Journal of Infection 79 (2019) 528–541 Contents lists available at ScienceDirect Journal of Infection journal homepage: www.elsevier.com/locate/jinf Prevention and control of meningococcal disease: Updates from the Global Meningococcal Initiative in Eastern Europe Xilian Bai a , Ray Borrow a , ∗, Suzana Bukovski b , Dominique A. Caugant c , Davor Culic d , Snezana Delic d , Ener Cagri Dinleyici e , Medeia Eloshvili f , Tímea Erd ̋osi g , Jelena Galajeva h , Pavla K ̌rížová i , Jay Lucidarme a , Konstantin Mironov j , Zuridin Nurmatov k , Marina Pana l , Erkin Rahimov m , Larisa Savrasova n , Anna Skoczy ́nska o , Vinny Smith p , Muhamed-Kheir Taha q , Leonid Titov r , Julio Vázquez s , Lyazzat Yeraliyeva t a Meningococcal Reference Unit, Public Health England, Manchester Royal Infirmary, Manchester M13 9WZ, UK b University Hospital for Infectious Diseases, Zagreb, Croatia c Norwegian Institute of Public Health, Oslo, Norway d Institute for Public Health, Sombor, Serbia e Eskisehir Osmangazi University, Eskisehir, Turkey f National Center for Disease Control & Public Health, Tbilisi, Georgia g National Public Health Center, Budapest, Hungary h Riga East University Hospital, Riga, Latvia i National Institute of Public Health, Prague, Czechia j Central Research Institute of Epidemiology, Moscow, Russia k Scientific and Production Association “Preventive Medicine”, Bishkek, Kyrgyzstan l Cantacuzino National Medico Military Institute for Research Development, Bucharest, Romania m Baku Medical Plaza, Baku, Azerbaijan n The Centre for Disease Prevention and Control of Latvia, Riga, Latvia o National Reference Centre for Bacterial Meningitis, National Medicines Institute, Warsaw, Poland p Meningitis Research Foundation, Bristol, UK q National Reference Centre for Meningococci, Institute Pasteur, Paris, France r Republican Research & Practical Center for Epidemiology & Microbiology, Minsk, Belarus s Institute of Health Carlos III, Madrid, Spain t Kazakh National Medical University, Almaty, Kazakhstan a r t i c l e i n f o Article history: Accepted 26 October 2019 Available online 1 November 2019 s u m m a r y The Global Meningococcal Initiative (GMI) aims to prevent invasive meningococcal disease (IMD) world- wide through education, research and cooperation. In March 2019, a GMI meeting was held with a multi- disciplinary group of experts and representatives from countries within Eastern Europe. Across the coun- tries represented, IMD surveillance is largely in place, with incidence declining in recent decades and now generally at < 1 case per 10 0,0 0 0 persons per year. Predominating serogroups are B and C, followed by A, and cases attributable to serogroups W, X and Y are emerging. Available vaccines differ between countries, are generally not included in immunization programs and provided to high-risk groups only. Available vaccines include both conjugate and polysaccharide vaccines; however, current data and GMI recommendations advocate the use of conjugate vaccines, where possible, due to the ability to interrupt the acquisition of carriage. Ongoing carriage studies are expected to inform vaccine effectiveness and im- munization schedules. Additionally, IMD prevention and control should be guided by monitoring outbreak progression and the emergence and international spread of strains and antibiotic resistance through use of genomic analyses and implementation of World Health Organization initiatives. Protection of high-risk ∗ Corresponding author. E-mail addresses: Xilian.Bai@phe.gov.uk (X. Bai), Ray.Borrow@phe.gov.uk (R. Borrow), sbukovski@bfm.hr (S. Bukovski), dominique.caugant@fhi.no (D.A. Cau- gant), mikrobiologija@zzjzsombor.org (D. Culic), mikrobiologija@zzjzsombor.org (S. Delic), m.eloshvili@ncdc.ge (M. Eloshvili), erdosi.timea@nnk.gov.hu (T. Erd ̋osi), jelena.galajeva@aslimnica.lv (J. Galajeva), pavla.krizova@szu.cz (P. K ̌rížová), Jay.Lucidarme@phe.gov.uk (J. Lucidarme), mironov@pcr.ru (K. Mironov), z.nurmatov@mail.ru (Z. Nurmatov), larisa.savrasova@spkc.gov.lv (L. Savrasova), a.skoczynska@nil.gov.pl (A. Skoczy ́nska), vinnys@meningitis.org (V. Smith), muhamed-kheir.taha@pasteur.fr (M.-K. Taha), leonidtitov@tut.by (L. Titov), jvazquez@isciii.es (J. Vázquez), l.yeraliyeva@gmail.com (L. Yeraliyeva). https://doi.org/10.1016/j.jinf.2019.10.018 0163-4453/Crown Copyright © 2019 Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY-NC-ND license. ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ) X. Bai, R. Borrow and S. Bukovski et al. / Journal of Infection 79 (2019) 528–541 529 Keywords: Antibiotic resistance Bacterial meningitis Conjugate vaccine Eastern Europe High-risk groups Immunization program Meningococcal disease Neisseria meningitidis Polysaccharide vaccine Refugees groups (such as those with com ommended. Crown Copyright © 201 I t s o 1 s I m r iA t w r a g a I i w i a a e t r m I T m TcS c fi a s m r t S p p t R wI b p f t W i t s o aI m g i t bN N 12 d d p2 h I b sd g sI r d n v pS t f i f e ntroduction Invasive meningococcal disease (IMD) is caused by the bac-erium Neisseria meningitidis (Nm), which may invade the blood-tream resulting in life-threatening illnesses, the most commonf which are meningitis and septicemia. 1 Nm is classified into2 serogroups based on the capsular polysaccharide and six mainerogroups (A, B, C, W, X, Y) are responsible for the majority of theMD burden worldwide. 2 , 3 Globally, IMD affects approximately 1.2illion individuals each year and is associated with high fatalityates (up to 40%), as well as long-term sequelae (such as neurolog-cal complications) in approximately 20% of infected individuals. 4 , 5 s such, effective surveillance and prevention strategies are essen-ial for the control of IMD. 6 The Global Meningococcal Initiative (GMI) was formed in 2009ith the objective to prevent IMD worldwide through education,esearch and cooperation. 7 Over the last decade, the GMI has held number of regional and global meetings with multidisciplinaryroups of experts across fields including vaccinology, immunologynd public health. Global recommendations for the management ofMD have been previously developed and published. 2 , 8 The GMI held a roundtable meeting in Prague, Czech Republicn March 2019, with attendees representing a number of countriesithin the Eastern European region. The objectives of the meet-ng were to: (i) discuss IMD surveillance, epidemiology, preventionnd control strategies in Eastern Europe, including current issuesnd barriers to implementation; (ii) share learnings and experi-nces from IMD immunization programs worldwide; (iii) discusshe importance of conjugate vaccines in the prevention of IMD; (iv)eview the emergence of antibiotic resistance and describe recom-ended antibiotics for treatment and prophylaxis, and (v) discussMD in high-risk groups and recommendations for immunization.he local data included within this article were presented at theeeting, and/or provided by the relevant author shortly thereafter.he epidemiology and surveillance of IMD, and prevention and ontrol strategies in Eastern Europe urveillance of IMD Implementation of effective surveillance strategies is key to theontrol of IMD, allowing the detection of cases and outbreaks, con-rmation of the epidemiology of disease (e.g. incidence, burdennd circulating serogroups), monitoring of strains and antibioticusceptibility, as well as determination of the impact of controleasures on disease. 6 , 9 IMD surveillance is in place in the majority of countries rep-esented at the meeting, with the exception of Azerbaijan, wherehere is a general surveillance program for infectious diseases.urveillance systems generally involve confirming cases througholymerase chain reaction (PCR) testing and/or culture, and re-orting suspected cases of IMD at a national level. In some coun-ries, isolates are further characterized. For example, in the Czechplement deficiencies, laboratory workers, migrants and refugees) is rec-9 Published by Elsevier Ltd on behalf of The British Infection Association.This is an open access article under the CC BY-NC-ND license.( http://creativecommons.org/licenses/by-nc-nd/4.0/ )epublic, multilocus sequence typing (MLST) and more recently,hole genome sequencing (WGS), are used in surveillance. 10 , 11 n Hungary, finetyping, MLST and WGS (the latter during out-reak investigations) are used to further characterize strains, withhenotypic testing to determine antimicrobial susceptibility to ri-ampicin. Differences in surveillance systems were noted. In Georgia, sen-inel surveillance of IMD is in place, with data submitted to theorld Health Organization (WHO) on a monthly basis. Conversely,n Latvia and Romania, only passive surveillance of IMD is under-aken, while in Serbia, both passive and active surveillance of pos-ible cases is performed. In most Eastern European countries, casesf IMD are reported to the European Centre for Disease Preventionnd Control via the European Surveillance System (TESSy). 4 , 12 ncidence of IMD The incidence of IMD has declined over recent decades acrossany Eastern European countries. 13–16 Incidence is similar andenerally < 1 case per 10 0,0 0 0 persons per year ( Table 1 ), rang-ng from 0.14 cases per 10 0,0 0 0 persons per year in Azerbaijan (al-hough, due to a lack of robust statistics, incidence is expected toe higher) to 1 case per 10 0,0 0 0 persons per year in Croatia. 13–18 otably, incidences of IMD and acute bacterial meningitis due tom have previously been documented at 2.45 and 1.9 cases per0 0,0 0 0 persons per year in Kazakhstan (2005) and Turkey (2005–006), respectively. 13 , 16 Incidence of IMD is highest among chil-ren < 5 years old, particularly in those < 1 year old, with inci-ences of 10.65, 5.4–38.7 and approximately 11 cases per 10 0,0 0 0ersons per year in Poland (2018), 18 the Czech Republic (1993–018) 13 and Latvia (2008–2018), 13 respectively. Gender differencesave been reported in Latvia and Croatia, with greater incidence ofMD recorded in males compared with females. 13 Case fatality rates (CFRs) range from approximately 3% to 30%oth within and across the Eastern European countries repre-ented. 13 , 17 , 18 In Poland, the greatest CFR (44%) was noted in in- ividuals aged > 65 years, while in the Czech Republic and Hun-ary, mortality is greatest among infants (16.4% and 11–29% forerogroups B and C among children aged ≤5 years, respectively). 13 n Kyrgyzstan, deaths from bacterial meningitis have declined inecent years (from 12.4% in 2015 to 4.7% in 2018) due to the intro-uction of guidance on surveillance, anti-epidemic measures, diag-osis and treatment of bacterial meningitis in 2015, and the pro-ision of training to physicians on the diagnosis and treatment ofatients ( Table 1 ). 13 erogroup distribution In the Eastern European countries participating in the meeting,he predominant serogroups of Nm were serogroup B (accountingor approximately 60–90% of cases) and serogroup C (re-emergingn a number of countries and accounting for up to 30% of cases),ollowed by serogroup A ( Table 1 ). 13–22 Cases of serogroup A dis-ase are still reported in Romania, 14 the Republic of Belarus (5%530 X. Bai, R. Borrow and S. Bukovski et al. / Journal of Infection 79 (2019) 528–541 Table 1 Overview of the epidemiology of IMD and available vaccines in Eastern European countries. Region/country Incidence of IMD (cases/10 0,0 0 0 persons/year) CFR Serogroup distribution Control strategies (vaccines) Poland • 0.45 (2018) 18 • 10.65 (infants < 1 year old) 18 • 14% (2013–2017) 18 • Increased in: • People aged 65 + (44% 2013–2017) 13 • 2016–2017 compared with earlier years (from 12.5% in 2013 to 18.8% in 2017) 13 • Cases of serogroup W disease (38.5% 2013–2017) 18 • Stable 2014–2018, with ∼70% B and 25–30% C 18 • Increase in serogroup W observed in 2018 (9.8%) relative to 2014–2017 (2.2–4.4%) 18 • Vaccines recommended but not reimbursed 30 Czech Republic • 0.4 to 2.2 (1993–2018); declining since 2003 13 • 5.4–38.7 (infants < 1 year old) 13 • 4.7–16.4% 13 • Highest rate seen in infants 13 • Serogroup B most prevalent and highest in infants < 1 year old 13 • Serogroup C re-emerging, particularly since 2011 13 • Few cases of serogroup W disease observed (22 cases from 1984 to 2017) 26 • Vaccines recommended but not included in the NIP 27 • Combination of conjugate tetravalent vaccine and MenB vaccine is recommended • Some insurance companies reimburse vaccination • Vaccination is free of charge for patients with underlying diseases since January 2018 Hungary • 0.4 (1988–2018) 13 • Serogroup C outbreaks 1999–20 0 0 and 2010–2011 13 • Average > 10% (2006–2018) 13 • 11–29% in children aged < 5 years old 13 • High for serogroups B and C 13 • 17–31% in individuals with serogroup C disease aged 10–24 years 13 • Serogroup B most prevalent ( ∼60% of all cases 2009–2018), followed by C, with cases of serogroup W (9.3% of cases in 2016; 2.4% in 2017–2018) and Y (8.7% of cases in 2013; 1% in 2014–2018) reported 19 • Incidence highest in infants < 1 year old and adolescents aged 15–19 years old 13 • Vaccination recommended but not mandatory 29 • Recommendations include: 29 • Vaccination from 2 to 3 months, maintained up to 25 years old (MenC conjugate vaccine (freely available to children < 2 years old) • Quadrivalent conjugate and MenB vaccine for international travellers, high-risk groups and special populations Croatia • 1 (1985–2017) 13 • ∼10% 13 • Serogroup B most prevalent ( ∼90% of cases 2008–2012); however, in 2017–2018, it accounted for 57%, C for 23% and Y for 11–13% of cases 13 • Serogroup W reported (4 cases from 2009 to 2018; 25 1 case in 2019) 13 • Serogroups B and C predominate in infants and children ≤5 years old; serogroups C and Y account for the majority of cases in adolescents and adults > 15–25 years old 13 • Incidence higher in males (69%) compared with females in 2018 13 • Meningococcal vaccine included in the NIP for high-risk groups • Conjugate MenACWY and MenB vaccines are available Georgia 13 • From 2010–2018, incidence varied from 0.32 (2016) to 0.67 (2011) • Data not available • Available data indicate that cases are largely attributable to serogroups B and C, with cases of serogroup W disease also reported (3 cases from 2015 onwards) • Pneumococcal vaccine PCV10 introduced December 2014 • Meningococcal vaccine not included in the NIP; although MenACWY conjugate vaccine is available if needed Romania • ∼0.5 (2008), declining to just over 0.3 (2017) 14 • Highest number of cases in 0–4-years (30 cases) and 15–19-years age groups ( < 10 cases) in 2017 14 • Data not available • Serogroup B predominates, with cases of serogroup W and A disease reported 14 • No meningococcal vaccines are available in the NIP • MenACWY conjugate vaccine approved in 2018 and available upon request Serbia 13 • 0.17 (12 reported cases in 2017) • 6.45% • Serogroup B: 5.76% • Serogroup C: 10% • From 2009–2018, the majority of confirmed cases serogroup B, except in the 25–49-year group, where serogroups B and Y are equally predominant (each accounting for ∼40% of cases) • From 2008–2018, 2 cases of serogroup W disease and 4 cases of serogroup Y disease were reported • Vaccination recommended but not mandatory • MenACWY conjugate vaccine for high-risk groups ( continued on next page ) X. Bai, R. Borrow and S. Bukovski et al. / Journal of Infection 79 (2019) 528–541 531 Table 1 ( continued ) Region/country Incidence of IMD (cases/10 0,0 0 0 persons/year) CFR Serogroup distribution Control strategies (vaccines) Republic of Belarus • 0.6 (2018), with a decline noted over the last 20 years 13 • During 1997–2018, deaths peaked in 1999–2004 and 2011–2016 13 • Predominant serogroups are B (65%), followed by C (11%), W (9%), A (5%) and Y (4%) (2011–2018) 20 • Increased detection of isolates belonging to serogroups W and Y from 2015 to 2018 13 • No meningococcal vaccines are available in the NIP • MenB vaccine registered and will soon be available Latvia 13 • 0.4 (2018), with incidence declining since 1970 • ∼11 (infants < 1 year old) • 12.5% (2018) • 28.57% (2013) • Most common serogroup is B • No meningococcal vaccines are available in the NIP • Registered vaccines are 4CMenB and MenACWY conjugate, but vaccination is voluntary Russia • Last outbreak in 1996, caused by serogroup A 145 • Incidence decreased over 2010–2016, but has increased recently (0.45 in 2016 to 0.48 in 2017) 17 • 19% (2017) 17 • In 2017, serogroup B predominated (27%), followed by serogroups C (14%), A (11%) and W (8%) 17 • In 2018, serogroup A was the predominant cause (41%), followed by serogroups W (25%), B (17%) and C (14%) at the 2nd Hospital for Infection Disease (Moscow) 13 • Mass vaccination is not carried out during non-epidemic periods, except is high-risk groups 28 • Licensed vaccines are: • MenA polysaccharide • MenC conjugate • MenAC polysaccharide • MenACWY conjugate • MenACWY polysaccharide Kazakhstan 146 • 2.45 (2015) 95 • Outbreaks of IMD in spring/summer 2016–2018 • Despite the decline in incidence since 2015, fatal cases have risen (from 4.9% in 2015 to 22% for 2018) • In 2018, 63% of cases in Almaty were serogroup A • In 2017, 18.4% of cases were serogroups W, X and Y • In 2013–2017, 63.3% of cases were in children aged < 14 years; serogroup B predominated (2009–2015) • No vaccine against IMD is included in the NIP • MenACWY conjugate is available, but vaccination is voluntary • Pilgrims travelling to Saudi Arabia can pay to receive the vaccine at a medical institution Azerbaijan 13 • 0.14 (2015) • Incidence varies: one case in 2009 and 2010, up to 14 cases in 2015; three cases in 2018 • In children < 5 years old, incidence ranges from 14 cases in 2011 to one case in 2018 • Data not available • Serogroup A (7 cases), B (33 cases, C (21 cases), W (11 cases) and X (1 case) reported from 2010 to 2018 in children < 5 years old • No meningococcal vaccines available • MenACWY conjugate registered in 2018 Kyrgyzstan 13 • Peak incidences 12.5 (1997) and 6.6 (2015) • 0.36 (2018) • Declined from 12.4% (2015) to 4.7% (2018) • Data not available • Meningococcal vaccinations not included in the NIP, but individuals (e.g. pilgrims travelling to Saudi Arabia) can pay to receive a vaccine at a medical institution Turkey • 3.5–4.0 in children < 5 years old (2005), with the majority of cases in those aged < 1 year a , 16 • 1.9 (2005) decrease to 0.9 (2014) a , 15 , 16 • 3.2% (2014) a , 13 • Serogroups W and B responsible for the majority of cases in 2005–2017 15 , 16 , 21 • Large increase in serogroup B disease in 2017 (65% of cases), with cases of serogroups A ( < 10% of cases), W ( < 10% of cases) and X ( < 5% of cases) also reported 15 , 16 , 21 • A NIP is in place, but does not include the conjugate quadrivalent (MenACWY) or MenB (4CMenB) vaccines available • MenACWY for military personnel and Hajj pilgrims • MenACWY (routine) and 4CMenB (since 2019) for patients receiving eculizumab • Vaccination recommended for other high-risk groups 4CMenB = multicomponent meningococcal serogroup B vaccine; CFR = case fatality rate; IMD = invasive meningococcal disease; MenA = meningococcal serogroup A; MenAC = meningococcal serogroups A and C vaccine; MenACWY = meningococcal serogroups A, C, W and Y vaccine; MenB = meningococcal serogroup B; MenC = meningococcal serogroup C; NIP = National Immunization Program; PCV10 = pneumococcal conjugate vaccine. a Incidence of/CFR for acute bacterial meningitis due to Neisseria meningitidis . oA T i o iH s l [S 2 2 r df cases from 2011 to 2018), 20 Russia (11% of cases in 2017), 17 , 23 zerbaijan (seven cases from 2010 to 2018 in < 5 year olds) 13 andurkey ( < 10% of cases since 2005). 16 Cases attributable to serogroup W, Y and X are also emerg-ng. 24 Serogroup W disease has been documented in Poland (9.8%f cases in 2018), 18 Croatia (four cases from 2009 to 2018; one casen 2019), 13 , 25 the Czech Republic (11 cases from 2010 to 2017), 26 ungary (seven cases from 2016 to 2018), 19 Georgia (three casesince 2015), 13 Romania (one case in 2011), 14 the Republic of Be-arus (9% of cases from 2011 to 2018), 20 Kazakhstan (18.4% of casesserogroups W, X, Y] in 2017), 13 Russia (8% of cases in 2017), 17 erbia (two cases from 2008 to 2018), Azerbaijan (11 cases from010 to 2018 among < 5 year olds) 13 and Turkey ( < 10% of cases in017). 14-16 , 21 Available data indicate that ST-3342 (cc865) has beenecorded in the Czech Republic since 2010, as well as in Polanduring 2013–2014. 13 , 26 532 X. Bai, R. Borrow and S. Bukovski et al. / Journal of Infection 79 (2019) 528–541 w c m i a r o o AM m p r oF ( t aH o a t Aa s s m pM a c c f b m c c l w d r c H H a M i a N s v t s t c T f f a w i Cases of serogroup W disease (including ST-9316 and cc11) haverecently increased in Poland (from 2.2% in 2014 to 9.8% in 2018), 18 Russia (8% of cases in 2017) 17 and Kazakhstan (from 2.6% in 2015–2016 to 18.4% in 2017 [serogroups W, X, Y]). 13 Conversely, the pro-portion of serogroup W cases in Turkey has declined followingpeaks in 2009–2010 and 2011–2012 (from > 50% to < 10% of casesin 2017), 21 together with cases in Hungary (from 9.3% of cases in2016 to 2.4% in 2017–2018). 19 In Poland, cases of serogroup W dis-ease are more common in males < 3 years of age and in femalesaged 25–65 years of age or above, with a CFR of 38.5% in 2013–2017. 13 , 18 Cases of serogroup Y disease appeared in Croatia in 2011 andaccounted for 11–13% of cases in 2017–2018 while in Serbia, fourcases were reported from 2008 to 2018, with serogroup Y andserogroup B disease equally prominent among individuals aged25–49 years (each accounting for approximately 40% of cases from2009 to 2018). 13 Cases of serogroup Y disease have also been doc-umented in Hungary (from 2013 onwards; 8.7% of cases in 2013and 1% of cases 2014–2018), 19 Kazakhstan 13 and the Republic ofBelarus (4% of cases from 2011 to 2018). 20 Since 2017, one caseof serogroup X has been recorded in both Turkey (2017) and inPoland (2018), while one case was documented in Azerbaijan in2011. 13 , 18 , 21 Prevention and control strategies Prevention and control strategies available across Eastern Euro-pean countries encompass vaccination and antimicrobial prophy-laxis. In the event of an outbreak, close contacts of cases of IMDare closely monitored and/or chemoprophylaxis is provided, 27 , 28 with vaccination as appropriate and increased epidemiological andlaboratory surveillance undertaken. Both conjugate and polysac-charide vaccines are available, although not provided via Na-tional Immunization Programs (NIPs) in the majority of countries( Table 1 ). Generally, Eastern European countries provide vaccina-tion to high-risk populations (e.g. immunocompromised individ-uals) and special populations (e.g. military recruits, the elderly,travelers) only. 27–29 However, in many countries, vaccination isrecommended, but not mandatory and/or not reimbursed. 27 , 29 , 30 Barriers to implementation of vaccination strategies include thelow incidence of IMD, high cost of meningococcal vaccines, lack ofuniversal vaccines against all meningococci and absence of effecton carriage for current MenB vaccines. Potential solutions includeprovision of additional vaccination recommendations, reduction ofthe price of vaccines, inclusion of additional vaccines in NIPs andimplementation of educational initiatives to change current atti-tudes towards vaccination. Meningococcal immunization: overview, recent developments and predicting coverage Conjugate vaccines and the prevention of IMD Conjugate vaccines, formed by binding the polysaccharide anti-gen of interest to a carrier protein that will induce a T cell-dependent immune response (e.g. the tetanus toxoid protein), haveseveral advantages when compared with pure polysaccharide vac-cines, including an ability to induce immunological T cell mem-ory and consequently high response to boosters, as well as alack of hypo-responsiveness following repeated dosing. 7 , 31–33 Im-portantly, conjugate vaccines also infer indirect (herd) protectionthrough hindering the acquisition of carriage. 34 As such, the GMIrecommends that conjugate vaccines replace plain polysaccharidevaccines whenever cost, availability, licensing, and immunizationpolicy allow. 9 A number of conjugate vaccines are available world-ide, although it should be noted that their availability varies fromountry to country. 9 As discussed previously, 9 introduction of the conjugateeningococcal serogroup C (MenC) vaccine in the UK infantmmunization schedule in 1999, with a catch-up program forll children and adolescents under the age of 18 years, led to aapid decline in the incidence of MenC disease, with reductionsbserved in carriage ( Fig. 1 (A)). 34 , 35 Similarly, the introductionf the meningococcal serogroup A (MenA) conjugate vaccine infrica in 2010 has eliminated carriage of MenA ( Fig. 1 (B)). 36–39 ultivalent conjugate vaccines that provide protection againsteningococcal serogroups A, C, W and Y (MenACWY) are alsoroving effective. For instance, prevention of the acquisition of car-iage of serogroup Y has been shown following the administrationf the MenACWY vaccine among university students in the UK. 40 urther, following an outbreak of meningococcal serogroup WMenW) disease in the UK, direct protection was reported amonghe MenACWY-vaccinated cohort of adolescents aged 14–18 years,s observed through a reduction in cases of MenW ( Fig. 2 ). 41 owever, further research is required to understand the impactf vaccine implementation on carriage of serogroup W. Currently, pentavalent ACWXY conjugate vaccine that will potentially beargeted at individuals aged 9 months to 29 years in sub-Saharanfrica is in clinical trials; the Phase I trial has been completed 42 nd Phase II trials are ongoing. While time-consuming, expen-ive and difficult to undertake, carriage studies will help us toupport and guide the introduction of conjugate vaccines andeasure the indirect impact of their addition to vaccinationrograms. 34 eningococcal serogroup B vaccines Unlike other meningococcal serogroups, it is not possible to cre-te vaccines that target the capsular polysaccharide of meningo-occal serogroup B (MenB) as the polysialic acid component of theapsule is homologous to an adhesion molecule found on the sur-ace of human neural cells. 43 As such, this polysaccharide woulde poorly immunogenic, with the potential to induce an autoim-une response. 44 Major breakthroughs in the development of vac-ines for MenB were (i) the development of outer membrane vesi-le (OMV) vaccines, which have previously been used to controlocal and clonal outbreaks in countries such as New Zealand, Nor-ay, Cuba and France, and are still used in Cuba, 45 , 46 and (ii) theevelopment of vaccines including recombinant surface proteins. 47 Currently, two vaccines targeting MenB are licensed in Eu-ope: (1) a multicomponent vaccine (4CMenB [Bexsero R ©]); li-ensed since 2013; including four main surface proteins (factor-binding protein [fHbp], Neisseria adhesin A [NadA], Neisserialeparin Binding Antigen [NHBA] and Porin A [PorA]); and (2) bivalent MenB vaccine (MenB-fHbp [Trumenba R ©]); licensed inay 2017; composed of two variants of fHbp. 48 , 49 Broadly speak-ng, 4CMenB provides protection against isolates expressing vari-nt 1 peptides of fHbp, variant NadA-1 and NadA-2/3 peptides ofadA, NHBA and/or PorA 1.4, with a gradient of protection ob-erved according to how homologous the respective peptide sub-ariants are to the antigens in the vaccine and the level to whichhey are expressed. 50 Given that the distribution of the peptideubvariants differs according to region and age, the coverage ofhese vaccines against circulating MenB strains is not certain, butan be predicted using assays such as the Meningococcal Antigenyping System (MATS; 4CMenB) and Meningococcal Antigen Sur-ace Expression (MEASURE; MenB-fHbp; see following section forurther detail) assay. The predicted coverage of 4CMenB differscross countries, ranging from 66% in Canada to 91% in the US,hile the predicted coverage of MenB-fHbp is 91%, based on 1923solates from the US, the UK, France, Norway, the Czech Republic,X. Bai, R. Borrow and S. Bukovski et al. / Journal of Infection 79 (2019) 528–541 533 Fig. 1. Reductions in carriage of (A) serogroup C, in contrast to other serogroups, and (B) serogroup A following the introduction of MenC and MenACWY, in the UK and Africa, respectively. 34 , 36 MenC = meningococcal serogroup C; MenACWY = meningococcal serogroups A, C, W and Y vaccine. Fig. 2. Age distribution of MenW cases in the UK following immunization of adolescents aged 14–18 years with conjugate MenACWY vaccine, which commenced in 2015. 41 MenW = meningococcal serogroup W; MenACWY = meningococcal serogroups A, C, W and Y vaccine. 534 X. Bai, R. Borrow and S. Bukovski et al. / Journal of Infection 79 (2019) 528–541 Table 2 Reductions in the carriage prevalence of N. meningitidis in subjects who received 4CMenB versus those who received control vaccination (Japanese Encephalitis vaccine) (adapted from Read et al. 40 ). N. meningitidis serogroup(s) Odds ratio (95% CI) Carriage reduction (95% CI) All NmB 0.8 (0.6–1.1) 15.6% (–11.0 to 35.9) Disease associated MenB 0.9 (0.7–1.2) 12.6% (–15 to 34.1) BCWY 0.7 (0.6–0.9) 26.6% (10.5 to 39.9) CWY 0.7 (0.5–0.9) 29.6% (8.1 to 46.0) 4CMenB = multicomponent meningococcal serogroup B vaccine; BCWY = capsular group B, C, W, Y; CI = confidence interval; CWY = capsular group C, W, Y; MenB = meningococcal serogroup B; NmB = Neisseria meningitidis serogroup B. Table 3 Summary of ongoing studies to determine the impact of serogroup B vaccination on carriage. Study (country) Participants Study arms Primary endpoint Initial findings and/or estimated completion Be on the Team (UK) 13 ∼24,000 adolescents (16–18 years) from schools/colleges across the UK • 4CMenB at 0 and 6 months • MenB-fHbp at 0 and 6 months • 4CMenB at the end of the study period Rate of oropharyngeal carriage prevalence of pathogenic meningococci (capsular groups B, C, W, Y, X) following immunization October 2020 (estimated completion of data collection) B Part of It (Australia) 57 , 58 34,483 adolescents (16–18 years; mean age 16 years) from 235 schools in South Australia • 4CMenB at baseline and 1–2 months following • 4CMenB at study completion (12 months) Rate of oropharyngeal carriage prevalence of pathogenic meningococci (capsular groups A, B, C, W, Y, X) following immunization Carriage rates were: • Lower than expected (4.9% in Year 12 students, 3% in Year 11 and 1.9% in Year 10 ( p < 0.001 [Year 12 versus Year 10]) • Higher in students with a current cold/sore throat (4.0% compared with 2.9% [ p = 0.001]) • Higher in cigarette, e-cigarette and water pipe users compared with non-users (13.7%, 9.8% and 9.9%, respectively) • Highest in Aboriginal students, followed by Caucasian students (5.3% versus 3.3%; p = 0.05) June 2020 (estimated completion) 4CMenB = multicomponent meningococcal serogroup B vaccine; MenB-fHbp = meningococcal serogroup B vaccine. 4 o c lh b w a tD c u 4 o P F a p t Spain and Germany. 50–55 While these assays may provide reason-able estimates of predicted coverage, this may differ in a real-lifesetting. Further, data are needed to determine the impact of thesevaccines on established carriage and on acquisition of carriage,in addition to the protection provided against other meningococ-cal serogroups. For instance, data have shown that 4CMenB maynot be effective against acquisition of carriage of serogroup B, al-though, reductions in carriage of capsular groups BCWY and CWYhas been demonstrated ( Table 2 ). 40 Similarly, vaccination withMenB-fHbp has not been shown to reduce meningococcal carriageor to prevent the acquisition of carriage of serogroup B. 56 Ongo-ing studies in the UK and South Australia ( Table 3 ) will fully an-swer the question of whether serogroup B vaccination affects car-riage, thus providing essential information for devising immuniza-tion schedules. 13 , 57 , 58 Both 4CMenB and MenB-fHbp have exhibited immunogenicity,although some concerns in relation to fever, seizures and Kawasakidisease were initially identified for 4CMenB. 59–61 In September 2015, the UK added 4CMenB to the infant im-munization schedule with a 2, 4 and 12-month regimen. Re-ductions in the number of cases of MenB have been observed,particularly in children aged < 1 to 2 years, following the im-plementation of 4CMenB, with primary doses administered at 2months and 4 months (and an opportunistic catch-up for 3- and-month olds). 62 When considering all MenB disease, effectivenessf two doses of vaccine has been estimated at 82.9%. 62 No safetyoncerns have been observed following the vaccination of 1.29 mil-ion children aged 2–18 months with 3 million doses of 4CMenB; 63 owever, further studies are required to determine the need foroosters and their frequency. Recently, pentavalent ABCWY vaccines have been developed,ith promising results in Phase II trials, 64 although additional datare required to identify the value of these vaccines compared withargeted co-administration of ACWY and MenB vaccines. etermination of strain coverage of serogroup B vaccines Determining the predicted coverage of serogroup B vaccinesan help to inform vaccine effectiveness and immunization sched-les at the country level. 65 To predict strain coverage, MATS (forCMenB) and MEASURE (for MenB-fHbp) assays have been devel-ped. 52 , 66 The MATS assay comprises (i) genotypic characterization oforA and (ii) phenotypic characterization of fHbp, NHBA and NadA.or the latter, detergent lysates of test and reference isolatesre applied to three enzyme-linked immunosorbent assay (ELISA)lates, one per antigen. The resulting test and reference curves arehen compared to provide a relative potency (RP) for each antigenX. Bai, R. Borrow and S. Bukovski et al. / Journal of Infection 79 (2019) 528–541 535 f g t f a t r t s s o M M M t t i w ( 9 d b e c t i ah a l a ( d v c N t p t W a u i t c c l M h s h t oCeNA l u la ( b bd w p i f s l H t b t g d a d t s c f f u t l r f s g r i t h cw r W r t c c lMe a s r c s e a ( b r p ( or each isolate. If a test isolate has PorA P10.4 and/or any sin-le RP exceeds a threshold level, known as the positive bactericidalhreshold (PBT), the isolate is considered MATS-positive and there-ore likely covered by the vaccine. Thus, the RP is determined by combination of antigenic expression and antigenic similarity tohe vaccine antigen variant against which the ELISA antisera wereaised. 66 Since the introduction of 4CMenB to the UK infant immuniza-ion program, MATS has formed an important part of enhancedurveillance. For example, up until the end of December 2017,urveillance data from England revealed that there were a totalf 202 laboratory confirmed cases of IMD in infants born fromay 1st 2015. Of these, 177 were eligible for vaccination, of whichenB accounted for 116 (66%) cases. Of the eleven vaccine-eligibleenB cases that had received three doses of vaccine, five were cul-ure confirmed and two were MATS positive (unpublished data). To determine MenB-fHbp coverage via MEASURE, flow cytome-ry is used to determine fHbp expression, with mean fluorescencentensity calculated to assess strain coverage. 52 Protein expressionith a mean fluorescence intensity of above 10 0 0 arbitrary unitscorresponding to 30 pg of fHbp/ μg of cell extract) predicts with1% accuracy that a MenB isolate would be killed by antibodies in-uced by the MenB-fHbp vaccine. 52 Currently, MenB-fHbp has noteen used as part of a NIP. As such, population-based MenB-fHbpffectiveness data are not available. The use of MATS and MEASURE assays to estimate the strainoverage of MenB vaccines has a number of limitations, such ashe inability to evaluate non-culture cases and limited availabil-ty for reference laboratories to be able to perform the assays. As result, Genetic Meningococcal Antigen Typing System (gMATS) 67 as been developed to assess strain coverage of 4CMenB in culturend potentially non-culture cases. gMATS was developed using aarge international genotypic/MATS dataset ( n = 3481 isolates) tossign antigen peptides to covered, not covered or unpredictablehalf of which are considered covered within national strain panelatasets). The Bexsero Antigen Sequence Type (BAST) scheme pro-ides a reproducible method for collective typing of 4CMenB vac-ine antigens whereby each unique combination of fHbp, NHBA,adA, PorA-VR1 and PorA-VR2 is assigned a unique arbitrary iden-ification number or ‘BAST’. BASTs can be used in conjunction withredictors of antigenic coverage such as MATS data to aid predic-ion of coverage for, and comparisons between, genotypic datasets.hen used in this way, it is important to define the basis on which given BAST is considered covered/not covered. 68 While gMATS and seven-locus MLST (used to demonstrate thetility of genotype-phenotype association) have previously exhib-ted 92% 67 and 80% 68 prediction accuracy versus MATS, respec-ively, both relied on correlation with MATS data for identifyingross-reactive variants. Data suggest that gMATS can accuratelyomplement MATS in predicting 4CMenB strain coverage in Eng-and and Wales in 20 07–20 08, with coverage estimated at 70% viaATS and 72–73% via gMATS, compared with 88% killing in theuman complement serum bactericidal antibody assay. 67 , 69 Con-equently, gMATS may constitute a reliable alternative to MATS;owever, ongoing MATS analysis is likely to be necessary to main-ain a relevant gMATS dataset (e.g. accounting for novel peptidesr peptides expanding in their frequency among IMD cases). hallenges in the management and surveillance of IMD: the mergence of antibiotic resistance and of new strains of eisseria meningitidis ntibiotic resistance The emergence of antibiotic resistance is a growing prob-em worldwide. 9 Nm is generally susceptible to the antibioticssed in the treatment and prevention of IMD. However, iso-ates with reduced susceptibility to penicillin are increasing 9 , 70 nd can arise through alterations of penicillin binding protein 2PBP2) involved in cell wall synthesis or from the production ofeta-lactamase (an enzyme that inactivates beta-lactams). 70 Rareeta-lactamase-producing (penicillin resistant) Nm strains were escribed in Canada, South Africa and Spain in the 1980s andere thought to arise through transfer of beta-lactamase-encodinglasmids from Neisseria gonorrhoeae (Ng). 71–76 In recent years,solates from France, Canada, the UK and Germany have beenound to produce beta-lactamase. 77–79 These isolates belonged toerogroup Y cc23 and possessed the ROB-1 gene that encodes beta-actamase, which was likely acquired through transformation fromaemophilus influenzae. 77 , 78 In terms of modifications of PBP2, mutations within the por-ion of the penA gene that encodes transpeptidase activity haveeen reported in isolates that demonstrate reduced susceptibilityo penicillin G and amoxicillin Y yet remain susceptible to third-eneration cephalosporins. 70 These altered penA alleles have beenocumented across a number of countries and it is thought thatpproximately 33% of isolates possess altered penA conferring re-uced susceptibility to penicillin, although, this varies from coun-ry to country (e.g. 88% in Italy versus 6% in Sweden). 80 Of concern, isolates harboring the penA327 allele that demon-trate reduced susceptibility to penicillin and third-generationephalosporins were identified in 2012. The penA327 allele wasound to originate from Ng 81 and has been observed in isolatesrom men who have sex with men (MSM) in France, as well asrethritis cases. 81 These isolates demonstrate intermediate suscep-ibility to cefotaxime and as such, should be kept under surveil-ance. Isolates that are resistant to rifampicin and ciprofloxacin areare; however, close surveillance is warranted. Resistance to ri-ampicin, which inhibits transcription by interacting with the betaubunit of RNA polymerase, arises from alterations in the rpoBene. 82 Ciprofloxacin inhibits DNA topoisomerases to inhibit DNAeplication, with ciprofloxacin resistance resulting from mutationsn the gyrA gene that were likely acquired through horizontal generansfer from other Neisseria species. 83 Isolates with modified rpoBave been documented in Europe, 84 while isolates resistant toiprofloxacin have been found in France, Italy, Spain and Sweden, 83 ith a recent outbreak (serogroup A) in India. 85–87 Ciprofloxacin-esistant isolates belonging to different serogroups (A, B, C, E, and Y) and possessing different gyrA alleles have also beenecorded in Shanghai. 88 , 89 Global surveillance of antibiotic resis-ance is therefore required to identify changes in antibiotic sus-eptibility of Nm to ensure that both cases and outbreaks of IMDan continue to be managed effectively, and appropriate prophy-axis can be utilized where indicated. onitoring outbreak progression, international spread and the mergence of new strains of Neisseria meningitidis The general advantages of genotypic analyses include their rel-tive simplicity, portability of data, utility in non-culture cases,ensitivity to detect and characterize broad variation, and relativeesolving power. The superiority of genome-based high-resolutionore genome multilocus sequence typing (cgMLST) over standardeven locus MLST in resolving population structure, identifyingmergent strains and tracing outbreak progression, both nationallynd internationally, has been demonstrated for the ST-11 complexcc11). 90 This includes (i) the progression of a MenW ccc11 out-reak that originated in South America before spreading to Eu-ope, Australia and North America, 26 , 77 , 90–93 (ii) the current ex-ansion of two unique serogroup C cc11 strains in the UK, 94 andiii) the heightened potential for cc11 lineage 11.2 meningococci to536 X. Bai, R. Borrow and S. Bukovski et al. / Journal of Infection 79 (2019) 528–541 f G t S dT o d t mS a i t n v m m v a p t i WW e a p e p o c a t fi b i g s g vMraR e t a e c m i c mescape MenB vaccine immunogenicity. 95 The well-establishedMeningitis Research Foundation meningococcus genome library,containing genome sequences for all invasive meningococcal iso-lates received by the Public Health England Meningococcal Refer-ence Unit since July 2010, 94 is a forerunner to a proposed GlobalMeningitis Genome Library, to include Nm, Streptococcus pneumo-niae, H. influenzae and Streptococcus agalactiae . This is in the earlystages of planning and is intended to support the new WHO GlobalRoadmap to defeat Meningitis by 2030. 96 Emergence of the US Neisseria meningitidis non-groupable urethritis clade Diverse Nm have been reported within the ano-genitourinarytract for decades, with a recent study documenting urethritis iso-lates among individuals from a number of countries spanning Eu-rope, Asia and North America from 2002 to 2016. 97 Since 2001,outbreaks of IMD due to cc11 lineage 11.2 have been recordedamong MSM in North America and Europe. 90 , 98–102 Since 2015, in-creased numbers of cases of Nm urethritis have been documentedacross sites in the US, predominantly involving heterosexual maleswho were recent oral sex recipients. 103 , 104 Comparison with geo-temporally diverse cc11 isolates revealed that a single clade withinlineage 11.2 was responsible for the increased reports of urethri-tis; the so-called United States of America (US) Nm non-groupableurethritis clade (US NmNG urethritis clade). 105 The US NmNG urethritis clade is thought to have emergedaround 2011, before expanding across at least 13 states in theEast of the US from 2013 to 2016. 106 With suspected transmis-sion during oral sex, this strain is a potential conduit between Ngand ‘nasopharyngeal’ Nm. The strain possesses gonococcal aniA (ni-trite reductase) and norB (nitric oxide reductase) genes, enablinganaerobic growth. 105 It is stably acapsulate 107 due to loss of sev-eral capsular synthesis genes, which may lead to difficulties fornon-culture diagnosis of IMD cases. Since its emergence, isolateswithin the clade have continued to acquire gonococcal DNA, withone isolate acquiring a gonococcal-like mtrR sequence, associatedwith reduced susceptibility to azithromycin. 106 , 108 Further, het-eroresistant sub-populations with resistance to antimicrobial pep-tides polymyxin B and colistin, and reduced susceptibility to otherantibiotics such as penicillin G, have been reported. 109 In additionto evolving antibiotic resistance, the strain has caused invasive dis-ease in four males (including two MSM) and one female for whomimmune status is not known. 106 In terms of prevention, existing subcapsular vaccines could pro-vide coverage; however, fHbp, NadA and NHBA are considerednon-essential genes elsewhere within lineage 11.2 and, as such,may be dispensed with. 95 , 105 , 106 Consequently, the clade couldescape MenB vaccine immunogenicity. However, current data 106 are promising, with 191 of 209 (91.4%) US NmNG urethritis cladeisolates potentially covered by three antigens – fHbp, NHBA andNadA, and the remaining 18 isolates potentially covered by twoantigens – fHbp and NHBA, or NHBA and NadA ( Fig. 3 ). Further-more, MATS analysis for several related MenB lineage 11.2 isolateswith matching NHBA (peptide 20) is encouraging, with all isolatespotentially covered for at least this antigen. 95 However, several USNmNG urethritis clade isolates were found to possess frameshiftedfHbp and disrupted NadA alleles (two and 16 isolates, respectively),and PorA was mismatched across all of the isolates. Thus, unlessNHBA serves a crucial function for colonizing the genitourinarytract, it seems likely that the US NmNG urethritis strain is as sus-ceptible to escaping the licensed MenB vaccines as the rest of lin-eage 11.2. This is a concern, particularly for immunocompromisedindividuals on antibiotic prophylaxis. As such, ongoing surveillanceand characterization of this and other potentially emerging Nmstrains is warranted. Expanded use of genomic analyses worldwide will further in-orm outbreak analyses and strain determination. The proposedlobal Meningitis Genome Library and WHO initiatives, such ashe Global Roadmap and Vaccine Preventable Disease Surveillancetandards documents, will also support disease surveillance to re-uce the burden associated with this disease. he Global Roadmap to defeat Meningitis by 2030 The Global Roadmap is being developed by the WHO, in collab-ration with organizations such as the Meningitis Research Foun-ation, technical partners and stakeholders at the regional, na-ional and global levels, with the aim of achieving a world in whicheningitis is no longer an ongoing public health threat by 2030. 96 pecific goals are to eliminate meningitis epidemics, reduce casesnd deaths from vaccine-preventable meningitis and decrease thempact of sequelae. 96 The Global Roadmap will describe the initia-ives and planned steps that countries, organizations and commu-ities need to take to achieve these goals, with a focus on the pre-ention of cases and deaths due to organisms responsible for theajority of non-tuberculous bacterial meningitis, i.e. Nm, S. pneu-oniae, H. influenzae and S. agalactiae. 96 As well as a pillar on pre-ention and epidemic control, four other pillars include: diagnosisnd treatment; disease surveillance; support and aftercare for peo-le affected; and advocacy and information, 96 and these will seeko address issues more broadly than the four main pathogens. Its anticipated that the Global Roadmap will be presented to theorld Health Assembly by 2020, for adoption at the global level. 96 HO Vaccine Preventable Disease Surveillance Standards In order to improve regional monitoring and estimation of dis-ase burden, and to achieve the goals of the roadmap, there is need to strengthen surveillance and improve disease data re-orting at the international level. WHO Vaccine Preventable Dis-ase Surveillance Standard documents have been developed torovide global guidance for disease-specific surveillance, includingutbreak investigation and response, based on available vaccines,urrent thinking and the latest laboratory techniques. Chapters arevailable for meningococcus, pneumococcus and H. influenzae . 110 Inerms of IMD, surveillance objectives include: (i) detect and con-rm cases (via culture and/or PCR), (ii) detect and confirm out-reaks, (iii) determine the epidemiology of disease, (iv) identify thempact of control measures and (v) establish populations and/oreographical areas at risk. 111 It is recommended that surveillancehould be nationwide, case-based and carried out across all ageroups. 111 Case definitions, and guidance in terms of laboratory in-estigations, data collection and reporting of cases are provided. 111 eningococcal carriage and disease: risk factors and ecommendations for the prevention and control of IMD in t-risk groups isk factors for meningococcal carriage and disease Meningococcal colonization of the respiratory tract (carriage)nables the microorganism to be transmitted from one persono another. 112 Transmission of bacterial infection primarily occursmong adolescents and young adults (15–25 years), 113 with sev-ral studies demonstrating the highest carriage rate in adoles-ents. 114–116 Key risk factors for the transmission/colonization ofeningococci are invasive respiratory tract infections, and smok-ng and overcrowded living conditions and specific adolescent so-ial behavior are risk factors for the local and global spread ofeningococcal disease. 117–121 X. Bai, R. Borrow and S. Bukovski et al. / Journal of Infection 79 (2019) 528–541 537 Fig. 3. 4CMenB antigen distribution and potential coverage among US NmNG urethritis clade isolates ( n = 209). Adapted from Retchless et al. 106 4CMenB = multicomponent meningococcal serogroup B vaccine; fHbp = factor H-binding protein; NadA = Neisseria adhesin A; NHBA = Neisserial Heparin Binding Antigen; PorA = Porin A; US NmNG urethritis clade = US Neisseria meningitidis non-groupable urethritis clade. f p t m t s wp 1O w w I a pC i i c m t t t i fi t r h Y v e c d e B e h i a s c r f p p eL f r s c o p o w s s eI s ic g mR t k g l a o s a Upon acquisition, the first barrier against meningococcal in-ection is a functional complement system. As such, factorsredisposing individuals to IMD include inherited deficiencies ofhe terminal complement pathway (e.g. deficiencies in comple-ent components C5–C9) and medical conditions or treatmenthat may lead to acquired or secondary complement deficiency,uch as treatment with eculizumab, a terminal complement path-ay inhibitor. 122–125 For instance, individuals with terminal com- lement pathway deficiencies are thought to have a 70 0 0- to0,0 0 0-fold higher risk of IMD versus the general population. 122 ther populations at increased risk of IMD include laboratoryorkers and Human Immunodeficiency Virus-positive individuals,ho have an estimated 184-fold 126 , 127 and 5-fold greater risk ofMD compared with the general population, 128 respectively, as wells migrants and refugees, who live in overcrowded conditions withoor sanitation. omplement deficiencies and meningococcal disease The complement system plays a major role in innate immunity;t is composed of complement proteins, activation of which resultsn cascade reactions to eliminate targeted cells or invaders. 129 Theomplement system therefore provides pivotal protection againsteningococcal infection, with deficiencies in late components ofhe complement system (proteins C5–C9), and in regulatory pro-eins including factor D and properdin, linked to IMD. 130 While complement deficiencies are primarily inherited as au-osomal recessive traits 131 and as such, are rare, IMD is commonn this population. Cases of IMD in patients with complement de-ciency indicate that these patients are prone to repeated infec-ions from identical or different isolates, with a theoretical risk forecurrent infection of 40–50%. 130 , 132 Further, in patients with in-erited complement deficiency, data suggest that capsular group predominates. 132 Conversely, patients receiving eculizumab de-elop IMD due to more diverse capsular groups, including non-ncapsulated strains. Vaccination with the ACWY conjugate vac-ine is therefore recommended in individuals with complementeficiencies, including patients receiving eculizumab, with boost-rs every 5 years. Immunization with a vaccine targeting serogroup isolates is also recommended, but the administration of boost-rs has not yet been defined. In addition, vaccination of house-old contacts of subjects with complement deficiencies (cocoon-ng vaccination) may be beneficial. Penicillin V is recommendeds the first-line antibiotic prophylaxis treatment; however, risk as-essment should inform the optimal approach. Further research is needed to determine the distribution ofomplement deficiencies, which are thought to vary according toegion and population, 130 , 133 , 134 as well as typical characteristicsor each complement deficiency, such as patient age and clinicalresentation. Further studies of isolates from patients with com-lement deficiencies are warranted, including typing, vaccine cov-rage and susceptibility to penicillin. aboratory workers Working with meningococci can lead to laboratory-acquired in-ections if appropriate safety precautions are not taken. 135 Indeed,eview of laboratory-acquired cases of IMD has identified acqui-ition of infections outside of a safety cabinet. 126 , 135 , 136 Further,ase reports of laboratory workers who have become critically illr have died following exposure to meningococci confirm the im-ortance of safe working practices when working with suspensionsf meningococci. 135 Guidance recommends that a safety cabinet is always usedhen performing microbiological work with meningococci, whichhould be reflected in local risk assessments. 135 Training on theigns and symptoms of meningitis, safe working practices andmergency procedures should be provided on a regular basis. 135 n addition, laboratory workers who may be exposed to Nmhould receive available vaccines and boosters in-line with localmmunization programs. 135 Further, antimicrobial prophylaxis (e.g. iprofloxacin) should be prescribed in conjunction with relevantuidance if there has been a credible risk of exposure to liveeningococci. 135 efugees and migrants In addition to the groups at high risk of IMD previously men-ioned, attendance at mass gatherings and international travel arenown to increase the likelihood of Nm transmission. 137 Data sug-est that there are approximately 5.2 million refugees and 1.4 mil-ion asylum seekers in the European Region. 138 These groups aret increased risk of meningococcal infection compared with theverall population due to overcrowded living conditions with pooranitation and the undertaking of long and dangerous journeys. Inddition, available health services can be sporadic or poor-quality538 X. Bai, R. Borrow and S. Bukovski et al. / Journal of Infection 79 (2019) 528–541 D P P m M s f c b C f G SC t - i C v M i P i e P v S r i i iA H l a t t a MR during travel to and/or within host countries, coverage of vacci-nations is low among these individuals and antibiotic resistance isbecoming a growing problem within crowded camps with poor hy-giene. Outbreaks of meningococcal disease in refugee camps havebeen successfully controlled through the implementation of timelyand high-coverage vaccination campaigns, as demonstrated fol-lowing an outbreak of serogroup A disease in a large refugeecamp in Zaire in 1994. 139 Further, individual cases of IMD havebeen effectively managed through chemoprophylaxis (e.g. with ri-fampicin or ciprofloxacin) for cases and persons directly exposedto them, as shown following unrelated cases of meningococcalserogroup X and MenB among migrants and refugees in Italy andTurkey, respectively. 140–142 Consequently, early diagnosis, treatmentand prophylaxis are key to protect these vulnerable populations,as well as host communities. However, surveillance is needed todetermine the prevalence of carriers of Nm and of circulatingserogroups among these populations in order to inform vaccinerecommendations. In addition, challenges relating to the vaccina-tion of migrants and refugees, such as refusal of vaccination forfear of legal consequences and lack of information on immuniza-tion status, and of co-ordination among public health authoritiesof neighboring countries 143 need to be addressed to facilitate theimplementation of effective prevention and control strategies. Conclusions Effective surveillance strategies are key to the control of IMD,allowing the detection of cases and outbreaks, confirmation of theepidemiology of disease, monitoring of strains and antibiotic sus-ceptibility, as well as determination of the impact of control mea-sures, such as vaccination, on control of disease. 6 IMD surveillanceis in place in the majority of Eastern European countries repre-sented at the recent GMI meeting. Across these countries, the in-cidence of IMD has declined in recent decades and is generally< 1 case per 10 0,0 0 0 persons per year. Predominating serogroupsof Nm are B and C, followed by serogroup A; exploration of thegenetic relationships between the serogroup A isolates and recentisolates from the meningitis belt is required. Cases attributable toserogroups W, X and Y are emerging. In terms of prevention, avail-able vaccinations include both conjugate and polysaccharide vac-cines, although, generally, these are not included in NIPs and areprovided to high-risk populations only. It is recognized that conjugate vaccines have a number advan-tages when compared with polysaccharide vaccines, including in-ferring both direct and indirect (herd) protection through the inter-ruption of the acquisition of carriage, as has been demonstrated forserogroups A, C and Y. 34 , 39 , 144 However, further research is neededto understand the impact of vaccination on carriage of serogroupW, as well as if/how protein-based MenB vaccines affect carriageand/or protect against other meningococcal serogroups. These data,in addition to the predicted coverage of vaccines, can inform esti-mates of vaccine effectiveness and immunization schedules at thecountry level. With the emergence of new strains of Nm and growingconcern of antibiotic resistance, it is recommended that effectiveprevention and control strategies also be informed by monitoringoutbreak progression, international spread of Nm and antibiotic re-sistance, as well as trends in risk factors. Expanded use of genomicanalyses and implementation of WHO initiatives worldwide are ex-pected to strengthen surveillance of IMD and reduce the burden ofdisease. Further, identification of individuals at high-risk of infec-tion, such as those with complement deficiencies, laboratory work-ers and migrants and refugees, and the implementation of appro-priate prophylactic measures within these populations, is essentialfor the prevention of outbreaks of IMD. eclaration of Competing Interest R Borrow, J Lucidarme and X Bai perform contract work forublic Health England on behalf of GSK, PATH, Sanofi Pasteur andfizer. EC Dinleyici performs contract work for the Eskisehir Os-angazi University funded by GSK, Sanofi Pasteur and Pfizer. A Skoczy ́nska has performed contract work for the Nationaledicines Institute funded by GSK and Pfizer, attended the Advi-ory Boards of GSK, Pfizer and Sanofi Pasteur and had personal feesrom GSK, Pfizer and Sanofi Pasteur. V Smith represents Meningitis Research Foundation that re-eives grants from Sanofi Pasteur, GSK and Pfizer. MK Taha performs contract work for the Institut Pasteur fundedy GSK, Pfizer and Sanofi Pasteur. JA Vázquez performs contract work for the Institute of Healtharlos III funded by GSK and Pfizer and he has received personalees from GSK, Pfizer and Sanofi Pasteur. S Bukovski, DA Caugant, D Culic, S Delic, M Eloshvili, T Erd ̋osi, Jalajeva, P K ̌rížová, K Mironov, Z Nurmatov, M Pana, E Rahimov, Lavrasova, LP Titov and L Yeraliyeva have no conflicts of interest. RediT authorship contribution statement Xilian Bai: Writing - review & editing. Ray Borrow: Concep-ualization, Funding acquisition, Writing - original draft, Writing review & editing. Suzana Bukovski: Writing - review & edit-ng. Dominique A. Caugant: Writing - review & editing. Davorulic: Writing - review & editing. Snezana Delic: Writing - re-iew & editing. Ener Cagri Dinleyici: Writing - review & editing.edeia Eloshvili: Writing - review & editing. Tímea Erd ősi: Writ-ng - review & editing. Jelena Galajeva: Writing - review & editing.avla K řížová: Writing - review & editing. Jay Lucidarme: Writ-ng - review & editing. Konstantin Mironov: Writing - review &diting. Zuridin Nurmatov: Writing - review & editing. Marinaana: Writing - review & editing. Erkin Rahimov: Writing - re-iew & editing. Larisa Savrasova: Writing - review & editing. Annakoczy ńska: Writing - review & editing. Vinny Smith: Writing -eview & editing. Muhamed-Kheir Taha: Writing - review & edit-ng. Leonid Titov: Writing - review & editing. Julio Vázquez: Writ-ng - review & editing. Lyazzat Yeraliyeva: Writing - review & edit-ng. cknowledgments Authors would like to thank Dr Olivier Ronveaux (Infectiousazard Management, World Health Organization, Geneva, Switzer-and) for his contributions during this GMI Roundtable Meetingnd for providing permission to use his presentation content inhis manuscript. 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