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Meningococcal disease in the Middle East and Africa: Findings and updates from the Global Meningococcal Initiative

Open AccessPublished:April 25, 2017DOI:https://doi.org/10.1016/j.jinf.2017.04.007

      Highlights

      • Vaccination for some types of planned mass gatherings should be considered.
      • GMI recommends vaccinating HIV-positive individuals against meningococcal disease.
      • Improved surveillance and vaccination efforts are needed to address serogroup W outbreaks.
      • Targeting carriage is vital to controlling invasive meningococcal disease.
      • Vaccine advocacy and disease awareness campaigns are still critical.

      Summary

      The Global Meningococcal Initiative (GMI) has recently considered current issues in Middle Eastern and African countries, and produced two recommendations: (i) that vaccination of attendees should be considered for some types of mass-gathering events, as some countries mandate for the Hajj, and (ii) vaccination of people with human immunodeficiency virus should be used routinely, because of increased meningococcal disease (MD) risk. Differences exist between Middle Eastern and African countries regarding case and syndrome definitions, surveillance, and epidemiologic data gaps. Sentinel surveillance provides an overview of trends and prevalence of different capsular groups supporting vaccine selection and planning, whereas cost-effectiveness decisions require comprehensive disease burden data, ideally counting every case. Surveillance data showed importance of serogroup B MD in North Africa and serogroup W expansion in Turkey and South Africa. Success of MenAfriVac® in the African “meningitis belt” was reviewed; the GMI believes similar benefits may follow development of a low-cost meningococcal pentavalent vaccine, currently in phase 1 clinical trial, by 2022. The importance of carriage and herd protection for controlling invasive MD and the importance of advocacy and awareness campaigns were also highlighted.

      Keywords

      Introduction

      Neisseria meningitidis is a leading causative agent of bacterial meningitis and septicemia, particularly in children <5 years old and young adults,
      • McGill F.
      • Heyderman R.S.
      • Michael B.D.
      • Defres S.
      • Beeching N.J.
      • Borrow R.
      • et al.
      The UK joint specialist societies guideline on the diagnosis and management of acute meningitis and meningococcal sepsis in immunocompetent adults.
      and is estimated to cause 500,000 cases and 50,000 deaths globally each year.
      • World Health Organization
      Meningococcal vaccines: polysaccharide and polysaccharide conjugate vaccines.
      Of 12 recognized serogroups, six (A, B, C, W, X, and Y) are responsible for nearly all meningococcal disease (MD) globally.
      • Broker M.
      • Jacobsson S.
      • Kuusi M.
      • Pace D.
      • Simoes M.J.
      • Skoczynska A.
      • et al.
      Meningococcal serogroup Y emergence in Europe: update 2011.
      It has been reported that MD causes substantial morbidity, with case-fatality ratios ranging between ∼10 and 20%.
      • Borrow R.
      • Lee J.S.
      • Vazquez J.A.
      • Enwere G.
      • Taha M.K.
      • Kamiya H.
      • et al.
      Meningococcal disease in the Asia-Pacific region: findings and recommendations from the Global Meningococcal Initiative.
      • Fellick J.M.
      • Sills J.A.
      • Marzouk O.
      • Hart C.A.
      • Cooke R.W.
      • Thomson A.P.
      Neurodevelopmental outcome in meningococcal disease: a case-control study.
      • Erickson L.J.
      • De Wals P.
      • McMahon J.
      • Heim S.
      Complications of meningococcal disease in college students.
      Most regions of Europe and North America have low MD incidence rates (e.g. ∼0.14 per 100,000 US population, 2014), associated predominantly with serogroups B (MenB), C (MenC), and Y (MenY).
      • CDC
      Active bacterial core surveillance report, emerging infections program network, Neisseria meningitidis.
      • Borrow R.
      • Alarcon P.
      • Carlos J.
      • Caugant D.A.
      • Christensen H.
      • Debbag R.
      • et al.
      The Global Meningococcal Initiative: global epidemiology, the impact of vaccines on meningococcal disease and the importance of herd protection.
      In contrast, the “meningitis belt” of sub-Saharan Africa has historically reported frequent epidemics of MD, but the incidence had fallen 10-fold by 2013, following the introduction of the serogroup A (MenA) vaccine in 2010; cases of MenC, W, and X are also reported in this region.
      • Borrow R.
      • Alarcon P.
      • Carlos J.
      • Caugant D.A.
      • Christensen H.
      • Debbag R.
      • et al.
      The Global Meningococcal Initiative: global epidemiology, the impact of vaccines on meningococcal disease and the importance of herd protection.
      • Lingani C.
      • Bergeron-Caron C.
      • Stuart J.M.
      • Fernandez K.
      • Djingarey M.H.
      • Ronveaux O.
      • et al.
      Meningococcal meningitis surveillance in the African meningitis belt, 2004-2013.
      The World Health Organization (WHO) has reported 26,029 meningitis cases in the African meningitis belt in 2016 with 2080 deaths—an overall case-fatality ratio of 8.0%.
      • World Health Organization
      Weekly feedback bulletin on cerebrospinal meningitis: West Africa, weeks 48-52.
      Only half of the laboratory-confirmed cases were caused by meningococci, while for the great majority of the samples the causative organism was not identified.
      The Global Meningococcal Initiative (GMI) was established in 2009 with a goal to prevent the occurrence of MD worldwide through education, research, cooperation, and vaccination. The GMI consists of more than 70 scientists, clinicians, and public health officials globally with expertise in MD immunology, epidemiology, microbiology, public health, and vaccinology. Six global and regional GMI roundtable meetings have been held since its inception, leading to research and publications, including global and regional recommendations for MD. The objective of this regional meeting was to gain a better understanding of MD in the Middle East, North Africa, and sub-Saharan Africa. This article summarizes the discussions that took place at the meeting and outlines regional recommendations for the control and prevention of MD, based on available data and regional expert opinion.

      Overview

      The current regional roundtable meeting, the first to be convened for the Middle East, North Africa, and sub-Saharan Africa, was held in Lisbon, Portugal, on October 17–18, 2016. The aim of the meeting was to gain an understanding on the current MD situation in this region and to provide recommendations specific to the region. Members from countries outside the region were also invited to share their experience and specific knowledge gained from their surveillance, immunization, and outbreak programs. Regional experts did not attend from every Middle East, North Africa, and sub-Saharan Africa nation; therefore, the current article focuses on the locations represented at the Lisbon GMI Roundtable Meeting.

      Objectives

      The specific objectives of the meeting were to provide an update on surveillance, epidemiology, prevention, and control strategies from the Middle East, North Africa, and sub-Saharan Africa and an update from other regions and countries across the globe; discuss the issues faced regarding surveillance, prevention, and control strategies with a focus on current barriers to implementation; share lessons learned and experience gained from immunization programs used across the globe; highlight the importance of conjugate vaccines and their impact; examine the health economic aspects of meningococcal vaccination strategies; emphasize the critical need for disease awareness and advocacy for invasive MD prevention and control; and determine future GMI outputs.

      Meningococcal vaccines

      Meningococcal plain polysaccharide and conjugate vaccines

      The first session of the meeting focused on meningococcal vaccines (those currently available and those that will become available). The relative effectiveness of polysaccharide and conjugate vaccines, and the advantages observed with conjugate vaccines were outlined. Both polysaccharide and conjugate vaccines have been shown to be effective, but in children <2 years old, polysaccharide vaccines have poor effectiveness, while conjugate vaccines are more immunogenic, effective, and do not induce hyporesponsiveness (Table 1).
      • Granoff D.M.
      • Feavers I.
      • Borrow R.
      Meningococcal vaccines.
      Table 1Comparison of plain polysaccharide and conjugate vaccines.
      ImmunogenicityPolysaccharide vaccinesConjugate vaccines
      AdultsHighHigh
      Young childrenPoorHigh
      AvidityLowHigh
      PersistenceLow/MediumHigh
      Functional activityLowHigh
      Response to a boosterPoorHigh
      Induction of hyporesponsivenessYesNo
      Induction of immunological memoryNoYes
      Prevention of acquisition of carriageNoYes
      It has been estimated that since its 1999 introduction to the United Kingdom, MenC conjugate vaccination has prevented >16,000 cases and >1600 deaths. The importance of indirect or “herd” protection was highlighted, using the example of MenC control in the United Kingdom (i.e. a 67% reduction in the MenC attack rate was observed in unvaccinated individuals in 2001) (Fig. 1).
      Figure 1
      Figure 1Direct and herd protection against MenC in the United Kingdom.
      In the United Kingdom, vaccination (usually multivalent) was recommended for: infant to adolescent routine vaccination, catch-up for individuals with underlying medical conditions (such as splenic dysfunction or complement disorders), first-year university students, some occupational groups (laboratory workers, military, etc), travelers to endemic destinations (Hajj pilgrimage, sub-Saharan Africa, etc), and for close contacts of a case or outbreak control. Conjugate vaccines have been preferred over polysaccharide vaccines.
      • Public Health England
      Meningococcal: meningococcal meningitis and septicaemia notifiable.
      An ACWYX conjugate vaccine is being developed by the Serum Institute of India/Program for Appropriate Technology in Health (PATH). If licensed, this will be the first vaccine to address serogroup X (MenX), making it of great interest. A further high-valency vaccine being developed is an ACWY conjugate combined with the MenB subcapsular vaccine (Bexsero®, GlaxoSmithKline, Brentford, UK). MenB vaccines were further discussed, outlining the details of the two available subcapsular vaccines, Bexsero® and Trumenba® (Pfizer, New York, NY, USA). Data from the first 10 months of the United Kingdom's implementation of Bexsero® were presented; Bexsero® was shown to have high vaccine effectiveness (83%) and no safety concerns were observed.
      • Parikh S.R.
      • Andrews N.J.
      • Beebeejaun K.
      • Campbell H.
      • Ribeiro S.
      • Ward C.
      • et al.
      Effectiveness and impact of a reduced infant schedule of 4CMenB vaccine against group B meningococcal disease in England: a national observational cohort study.
      The new-generation MenB vaccines have the potential to replace outer membrane vesicle vaccines in epidemic settings.
      The question of vaccinating travelers to mass-gathering events, such as the Hajj pilgrimage mentioned above, requires careful consideration. The conditions under which vaccination for mass gatherings should be recommended require further study. Factors to consider include examining the number of attendees that defines “mass” and what risks are consequent to “gathering” (e.g. geographic spread and diversity, location of the gathering itself, duration of the gathering, homogeneity and/or diversity of the group gathered, and propensity for behavioral risk factors). To develop meaningful recommendations, research is needed to categorize gatherings by risk factors to identify those with greatest potential for life-threatening outbreak conditions and analyze the practicalities and costs for vaccination in advance of those attending such gatherings.

      Surveillance/epidemiology/prevention and control strategies

      N. meningitidis is usually reported to be a leading cause of bacterial meningitis in the Middle East and North Africa region
      • Ceyhan M.
      • Anis S.
      • Htun-Myint L.
      • Pawinski R.
      • Soriano-Gabarro M.
      • Vyse A.
      Meningococcal disease in the Middle East and North Africa: an important public health consideration that requires further attention.
      ; however, most surveillance focuses on the Hajj pilgrimage and few other data are available. Characteristics of MD and its surveillance in specific countries of the Middle East, North Africa, and sub-Saharan Africa were discussed.

      Tunisia

      In Tunisia, reporting of MD is mandatory; however, there is no national surveillance network currently operating. National data generally underestimate the actual burden. Conventional and molecular biology–based diagnosis and typing methods are available in only one hospital. Overall, 85% of cases are in children <5 years old and 38% in infants <1 year old. MenB is by far the most prevalent serogroup (80%), and case fatality ratios are around 18%. Only polysaccharide vaccine (ACWY) is available in Tunisia and is recommended for pilgrims and children with high-risk medical conditions.

      Morocco

      In Morocco, MD is endemic with sporadic emergence of micro-outbreaks. The incidence rate is ∼2–3.6 per 100, and the case fatality ratio is 7–13%. In Casablanca, in a study using whole genome sequencing (WGS), MenB was identified in 95% of cases (2011–2015; 2% MenC, 2% MenY, 1% MenW). Prevalence was highest in those aged 1–4 years. A single isolate of MenW was related to the Hajj strain.
      • Razki A.
      • Hong E.
      • Zerrouli K.
      • Ezzaki B.
      • Diawara I.
      • Bouayad A.
      • et al.
      Invasive meningococcal disease: surveillance in Casablanca (Morocco).
      Surveillance of invasive MD is currently underway, involving Moroccan partners with the Meningococcal Unit of the Pasteur Institute in Paris, France.

      Algeria

      MD is a notifiable disease in Algeria; microbiological data are collected via a network of laboratories coordinated by the Algerian Pasteur Institute. Disease is most frequent in infants <2 years old and the overall incidence reported in 2012 was 0.09 per 100,000 individuals (0.48 per 100,000 in children <5 years old).
      • Algerie Sante
      Situation epidemiologique de l'annee 2012.
      In recent years, both MenB and MenW have been identified, but MenY seems to be very rare. Vaccination is not included in the national immunization program, but quadrivalent polysaccharide vaccine is recommended for pilgrims and during epidemics. The need for improved diagnosis in laboratories through the introduction of polymerase chain reaction (PCR) and blood culture, as well as improved collection and preservation of isolates was discussed.

      African meningitis belt

      The African meningitis belt includes parts of 26 countries; within this zone, the burden of disease is usually high, with 7000–180,000 cases annually. There is a clear seasonal pattern and most disease occurs in the first 6 months of the year in the dry season with airborne dust and high temperatures being risk factors. Currently, two surveillance systems are operating in this region. There is an enhanced nationwide system in all these countries for the detection of outbreaks, reporting of suspected cases, and routine data aggregation and management. A case-based system located at sentinel sites monitors vaccine impact, conducts laboratory investigations, links epidemiologic and laboratory data for cases and analyses, and manages case-level data.
      The case definitions employed include sudden onset of fever with meningeal signs (i.e. severe headache, neck stiffness, altered consciousness), thus overlooking cases of meningeal sepsis without meningeal signs. It may be difficult to update these case definitions rapidly due to the lack of blood culture capability. Polysaccharide vaccine is used for the reactive programs, such as for the 2016 MenC outbreak in Niger, although vaccine shortages have been an issue. The use of conjugate vaccines seems to be typically problematic as it requires a cold chain, with MenAfriVac® being a notable exception.

      World Health Organization. Immunization standards – MenAfriVac: Meningococcal A conjugate 10 dose presentation. WHO web site. Available at: http://www.who.int/immunization_standards/vaccine_quality/PQ_197_MenAconjugate_10dose_SII/en/. [Accessed 22 December 2016].

      Rapid diagnostic tests have been employed in this region, such as Pastorex™ Meningitis (Bio-Rad, Hercules, CA, USA) for latex agglutination, as well as dipsticks; however, verification by PCR or culture is recommended before a vaccine response is triggered. Improved dipsticks are needed, in particular for detection of MenX.
      Prior to MenAfriVac® vaccination (2009–2010), MenA was the predominant strain in Burkina Faso, Chad, Niger, and Nigeria.
      • Lingani C.
      • Bergeron-Caron C.
      • Stuart J.M.
      • Fernandez K.
      • Djingarey M.H.
      • Ronveaux O.
      • et al.
      Meningococcal meningitis surveillance in the African meningitis belt, 2004-2013.
      Since 2011–2012, the main pathogens detected have been MenW and Streptococcus pneumoniae in areas where MenAfriVac® was employed; there have also been non-MenA epidemics, including MenX, MenW, and MenC.
      • Lingani C.
      • Bergeron-Caron C.
      • Stuart J.M.
      • Fernandez K.
      • Djingarey M.H.
      • Ronveaux O.
      • et al.
      Meningococcal meningitis surveillance in the African meningitis belt, 2004-2013.
      The MenAfriNet program started in 2014 and is designed to obtain high-quality data and strengthen regional capacity through the use of standardized tools and databases, training, and laboratory capacity. To date, MenAfriNet surveillance operates in Burkina Faso, Chad, Mali, Niger and Togo, with the possibility to expand to other countries in the region. However, there is a need for greater national preparedness and an international emergency vaccine stockpile to ensure availability, because market availability of polysaccharide vaccine is decreasing and ACWY conjugate vaccines are currently unaffordable.

      Turkey

      Three childhood invasive infection surveillance studies are currently underway in Turkey. A nationwide bacterial meningitis study using multiplex PCR was started in 2005, a S. pneumoniae study was started in 2008, and a study of N. meningitidis bacterial isolates was started in 2013.
      • Ceyhan M.
      • Gurler N.
      • Ozsurekci Y.
      • Keser M.
      • Aycan A.E.
      • Gurbuz V.
      • et al.
      Meningitis caused by Neisseria meningitidis, Hemophilus influenzae type B and Streptococcus pneumoniae during 2005-2012 in Turkey. A multicenter prospective surveillance study.
      • Ceyhan M.
      • Yildirim I.
      • Balmer P.
      • Borrow R.
      • Dikici B.
      • Turgut M.
      • et al.
      A prospective study of etiology of childhood acute bacterial meningitis, Turkey.
      MD in Turkey largely affects those ≤18 years old, with estimated incidences (in 2005–2006) of bacterial meningitis at 3.5 per 100,000 (56.5% N. meningitidis), meningococcal meningitis at 2.0 per 100,000, and MD at 3.5–4 per 100,000.
      • Ceyhan M.
      • Yildirim I.
      • Balmer P.
      • Borrow R.
      • Dikici B.
      • Turgut M.
      • et al.
      A prospective study of etiology of childhood acute bacterial meningitis, Turkey.
      From 1985 to 2006, the reported incidence ranged from 1.01 to 5.5 cases per 100,000, indicating an intermediate level of endemic disease.
      • Kurugol Z.
      Meningococcal disease and control measures.
      • Tuysuz B.
      • Ozlu I.
      • Erginal A.
      Epidemiology of meningococcal diseases: a study of 140 patients.
      In 2005–2006, MenW (42.7% of all bacterial meningitis) and MenB (31.1%) were the most prevalent capsular groups in children,
      • Ceyhan M.
      • Yildirim I.
      • Balmer P.
      • Borrow R.
      • Dikici B.
      • Turgut M.
      • et al.
      A prospective study of etiology of childhood acute bacterial meningitis, Turkey.
      while in 2009–2010, the prevalence of MenA had increased (36.6%; MenW: 56.1%; MenB: 7.3%). By 2011–2012, MenW was by far the most prevalent capsular group (56.5% vs. 6.5% for MenB and 6.5% for MenA).
      • Ceyhan M.
      • Gurler N.
      • Ozsurekci Y.
      • Keser M.
      • Aycan A.E.
      • Gurbuz V.
      • et al.
      Meningitis caused by Neisseria meningitidis, Hemophilus influenzae type B and Streptococcus pneumoniae during 2005-2012 in Turkey. A multicenter prospective surveillance study.
      Prevalence of MenB increased in 2013–2014 (32.9% vs. 42.4% for MenW), but decreased in 2015 relative to MenW (15.8% vs. 42.1%, respectively).
      • Ceyhan M.
      • Ozsurekci Y.
      • Gurler N.
      • Karadag O.E.
      • Camcioglu Y.
      • Salman N.
      • et al.
      Bacterial agents causing meningitis during 2013-2014 in Turkey: a multi-center hospital-based prospective surveillance study.
      Other data showed that relative overall prevalence of different capsular groups of MD in Turkey has been similar to that in Saudi Arabia over recent years, with MenA and MenW the most common capsular groups detected. Antibodies to the four main capsular groups have been detected in the Turkish population.
      • Ceyhan M.
      • Yildirim I.
      • Balmer P.
      • Riley C.
      • Laher G.
      • Andrews N.
      • et al.
      Age-specific seroprevalence of serogroup C meningococcal serum bactericidal antibody activity and serogroup A, C, W135 and Y-specific IgG concentrations in the Turkish population during 2005.
      In a recent, multi-center study of 1518 healthy adolescents and young adults aged 10–24 years, PCR serogroup analysis indicated that the nasopharyngeal carriage rate was 6.3% and the most prevalent serogroup was W, with no serogroup C found.
      • Tekin R.
      • Dinleyici E.
      • Ceyhan M.
      • Karbuz A.
      • Salman N.
      • Sutçu M.
      • et al.
      The prevalence, serogroup distribution and risk factors of meningococcal carriage in adolescents and young adults in Turkey.
      The conjugated quadrivalent (MenACWY) vaccine is marketed in Turkey, but thus far is not included in the national immunization plan. This vaccine is recommended for those <50 years old who are traveling to the Hajj or to Umrah.
      • Dinleyici E.C.
      • Ceyhan M.
      The dynamic and changing epidemiology of meningococcal disease at the country-based level: the experience in Turkey.
      No recommendations for vaccination against MenB are currently available in Turkey.

      South Africa

      In South Africa, MD is a notifiable condition; the local health authority must be contacted by telephone if invasive MD is suspected and prophylaxis is recommended for contacts.
      • Department of Health, South Africa
      Guidelines for the management, prevention and control of meningococcal disease in South Africa.
      MD is endemic, peaking between May and October.
      • Coulson G.B.
      • du Plessis M.
      • Smith A.M.
      • de Gouveia L.
      • Klugman K.P.
      • von Gottberg A.
      Meningococcal disease in South Africa, 1999−2002.
      • von Gottberg A.
      • du Plessis M.
      • Cohen C.
      • Prentice E.
      • Schrag S.
      • de Gouveia L.
      • et al.
      Emergence of endemic serogroup W135 meningococcal disease associated with a high mortality rate in South Africa.
      The incidence rate was 0.44 per 100,000 in 2013 and 0.36 per 100,000 in 2014. The main capsular group-causing disease is MenW (67–77% of disease is MenACWY), followed by MenB.
      • Meiring S.
      • Cohen C.
      • Lengana S.
      • von Mollendorf C.
      • de Gouveia L.
      • du Plessis M.
      • et al.
      Invasive meningococcal serogroup C and W disease in South Africa: 2003-2014. Poster E25.
      The burden of disease is highest in infants <1 year old, but the case fatality ratio is highest in adults and increases with age; in addition, human immunodeficiency virus (HIV) infection is a risk factor for contracting MD.
      • Cohen C.
      • Singh E.
      • Wu H.M.
      • Martin S.
      • de Gouveia L.
      • Klugman K.P.
      • et al.
      Increased incidence of meningococcal disease in HIV-infected individuals associated with higher case-fatality ratios in South Africa.
      Meningococcal polysaccharide vaccines are available and the conjugate ACWY vaccine, Menactra®, has been available since 2014.
      • Department of Health, South Africa
      Guidelines for the management, prevention and control of meningococcal disease in South Africa.
      Vaccination is recommended for Hajj pilgrims and travelers to Saudi Arabia, those with hazardous occupations, travelers to hyper-endemic areas, and those with certain medical conditions.
      • Department of Health, South Africa
      Guidelines for the management, prevention and control of meningococcal disease in South Africa.

      Summary: surveillance/epidemiology/prevention and control

      The global Invasive Bacterial Vaccine Preventable Diseases surveillance network (IBVPD)

      World Health Organization. Surveillance for vaccine preventable diseases (VPDs). WHO web site. Available at: http://www.who.int/immunization/monitoring_surveillance/burden/VPDs/en/. [Accessed 22 December 2016].

      has been coordinated by the WHO since 2008, using active sentinel-site, case-based, syndromic surveillance with laboratory confirmation with a range of technical and standard methodology supports, and funding opportunities. PCR and WGS help in deriving more data on MD.

      Carriage and herd protection

      Nasopharyngeal carriage of Neisseria and herd protection

      Carrier studies are needed to support and guide the introduction of meningococcal conjugate vaccines by understanding the transmission of the hyper-virulent strains and to measure the indirect impact of the introduction of such conjugate vaccines in vaccination programs. Plain polysaccharide vaccines have little or no impact on carriage, give only short-term immunity, and do not provide herd protection,
      • Hassan-King M.K.
      • Wall R.A.
      • Greenwood B.M.
      Meningococcal carriage, meningococcal disease and vaccination.
      whereas protein-conjugate polysaccharide vaccines reduce acquisition of nasopharyngeal carriage and transmission, and provide longer lasting immunity and herd protection.
      • Maiden M.C.
      • Stuart J.M.
      Carriage of serogroup C meningococci 1 year after meningococcal C conjugate polysaccharide vaccination.
      • Kristiansen P.A.
      • Diomande F.
      • Ba A.K.
      • Sanou I.
      • Ouedraogo A.S.
      • Ouedraogo R.
      • et al.
      Impact of the serogroup A meningococcal conjugate vaccine, MenAfriVac, on carriage and herd immunity.
      • Daugla D.M.
      • Gami J.P.
      • Gamougam K.
      • Naibei N.
      • Mbainadji L.
      • Narbe M.
      • et al.
      Effect of a serogroup A meningococcal conjugate vaccine (PsA-TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study [corrected].
      Data from a number of studies have shown that conjugate vaccination, as with adolescents in the United Kingdom and also with the MenAfriVac® program, substantially reduces acquisition of carriage.

      Conducting carriage studies

      At some time in their lives, most people will be carriers of N. meningitidis. Carriage is age-dependent, with a point prevalence of 10–35% in young adults in Europe
      • Christensen H.
      • May M.
      • Bowen L.
      • Hickman M.
      • Trotter C.L.
      Meningococcal carriage by age: a systematic review and meta-analysis.
      ; in sub-Saharan Africa, it is highest in children.
      • Trotter C.L.
      • Greenwood B.M.
      Meningococcal carriage in the African meningitis belt.
      A number of factors affect carriage, such as contact with other carriers, age, sex, respiratory tract infections, tobacco smoke exposure, social behavior, living conditions, etc.
      For a study in Burkina Faso, a timeframe before and after vaccination was chosen, with sites selected in different urban and rural settings, households randomly selected, and locations mapped by a global positioning system. Demographic and other data were collected with a specially designed questionnaire and sampling undertaken from pre-specified oropharyngeal sites. Swabs were taken, transported, and evaluated (for serogrouping, antibiotic resistance, genotyping, etc), following specified methods under monitored and quality-controlled conditions. As large numbers of samples and data were generated, well-organized data management processes were required.
      • Kristiansen P.A.
      • Diomande F.
      • Ba A.K.
      • Sanou I.
      • Ouedraogo A.S.
      • Ouedraogo R.
      • et al.
      Impact of the serogroup A meningococcal conjugate vaccine, MenAfriVac, on carriage and herd immunity.
      Careful interpretation of carriage study data is necessary as the carriage situation in a population will be temporally and geographically dynamic and can change rapidly.

      Carriage, herd effects, and modeling

      To understand the epidemiology of MD, an understanding of carriage is very important. Modeling can be used to explore the complex process of N. meningitidis transmission. It is assumed that the effects of vaccines are mediated through inhibiting individual colonization (infection), as well as MD itself. Transmission-dynamic models, allowing for dynamic carriage epidemiology, can be used to improve our understanding of the epidemiology of an infection, to make predictions about the future incidence of an infection under particular conditions, and to identify knowledge gaps where more epidemiologic data are required. Modeling was used to demonstrate the important effects of MenC vaccination—in particular, the impact of the large United Kingdom catch-up campaign on herd protection and carriage
      • Maiden M.C.
      • Stuart J.M.
      Carriage of serogroup C meningococci 1 year after meningococcal C conjugate polysaccharide vaccination.
      —to examine carriage prevalence by age in Europe, and to explore how long herd protection might last. For rational decision-making, models are best used in combination with real-world data from disease surveillance, carriage studies, and seroepidemiology.
      Modeling has been used to explore the direct effects of MenAfriVac® in Africa, such as vaccine effectiveness against MenA, and indirect effects, such as the effect of vaccination on disease risk in the unvaccinated population. Modeling requires good quality surveillance data, as was collected in Chad in 2011–2012, for example. An age-structured transmission model was used that captured all the key epidemiologic features of MenA in the African meningitis belt and a number of different vaccine strategies were modeled.
      • Karachaliou A.
      • Conlan A.J.K.
      • Preziosi M.P.
      • Trotter C.L.
      Modeling long-term vaccination strategies with MenAfriVac in the African meningitis belt.
      Modeling showed that follow-up vaccine strategies were needed to maintain protection and helped to inform current WHO MenA vaccine recommendations for sub-Saharan Africa.

      Roundtable discussion: global control of MenW disease

      MenW global epidemiology

      From around 2000 onward, MenW started to appear at significant levels in Europe
      • Ladhani S.N.
      • Beebeejaun K.
      • Lucidarme J.
      • Campbell H.
      • Gray S.
      • Kaczmarski E.
      • et al.
      Increase in endemic Neisseria meningitidis capsular group W sequence type 11 complex associated with severe invasive disease in England and Wales.
      • Abad R.
      • Vazquez J.A.
      Early evidence of expanding W ST-11 CC meningococcal incidence in Spain.
      and South Africa,
      • von Gottberg A.
      • du Plessis M.
      • Cohen C.
      • Prentice E.
      • Schrag S.
      • de Gouveia L.
      • et al.
      Emergence of endemic serogroup W135 meningococcal disease associated with a high mortality rate in South Africa.
      and eventually globally. Historically, MenW has been present (e.g. in the 1960s), with outbreaks of various clones in sub-Saharan Africa in the 1980s and 1990s. Molecular techniques, such as WGS, have now enabled precise characterization of isolates and construction of genetic lineages of the emerging MenW strains. The Hajj (or Anglo-French-Hajj) clone and other recent outbreaks of MenW had been identified by techniques such as multilocus sequence typing (MLST) as an expansion of MenW ST-11. However, it was not clear if all the outbreaks were due to the re-emergence of the same strain. WGS enabled building a high-resolution phylogenetic tree for MenW ST-11. These data suggested that an original UK strain in 2008 corresponded to a new lineage within the MenW ST-11 that was distinct from the Anglo-French-Hajj clone. Cases due to this original clone leveled off after 4 or 5 years, followed by the emergence of a new lineage in the United Kingdom in 2013, and reductions in case fatality ratios after another 3 years. In other countries, both the 2008 and 2013 strains were found; it appears that the 2013 strain is expanding rapidly (relative to the United Kingdom) in other countries.
      • Lucidarme J.
      • Hill D.M.C.
      • Bratcher H.B.
      • Gray S.J.
      • du Plessis M.
      • Tsang R.S.W.
      • et al.
      Genomic resolution of an aggressive, widespread, diverse and expanding meningococcal serogroup B, C and W lineage.
      The reasons for this rapid expansion are unclear and further investigation is required. In addition, a number of groups in the United Kingdom and France have recently noted that MenW ST-11 is associated with some unusual symptoms, such as septic arthritis.
      • Ladhani S.N.
      • Beebeejaun K.
      • Lucidarme J.
      • Campbell H.
      • Gray S.
      • Kaczmarski E.
      • et al.
      Increase in endemic Neisseria meningitidis capsular group W sequence type 11 complex associated with severe invasive disease in England and Wales.
      • Gaschignard J.
      • Levy C.
      • Deghmane A.E.
      • Dubos F.
      • Muszlak M.
      • Cohen R.
      • et al.
      Invasive serogroup W meningococcal disease in children: a national survey from 2001 to 2008 in France.
      In Europe and the United Kingdom, MenW has also been found to present atypical symptoms such as diarrhea and vomiting without classic signs of meningitis or hemorrhagic rash.
      • Campbell H.
      • Parikh S.R.
      • Borrow R.
      • Kaczmarski E.
      • Ramsay M.E.
      • Ladhani S.N.
      Presentation with gastrointestinal symptoms and high case fatality associated with group W meningococcal disease (MenW) in teenagers, England, July 2015 to January 2016.
      There is a need for surveillance that combines exhaustive reporting and microbiological typing. As previous genotyping studies were unable to discriminate sporadic and epidemic MenW isolates reliably, WGS should and can be the standard typing scheme for MenW isolates given that techniques such as MLST do not provide sufficient resolution.

      Best strategies to control serogroup W disease

      Following the Hajj outbreak in 2000, MenW persisted in Saudi Arabia
      • Taha M.K.
      • Achtman M.
      • Alonso J.M.
      • Greenwood B.
      • Ramsay M.
      • Fox A.
      • et al.
      Serogroup W135 meningococcal disease in Hajj pilgrims.
      and a quadrivalent polysaccharide vaccine was introduced and deployed in children <5 years old in the early 2000s (two doses for those <2 years old and one dose for those ≥2 years old); however, only the older children had a serum bactericidal antibody response.
      • Al-Mazrou Y.
      • Khalil M.
      • Borrow R.
      • Balmer P.
      • Bramwell J.
      • Lal G.
      • et al.
      Serologic responses to ACYW135 polysaccharide meningococcal vaccine in Saudi children under 5 years of age.
      Three quadrivalent ACWY conjugate vaccines are now available. In Chile, MenW cases increased rapidly and a conjugate quadrivalent vaccine was introduced in 2012 for children <4 years old, with two doses for those <2 years old and one dose for those 2–4 years old. The estimated coverage for one dose was 84% but only 69% completed the full two-dose regimen. In 2014, the schedule was changed to a single dose at 1 year old and the program has reduced mortality; however, the percentage of MenW is continuing to increase in the unvaccinated population.

      Departamento de Epidemiología. Informe vigilancia de enfermedad meningocócica. Departamento de Epidemiología. Available at: http://epi.minsal.cl/enfermedad-meningococcica-vigilancia/. [Accessed 3 March 2017].

      A carriage study in Chile found a low carriage rate overall (0.2%); however, ST-11 is known to have a low carriage rate but to cause severe disease.
      • Maiden M.C.
      • Stuart J.M.
      Carriage of serogroup C meningococci 1 year after meningococcal C conjugate polysaccharide vaccination.
      • Departamento de Epidemiología
      Enfermedad meningocócica (CIE10:A39) situación epidemiológica, Enero-Diciembre.
      UK data for MenC show the importance of reducing carriage on the overall disease burden. In the United Kingdom, MenW affects all age groups, including older patients, thus differing from MenC in the 1990s, which largely affected teenagers and young adults. The increase of MenW was considered a public health emergency and a strategy of vaccinating adolescents (aged 14–18 years) with quadrivalent conjugate vaccine was adopted in 2015.
      • Ladhani S.N.
      • Ramsay M.
      • Borrow R.
      • Riordan A.
      • Watson J.M.
      • Pollard A.J.
      Enter B and W: two new meningococcal vaccine programmes launched.
      To date, direct protection has been reported and it is hoped that herd protection will follow. Thus, programs targeting young children give direct protection, but are time-limited as antibody persistence is poor; however, programs targeting adolescents and carriers can induce herd protection and antibody persistence is good. MenW cases in the elderly remain a concern and it is not yet known whether they will be covered by herd protection through immunizing adolescents.

      Roundtable discussion: cost-effectiveness assessment in decision-making about vaccines

      Cost-effectiveness analyses have become increasingly important in decision-making.
      • Christensen H.
      • Trotter C.L.
      • Hickman M.
      • Edmunds W.J.
      Re-evaluating cost effectiveness of universal meningitis vaccination (Bexsero) in England: modelling study.
      • Christensen H.
      • Trotter C.L.
      Modelling the cost-effectiveness of catch-up 'MenB' (Bexsero) vaccination in England.
      • Trotter C.L.
      • Edmunds W.J.
      Reassessing the cost-effectiveness of meningococcal serogroup C conjugate (MCC) vaccines using a transmission dynamic model.
      For example, in the United Kingdom, new vaccines cannot be recommended for introduction by the Joint Committee on Vaccination and Immunization (JCVI) unless they are deemed cost-effective. A cost-effectiveness analysis compares both the costs and health effects of an intervention to an alternative to determine the extent to which the intervention provides “value for money.” Cost-effectiveness evaluations for vaccines can be more complex than for other interventions as benefits are accrued over a long time, most recipients are young children, there may be direct and indirect effects (such as transmission and herd protection), and the vaccines available may have different valences. A workshop was held to explore scenarios of cost-effectiveness, in which participants considered the healthcare and societal costs and wider societal benefits of different scenarios. Several factors need to be considered when planning analyses, including the choice of what costs to include (the perspective), how to capture benefits, what comparisons to make, how to capture uncertainty, how to value items in the future (discounting), and the time period (time horizon) to be considered. The benefit measured needs to be selected according to the type of intervention or illness. Inclusion of discounting in analyses has a greater impact on interventions that have lifelong effects, compared with short-term interventions, so cost-effectiveness analyses of vaccination can be particularly affected by the choice of discount rate used. Discounting is highly controversial and countries have their own guidelines on the levels of discounting employed. Participants indicated that cost-effectiveness analyses are used in France, Norway, South Africa, Switzerland, and Turkey. The JCVI has allowed representatives from other countries to observe cost-effectiveness presentations.

      MenAfriVac® immunization program, learnings, and future activities

      Where do we go from here?

      MenAfriVac® was the outcome of a Meningitis Vaccine Project (MVP; lead by WHO-PATH), involving international cooperation and technology transfers. It was licensed by the Indian National Regulatory Authority in December 2009 and pre-qualified by the WHO in June 2010.

      World Health Organization. Immunization standards – MenAfriVac: Meningococcal A conjugate 10 dose presentation. WHO web site. Available at: http://www.who.int/immunization_standards/vaccine_quality/PQ_197_MenAconjugate_10dose_SII/en/. [Accessed 22 December 2016].

      It was first introduced in Burkina Faso, Mali, and Niger in Q4 2010 as a 10-dose vial. New dosage presentations were developed for use in the routine infant schedule from 2015, and it remains an affordable vaccine for developing countries. The vaccine gives direct protection and reduces carriage.
      • Kristiansen P.A.
      • Diomande F.
      • Ba A.K.
      • Sanou I.
      • Ouedraogo A.S.
      • Ouedraogo R.
      • et al.
      Impact of the serogroup A meningococcal conjugate vaccine, MenAfriVac, on carriage and herd immunity.
      The WHO MenA strategy induced herd protection through mass vaccination campaigns, targeting 1–29 year olds. More recently, MenAfriVac® MenA conjugate vaccine was introduced into the routine immunization schedule (for infants aged 9–18 months), thus protecting birth cohorts. As well as this, surveillance and epidemic response were strengthened.

      World Health Organization. WHO position paper on meningococcal A conjugate vaccine. WHO web site. Available at: http://www.who.int/immunization/policy/position_papers/pp_menA_2015_presentation.pdf?ua=1. [Accessed 22 December 2016].

      By August 2016, 265 million people had been vaccinated in 19 countries (Benin, Burkina Faso, Cameroon, Chad, Democratic Republic of Congo, Ethiopia, Gambia, Ghana, Guinea, Guinea Bissau, Ivory Coast, Mali, Mauritania, Niger, Nigeria, Senegal, South Sudan, Sudan, and Togo); around 30 million are still to be vaccinated in the remaining seven countries (Burundi, Central African Republic, Eritrea, Kenya, Rwanda, South Sudan [second phase], and Tanzania). In 12 countries, vaccination programs were prioritized and introduced following risk assessment using a standard tool based on risk indicators, mapping information, and local expert opinion.
      This was the first vaccine to be deployed locally using a controlled temperature chain (CTC) rather than needing a cold chain
      • Zipursky S.
      • Djingarey M.H.
      • Lodjo J.C.
      • Olodo L.
      • Tiendrebeogo S.
      • Ronveaux O.
      Benefits of using vaccines out of the cold chain: delivering meningitis A vaccine in a controlled temperature chain during the mass immunization campaign in Benin.
      and, in 2016, >2.5 million people were vaccinated using the CTC method. Wastage was low, high coverage was achieved, there were no serious adverse events after vaccination, and the CTC protocol was well understood and accepted. Carriage of MenA was substantially reduced in areas where vaccination had been introduced (by 98% in Chad).
      • Daugla D.M.
      • Gami J.P.
      • Gamougam K.
      • Naibei N.
      • Mbainadji L.
      • Narbe M.
      • et al.
      Effect of a serogroup A meningococcal conjugate vaccine (PsA-TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study [corrected].
      In addition, MenAfriVac® uses tetanus toxin as a carrier, and some serologic data have suggested protection against tetanus.
      • Borrow R.
      • Tang Y.
      • Yakubu A.
      • Kulkarni P.S.
      • Laforce F.M.
      MenAfriVac as an antitetanus vaccine.
      In 2010–2012, MenW disease reemerged in Burkina Faso.
      • MacNeil J.R.
      • Medah I.
      • Koussoube D.
      • Novak R.T.
      • Cohn A.C.
      • Diomande F.V.
      • et al.
      Neisseria meningitidis serogroup W, Burkina Faso, 2012.
      MenC emerged in northern Nigeria in 2013 and western Niger in 2015, resulting in the largest post-MenAfriVac® outbreak and the largest MenC outbreak on record, and it has now spread into neighboring countries. The outbreak was large, rapid, and attack rates were high; it was found to be caused by a previously unrecorded MenC clone. It appeared to have emerged in Nigeria before the MenAfriVac® campaign and was not likely to be associated with the elimination of MenA epidemics following the vaccine's introduction.
      • Chow J.
      • Uadiale K.
      • Bestman A.
      • Kamau C.
      • Caugant D.A.
      • Shehu A.
      • et al.
      Invasive meningococcal meningitis serogroup C outbreak in northwest Nigeria, 2015-third consecutive outbreak of a new strain.
      All the MenC strains isolated were ST10217, they belong to an unassigned clonal complex, and all have the same molecular profile.
      • Chow J.
      • Uadiale K.
      • Bestman A.
      • Kamau C.
      • Caugant D.A.
      • Shehu A.
      • et al.
      Invasive meningococcal meningitis serogroup C outbreak in northwest Nigeria, 2015-third consecutive outbreak of a new strain.
      • Kretz C.B.
      • Retchless A.C.
      • Sidikou F.
      • Issaka B.
      • Ousmane S.
      • Schwartz S.
      • et al.
      Whole-genome characterization of epidemic Neisseria meningitidis serogroup C and resurgence of serogroup W, Niger, 2015.
      They are genetically unrelated to the epidemic clones causing disease in Africa in the past decades, or to the rare MenC isolates that have circulated since the 1980s.
      • Funk A.
      • Uadiale K.
      • Kamau C.
      • Caugant D.A.
      • Ango U.
      • Greig J.
      Sequential outbreaks due to a new strain of Neisseria meningitidis serogroup C in northern Nigeria, 2013-14.
      A further outbreak of MenW occurred in Togo in 2016 and also in northern Ghana. In the past 16 years, there have been a number of non-MenA outbreaks in the region and MenA is still circulating at a low level, although the vaccine failure rate is very low.
      The success of MenAfriVac® to date needs to be sustained, with rollout into other countries, continuing introduction into routine programs, and ongoing surveillance to monitor long-term impact, effectiveness, failure, and non-MenA serogroups. There are a number of challenges to overcome for MenAfriVac®, such as bridging the gap between campaign and routine vaccinations, with a need for further catch-up vaccinations. Finally, there needs to be clear communication about the new dose sizes available, and vaccine supply must be maintained and programs financially enabled.
      A new initiative was started by the United Kingdom Department for International Development in 2008 in partnership with PATH and the Serum Institute of India to develop an affordable thermostable pentavalent ACWYX vaccine.

      Serum Institute of India. Product pipeline. Serum Institute of India. Available at: http://www.seruminstitute.com/content/prod_pipe.htm. [Accessed 25 January 2017].

      Clinical development will be mainly in Africa (with some trials in India and in the USA), with immunoassays undertaken by Public Health England and initial licensing planned for export from India. The vaccine is currently in phase 1 clinical trial, and it is hoped that it will be available for use in 2020–2022.

      Meningococcal vaccination and HIV

      A number of recent studies have shown that the risk of MD is higher in individuals with HIV.
      • MacNeil J.R.
      • Rubin L.G.
      • Patton M.
      • Ortega-Sanchez I.R.
      • Martin S.W.
      Recommendations for use of meningococcal conjugate vaccines in HIV-infected persons - advisory Committee on Immunization Practices, 2016.
      • Kipp W.
      • Kamugisha J.
      • Rehle T.
      Meningococcal meningitis and HIV infection: results from a case-control study in western Uganda.
      • Morla N.
      • Guibourdenche M.
      • Riou J.Y.
      Neisseria spp. and AIDS.
      • Couldwell D.L.
      Invasive meningococcal disease and HIV coinfection.
      • Stephens D.S.
      • Hajjeh R.A.
      • Baughman W.S.
      • Harvey R.C.
      • Wenger J.D.
      • Farley M.M.
      Sporadic meningococcal disease in adults: results of a 5-year population-based study.
      In the past, some studies have looked at all types of meningitis rather than purely MD, and findings have been unclear; some of the older studies were also conducted before the introduction of highly active antiretroviral HIV therapy. However, results of surveillance data analysis from 2003 to 2007 in patients of all ages conducted in South Africa showed that HIV was associated with a higher incidence of MD and higher case fatality ratios.
      • Cohen C.
      • Singh E.
      • Wu H.M.
      • Martin S.
      • de Gouveia L.
      • Klugman K.P.
      • et al.
      Increased incidence of meningococcal disease in HIV-infected individuals associated with higher case-fatality ratios in South Africa.
      Other recent studies, including two from the United States from the 2000s, have found a 13-fold and 10-fold greater risk of MD for those with HIV,
      • Miller L.
      • Arakaki L.
      • Ramautar A.
      • Bodach S.
      • Braunstein S.L.
      • Kennedy J.
      • et al.
      Elevated risk for invasive meningococcal disease among persons with HIV.
      although the findings on case fatality ratios were less clear. Importantly, patients in these recent studies were receiving antiretroviral therapy and a good standard of healthcare.
      The responses to vaccination in people with HIV have been shown in immunogenicity studies; however, two doses of vaccine are required.
      • Siberry G.K.
      • Warshaw M.G.
      • Williams P.L.
      • Spector S.A.
      • Decker M.D.
      • Jean-Philippe P.
      • et al.
      Safety and immunogenicity of quadrivalent meningococcal conjugate vaccine in 2- to 10-year-old human immunodeficiency virus-infected children.
      • Siberry G.K.
      • Williams P.L.
      • Lujan-Zilbermann J.
      • Warshaw M.G.
      • Spector S.A.
      • Decker M.D.
      • et al.
      Phase I/II, open-label trial of safety and immunogenicity of meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine in human immunodeficiency virus-infected adolescents.
      Some countries now have recommendations for vaccination with the MenACWY conjugate vaccine, for example, in the United States, where the Advisory Committee on Immunization Practices has proposed that children ≥2 years old with HIV who have not been previously vaccinated should receive a two-dose primary series of MenACWY (at ages 0–2 months), and a multi-dose schedule for children <2 years old.
      • British HIV Association
      British HIV Association guidelines on the use of vaccines in HIV-positive adults.
      Individuals with HIV who have been previously vaccinated with one dose of MenACWY should receive a second dose at the earliest opportunity, and continue to receive boosters at the appropriate interval.
      • MacNeil J.R.
      • Rubin L.G.
      • Patton M.
      • Ortega-Sanchez I.R.
      • Martin S.W.
      Recommendations for use of meningococcal conjugate vaccines in HIV-infected persons - advisory Committee on Immunization Practices, 2016.
      Current booster recommendations are 3 years if <7 years at previous dose and at 5 years if ≥7 years at previous dose.
      An important issue with such recommendations, however, is the cost of the conjugate vaccine, particularly in low-/middle-income countries with high rates of HIV. There also have been recent outbreaks involving two ST-11 strains of MenC in several countries among men who have sex with men (regardless of HIV status), and this group may need to be included in immunization recommendations.
      • Taha M.K.
      • Claus H.
      • Lappann M.
      • Veyrier F.J.
      • Otto A.
      • Becher D.
      • et al.
      Evolutionary events associated with an outbreak of meningococcal disease in men who have sex with men.

      Advocating for vaccines

      Advocating for vaccines needs to be contextually sensitive, and therefore can have different objectives by region and country. Defining clear objectives from the outset is vital as subsequent actions undertaken may be radically different dependent on the setting. For example, the MVP used a combination of country visits, workshops, a website, the mass media, and vaccination champions to achieve its mass vaccination goals at international, national, and sub-national levels, whereas the Confederation of Meningitis Organizations (CoMO), which exists to help patient groups meet their goals, supported a campaign in Spain to make the MenB vaccine available through pharmacies by advising on use of a targeted letter to the appropriate health authority (eg, Minister of Health, Surgeon General, etc) in that country. CoMO also holds conferences and provides a website to help share advocacy tools (http://www.comomeningitis.org/). The Advocacy for Immunization website developed by the PATH campaign with Johns Hopkins University also provides a set of useful tools and guides to advocacy.

      Advocacy for Immunization. Welcome to advocacy for immunisation. Advocacy for Immunization. Available at: http://advocacy.vaccineswork.org/. [Accessed 22 December 2016].

      The MenB campaign of the Meningitis Research Foundation (MRF) in the United Kingdom had two objectives: to get the vaccine introduced into the national immunization program and to make the decision-making framework fair. Before the vaccine was available, a multifaceted campaign to support meningitis vaccination began, including petitions, cost evaluations, evidence to support more favorable parameters for cost effectiveness evaluation, letters to the appropriate health authority (eg, Minister of Health) from clinicians, scientists, and professional medical bodies (e.g. the Royal Colleges), events for members of parliament, use of social media, etc. Following recommendation by the United Kingdom's JCVI, advocacy continued until the vaccine was introduced for infants <1 year old. An online petition to the United Kingdom government with >800,000 signatures was made to expand the age range for MenB vaccination, which led the MRF to act with press releases, develop a 10-point action plan for the government (with Meningitis Now, UK),

      Meningitis Now. Meningis Now web site. Available at: https://www.meningitisnow.org/. [Accessed 22 December 2016].

      and take various other measures. The petition and campaign resulted in a parliamentary select committee hearing, a debate in the United Kingdom parliament, a ministerial commitment to fund a national study of the MenB vaccine's impact on carriage in teenagers, and a ministerial commitment to publish findings of the cost-effectiveness working group. This work is ongoing, especially to make sure that the decision-making framework is fair.
      A number of approaches can be successful in this regard, as shown in Fig. 2. There are challenges to successful advocacy campaigns, including vested interests affecting decision-making frameworks, political will, actual resource (human and financial), the need for collaborative working, and the need to work with the media to simplify complex issues.
      Figure 2
      Figure 2Possible approaches for vaccine advocacy.

      Updates to the GMI recommendations

      Two proposals for updates to the GMI recommendations were considered during the meeting:
      • A recommendation that local public health authorities should assess the value of issuing an advisory for those attending a planned mass-gathering event to be vaccinated. This proposal follows the model adopted in several countries with respect to the Hajj pilgrimage and the experience of outbreaks related to the World Scout Jamboree in Japan in 2015 and a case of MD at the World Youth Day Catholic Gathering in Poland in 2016, as well as recent outbreaks among men who have sex with men. However, further work is needed to characterize the aspects of mass gatherings that may pose significant risks for transmission of MD.
      • A recommendation for the vaccination of individuals who are HIV positive. This proposal is based on studies showing an increased risk of MD in those with HIV and the incorporation of such recommendations into a number of national vaccination guidelines.

      Summary and conclusion

      Conjugate vaccines are, in most respects, superior to plain polysaccharide vaccines, which do not provide long-term direct protection in infants, toddlers, or younger children. Indirect (herd) protection has been instrumental for MenC disease control in the United Kingdom, and adolescent vaccination programs have been introduced with the aim of providing direct protection to those vaccinated and indirect protection to other age groups. Further consideration is required regarding revaccination recommendations for conjugate vaccines and recommendations for mass-gathering events. It is difficult to define clear criteria for this recommendation, but aspects to consider include the age of attendees (adolescents and young adults being more likely to carry meningococcus) and the type of mass gathering (e.g. camping or living in communal quarters). Further work is needed to characterize those types of mass gatherings that may pose significant risk for transmission of MD. Pentavalent meningococcal vaccines are under development, including an ACWYX conjugate and an ACWY conjugate combined with Bexsero®. The new-generation MenB vaccines have the potential to replace outer membrane vesicle vaccines in epidemics. The IBVPD offers a range of technical and standard methodology support, quality assurance and quality control, partnering, data management, and funding opportunities, and in the future will focus on disease burden and vaccine impact, as well as surveillance for other vaccine-preventable pathogens and antimicrobial resistance. Presentations on invasive MD in Algeria, Morocco, Tunisia, and Turkey illustrated the differences of surveillance, epidemiology, case definitions, and control (i.e. vaccination and chemoprophylaxis) in North Africa and the Middle East. It has been shown that although the MenAfriVac® campaign has been a success, there have been recent outbreaks of non-MenA serogroups. Carriage studies are needed to support and guide the introduction of meningococcal vaccines, and it was shown how study design was the most critical point in these studies. New GMI recommendations on vaccination of patients with HIV and of those attending certain types of mass-gathering events were proposed. The role of vaccine advocacy was also highlighted in the effective prevention of MD.

      Author contribution

      All authors have contributed original content, reviewed and revised the manuscript, and approved the final version.

      Conflict of interest

      The authors are the members of the Global Meningococcal Initiative (GMI) which is sponsored by Sanofi Pasteur. The GMI is not influenced in any way by Sanofi Pasteur. GMI members hold the full right to determine meeting agenda items and lead the discussions and outputs. Sanofi Pasteur representatives have attended the meetings, but as observers only, and they do not influence the findings of the group. RB and JF perform contract research on behalf of Public Health England for GlaxoSmithKline, Pfizer, and Sanofi Pasteur. DAC has performed in the past contract research on behalf of the Norwegian Institute of Public Health for Novartis, Pfizer, and Sanofi Pasteur. HC reports receiving an honorarium from Sanofi Pasteur in 2015 and 2016, and consultancy fees from AstraZeneca and IMS Health, all paid to her employer. JVM has received honoraria from GlaxoSmithKline, Pfizer, and Sanofi Pasteur. MC, ECD, LG, AVG, AK, AR, VS, M-KT, HT-M, and KZ report no conflicts of interest.

      Acknowledgements

      Authors would like to thank Dr Adam L. Cohen, World Health Organization, Geneva, Switzerland, Dr Olivier Ronveaux, Control of Epidemic Diseases, World Health Organization, Geneva, Switzerland, and Dr Fatima Serhan, Division of Viral Diseases, World Health Organization, Geneva, Switzerland, for their contribution during the Lisbon GMI Roundtable Meeting and for providing permission to use their presentation content in this manuscript.
      Medical writing support was provided by Debaditya Das, PhD, and Robert Axford-Gatley, MD, of the GMI Secretariat, PAREXEL International, which was funded by Sanofi Pasteur . HC is supported by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Evaluation of Interventions at the University of Bristol in partnership with Public Health England. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or Public Health England.

      References

        • McGill F.
        • Heyderman R.S.
        • Michael B.D.
        • Defres S.
        • Beeching N.J.
        • Borrow R.
        • et al.
        The UK joint specialist societies guideline on the diagnosis and management of acute meningitis and meningococcal sepsis in immunocompetent adults.
        J Infect. 2016; 72: 405-438
        • World Health Organization
        Meningococcal vaccines: polysaccharide and polysaccharide conjugate vaccines.
        Wkly Epidemiol Rec. 2002; 77: 331-339
        • Broker M.
        • Jacobsson S.
        • Kuusi M.
        • Pace D.
        • Simoes M.J.
        • Skoczynska A.
        • et al.
        Meningococcal serogroup Y emergence in Europe: update 2011.
        Hum Vaccin Immunother. 2012; 8: 1907-1911
        • Borrow R.
        • Lee J.S.
        • Vazquez J.A.
        • Enwere G.
        • Taha M.K.
        • Kamiya H.
        • et al.
        Meningococcal disease in the Asia-Pacific region: findings and recommendations from the Global Meningococcal Initiative.
        Vaccine. 2016; 34: 5855-5862
        • Fellick J.M.
        • Sills J.A.
        • Marzouk O.
        • Hart C.A.
        • Cooke R.W.
        • Thomson A.P.
        Neurodevelopmental outcome in meningococcal disease: a case-control study.
        Arch Dis Child. 2001; 85: 6-11
        • Erickson L.J.
        • De Wals P.
        • McMahon J.
        • Heim S.
        Complications of meningococcal disease in college students.
        Clin Infect Dis. 2001; 33: 737-739
        • CDC
        Active bacterial core surveillance report, emerging infections program network, Neisseria meningitidis.
        (US Centers for Disease Control and Prevention web site)2014 (Available at:) ([Accessed 22 December 2016])
        • Borrow R.
        • Alarcon P.
        • Carlos J.
        • Caugant D.A.
        • Christensen H.
        • Debbag R.
        • et al.
        The Global Meningococcal Initiative: global epidemiology, the impact of vaccines on meningococcal disease and the importance of herd protection.
        Expert Rev Vaccines. 2016; : 1-16
        • Lingani C.
        • Bergeron-Caron C.
        • Stuart J.M.
        • Fernandez K.
        • Djingarey M.H.
        • Ronveaux O.
        • et al.
        Meningococcal meningitis surveillance in the African meningitis belt, 2004-2013.
        Clin Infect Dis. 2015; 61: S410-S415
        • World Health Organization
        Weekly feedback bulletin on cerebrospinal meningitis: West Africa, weeks 48-52.
        (WHO web site)2016 (Available at:) ([Accessed 27 February 2017])
        • Granoff D.M.
        • Feavers I.
        • Borrow R.
        Meningococcal vaccines.
        in: Plotkin S.A. Orenstein W.A. Vaccines. W.B. Saunders Company, Philadelphia2003: 959-987
        • Public Health England
        Meningococcal: meningococcal meningitis and septicaemia notifiable.
        Green Book, 2016: 1-24
        • Parikh S.R.
        • Andrews N.J.
        • Beebeejaun K.
        • Campbell H.
        • Ribeiro S.
        • Ward C.
        • et al.
        Effectiveness and impact of a reduced infant schedule of 4CMenB vaccine against group B meningococcal disease in England: a national observational cohort study.
        Lancet. 2016; 388: 2775-2782
        • Ceyhan M.
        • Anis S.
        • Htun-Myint L.
        • Pawinski R.
        • Soriano-Gabarro M.
        • Vyse A.
        Meningococcal disease in the Middle East and North Africa: an important public health consideration that requires further attention.
        Int J Infect Dis. 2012; 16: e574-e582
        • Razki A.
        • Hong E.
        • Zerrouli K.
        • Ezzaki B.
        • Diawara I.
        • Bouayad A.
        • et al.
        Invasive meningococcal disease: surveillance in Casablanca (Morocco).
        in: Presented at: 36ème Réunion Interdisciplinaire de Chimiothérapie Anti Infectieuse. December 13, 2016 (Paris, France)
        • Algerie Sante
        Situation epidemiologique de l'annee 2012.
        Relev Epidémiol Mens. 2012; 23: 1-22
      1. World Health Organization. Immunization standards – MenAfriVac: Meningococcal A conjugate 10 dose presentation. WHO web site. Available at: http://www.who.int/immunization_standards/vaccine_quality/PQ_197_MenAconjugate_10dose_SII/en/. [Accessed 22 December 2016].

        • Ceyhan M.
        • Gurler N.
        • Ozsurekci Y.
        • Keser M.
        • Aycan A.E.
        • Gurbuz V.
        • et al.
        Meningitis caused by Neisseria meningitidis, Hemophilus influenzae type B and Streptococcus pneumoniae during 2005-2012 in Turkey. A multicenter prospective surveillance study.
        Hum Vaccin Immunother. 2014; 10: 2706-2712
        • Ceyhan M.
        • Yildirim I.
        • Balmer P.
        • Borrow R.
        • Dikici B.
        • Turgut M.
        • et al.
        A prospective study of etiology of childhood acute bacterial meningitis, Turkey.
        Emerg Infect Dis. 2008; 14: 1089-1096
        • Kurugol Z.
        Meningococcal disease and control measures.
        Turk Klin J Pediatr. 2006; 15: 98
        • Tuysuz B.
        • Ozlu I.
        • Erginal A.
        Epidemiology of meningococcal diseases: a study of 140 patients.
        Ist Cocuk Klin Derg. 1992; 27: 32-35
        • Ceyhan M.
        • Ozsurekci Y.
        • Gurler N.
        • Karadag O.E.
        • Camcioglu Y.
        • Salman N.
        • et al.
        Bacterial agents causing meningitis during 2013-2014 in Turkey: a multi-center hospital-based prospective surveillance study.
        Hum Vaccin Immunother. 2016; 12: 2940-2945
        • Ceyhan M.
        • Yildirim I.
        • Balmer P.
        • Riley C.
        • Laher G.
        • Andrews N.
        • et al.
        Age-specific seroprevalence of serogroup C meningococcal serum bactericidal antibody activity and serogroup A, C, W135 and Y-specific IgG concentrations in the Turkish population during 2005.
        Vaccine. 2007; 25: 7233-7237
        • Tekin R.
        • Dinleyici E.
        • Ceyhan M.
        • Karbuz A.
        • Salman N.
        • Sutçu M.
        • et al.
        The prevalence, serogroup distribution and risk factors of meningococcal carriage in adolescents and young adults in Turkey.
        Hum Vaccines Immunother. 2017; : 1-8
        • Dinleyici E.C.
        • Ceyhan M.
        The dynamic and changing epidemiology of meningococcal disease at the country-based level: the experience in Turkey.
        Expert Rev Vaccines. 2012; 11: 515-518
        • Department of Health, South Africa
        Guidelines for the management, prevention and control of meningococcal disease in South Africa.
        (Department of Health, South Africa)2011 (Available at:) ([Accessed 3 March 2017])
        • Coulson G.B.
        • du Plessis M.
        • Smith A.M.
        • de Gouveia L.
        • Klugman K.P.
        • von Gottberg A.
        Meningococcal disease in South Africa, 1999−2002.
        Emerg Infect Dis. 2007; 13: 273-281
        • von Gottberg A.
        • du Plessis M.
        • Cohen C.
        • Prentice E.
        • Schrag S.
        • de Gouveia L.
        • et al.
        Emergence of endemic serogroup W135 meningococcal disease associated with a high mortality rate in South Africa.
        Clin Infect Dis. 2008; 46: 377-386
        • Meiring S.
        • Cohen C.
        • Lengana S.
        • von Mollendorf C.
        • de Gouveia L.
        • du Plessis M.
        • et al.
        Invasive meningococcal serogroup C and W disease in South Africa: 2003-2014. Poster E25.
        in: Presented at: Meningitis Research Foundation (MRF) Conference. Meningitis and septicaemia in children and adults. November 4, 2015 (London, UK)
        • Cohen C.
        • Singh E.
        • Wu H.M.
        • Martin S.
        • de Gouveia L.
        • Klugman K.P.
        • et al.
        Increased incidence of meningococcal disease in HIV-infected individuals associated with higher case-fatality ratios in South Africa.
        AIDS. 2010; 24: 1351-1360
      2. World Health Organization. Surveillance for vaccine preventable diseases (VPDs). WHO web site. Available at: http://www.who.int/immunization/monitoring_surveillance/burden/VPDs/en/. [Accessed 22 December 2016].

        • Hassan-King M.K.
        • Wall R.A.
        • Greenwood B.M.
        Meningococcal carriage, meningococcal disease and vaccination.
        J Infect. 1988; 16: 55-59
        • Maiden M.C.
        • Stuart J.M.
        Carriage of serogroup C meningococci 1 year after meningococcal C conjugate polysaccharide vaccination.
        Lancet. 2002; 359: 1829-1831
        • Kristiansen P.A.
        • Diomande F.
        • Ba A.K.
        • Sanou I.
        • Ouedraogo A.S.
        • Ouedraogo R.
        • et al.
        Impact of the serogroup A meningococcal conjugate vaccine, MenAfriVac, on carriage and herd immunity.
        Clin Infect Dis. 2013; 56: 354-363
        • Daugla D.M.
        • Gami J.P.
        • Gamougam K.
        • Naibei N.
        • Mbainadji L.
        • Narbe M.
        • et al.
        Effect of a serogroup A meningococcal conjugate vaccine (PsA-TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study [corrected].
        Lancet. 2014; 383: 40-47
        • Christensen H.
        • May M.
        • Bowen L.
        • Hickman M.
        • Trotter C.L.
        Meningococcal carriage by age: a systematic review and meta-analysis.
        Lancet Infect Dis. 2010; 10: 853-861
        • Trotter C.L.
        • Greenwood B.M.
        Meningococcal carriage in the African meningitis belt.
        Lancet Infect Dis. 2007; 7: 797-803
        • Karachaliou A.
        • Conlan A.J.K.
        • Preziosi M.P.
        • Trotter C.L.
        Modeling long-term vaccination strategies with MenAfriVac in the African meningitis belt.
        Clin Infect Dis. 2015; 61: S594-S600
        • Ladhani S.N.
        • Beebeejaun K.
        • Lucidarme J.
        • Campbell H.
        • Gray S.
        • Kaczmarski E.
        • et al.
        Increase in endemic Neisseria meningitidis capsular group W sequence type 11 complex associated with severe invasive disease in England and Wales.
        Clin Infect Dis. 2015; 60: 578-585
        • Abad R.
        • Vazquez J.A.
        Early evidence of expanding W ST-11 CC meningococcal incidence in Spain.
        J Infect. 2016; 73: 296-297
        • Lucidarme J.
        • Hill D.M.C.
        • Bratcher H.B.
        • Gray S.J.
        • du Plessis M.
        • Tsang R.S.W.
        • et al.
        Genomic resolution of an aggressive, widespread, diverse and expanding meningococcal serogroup B, C and W lineage.
        J Infect. 2015; 71 (S0163-4453(15)00232-7[PII];26226598[pmid]): 544-552
        • Gaschignard J.
        • Levy C.
        • Deghmane A.E.
        • Dubos F.
        • Muszlak M.
        • Cohen R.
        • et al.
        Invasive serogroup W meningococcal disease in children: a national survey from 2001 to 2008 in France.
        Pediatr Infect Dis J. 2013; 32: 798-800
        • Campbell H.
        • Parikh S.R.
        • Borrow R.
        • Kaczmarski E.
        • Ramsay M.E.
        • Ladhani S.N.
        Presentation with gastrointestinal symptoms and high case fatality associated with group W meningococcal disease (MenW) in teenagers, England, July 2015 to January 2016.
        Euro Surveill. 2016; 21
        • Taha M.K.
        • Achtman M.
        • Alonso J.M.
        • Greenwood B.
        • Ramsay M.
        • Fox A.
        • et al.
        Serogroup W135 meningococcal disease in Hajj pilgrims.
        Lancet. 2000; 356: 2159
        • Al-Mazrou Y.
        • Khalil M.
        • Borrow R.
        • Balmer P.
        • Bramwell J.
        • Lal G.
        • et al.
        Serologic responses to ACYW135 polysaccharide meningococcal vaccine in Saudi children under 5 years of age.
        Infect Immun. 2005; 73: 2932-2939
      3. Departamento de Epidemiología. Informe vigilancia de enfermedad meningocócica. Departamento de Epidemiología. Available at: http://epi.minsal.cl/enfermedad-meningococcica-vigilancia/. [Accessed 3 March 2017].

        • Departamento de Epidemiología
        Enfermedad meningocócica (CIE10:A39) situación epidemiológica, Enero-Diciembre.
        (Departamento de Epidemiología)2015 (Available at:) ([Accessed 3 March 2017])
        • Ladhani S.N.
        • Ramsay M.
        • Borrow R.
        • Riordan A.
        • Watson J.M.
        • Pollard A.J.
        Enter B and W: two new meningococcal vaccine programmes launched.
        Arch Dis Child. 2016; 101: 91-95
        • Christensen H.
        • Trotter C.L.
        • Hickman M.
        • Edmunds W.J.
        Re-evaluating cost effectiveness of universal meningitis vaccination (Bexsero) in England: modelling study.
        BMJ. 2014; 349: g5725
        • Christensen H.
        • Trotter C.L.
        Modelling the cost-effectiveness of catch-up 'MenB' (Bexsero) vaccination in England.
        Vaccine. 2017; 35: 208-211
        • Trotter C.L.
        • Edmunds W.J.
        Reassessing the cost-effectiveness of meningococcal serogroup C conjugate (MCC) vaccines using a transmission dynamic model.
        Med Decis Mak. 2006; 26: 38-47
      4. World Health Organization. WHO position paper on meningococcal A conjugate vaccine. WHO web site. Available at: http://www.who.int/immunization/policy/position_papers/pp_menA_2015_presentation.pdf?ua=1. [Accessed 22 December 2016].

        • Zipursky S.
        • Djingarey M.H.
        • Lodjo J.C.
        • Olodo L.
        • Tiendrebeogo S.
        • Ronveaux O.
        Benefits of using vaccines out of the cold chain: delivering meningitis A vaccine in a controlled temperature chain during the mass immunization campaign in Benin.
        Vaccine. 2014; 32: 1431-1435
        • Borrow R.
        • Tang Y.
        • Yakubu A.
        • Kulkarni P.S.
        • Laforce F.M.
        MenAfriVac as an antitetanus vaccine.
        Clin Infect Dis. 2015; 61: S570-S577
        • MacNeil J.R.
        • Medah I.
        • Koussoube D.
        • Novak R.T.
        • Cohn A.C.
        • Diomande F.V.
        • et al.
        Neisseria meningitidis serogroup W, Burkina Faso, 2012.
        Emerg Infect Dis. 2014; 20: 394-399
        • Chow J.
        • Uadiale K.
        • Bestman A.
        • Kamau C.
        • Caugant D.A.
        • Shehu A.
        • et al.
        Invasive meningococcal meningitis serogroup C outbreak in northwest Nigeria, 2015-third consecutive outbreak of a new strain.
        PLoS Curr. 2016; 8
        • Kretz C.B.
        • Retchless A.C.
        • Sidikou F.
        • Issaka B.
        • Ousmane S.
        • Schwartz S.
        • et al.
        Whole-genome characterization of epidemic Neisseria meningitidis serogroup C and resurgence of serogroup W, Niger, 2015.
        Emerg Infect Dis. 2016; 22: 1762-1768
        • Funk A.
        • Uadiale K.
        • Kamau C.
        • Caugant D.A.
        • Ango U.
        • Greig J.
        Sequential outbreaks due to a new strain of Neisseria meningitidis serogroup C in northern Nigeria, 2013-14.
        PLoS Curr. 2014; 6
      5. Serum Institute of India. Product pipeline. Serum Institute of India. Available at: http://www.seruminstitute.com/content/prod_pipe.htm. [Accessed 25 January 2017].

        • MacNeil J.R.
        • Rubin L.G.
        • Patton M.
        • Ortega-Sanchez I.R.
        • Martin S.W.
        Recommendations for use of meningococcal conjugate vaccines in HIV-infected persons - advisory Committee on Immunization Practices, 2016.
        MMWR Morb Mortal Wkly Rep. 2016; 65: 1189-1194
        • Kipp W.
        • Kamugisha J.
        • Rehle T.
        Meningococcal meningitis and HIV infection: results from a case-control study in western Uganda.
        AIDS. 1992; 6: 1557-1558
        • Morla N.
        • Guibourdenche M.
        • Riou J.Y.
        Neisseria spp. and AIDS.
        J Clin Microbiol. 1992; 30 (1400993[pmid];1400993[pmid]): 2290-2294
        • Couldwell D.L.
        Invasive meningococcal disease and HIV coinfection.
        Commun Dis Intell Q Rep. 2001; 25: 279
        • Stephens D.S.
        • Hajjeh R.A.
        • Baughman W.S.
        • Harvey R.C.
        • Wenger J.D.
        • Farley M.M.
        Sporadic meningococcal disease in adults: results of a 5-year population-based study.
        Ann Intern Med. 1995; 123: 937-940
        • Miller L.
        • Arakaki L.
        • Ramautar A.
        • Bodach S.
        • Braunstein S.L.
        • Kennedy J.
        • et al.
        Elevated risk for invasive meningococcal disease among persons with HIV.
        Ann Intern Med. 2014; 160: 30-37
        • Siberry G.K.
        • Warshaw M.G.
        • Williams P.L.
        • Spector S.A.
        • Decker M.D.
        • Jean-Philippe P.
        • et al.
        Safety and immunogenicity of quadrivalent meningococcal conjugate vaccine in 2- to 10-year-old human immunodeficiency virus-infected children.
        Pediatr Infect Dis J. 2012; 31: 47-52
        • Siberry G.K.
        • Williams P.L.
        • Lujan-Zilbermann J.
        • Warshaw M.G.
        • Spector S.A.
        • Decker M.D.
        • et al.
        Phase I/II, open-label trial of safety and immunogenicity of meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine in human immunodeficiency virus-infected adolescents.
        Pediatr Infect Dis J. 2010; 29: 391-396
        • British HIV Association
        British HIV Association guidelines on the use of vaccines in HIV-positive adults.
        (British HIV Association)2015 (Available at:) ([Accessed 23 January 2017])
        • Taha M.K.
        • Claus H.
        • Lappann M.
        • Veyrier F.J.
        • Otto A.
        • Becher D.
        • et al.
        Evolutionary events associated with an outbreak of meningococcal disease in men who have sex with men.
        PLoS One. 2016; 11: e0154047
      6. Advocacy for Immunization. Welcome to advocacy for immunisation. Advocacy for Immunization. Available at: http://advocacy.vaccineswork.org/. [Accessed 22 December 2016].

      7. Meningitis Now. Meningis Now web site. Available at: https://www.meningitisnow.org/. [Accessed 22 December 2016].