagnosis of meningitis or septicemia AND at least one of the following: purpuric rash where IMD is considered the most likely cause (linked to confirmed cases with other causes of hemorrhagic rash excluded or considered less likely); or gram-negative diplococci identified from normally sterile site or from a purpuric skin lesion; or positive Neisseria meningitidis antigen detection (e.g., by latex agglutination testing) from any normally sterile site or purpuric skin lesion. Confirmed IMD case, Neisseria meningitidis is identified via culture or PCR from a purpuric skin lesion or any normally sterile site.

Table 2. Diagnostic methods across the included countries.

Country	Microbial diagnosis	Typing	Antimicrobial suspect testing
Croatia	Yes	Serogrouping (PCR at 1 site)	Yes
Czech Republic	Yes	Serogrouping, PCR, PorA, fetA, MLST, WGS, fHbp, nhba, nadA	Yes
Greece	Yes	Serogrouping, PCR, PorA, fetA, fHbp, nhba, nadA, MLST, WGS	Yes
Hungary	Yes	Serogrouping, WGS, PorA, fetA, MLST	Yes
Poland	Yes	Serogrouping, PorA, fetA, fHbp, MLST, WGS	Yes
Romania	Yes	Serogrouping	Yes
Serbia	Yes	Serogrouping, PorA, fetA	Yes
Slovenia	Yes	Serogrouping, WGS	Yes
Ukraine	Yes	Serogrouping	Yes

fHbp, factor H binding protein; MLST, multilocus sequence typing; nadA, neisserial adhesion A; nhba, neisserial heparin binding protein; PCR, polymerase chain reaction; WGS, whole genome sequencing

Figure 1. Average notification rates for IMD across the included countries for the period 2010 to 2019.

*Data available for 2012–2019

Table 3. Notification rates (confirmed cases) per 100,000 population across the included countries, 2010 to 2020.

Notification rate, per 100,000	2010	2011	2012	2013	2014	2015	2016	2017	2018	2019	2020
Croatia	NA	NA	0.96	0.61	0.78	0.99	0.72	0.89	0.76	0.83	0.34
Czech Republic	0.57	0.60	0.56	0.56	0.40	0.46	0.41	0.63	0.53	0.46	0.23
Greece	0.49	0.47	0.53	0.54	0.55	0.50	0.48	0.39	0.32	0.30	0.20
Hungary	0.37	0.67	0.51	0.47	0.33	0.36	0.48	0.40	0.41	0.47	0.33
Poland	0.60	0.74	0.63	0.66	0.49	0.58	0.44	0.60	0.52	0.51	0.28
Romania	0.26	0.34	0.35	0.26	0.34	0.25	0.28	0.25	0.33	0.26	0.12
Serbia	0.20	0.18	0.15	0.05	0.17	0.11	0.07	0.17	0.11	0.11	0.03
Slovenia	0.44	0.63	0.44	0.53	0.39	0.78	0.34	0.44	0.87	0.43	0.24
Ukraineb	1.00	1.10	0.75	0.92	0.74	0.72	0.63	0.77	0.63	0.71	0.33

Notification rates from the ECDC Atlas²⁶ are calculated per 100,000 population: the number of reported confirmed cases, divided by the official Eurostat estimate of the population for that year, multiplied by 100,000.

^aSerbia, incidence rate per 100,000 population from the Health Statistical Yearbook Republic of Serbia.²⁰

^bUkraine, incidence rate per 100,000 population from Ministry of Health of Ukraine Public Health Centre.²¹

NA, not available.

Figure 2. Age standardized rates of IMD per 100,000 population across included countries for 2019.²⁶.

Serbia: In 2019, 1 case in 2 year old, 1 case 10–14, 1 case 15–19, 1 case 40–49, 1 case 50–59 and 2 cases ≥60 years (Health Statistical Yearbook Republic of Serbia).²⁰ Ukraine: In 2019, 30 cases in up to 1 years, 26 cases in 2–4 years, 18 cases 5–9 years, 11 cases 10–14 years, 3 cases 15–17 years, 30 cases ≥18 years (Ministry of Health of Ukraine Public Health Centre, unpublished).

Table 4. Number of deaths and case fatality rates across the included countries, n deaths (CFR %) 2010 to 2020.

n deaths (CFR %)	2010	2011	2012	2013	2014	2015	2016	2017	2018	2019	2020
Croatia^a	4 (9.3)	4 (7.4)	3 (7.3)	1 (3.8)	1 (3.1)	1 (2.8)	3 (10.0)	3 (7.9)	3 (9.7)	2 (5.9)	2 (14.3)
Czech Republic^b	5 (8.3)	8 (12.7)	3 (5.1)	3 (5.1)	5 (11.9)	3 (6.3)	6 (14.0)	10 (14.9)	3 (5.4)	3 (6.1)	3 (12.0)
Greece^b	3 (5.5)	0 (0.0)	6 (10.2)	3 (5.1)	5 (8.3)	1 (1.9)	4 (7.7)	3 (7.1)	4 (11.8)	3 (9.4)	0 (0.0)
Hungary^b	4 (10.8)	12 (17.9)	6 (11.8)	9 (19.6)	3 (9.4)	9 (25.7)	9 (19.6)	6 (18.8)	6 (15.0)	8 (17.4)	5 (15.6)
Poland^b	22 (9.6)	21 (7.4)	21 (8.8)	25 (10.0)	14 (7.5)	20 (9.1)	25 (15.0)	30 (13.3)	23 (11.6)	26 (13.5)	4 (3.8)
Romania^b	6 (11.5)	9 (13.2)	9 (12.7)	4 (7.7)	4 (6.0)	8 (16.0)	8 (14.5)	6 (12.0)	13 (20.3)	10 (20.0)	2 (8.3)
Serbia^c	1 (6.7)	0 (0.0)	1 (9.1)	0 (0.0)	0 (0.0)	1 (12.5)	0 (0.0)	2 (16.7)	2 (25.0)	0 (0.0)	1 (50.0)
Slovenia^b	1 (11.1)	1 (7.7)	0 (0.0)	1 (9.1)	1 (12.5)	2 (12.5)	1 (14.3)	0 (0.0)	2 (11.1)	0 (0.0)	0 (0.0)
Ukrained^†	68	103	58	NA	60	60	NA	49	39	46	NA

^aData from the Croatian health statistics yearbook 2019¹⁹; ^bData from the ECDC Atlas²⁶; ^cData from the Health Statistical Yearbook Republic of Serbia.^{20 d}Data from the WHO European Health Information Gateway.²⁹

NA, not available.

^†Only n deaths available.

Figure 3. Number of reported cases by serogroups, 2010 to 2020 in selected age groups, as indicated in Table S1.²⁶.

Serbia: In 2019, 1 case in 2 year old, 1 case 10–14, 1 case 15–19, 1 case 40–49, 1 case 50–59 and 2 cases ≥60 years.20 Ukraine: In 2020, 30 cases in up to 1 years, 26 cases in 2–4 years, 18 cases 5–9 years, 11 cases 10–14 years, 3 cases 15–17 years, 30 cases ≥18 years (Ministry of Health of Ukraine Public Health Centre, unpublished). Romania: Data from the National Center of Surveillance and Control of Infectious Diseases, Annual report for 2012,³⁰ 2014³¹ and 2015.³²

Table 5. Meningococcal vaccination strategies and recommendations for each included country.

	MenB vaccination	MenC vaccination	MenACWY vaccination
Croatia	High risk groups		High risk groups
Czech Republic	High risk groups (reimbursed), infants (reimbursed since 2020), adolescents in the 15^th year of life (reimbursed since 2022)		High risk groups (reimbursed), toddlers in the 2^nd year of life (reimbursed since 2020), adolescents in the 15^th year of life (reimbursed since 2022)
Greece	Recommended + high risk (not reimbursed) Available privately (since 2014)	12 months (reimbursed since 2005)	Adolescents (reimbursed since 2012), infants >2 months, high risk (reimbursed since 2017)
Hungary	Recommended infants and adolescents (not reimbursed since 2014)	Up to 2 years (reimbursed since 2006)	Recommended adolescents (not reimbursed since 2010)
Poland	Recommended (not reimbursed)	Recommended (not reimbursed)	Recommended (not reimbursed)
Romania	Available privately		High risk Available privately^Citation33
Serbia			High risk (since March 2016)
Slovenia	Recommended for high risk (reimbursed)		Recommended for high risk (reimbursed)
Ukraine			High risk (not reimbursed) Available privately

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Data Availability Statement

The data that support the findings of this study are included in the study/or can be requested from the corresponding author upon reasonable request.