The important lessons lurking in the history of meningococcal epidemiology

ABSTRACT

Introduction

The epidemiology of invasive meningococcal disease (IMD), a rare but potentially fatal illness, is typically described as unpredictable and subject to sporadic outbreaks.

Areas covered

Meningococcal epidemiology and vaccine use during the last ~ 200 years are examined within the context of meningococcal characterization and classification to guide future IMD prevention efforts.

Expert opinion

Historical and contemporary data highlight the dynamic nature of meningococcal epidemiology, with continued emergence of hyperinvasive clones and affected regions. Recent shifts include global increases in serogroup W disease, meningococcal antimicrobial resistance (AMR), and meningococcal urethritis; additionally, unvaccinated populations have experienced disease resurgences following lifting of COVID-19 restrictions. Despite these changes, a close analysis of meningococcal epidemiology indicates consistent dominance of serogroups A, B, C, W, and Y and elevated IMD rates among infants and young children, adolescents/young adults, and older adults. Demonstrably effective vaccines against all 5 major disease-causing serogroups are available, and their prophylactic use represents a powerful weapon against IMD, including AMR. The World Health Organization's goal of defeating meningitis by the year 2030 demands broad protection against IMD, which in turn indicates an urgent need to expand meningococcal vaccination programs across major disease-causing serogroups and age-related risk groups.

KEYWORDS:

• Epidemiology
• meningococcal disease
• meningococcal vaccines
• Neisseria meningitidis
• outbreaks

1. Introduction

Neisseria meningitidis is a Gram-negative bacterium that commensally colonizes the human upper respiratory tract but can also cause invasive meningococcal disease (IMD) [1]. IMD is potentially life threatening, presenting most commonly as meningitis and/or septicemia and less commonly as pneumonia, septic arthritis, or pericarditis [1–5]. Initial IMD symptoms are generally nonspecific (e.g. headache, fever, nausea, sore throat, drowsiness), complicating distinction from other, more common, and less serious viral illnesses [1,6]. Symptoms more specific to IMD (e.g. neck stiffness; photophobia; bulging fontanel [in infants]; petechial, hemorrhagic rash) generally develop ~ 12 − 15 h later, shortly after which disease may become fatal [1,6]. Once suspected or diagnosed, IMD is treated with broad-spectrum antibiotics [3,4].

Estimated overall case-fatality rates (CFRs) of IMD when treated are up to 15% [1,4,7] but vary between age groups (infants/young children, 7.0%−9.0%; adolescents/young adults, 10.4%−15.0%; elderly adults, 32.8%) [7]. Without treatment, the CFR can reach 50% [3]. Additionally, ~ 10%−20% of survivors experience long-term disabling sequelae, including amputations; skin necrosis causing severe scarring; brain damage; hearing loss; and emotional, behavioral, and learning difficulties [2,3].

The epidemiology of IMD is typically considered unpredictable and is associated with sporadic outbreaks, with cases most often occurring during winter and early spring [1,8,9]. Although IMD affects all ages, infants, young children, and adolescents/young adults typically experience the highest disease rates [9]. IMD rates drop after early adulthood but increase again in the elderly, often presenting as pneumonia [8,9].

This review principally focuses on meningococcal epidemiology during the last ~ 200 years within the context of microbiological characterization and typing of N meningitidis, as well as meningococcal vaccines. We draw upon past epidemiologic trends and vaccine use to guide future meningococcal vaccination recommendations with a view toward the World Health Organization (WHO) goal of eliminating meningitis and IMD as public health threats by the year 2030 [10].

2. Microbiologic characterization of Neisseria meningitidis

Basic microbiologic features, genomic characteristics, capsular structure, and key surface molecules exert important influences on meningococcal virulence [11] and, in turn, epidemiology and vaccine development. These factors are briefly reviewed below.

2.1. Basic microbiology

N meningitidis is a Gram-negative aerobic diplococcus that is a β-proteobacterium of the Neisseriaceae family [1,11]. Meningococcus optimal growing conditions are 35°C − 37°C and 5%−10% (v/v) CO₂ [11]. Humans, especially adolescents and young adults, provide the only natural reservoir of meningococci, with up to 25% of individuals being asymptomatic nasopharyngeal carriers [1,11,12]. Human colonization involves meningococci overcoming human host defenses to bind nasopharyngeal and oropharyngeal mucosal cells via pili on the bacterial surface [1,4,11]. Following subsequent engulfment by epithelial cells, meningococci multiply within the nasopharyngeal mucosal cells [1,4]. Meningococcal colonization can last several months, with person-to-person transmission occurring via respiratory droplets or secretions [4,11].

Although carriage is a prerequisite for IMD development, meningococcal acquisition rarely progresses to disease [13,14]. Factors contributing to the transition from carriage to meningococcal infection are not well elucidated, although several virulence factors are known to facilitate binding of the host epithelium, microcolony formation, and ultimately invasion into the bloodstream and/or through the blood−brain barrier [13,14].

2.2. Genome

The meningococcal genome constitutes a single chromosome extending 2.0 − 2.2 megabases, depending on strain, that contains ~ 2000 genes [11]. Approximately 70% of the genome encodes for essential metabolic functions; the remainder includes large strain-specific genetic islands believed to encode hypothetical surface proteins and virulence factors [11].

Genomic plasticity results in phenotypic diversity, which is integral to meningococcal virulence [11]. Specifically, the meningococcal nucleotide sequence is ~ 90% homologous with the N gonorrhoeae or N lactamica genomes; ~ 10% of the meningococcal genome comprises mobile genetic elements (e.g. insertion and prophage sequences) that enable DNA transfer between meningococci, gonococci, and other bacterial species [11]. Meningococci use capsular switching (i.e. horizontal exchange by transformation and recombination of serogroup-specific capsule biosynthesis genes) as a mechanism to resist natural or vaccine-induced immunity [11]. The meningococcal genome is further distinguished by multiple genetic switches that contribute to variation in pathogenic gene expression [11].

2.3. Capsule

Although many meningococcal strains are unencapsulated, invasive strains generally express a polysaccharide capsule (Figure 1) [11,15,16]. The capsule, a major meningococcal virulence factor, is encoded by a 24-kb capsule polysaccharide synthesis (cps) island that is believed to have been acquired by horizontal gene transfer from other species, likely including N subflava [11,15,16]. The cps locus comprises 3 regions: Region A genes encode for polysaccharide synthesis and polymerization, and Regions B and C contain genes directing polysaccharide translocation from the cytoplasm to the meningococcal surface [11]. The horizontal gene transfer event may have occurred ~ 200 years ago, corresponding with the first IMD case reports in Switzerland in 1805 [17] (see Section 5).

Figure 1. Cross-sectional diagram of the meningococcal cell envelope and capsule [1], with an insert highlighting fHbp as an example of the production, transport, and cellular expression of outer membrane proteins [18]. fHbp=factor H binding protein. Main figure is adapted with permission from Rosenstein NE et al. N Engl J Med. 2001;344:1378–1388 [1]. Inset is adapted under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) from da Silva RAG et al. Front Microbiol. 2019;10:2847 [18].

Meningococcal strains are distinguished by serogroup-specific polysaccharides expressed in the capsule; 12 antigenically and chemically distinct meningococcal serogroups (A, B, C, E, H, I, K, L, W, X, Y, Z) have been identified to date [4,19]. The previously identified serogroup D was later ascertained as an unencapsulated meningococcal serogroup C (MenC) variant [19]. Serogroups W and E were amended from their original designations of W-135 and 29E, respectively, because the historic numbers were considered extraneous [19].

The polysaccharide capsule confers resistance to phagocytosis and complement-mediated lysis; unencapsulated meningococcal strains are susceptible to phagocytosis and rarely cause invasive infection in immunocompetent individuals [20,21]. Undetected by humoral immunity, encapsulated meningococcal strains can enter and disseminate via the bloodstream, causing systemic disease and subsequently crossing the blood−brain barrier [4,20]. Type IV pili on the surface of encapsulated meningococci mediate adhesion to brain endothelial cells to facilitate meningeal invasion [20].

2.4. Cell envelope

The meningococcal cell envelope includes a peptidoglycan layer sandwiched between outer and cytoplasmic (inner) membranes (Figure 1) [11]. The peptidoglycan layer comprises up to 2 layers joined by cross-linking and O-acetylation, the extent of which varies by strain [11]. The outer membrane comprises an outer layer containing lipooligosaccharides (LOS) and proteins and an inner layer of phospholipids and proteins that help regulate the flow of nutrients and metabolic products [11].

2.5. Key surface molecules

Besides capsular polysaccharide, outer-membrane molecules, some of which have been harnessed as vaccine antigens (see Section 4), are key to meningococcal survival and virulence; some are discussed here and shown in Figure 1.

Outer membrane porins (e.g. Porin A [PorA], Porin B [PorB]) create pores (cation- or anion-selective) for small hydrophilic solute diffusion [1,11,22]. They also interact with host cells, with PorB being the major porin regulating insertion into membranes and apoptosis [11,22].

Another important outer membrane antigen is LOS, which has potent endotoxic activity [1]. LOS is naturally released into the bloodstream within blebs containing 50% LOS and 50% outer-membrane proteins, phospholipids, and capsular polysaccharides [1]. Upon binding to host monocytic and dendritic cells, LOS triggers the release of various cytokines [11]. The classic clinical IMD symptoms result from cytokine-induced microvascular dysfunctions, including increased endothelial permeability and myocardial dysfunction, which can cause shock, as well as intravascular thrombosis and vasoconstriction (a natural response to decreased cardiac output), which causes purpura fulminans [23].

Iron acquisition from human lactoferrin, transferrin, and hemoglobin via outer membrane iron-binding proteins also promotes meningococcal growth and intravascular survival [1,11,24]. Some such proteins may also facilitate host cell invasion [25]. Known meningococcal iron-acquiring proteins include HmbR (interacts with hemoglobin), TbpA and TbpB (transferrin), LbpA and LbpB (lactoferrin), HpnA and HpnB (hemoglobin−haptoglobin complexes), and FetA (xeno-siderophores) [11,26].

Meningococci expresses multiple surface proteins that specifically bind human factor H, a negative regulator of complement, to downregulate complement-mediated killing and thus promote meningococcal survival in human blood [18,27–29]. Factor H binding protein (fHbp) is a 27-kDa outer membrane protein encoded by a wide variety of genetic sequences, the resulting peptides of which are classified within 2 phylogenetic subfamilies, termed A and B, using unique alphanumeric characters (e.g. A26); an alternative classification scheme uses 3 phylogenetic variant groups, with specific variants designated by additional identification numbers within the PubMLST database (e.g. 2.23; see Section 3.3 for more information on PubMLST) [18,28,30–32]. Like other similar meningococcal proteins, fHbp is synthesized as a preprotein in the cytoplasm; it then emerges from the ribosomes, binds chaperones, and is translocated across the inner membrane (Figure 1) [18]. Following inner membrane fHbp processing (deacetylation, cleaving, acylation) by a series of enzymes, additional molecules aid in sorting and translocating the triacylated fHbp to the outer membrane and finally the cell surface [18]. fHbp expression levels vary by more than 100-fold between strains [33], with expression influenced by external factors, including iron and oxygen availability as well as temperature [18]. Neisserial surface protein A is another factor H ligand that functions similarly to fHbp [29].

3. Typing and classification

3.1. Detection

Culture of meningococci from a normally sterile site (e.g. blood, cerebrospinal fluid [CSF]) or purpuric lesions has been traditionally viewed as the gold standard for IMD diagnosis and confirmation [4,34,35]. Additionally, Gram staining of a biological sample can preliminarily detect meningococci, providing evidence of infection should cultures fail to grow [34,36]. Being a Gram-negative bacterium, N meningitidis takes up the counterstain (red or pink) rather than the primary stain (dark violet or purple) [36]. Meningococci appear under the microscope as coffee-bean shaped diplococci and can be located extracellularly or within polymorphonuclear leukocytes [36].

3.2. Antibody-based classification methods

Meningococcal serogroup-specific capsular polysaccharides can be detected using multiple antibody-based methods. One such diagnostic test is latex agglutination, which can be used for uncultured biological samples and is therefore useful in cases of negative culture results (as may occur when antibiotic treatment has already started) [34,36,37]. In this technique, latex beads coated with serogroup-specific antibodies are incubated with the clinical sample, with positive agglutination (i.e. clumping) easily visualized; negative reactions remain milky in appearance [36,37]. Serogrouping can also be performed using dot-blotting, in which culture samples dried on nitrocellulose paper are probed with serogroup-specific monoclonal antibodies [38,39].

Beyond serogrouping, antibody-based methods can also characterize meningococcal strains according to antigenic differences in major outer-membrane proteins and LOS. PorB serotyping, PorA serosubtyping, and LOS immunotyping can be performed using dot-blotting [38,40]. Twelve distinct LOS immunotypes (L1−L12) have been identified, with different immunotypes generally associated with 1 or more specific serogroups [41]. Similarly, PorA serosubtypes are classified based on 2 major variable regions (VR1 and VR2) and 1 minor variable region (VR3), whereas PorB serotypes are grouped into 2 classes (PorB2 and PorB3) defined by size and amino acid sequences [42]. Early meningococcal classification systems were formulated as serogroup: serotype: serosubtype (designated as ‘P1.VR1 variant, VR2 variant’): immunotypes (e.g. B: 15: P1.7,16: L3,7,9) [38,42].

3.3. Molecular detection and classification methods

In addition to culture, polymerase chain reaction (PCR) can detect N meningitidis−specific DNA sequences to confirm IMD [4,34,35]. PCR-based meningococcal detection can be especially useful in cases of antibiotic receipt before sampling or limited resources for culture-based assays [4,34,35]. PCR can also facilitate further meningococcal characterization, such as capsular genogrouping for serogroup determination [4,35].

Meningococcal classification can also utilize other molecular methods [43,44]. Multilocus enzyme electrophoresis (MLEE) used electrophoretic techniques to measure allelic variation at multiple structural gene loci across strains, enabling estimation of genetic distance between isolates and groups thereof [43]. In this way, clusters of closely related isolates (clones), including those particularly liable to cause disease, could be identified [44]. The major drawback of MLEE was the difficulty in comparing results between laboratories [44]. MLEE was therefore superseded by multilocus sequence typing (MLST), which directly examines variation in allelic nucleotide sequences rather than encoded proteins; this approach addresses interlaboratory reproducibility issues and also enables detection of far more allelic variation than MLEE could achieve [44]. Genetic sequencing for MLST originally used the Sanger method, which is relatively low-throughput and, thus, suitable for gene fragments [32,44,45]. The sequence type (ST) of a given meningococcal isolate refers to the collective group of alleles it harbors for each of 7 (originally 6; a seventh was added to increase differentiation) housekeeping genes analyzed, which can be studied in association with certain biological properties (e.g. propensity to cause invasive disease) [32,44,46]. Certain STs exhibit high frequency that is temporally and geographically stable, with STs grouped into clonal complexes based on matching these ‘central genotypes’ at ≥ 4 of the 7 MLST loci [46]. Sequence data generated using MLST are easily amenable to database storage [44]; thus, the PubMLST.org website has been running since 2003 as an open-access, curated database originally established to support the Neisseria MLST scheme [32].

Sanger sequencing has also been used to type historical antigen-encoding genes, including porA, porB, and fetA, to facilitate the investigation of outbreaks and antigenic variation; sequences of these genes were linked with the PubMLST database to enable searching for matching isolates [32,42,47]. Availability of these data prompted the advent of a newer, high-resolution, meningococcal typing scheme based on the variable regions of some of these genes as well as the 7 MLST loci, which took the form of serogroup: PorA type: FetA type: sequence type (clonal complex; e.g. B: P1.19,15: F5–1: ST-33 [cc32]) [42]. Sanger sequencing was subsequently used for other genes of interest, including those for vaccine antigens, such as fHbp, Neisseria adhesin A, and Neisseria heparin-binding antigen [48], with typing schemes for each unique allele sequence and MLST profile searchable within PubMLST [32].

More recently, the development of next-generation sequencing has facilitated the widespread use of whole-genome sequencing (WGS) for cultured bacterial isolates [45]. PubMLST now uses the Bacterial Isolate Genome Sequence Database genomics software platform, which was developed in 2010, to store data ranging from single gene fragments to complete genomes for > 100 microbial species and genera [32,49]. Deposited sequences are annotated with identified genes, and their specific loci and alleles are systematically cataloged [32]. Whole genome sequences within PubMLST can be linked to standard (i.e. 7-locus) or higher-resolution MLST schemes, such as core genome MLST, which typically includes genes present in ≥ 95% of sequences [32]. Elucidating the origin and spread of new meningococcal strains, aided by WGS, and linking genotypic and phenotypic data are important for epidemiologic surveillance, including antimicrobial resistance (AMR), as well as proactive (i.e. vaccination) and reactive disease responses [49]. As part of the WHO global roadmap toward defeating meningitis by 2030, the Global Meningitis Genome Partnership was established to link resources for the proactive collection and curation of comprehensive country-specific meningococcal data to PubMLST [49].

As noted, other molecular techniques (e.g. PCR, DNA sequencing) can be used for characterizing non-cultured isolates, which may be particularly useful when WGS is limited due to low DNA concentration and/or human DNA interference [4,35,44,45,50]. Non-cultured isolates may differ from cultured isolates in disease representation. For example, the use of a nested PCR-based assay showed that fHbp distribution differed between cultured isolates and non-cultured specimens: non-cultured specimens had a comparatively greater proportion of fHbp peptide B44 (1.15 using the alternative classification scheme [31,32]) associated with the ST-269 cluster sublineage, and cultured isolates were more frequently meningococcal serogroups W (MenW) and Y (MenY) [30,50]. More recently, newer DNA amplification technologies have been implemented with the goal of enabling WGS for non-cultured isolates [51,52].

3.4. Antimicrobial susceptibility testing

As discussed further in Section 5, meningococcal AMR is historically rare but has been increasing in frequency [53]. AMR-associated genes include mutations in penicillin-binding protein genes and, more rarely, beta-lactamase genes, that confer resistance to beta-lactam antibiotics; gyrA and parC gene mutations, which are affiliated with specific clonal complexes, are linked with ciprofloxacin resistance [53,54].

Antimicrobial susceptibility of meningococcal isolates can be evaluated phenotypically, using broth microdilution methods; additionally, DNA sequencing can detect mutations associated with resistance and reduced susceptibility to antibiotic agents [55].

4. Vaccines

Developed in the 1960s, the first demonstrably effective meningococcal vaccines were based on the capsular polysaccharide (Table 1) [56,57]. These were initially monovalent MenC and then monovalent meningococcal serogroup A (MenA) vaccines, followed by bivalent vaccines; a polysaccharide quadrivalent ACWY vaccine first became available in 1981 [56,57]. Although safe and immunogenic in older children and adults, these vaccines were generally poorly immunogenic and therefore not predicted to protect against IMD in the very young [56,57]. Polysaccharides are also largely T-cell−independent antigens incapable of inducing immunologic memory, necessitating dosing every 3 − 5 years; however, repeated dosing may promote immune hyporesponsiveness [56,57].

Table 1. Meningococcal vaccine classes and their attributes.

	Attributes					References
Serogroup Vaccine class	Cross-reactivity	Persistence	Immunologic memory	Acquisition and carriage	Other
A, C, W, Y
Plain polysaccharide	Protect against all strains within the corresponding serogroup(s)	Relatively short persistence of protective antibodies, necessitating dosing every 3−5 years; however, repeated dosing may lead to immune hyporesponsiveness	Induce a T-cell–independent response that is not associated with immunologic memory	Not thought to reduce meningococcal acquisition and carriage	Safe and immunogenic in older children and adults, but generally poorly immunogenic (and therefore anticipated to be ineffective) in the very young	[13,56–58]
Polysaccharide conjugate*^†	Protect against all strains within the corresponding serogroup(s)	Persistence of antibody levels generally demonstrated over multiple years	Induce a T-cell–dependent response that is associated with immunologic memory	Reduce meningococcal acquisition and carriage	Immunogenic in all ages, including infants	[14,56–64]
B
Outer membrane vesicle	Protect predominantly against the strain used to produce the vaccine but not against other diverse MenB strains	Protective antibody levels and effectiveness show substantial waning within months after primary series, particularly in infants	Booster dosing induces anamnestic immune responses, indicative of immunologic memory	Mixed findings regarding effects on meningococcal acquisition and carriage		[13,57,65,66]
Subcapsular protein-based^†‡	Intended to provide broad protection against MenB disease, with protection against a given strain depending on the strain’s susceptibility to vaccine-induced antibodies	Antibody levels show waning within ≥12 months after primary vaccination series, depending on test strain	Booster dosing induces anamnestic immune responses, indicative of immunologic memory	Do not reduce meningococcal acquisition and carriage		[58,67–71]

fHbp=factor H binding protein; MenABCWY=meningococcal serogroups A, B, C, W, and Y; MenACWXY=meningococcal serogroups A, C, W, X, and Y; MenACWY=meningococcal serogroups A, C, W, and Y; MenB=meningococcal serogroup B; MenB-4C=4-component MenB vaccine; MenB-fHbp=bivalent fHbp MenB vaccine.

*A MenACWXY vaccine that received prequalification from the World Health Organization in July 2023 [72] is also formulated using polysaccharide conjugates from serogroups A, C, W, X, and Y [73,74].

^†MenABCWY vaccines, one of which received US licensure in October 2023 [75] and another of which remains investigational [61,76,77], are both based on licensed MenACWY polysaccharide conjugate and MenB subcapsular protein-based vaccines.

^‡The 2 currently approved serogroup B subcapsular protein-based vaccines differ in antigenic composition: MenB-4C includes single variants of each of 3 surface-exposed antigens (nonlipidated fHbp [variant B24/1.1], Neisseria adhesin A, and Neisserial heparin binding antigen), as well as outer membrane vesicles, whereas MenB-fHbp includes 2 lipidated fHbp variants, 1 from each subfamily (A05/3.45 and B01/1.55) [58,61].

Conjugation of polysaccharide to a protein carrier was subsequently used to produce a T-cell−dependent antigen capable of inducing immunologic memory (Table 1) [56]. MenC polysaccharide conjugate (MCC) vaccines first became available in 1999 and were introduced into the UK infant immunization schedule along with a catch-up program in older pediatric populations, with eligibility later extended through age 24 years [60,78]; this strategy precipitated notable decreases in MenC carriage and disease in vaccinated and unvaccinated populations [63,79–81].

Licensed quadrivalent ACWY (MenACWY) meningococcal polysaccharide conjugate vaccines are now available using various carrier proteins (i.e. tetanus toxoid [MenACWY-TT and MenACYW-TT], CRM₁₉₇ [MenACWY-CRM₁₉₇]; Table 1) [61]. Monovalent meningococcal conjugate vaccines, including MCC and MenA tetanus toxoid conjugate (MenA-TT) vaccines, and a conjugate vaccine combining MenC and Haemophilus influenzae type b, are also available [61]. Persistence of protective antibody levels several years after vaccination have been reported for most of these vaccines [61]; for example, 10 years after primary childhood vaccination with MenACWY-TT, 34.8%, 91.1%, 61.2%, and 72.6% of the individuals had serum bactericidal antibody using human complement titers ≥ 1:4 for serogroups A, C, W, and Y, respectively [82]. Data also indicate that these vaccines reduce the acquisition of meningococcal carriage, thus inducing indirect, or herd, protection. For MCC vaccines, cross-sectional carriage surveys among > 15,000 UK adolescents indicated that MenC carriage significantly decreased following implementation of the vaccination program (rate ratio, 0.19; p < 0.001) [63]; observed vaccine effectiveness in unvaccinated individuals supported these findings [79,80]. For MenA-TT, no MenA carriage was detected even among unvaccinated individuals following mass vaccination of 1- to 29-year-olds, suggesting long-term effects of vaccination on carriage in addition to disease [64]. UK and US data have demonstrated the impact of MenACWY conjugate vaccination programs on reducing cases among the unvaccinated [83,84], with further support from findings in the Netherlands [85]; reduction in MenW and MenY carriage following MenACWY immunization has also specifically been demonstrated among UK adolescents [62].

Because of the low immunogenicity and potential of the capsular B polysaccharide to induce auto-antibodies [86,87], development of protective meningococcal serogroup B (MenB) vaccines necessitated alternative approaches. Early vaccine strategies used outer membrane vesicles (OMVs), which were effective and safe but protected predominantly against the OMV-based strain and not other diverse MenB strains (Table 1) [66]. Subsequently, recombinant subcapsular MenB vaccines intended to broadly protect against diverse MenB strains became available, beginning with the 4-component MenB vaccine (MenB-4C) in 2013 and the bivalent fHbp MenB vaccine (MenB-fHbp) in 2014 [61]. These vaccines differ substantially in formulation – MenB-4C includes single variants of each of 3 surface-exposed antigens (nonlipidated fHbp [variant B24/1.1], Neisseria adhesion A, and Neisserial Heparin Binding Antigen), along with OMVs; MenB-fHbp includes 2 lipidated fHbp variants, one from each subfamily (A05/3.45 and B01/1.55) – and differ in the age groups for which they are approved [58,61]. Development of these vaccines required identification of protein antigens that are harbored and conserved across MenB disease−causing strains; expressed on the bacterial surface; antibody-accessible; and capable of inducing functional antibody that can kill the bacteria via complement-mediated lysis [88], an established surrogate measure of vaccine efficacy that is consistently used as the basis for licensure of meningococcal vaccines [58]. Although data support direct effectiveness of MenB-4C against MenB disease [89], a large study found no evidence that MenB-4C affects carriage and can therefore provide herd protection [67]. The ability of MenB-fHbp to impact carriage remains undetermined, despite 2 opportunistic and limited university MenB outbreak response studies suggesting no effect [68,69].

Current approaches for meningococcal vaccine development include pentavalent formulations, including a MenACWXY vaccine, which was prequalified by the WHO in July 2023 [72–74], and two MenABCWY vaccines, the first of which received US licensure in October 2023 [75] and another of which remains investigational [76,77]. A MenACWXY vaccine is expected to provide protection against meningococcal serogroup X (MenX) disease [72–74]. A MenABCWY vaccine would simplify and reduce existing dosing schedules, promoting increased uptake and ultimately reductions in IMD cases, long-term adverse outcomes, and outbreaks [90] in line with the WHO roadmap toward defeating IMD [10].

5. Epidemiology

5.1. Nineteenth century

Early meningococcal epidemiology has been extensively reviewed previously [17]; a brief overview follows. The Swiss physician Gaspard Vieusseux provided the first clear account of a meningitis outbreak in Geneva in 1805, with subsequent European and US outbreaks and epidemics documented throughout the 1800s [17]. Only in 1887 were meningococcal bacteria first isolated from the meningeal exudate of primary meningitis cases by the Austrian physician Anton Weichselbaum, and then in 1896 from the CSF of acutely unwell patients [17]. Oropharyngeal carriage of meningococci was identified around the same time [17].

5.2. Early to mid-twentieth century

The United Kingdom introduced nationwide compulsory notification of meningitis (then termed cerebrospinal fever) in 1912 [17]. Figure 2 shows meningitis notifications from 1912–1998 in England and Wales and invasive meningococcal infections in England during 1999–2021 [81,91]. Large outbreaks occurred during both world wars, particularly the Second World War [91,92]. During the First World War, no treatments were available, although practical measures, including spaced sleeping accommodation and ventilation, aimed to reduce carriage rates and transmission [17]. Sulfonamides were introduced during the Second World War and led to dramatic reductions in meningitis mortality; penicillin became available later in the Second World War [17].

Figure 2. Number of cases of meningococcal disease during 1912 to 1998 in England and Wales and 1999 to 2021 in England. Sections indicate reporting terms during different periods. Adapted under the terms of the Creative Commons Attribution-Non Commercial license (https://creativecommons.org/licenses/by-nc/3.0/) from Christensen H et al. BMJ. 2014;349:g5725 [92]. Data from 1912 to 1998 are from Ramsay M. Use of MLST in the epidemiology of meningococci (https://webarchive.Nationalarchives.gov.uk/ukgwa/20140714074352/http://www.Hpa.org.uk/webc/hpawebfile/hpaweb_c/1194947392421) [91]. Data from 1999 through 2021 are from UK Health Security Agency. Laboratory confirmed cases of invasive meningococcal infection in England: annual report for 2021 to 2022 supplementary data tables (https://www.Gov.uk/government/publications/meningococcal-disease-laboratory-confirmed-cases-in-england-in-2021-to-2022) [81], with 1998/1999 data used for 1999, 1999/2000 data used for 2000, etc.

Meningococcal serogroup classification started in 1915; all major outbreaks during 1914–1945, which occurred in widespread global regions, including China, Russia, the Americas, Australia, and various African and European countries, are now attributed to MenA [17,93]. In Africa specifically, large periodic MenA epidemics occurred every 8–10 years in sub-Saharan countries from Senegal to Ethiopia, known as the African meningitis belt, since 1905 [94], with MenA epidemics transpiring in the 1950s in Nigeria, Sudan, and Burkina Faso [93]. Considerable MenB and MenC disease presence emerged in the 1960s, although outbreaks due to these serogroups were not reported until the 1970s in Europe and the Americas [93,95,96].

5.3. Late twentieth century

MenA remained a public health threat in Africa throughout the latter half of the 1900s [94]. In 1996, a major MenA outbreak in Burkina Faso, Chad, and Niger involved 250,000 cases and 25,000 deaths [97]. MenA outbreaks or case clusters were reported during the 1960s − 1980s in various other global regions, including Russia, Southeast Asia, Northern Europe, and the Americas, and among indigenous Australian and New Zealander populations; however, MenA outbreaks were largely limited to sub-Saharan Africa since the 1990s, with MenB and MenC generally becoming dominant in other regions [93]. In the mid-1960s to early 1970s, MenB caused > 50% of UK IMD cases and was becoming dominant in Germany, Norway, and the present-day Czechia [97]. MenB was a marked cause of prolonged outbreaks, including a major outbreak in Iceland and Norway from 1976 − 1986 that was associated with high CFRs [93,94]. Important MenB outbreaks also occurred in Cuba in the early 1980s [93].

In one early example of MenC prevalence during this period, a prospective study during December 1967−March 1968 of 14,744 US army recruits identified 60 IMD cases, all MenC [96]. MenC outbreaks first occurred in the 1970s in the Americas; they then emerged in other global regions to cause the highest number of outbreaks outside of Africa during the remainder of the twentieth century [93,95]. Large MenC outbreaks, mainly due to clonal complex 11 (cc11), occurred in Europe and South America in the mid-1990s [93,98].

MenY disease emerged in the early 1990s in the United States, causing > 30% of annual IMD cases at its peak in 1997 [21,94,99]. Although MenY disease incidence has since markedly decreased in the United States, it remains a substantial cause of IMD both there and in other global regions (see Section 5.4) [9,21,99]. MenY was also identified among 21% of Japanese isolates collected during 1974 − 2003 [93].

5.4. Twenty-first century

Figure 3 illustrates recent IMD serogroup distribution in various global regions. MenA continued to cause disease in Africa and other regions (e.g. India) through the year 2012 [9,93,95,100]. Beginning in 2010, >270 million individuals 1–29 years of age in African meningitis belt countries received MenA-TT as part of mass vaccination campaigns [100,101], prompting a > 99% decline in confirmed MenA disease among fully vaccinated populations [100]. However, MenA still causes a significant disease burden in some countries (e.g. China, Russia) and sporadic cases elsewhere (e.g. Europe) [9]. Although relatively low MenA disease incidence in most countries is not associated with vaccine implementation [83,102], vaccination may have prevented its recent reemergence.

Figure 3. IMD percentage serogroup distribution across worldwide regions in recent years. IMD=invasive meningococcal disease; NG=nongroupable. *Serogroup A is included in the “other” category. ^†Serogroups other than B, C, W, and Y are included in the NG category. ^‡Specific countries include Benin, Burkina Faso, Cameroon, Central African Republic, Ghana, Mali, Niger, Nigeria, Senegal, South Sudan, Chad, and Togo. Reproduced under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) from Pardo de Santayana C et al. Epidemiol Infect. 2023;151:e57 [9].

Currently, MenB remains the most common cause of IMD in many global regions [9]. Along with endemic disease, variably sized MenB outbreaks have continued to occur globally, notably including a 2003–2006 outbreak in Seine-Maritime in France (~ 90 cases); a prolonged New Zealand outbreak during 1991–2007 (>6000 cases by 2006); a 2006–2013 outbreak in the Saguenay-Lac-Saint-Jean region in Quebec, Canada (74 cases); and 14 outbreaks on various US college campuses during 2011–2019 (50 cases total) [66,103–105]. The Seine-Maritime outbreak prompted mass vaccination of individuals <20 years of age during 2006–2009 using an OMV vaccine previously developed for the Norwegian outbreak (which was caused by a strain sharing the same PorA serosubtype), effectuating an 81% reduction in disease due to the causative strain compared with the prevaccination period [105]. The New Zealand outbreak stimulated a collaboration between governmental agencies, research institutions, and the pharmaceutical industry to develop a novel OMV vaccine based on the outbreak-associated strain [66]. After a robust clinical research program, mass vaccination was implemented for individuals <20 years of age during 2004–2008, with ~ 77% effectiveness during a 3.2-year period among fully vaccinated individuals [66]. Successful mass vaccination campaigns using protein-based MenB vaccines were implemented for several more recent outbreaks, including those in Saguenay-Lac-Saint-Jean and on US college campuses [103]. MenB vaccination has also expanded beyond outbreak situations to routine use, with several countries incorporating MenB vaccines into regional or national immunization programs (NIPs) [89,106]. In the United Kingdom, the first country to add MenB-4C to the infant NIP (in 2015), MenB disease incidence decreased by 75% in the first 3 years of the program; substantial decreases also occurred following implementation of infant programs in Italy and Spain, and infant and adolescent programs in South Australia [89,107,108].

Recent data indicate that MenC continues to cause a sustained proportion of disease throughout global regions [9]. Following the United Kingdom in 1999, many countries integrated MCC vaccines into their NIPs, usually targeting infants or toddlers and often with catch-up campaigns for older ages [109]. A systematic review spanning 17 studies found that 146 of 147 MCC vaccine effectiveness estimates across age groups, vaccination schedules, and time intervals since vaccination were positive, ranging from 34%−100%; 138 of these estimates were statistically significant, and protection against MenC disease was maintained in countries with high uptake [109]. In the United States, the rate of decrease in serogroup CWY disease incidence accelerated among vaccine-eligible age groups following routine MenACWY vaccination recommendations in 2005 and 2010, as well as among some unvaccinated age groups after 2010, with reductions most evident in states with high vaccination coverage [83]. A US case-control study also estimated effectiveness of a previously available MenACWY conjugate vaccine that used diphtheria toxoid as a carrier protein (MenACWY-D) at 77% against MenC disease among individuals 11–27 years of age [110]. Many other countries worldwide, beginning with Greece in 2011, implemented MenACWY vaccination programs across infant, toddler, and/or adolescent age groups to address the rising MenW and/or MenY IMD cases; these programs often replaced previous MCC vaccination programs (Figure 4) [102,111]. Protection against MenC IMD has been maintained in England and the Netherlands following transitions from MCC to MenACWY programs [84,85], supporting observations of comparable immunogenicity between MCC and MenACWY-TT vaccines [102]. MenC still causes a large proportion of IMD in some countries, including Brazil, Colombia, Venezuela, and Eastern European countries [9]. In African meningitis belt countries, disease incidence due to non-A serogroups, including C, increased after MenA-TT introduction in 2010; MenC cases in this region have been inconsistent and clustered around large outbreaks, including those in Niger and Nigeria in 2015 and 2017 [100,101,112]. Interestingly, since 2001, meningococcal outbreaks concentrated among men who have sex with men (MSM) in North America and Europe, including an ongoing outbreak that originated in Florida in 2021, have predominantly been MenC [113,114]. The distinct hypervirulent lineage associated with most of these outbreaks may be sexually transmitted and/or include genetic adaptations to promote survival in the urogenital and anorectal tracts [114].

Figure 4. Countries with recent MenACWY vaccine recommendations. MenACWY=meningococcal serogroups A, C, W, and Y. *In all provinces apart from Quebec. ^†Hawaii (United States), Malta, and Cyprus are not shown to scale or to shape. Adapted under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives license (https://creativecommons.org/licenses/by-nc-nd/4.0/) from Serra L et al. Hum Vaccin Immunother. 2021;17:2205–2215 [102]. Additional data from MacNeil JR et al. Clin Infect Dis. 2018;66:1276–1281 [99]; Koliou M et al. Euro Surveill. 2020;25:1900534 [111]; and Badur S et al. Infect Dis Ther. 2021;10:2035–2049 [115].

Global MenW disease shifts during the twenty-first century underscore the dynamic nature of IMD epidemiology [9]. Before the year 2000, MenW was considered a peripheral source of IMD, causing only sporadic cases; however, international outbreaks caused by a MenW cc11 clone originating among Hajj pilgrims returning from Saudi Arabia in 2000 and 2001 demonstrated the epidemic potential of MenW [116]. MenW cases attributed to the Hajj cc11 clone were detected in African countries beginning in 2000 and were linked with several epidemics, including a 2002 epidemic in Burkina Faso comprising > 12,000 cases and > 1400 deaths [116]. However, phylogenetic analyses indicated that the global increase in Hajj-related MenW strains subsided, with MenW cases beginning in the mid-2000s largely attributed to genetically unrelated strains [116,117]. MenW disease began to increase drastically in Brazil in 2003 (from 3.2% [1995–2002] to 17.8% [2003–2005] of all invasive strains) and spread thereafter within the Southern Cone of Latin America, including to Argentina (7% [2006] to 50% [2008–2011]) and Chile (6.6% [2010] to 58.3% [2012]); reported CFRs were as high as 28% [116,117]. Data from Brazil and Argentina suggested that these cases were caused by cc11 strains that were genetically distinct from the Hajj strains [117]. A cc11 strain closely related to the South American strain, termed the ‘original UK strain,’ emerged in the United Kingdom in 2009, with 21 laboratory-confirmed MenW cases (1.8%) in England and Wales in 2008–2009 progressing to 98 (15%) in 2013–2014 [117–119]. The ‘UK 2013 strain,’ a descendent of the original UK strain, emerged in the United Kingdom in 2013 and rapidly expanded, with associated cases approximately doubling each year before superseding the original UK strain and spreading throughout Europe; this strain was linked with an outbreak at the 2015 World Scout Jamboree in Japan [118,120]. Rising MenW cases in Australia starting in 2013 also genetically clustered with the South American/UK isolates [120]. Similar to MenC, MenW emergence in the African meningitis belt after MenA-TT introduction has been inconsistent, with large MenW outbreaks occurring in Burkina Faso (2012) and Togo (2016) [100,101,112]; nevertheless, MenW was the most common disease-causing serogroup in the African meningitis belt during 2010–2019 [9,116].

As noted previously, many countries have implemented MenACWY vaccination programs to address MenW disease increases [102]. In Chile, where a pediatric MenACWY vaccination campaign was initiated in 2012, followed by the addition of toddler MenACWY-TT vaccination to the NIP in 2014, median MenW disease incidence declined from 0.56 (2014) to 0.16 (2019) per 100,000; decreases were most evident among children 1–4 years old but also occurred among infants and older adults after several years, possibly indicating herd effects [121]. An adolescent MenACWY vaccination program that commenced in England in 2015 was associated with significant reductions in MenW disease among the vaccine-eligible population during the first 4 years of the program (incidence rate ratio, 0.35) [84]. Similarly, toddler and adolescent MenACWY-TT vaccination programs implemented in the Netherlands in 2018 were associated with an 82% reduction in MenW disease among vaccine-eligible age groups; only 1 case in the postvaccination period occurred in a vaccinated individual [85]. Importantly, unlike in many other countries, MenW disease did not increase in the United States in recent years [9,99], perhaps reflecting success of the preexisting adolescent MenACWY vaccination program.

The MenY disease burden has trended differently among geographic regions in recent years [9]. In the United States, MenY disease declined considerably through 2015 but then appeared to stabilize through 2018 [9,99]. By contrast, MenY cases increased throughout Europe, Israel, Australia, and New Zealand during 2010–2018; MenY was a major contributor to IMD in Northern European countries in 2018, including Norway, where it predominated [9]. Interestingly, MenY often causes a greater proportion of IMD among older adults compared with younger age groups [9]. In the United States, MenACWY-D vaccine effectiveness against MenY disease was estimated at 51% among individuals 11–27 years of age [110], and the proportion of IMD caused by MenY decreased after implementation of adolescent vaccination programs [83]. MenY disease in the United Kingdom decreased during the first 4 years of the adolescent MenACWY program, with combined direct and indirect vaccination effects preventing ~ 79–125 MenY cases during this period [84]. In the Netherlands, no MenY cases occurred among MenACWY-TT vaccine−eligible age groups during a postvaccination follow-up period compared with 2 cases during a comparable prevaccination period [85].

IMD due to serogroups other than A, B, C, W, and Y remains limited. Occasional MenX outbreaks have been reported in Africa both before and after MenA-TT implementation; sporadic MenX cases have also occurred elsewhere [9,21,112]. Similarly, IMD caused by serogroups E or Z or nongroupable (NG) strains is rare and usually occurs in immunocompromised individuals [9,21]. Importantly, the high percentages of NG isolates reported by some countries may reflect limitations in serogroup detection capabilities rather than accurate estimates [9]. This is suggested by comparing 2018 US data, for which 8% and 9% of isolates were NG and ‘other’ serogroups (i.e. not B, C, W, or Y), respectively, to 2018 Brazilian data, which categorized 52% of isolates as ‘ignored serogroups’ [9].

Recent meningococcal epidemiology has featured additional shifts beyond serogroup-specific trends. Reduced susceptibility to penicillin is increasing among meningococcal strains globally; although less common, ciprofloxacin-resistant isolates have been identified throughout Europe, the Americas, and Africa and predominate in China [53,54]. In the United States, resistance of meningococcal isolates, particularly MenY, to penicillin and/or ciprofloxacin has been increasing since the mid-2010s, with 22.8% of 57 MenY isolates from 2019 resistant to both agents or penicillin only [55,122]. Ciprofloxacin-resistant meningococcal isolates have also been identified among Hajj pilgrims in recent years, with this trend possibly influenced by widespread prophylactic ciprofloxacin administration as mandated by the Saudi Ministry of Health [123]. Vaccines represent a powerful tool that may not only prophylactically prevent IMD caused by antibiotic-resistant strains, but may mitigate AMR by reducing meningococcal circulation and overall antibiotic use [124].

Meningococcal urethritis is also increasing in prevalence [114]. The aforementioned hypervirulent MenC strain associated with outbreaks among MSM has also been linked to urethritis cases in this population [114]. Additionally, an NG meningococcal clade associated with urethritis, mostly among heterosexual men, emerged in the United States in 2013 and was subsequently detected in the United Kingdom [114,125]. Genomic characterization of isolates within this clade indicates acquisition of gonococcal genes that may facilitate anaerobic growth; at least 1 UK isolate also contained a gonococcal gene conferring ciprofloxacin resistance [114,125].

The COVID-19 pandemic precipitated dramatic shifts in meningococcal epidemiology. Many countries reported drastic IMD decreases in 2020 compared with previous years, likely resulting from lockdown strategies [53,126]. However, easing of restrictions has triggered disease rebounds in several countries [127–129]. In England and France, MenB cases among adolescents/young adults, for whom MenB vaccination programs are lacking [106], exceeded pre-pandemic levels during April 2022−March 2023 and 2022, respectively [128,129]. In the United States, a MenY outbreak began in June 2022; of the 27 cases reported through August 2023, 26 were unvaccinated [130]. These data illustrate that IMD in the post-pandemic period will likely affect individuals who remain vulnerable due to the absence of vaccination, which increased during the pandemic in the context of missed or delayed vaccinations [131].

5.5. Carriage

As an obligate human pathogen, meningococcus is susceptible to disruption in person-to-person transmission, which ultimately reduces the spread of disease-causing strains and thus affects population-level disease incidence [13]. However, meningococcal carriage epidemiology is not well characterized [14]. For instance, the lack of a polysaccharide capsule on many carriage isolates precludes serogroup-level typing and classification [4,14]. Additionally, clonal complexes associated with both encapsulated and unencapsulated carriage isolates often differ from those of disease isolates [14,132]. Finally, carriage determination methods are not standardized [133], limiting comparison between studies and meta-analysis conduct.

Given these limitations, data indicate that meningococcal carriage in Western regions peaks at age 19 years (23.7% prevalence) [12], likely related to common social mixing behaviors in this age group that promote transmission and acquisition (e.g. dormitory living, sharing beverages, smoking) [14]. In a meta-analysis of meningococcal carriage epidemiology from 2007 − 2016, ‘other’ serogroups (i.e. not A, B, C, W, X, and Y, but including NG), were the most prevalent (11.5% among 18- to 24-year-olds) among American carriage isolates, followed by C (2.5%) and B (1.6%); in Europe, ‘other’ serogroups along with B and Y were the most common (≤6.4%, ≤5.0%, and ≤ 3.9%, respectively, among adolescent and young adult age groups) [133].

In contrast to Western regions, meningococcal carriage rates in the African meningitis belt are low (≤1.3%), peaking from age 5 years to late adolescence [133,134]. In Africa, carriage risk may significantly increase during the dry season and disease outbreaks [134]. Although varying by year, available data from 2008–2014 indicate that ‘other’ serogroups (i.e. not A, B, C, W, X, and Y, but including NG), followed by MenW, were the most prevalent among carriage isolates in African meningitis belt countries apart from Burkina Faso, where MenW, MenX, or MenY predominated in different studies [133].

As noted earlier, carriage of included serogroups may be reduced by vaccination with polysaccharide conjugate vaccines, including MCC [63], MenA-TT [14,64], and MenACWY vaccines [62] but likely not protein-based MenB vaccines [67–69].

6. Conclusion

A detailed consideration of historical and current meningococcal epidemiology within the context of meningococcal microbiology and classification highlights the continued susceptibility of IMD to sporadic cases and outbreaks, and, relatedly, the emergence of new disease-causing clones. Although timing, locations, and causative strains of specific outbreaks remain unpredictable, past and present epidemiology all but guarantee that outbreaks will continue to occur, primarily affect age groups consistently at increased risk, and be caused by serogroups A, B, C, W, and/or Y. Thus, comprehensive protection from IMD, as mandated by the WHO roadmap to defeating meningitis by 2030 [10], may be achievable if vaccination schedules are improved to include the use of demonstrably effective vaccines for all 5 of these serogroups across age groups. As outlined within specific strategic goals of the WHO roadmap, comprehensive attainment of vaccine-based protection will require its prioritization by funders and policymakers, identifying evidence-based vaccination strategies to optimize protection, and addressing additional challenges related to cost-effectiveness, feasibility, and acceptability [10].

7. Expert opinion

A key pillar of the WHO roadmap to defeating IMD by the year 2030 is prevention and epidemic control, which can largely be achieved using effective prophylactic vaccines [10]. Importantly, the roadmap aims to reduce vaccine-preventable meningitis cases, including those caused by N meningitidis, by 50% and deaths by 70% compared with 2015 estimates across global regions; thus, all countries are urged to promote increased IMD vaccination [10]. Pigeonholing IMD epidemiology as ‘unpredictable,’ as it is typically described [8], may hinder the institution of epidemiologically appropriate vaccination programs in pursuit of this goal. By contrast, the close analysis of historical data in the current review highlights some general disease trends that may in turn inform development of successful vaccination strategies. Overarchingly, IMD is an endemic disease characterized by periodic emergence of new clones that may precipitate increases in disease incidence or outbreaks [8]. Disease has been generally caused by serogroups A, B, C, W, and Y; at present, MenX is largely limited to sporadic outbreaks in Africa [9], but continued surveillance is necessary to detect any future changes in MenX epidemiology. Serogroup-specific epidemiology is age-dependent; however, IMD risk is predictably elevated among infants and young children, adolescents/young adults, and older adults [9]. Collectively, these findings enable a confident prediction that future disease surges will likely be caused by one of these serogroups and affect at least one of the age groups at greatest risk, thus mitigating the uncertainty of future IMD epidemiology.

Vaccines complement the capacity for prediction by providing the capacity for protection. The 2 major vaccine classes currently available – polysaccharide-based conjugate vaccines for serogroups A, C, W, and Y, and subcapsular protein-based MenB vaccines – have been used successfully in the past [83–85,89,103,107,108,110,121]; thus, future IMD surges might be averted by comprehensive uptake of these vaccines among age-related risk groups. The global variation in recent MenW disease epidemiology underscores the importance of proactive vaccination strategies: as noted, many countries (e.g. Chile, Australia, the United Kingdom, the Netherlands) implemented MenACWY vaccination programs only after experiencing drastic MenW disease increases [9,102,121], whereas the preexisting MenACWY vaccination platform in the United States may have prevented such increases from occurring at all [9,99]. Accordingly, the WHO roadmap for defeating meningitis mandates achieving and maintaining high coverage globally with meningococcal vaccines [10]. However, current meningococcal vaccine programs fall short of this goal: beyond incomplete serogroup coverage of routine NIPs across pediatric age groups at elevated IMD risk (Figure 5), meningococcal vaccine recommendations generally exclude older adults [106,135–143] and are lacking in many countries entirely (e.g. Bulgaria, Finland, Israel) [106,144]). Importantly, memory cells require multiple days to produce antibody [145], which may exceed the short meningococcal incubation period [146]. Vaccine-induced protection from IMD therefore relies upon the presence of circulatory antibody, which demonstrably wanes after MenB [70,71] and, to a much lesser extent, MCC and MenACWY [59] vaccination; waning effectiveness has also been observed for MCC [109] and MenACWY-D [110] vaccines. Sustained protection from IMD thus cannot rely on memory responses to vaccines administered earlier in life and instead necessitates expanding existing recommendations to include MenACWY and MenB vaccines for all age-related risk groups.

Figure 5. Current routine meningococcal vaccination recommendations across select countries [106,135–142]. ACWY=meningococcal serogroups A, C, W, and Y; B=meningococcal serogroup B; C=meningococcal serogroup C. *Catch-up vaccination. ^†Based on shared clinical decision-making. ^‡Depending on local epidemiology and programmatic considerations.

The recently licensed MenABCWY vaccine [75] may crucially support broad expansion of meningococcal vaccination programs by enabling comprehensive protection against all 5 major disease-causing serogroups using a single vaccine and vaccination schedule, along with fewer injections [90]. As for other combination vaccines, MenABCWY vaccine use may also increase vaccination coverage beyond current rates for MenACWY and MenB vaccines, in turn contributing to both direct and herd (for MenACWY only) protection [90]. Positive clinical data for the WHO-prequalified MenACWXY vaccine encourage its replacement of MenA-TT within the African meningitis belt to expand the MenA-TT program success to currently circulating serogroups [72–74], including MenX [9,21,112]. However, the high proportion of MenB and rarity of MenX disease [9] suggest limited MenACWXY vaccine utility in other regions.

Implementation and success of broad vaccination programs against IMD are expected to face challenges on multiple levels. The WHO roadmap outlines specific strategies to combat anticipated public health obstacles, including prioritization among policymakers and funders; identification of optimal vaccination strategies based on local epidemiology; and concerns related to cost-effectiveness, feasibility, and vaccine acceptance [10]. In addition to practical considerations surrounding implementation, widespread use of polysaccharide-based meningococcal vaccines has prompted concerns of immune pressure leading to capsular switching [11]. However, although capsular switching has been observed genomically [11,21,116,117], polysaccharide-based meningococcal vaccination programs have typically led to serogroup replacement resulting from the emergence of new or previously circulating clones rather than capsular switching [63,147]. The general confinement of serogroup replacement to serogroups A, B, C, W, and Y underscores the importance of widespread vaccination against these serogroups.

Future focal areas for meningococcal vaccination should consider optimizing existing MenB vaccine formulations to improve breadth of coverage. As reviewed previously, using subcapsular proteins rather than the capsular polysaccharide as MenB vaccine antigens may not provide complete protection against all MenB strains, with the susceptibility of a given strain to vaccine-induced antibodies dependent on the strain harboring the gene encoding the protein antigen, similarity between the strain and vaccine antigens, sufficient antigenic expression at the bacterial surface, and cross-reactivity of the vaccine-induced immune response against different antigenic variants [58]. For MenB-4C, which uses 4 different antigens to increase the breadth of coverage, MenB coverage predictions accounting for these factors have ranged from 66%−91% across different countries [58]. Conversely, the lipidated, bivalent MenB-fHbp formulation was designed to provide broad, intra-subfamily cross-reactive coverage against isolates harboring fHbp variants from both subfamilies, limiting the concerns of gene presence/absence and antibody cross-reactivity [58]. Nevertheless, MenB strains with lower fHbp expression are more likely to have decreased susceptibility to MenB-fHbp−induced antibodies, and a few invasive MenB isolates lacking the fHbp gene have been identified; MenB-fHbp is expected to protect against ~ 91% of MenB isolates based on fHbp expression levels [58]. Additional goals for future MenB vaccines should be improved maintenance of protective antibody levels, which wane over time for existing vaccines [70,71], and the ability to induce herd protection, which current vaccines also lack [67–69].

Article highlights

• Basic microbiologic characteristics of Neisseria meningitidis, including structural features and genomic plasticity, yield important influence on meningococcal virulence, and, in turn, epidemiology and vaccine development.

• Comprehensive and open-access meningococcal classification data, which generally rely on continually evolving immunologic or molecular methods, are crucial for global meningococcal surveillance.

• Currently available, demonstrably effective vaccines against invasive meningococcal disease (IMD) include polysaccharide vaccines for serogroups A, C, W, and Y and subcapsular protein vaccines for serogroup B, with a first-in-class pentavalent MenABCWY vaccine licensed in the United States in October 2023.

• Historical and contemporary data highlight that serogroups A, B, C, W, and Y have consistently caused the vast majority of IMD, with serogroup X limited to occasional outbreaks in Africa and sporadic cases elsewhere.

• Meningococcal epidemiology is also characterized by dynamic evolution of hyperinvasive clones and affected regions, with recent concerns including the global rise in serogroup W disease, increases in the prevalence of meningococcal antimicrobial resistance (AMR) and urethritis, and IMD rebounds among unvaccinated populations following lifting of COVID-19 restrictions.

• Despite these everchanging developments, future IMD surges are likely to conform with established trends of major disease-causing serogroups and affected age groups (infants and young children, adolescents/young adults, and the elderly).

• In addition to playing a key role in the fight against AMR, expanding meningococcal vaccination programs to include vaccination against all 5 major serogroups and in all risk-based age groups thus represents a key strategy in pursuit of the World Health Organization's goal of defeating meningitis by the year 2030.

Abbreviations

Table

AMR	Antimicrobial resistance
cc11	Clonal complex 11
CFR	Case-fatality rate
cps	Capsule polysaccharide synthesis gene
CSF	Cerebrospinal fluid
fHbp	Factor H binding protein
IMD	Invasive meningococcal disease
LOS	Lipooligosaccharide
MCC	Meningococcal serogroup C polysaccharide conjugate vaccine
MenA	Meningococcal serogroup A
MenA-TT	Meningococcal serogroup A polysaccharide tetanus toxoid conjugate vaccine
MenABCWY	Meningococcal serogroups A, B, C, W, and Y vaccine
MenACWXY	Meningococcal serogroups A, C, W, X, and Y vaccine
MenACWY	Meningococcal serogroups A, C, W, and Y
MenACWY-CRM197	Meningococcal serogroups A, C, W, and Y polysaccharide CRM197 conjugate vaccine
MenACWY-D	Meningococcal serogroups A, C, W, and Y polysaccharide diphtheria toxoid conjugate vaccine
MenACWY-TT	Meningococcal serogroups A, C, W, and Y polysaccharide tetanus toxoid conjugate vaccine
MenACYW-TT	Meningococcal serogroups A, C, Y, and W polysaccharide tetanus toxoid conjugate vaccine
MenB	Meningococcal serogroup B
MenB-4C	4-component MenB vaccine
MenB-fHbp	Bivalent fHbp MenB vaccine
MenC	Meningococcal serogroup C
MenW	Meningococcal serogroup W
MenX	Meningococcal serogroup X
MenY	Meningococcal serogroup Y
MLEE	Multilocus enzyme electrophoresis
MLST	Multilocus sequence typing
MSM	Men who have sex with men
NG	Nongroupable
NIP	National immunization program
OMV	Outer membrane vesicle
PCR	Polymerase chain reaction
PorA	Porin A
PorB	Porin B
ST	Sequence type
WGS	Whole-genome sequencing
WHO	World Health Organization

Declaration of interest

R Borrow performs contract research on behalf of the UK Health Security Agency for GSK, Pfizer, and Sanofi Pasteur. J Findlow is an employee of Pfizer and may hold stock or stock options. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have worked on a meningococcal vaccine project which was funded by the Serum Institute of India awarded to current supervisor, not themselves. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Author contributions

Both authors substantially contributed to the conception and design of the review article, interpretation of the relevant literature, and writing of the article or revising it for intellectual content.

Acknowledgments

Editorial/medical writing support was provided by Judith Kandel, PhD, Andrea Bothwell, BSc, Tricia Newell, PhD, and Sheena Hunt, PhD (all of ICON; Blue Bell, PA, USA) and was funded by Pfizer Inc.

Additional information

Funding

This work was supported by Pfizer Inc.