Global Epidemiology of Meningococcal Disease-Causing Serogroups Before and After the COVID-19 Pandemic: A Narrative Review

Abstract

Invasive meningococcal disease (IMD) is associated with high morbidity and mortality and predominantly caused by five Neisseria meningitidis serogroups (A/B/C/W/Y). Polysaccharide conjugate vaccines induce T-cell-dependent immune responses, are immunogenic in infants and adults, and reduce carriage, and vaccination of age groups associated with high-carriage can provide indirect protection in the unvaccinated (herd immunity). Successful vaccination programs must be tailored to local epidemiology, which varies geographically, temporally, and by age and serogroup. Serogroup A IMD once predominated globally, but has largely disappeared following mass vaccination programs. Serogroup B was a predominant cause of IMD in many global regions from 2010 to 2018, typically affecting younger age groups. Spread of serogroup C clonal complex-11 IMD in the 1990s prompted implementation of MenC vaccine programs in many countries, resulting in declines in prevalence. Serogroup C still caused > 20% of global IMD through the mid-2010s. Serogroup W became a significant contributor to global IMD after Hajj pilgrimage outbreaks in 2000; subsequent increases of endemic disease and outbreaks were reported pre-pandemic in many regions. Serogroup Y emerged in the 1990s as a significant cause of IMD throughout various regions and prevalence had increased or stabilized from 2010 to 2018. Serogroup X is uncommon outside the African meningitis belt, and its prevalence has declined since before the COVID-19 pandemic. Global IMD declines during the pandemic were followed by resurgences generally caused by serogroups that were prevalent pre-pandemic and affecting mainly unvaccinated age groups (particularly adolescents/young adults). Recent IMD epidemiology underscores the importance of vaccinating at-risk age groups against regionally prevalent serogroups; for example, the anti-serogroup X component of the recently prequalified MenACWXY vaccine is likely to provide limited protection outside the African meningitis belt. In other regions, comprehensive vaccination against MenB and MenACWY, which could be streamlined by the recently approved MenABCWY vaccine, seems more appropriate.

Key Summary Points

Invasive meningococcal disease (IMD), caused by the bacterium Neisseria meningitidis, is a continuing global health threat that has historically been caused by serogroups A, B, C, W, and Y.

Successful vaccination programs must be tailored to local epidemiology, which over the past 25 years has varied geographically, temporally, and by age and serogroup.

Resurgences in IMD have been reported across the globe within the last 2−3 years following declines during the COVID-19 pandemic, generally caused by serogroups that were prevalent in a particular region before the pandemic, and have been most concentrated in unvaccinated age groups that are typically vulnerable to those serogroups, particularly adolescents/young adults.

Collectively, recent IMD epidemiology underscores the importance of maintaining high vaccination rates.

In particular, the continued absence of serogroup X and predominance of serogroup B in many regions outside the African meningitis belt indicate the need for widespread vaccination against serogroup B in addition to serogroups ACWY in these regions, perhaps using the newly available pentavalent ABCWY vaccine, whereas protection against serogroup X is expected to provide utility only in specific regions.

Introduction

Invasive meningococcal disease (IMD), caused by Neisseria meningitidis, is a continued public health concern that is associated with high morbidity and mortality [1]. Globally, more than 400,000 cases of meningococcal meningitis, the most common clinical presentation of IMD [1], were estimated to have occurred in 2019, resulting in approximately 32,000 deaths [2]. Moreover, a 2022 report from the European Centre for Disease Prevention and Control (ECDC) found that nearly half of IMD cases with known clinical presentation included nonmeningitic manifestations such as septicemia [3]; thus, the true global burden of IMD in 2019 may have exceeded 700,000 cases. IMD incidence is consistently highest in infants and young children, with a secondary peak often occurring in adolescents and young adults; incidence among older adults is also relatively elevated in some countries[4].

N. meningitidis is distinguished by remarkable genomic plasticity, which gives rise to continuous evolution of disease-causing strains harboring potential to cause unpredictable outbreaks [5, 6]. Although incidence and duration thresholds for outbreak declarations vary by country, outbreaks are generally defined on the basis of multiple cases in a short period that represent an incidence exceeding that expected for a given community during a 3-month period; epidemics typically refer to very large outbreaks [6]. Of the 12 meningococcal serogroups identified [7], serogroups A, B, C, W, and Y cause the vast majority of cases associated with both endemic disease and outbreaks or epidemics [4, 6, 8, 9]. In addition, serogroup X has been implicated in several outbreaks during the 1990s–2010s in the African meningitis belt, a region that has been subject historically to increased IMD risk [6, 9–11].

Meningococcal epidemiology has propelled vaccine development, with previously and currently available meningococcal vaccines designed to provide protection against some individual or various combinations of serogroups (i.e., A, B, C, W, X, and Y; see Table 1 for details of currently available, prequalified and investigational meningococcal vaccines) [12–15]. Furthermore, because predominant meningococcal serogroups can vary temporally, geographically, and by age group [4, 9], understanding changes in serogroup-specific incidence and the relative distribution of different serogroups among different age groups within a given region is critical for formulating and evaluating effective meningococcal vaccines and vaccination programs [16]. This narrative review (1) considers vaccination strategies for IMD prevention with a focus on currently available vaccines; (2) reviews and summarizes observational data describing the global meningococcal serogroup landscape over the last 25 years, in particular, recent changes in IMD epidemiology following the global COVID-19 pandemic; and (3) reflects on the implications of trends in IMD epidemiology for future vaccination strategies. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Table 1.

Select currently licensed, prequalified, and investigational meningococcal vaccines

Vaccine class
Vaccine	Serogroup(s)	Formulation	Approved agesa
Capsular polysaccharide conjugate
MenA-TT [24]	A	Serogroup A capsular polysaccharide conjugated to TT	1–29 years
MenC-CRM197 [21]	C	Serogroup C capsular polysaccharide conjugated to CRM197	≥ 2 months
MenC-TT [22]	C	Serogroup C capsular polysaccharide conjugated to TT	≥ 2 months
MenACWY-CRM197 [23]	ACWY	Serogroup A, C, W, and Y capsular polysaccharides, each individually conjugated to CRM197	≥ 2 months
MenACWY-TT [20]	ACWY	Serogroup A, C, W, and Y capsular polysaccharides, each individually conjugated to TT	≥ 6 weeks
MenACYW-TT [26]	ACWY	Serogroup A, C, W, and Y capsular polysaccharides, each individually conjugated to TT	≥ 12 months
MenACWY-D [27]	ACWY	Serogroup A, C, W, and Y capsular polysaccharides, each individually conjugated to D	9 months–55 years
NmCV-5 [19]	ACWXY	Serogroup A and X capsular polysaccharides, each individually conjugated to TT; and serogroup C, W, and Y capsular polysaccharides, each individually conjugated to CRM197	1–85 years
Combination capsular polysaccharide conjugate
Hib-MenC-TT [25]	C	Haemophilus influenzae type b polysaccharide and serogroup C capsular polysaccharide, each individually conjugated to TT	2 months–2 years
Subcapsular protein
MenB-4C [29, 31, 104]	B	1 recombinant variant of each of NadA (peptide 8 variant 2/3), NHBA (peptide 2), and nonlipidated fHbp (variant B24 from subfamily B); and OMVs from strain NZ98/254	≥ 2 months
MenB-fHbp [30, 105]	B	2 recombinant, lipidated fHbp variants (A05 from subfamily A and B01 from subfamily B)	≥ 10 years
MenB (investigational) [38, 106]	B	1 nonlipidated fHbp variant from each of subfamilies A and B, 1 NadA variant, and OMVs	N/A
Capsular polysaccharide conjugate and subcapsular protein combination
MenABCWY [14, 107]	ABCWY	Components from MenACWY-TT (serogroups A, C, W, and Y capsular polysaccharides, each individually conjugated to TT) and MenB-fHbp (2 recombinant, lipidated fHbp variants [A05 from subfamily A and B01 from subfamily B])	10–25 years
MenABCWY first generation (investigational) [9, 34–36]	ABCWY	Components from MenACWY- CRM197 (serogroups A, C, W, and Y capsular polysaccharides, each individually conjugated to CRM197) and MenB-4C (1 recombinant variant of each of NadA [peptide 8 variant 2/3], NHBA [peptide 2], and nonlipidated fHbp [variant B24 from subfamily B]; and OMVs from strain NZ98/254)	N/A
MenABCWY second generation (investigational) [34, 37]	ABCWY	Recombinant proteins, OMVs, conjugated capsular polysaccharides	N/A
MenABCYW (investigational) [38, 106, 108]	ABCWY	Serogroups A, C, W, and Y capsular polysaccharides, each individually conjugated to TT; 1 nonlipidated fHbp variant from each of subfamilies A and B; 1 NadA variant; and OMVs	N/A

CRM₁₉₇ nontoxic mutant of diphtheria toxin, D diphtheria toxoid, fHbp factor H binding protein, N/A not applicable, NadA neisserial adhesin A, NHBA neisserial heparin binding antigen, OMV outer membrane vesicle, TT tetanus toxoid

^aBroadest age range for which vaccine is approved; approved age groups may vary by country/organization

Meningococcal Vaccines and Vaccination Strategies

Design of optimal vaccination strategies for IMD prevention must be grounded in available meningococcal vaccines, which have undergone major advances since the initial debut of monovalent plain polysaccharide vaccines in the 1960s [9, 13, 15]. Compared with plain polysaccharide vaccines, currently used polysaccharide conjugate vaccines are formulated using chemical conjugation of polysaccharides to carrier proteins to provoke a T-cell-dependent immune response, which imparts the added advantages of being immunogenic in infants and young children, improved immunopersistence, induction of immunologic memory, avoidance of vaccine-induced hyporesponsiveness, and reduction of meningococcal acquisition and carriage [13, 15, 17]. Targeted use of polysaccharide conjugate vaccines in age groups associated with high-carriage acts to reduce onward transmission, and, if the level of uptake in high-carriage age groups is great enough, this strategy can provide a level of indirect protection in the unvaccinated (i.e., herd immunity) [18].

Currently available polysaccharide conjugate vaccines use tetanus toxoid (TT), diphtheria toxoid, or a nontoxic mutant of diphtheria toxin (CRM₁₉₇) as carrier proteins and include monovalent meningococcal serogroup C (MenC) and serogroup A (MenA) vaccines, a combination MenC and Haemophilus influenzae type b vaccine, and quadrivalent MenACWY vaccines (Table 1) [19–27]. Most recently, a pentavalent MenACWXY polysaccharide conjugate vaccine that uses a combination of TT and CRM₁₉₇ carrier proteins received prequalification from the World Health Organization (WHO) in July 2023 [12, 19].

Limited immunogenicity and potential for induction of autoantibodies precluded use of capsular polysaccharides for meningococcal serogroup B (MenB) vaccines [15, 28]. MenB vaccines were instead initially based on outer membrane vesicles (OMVs), which, although effective, generally only provided strain-specific protection and not broad coverage of all MenB strains [15, 28]. Development of more broadly protective MenB vaccines sought to identify proteins that are conserved across all pathogenic serogroup B strains, accessible to antibodies, and capable of inducing bactericidal antibodies when used as vaccine antigens [29]. No such single candidate that would be universally protective for all MenB strains has been identified, and newer vaccines are instead based on antigens that fulfill the last 2 criteria but are not consistently present and/or vary considerably in sequence across MenB strains [28]. The MenB-fHbp vaccine was developed to overcome the challenges of developing a broadly protective MenB vaccine; it incorporates antigens derived from factor H binding protein (fHbp), a meningococcal surface protein critical for survival (Table 1) [29, 30]. The different variants of fHbp harbored by different meningococcal strains segregate into 2 immunologically distinct subfamilies (A and B) with each strain expressing 1 variant. To increase coverage across diverse MenB strains, the MenB-fHbp vaccine includes 1 antigen from subfamily A and 1 from subfamily B, both of which are lipidated to increase immunogenicity and cross-reactivity of induced antibodies. A 4-component MenB vaccine (MenB-4C) was developed that contains 3 main recombinant protein antigens, fHbp, neisserial heparin binding antigen (NHBA), and neisserial adhesion antigen (NadA), based on their ability to induce bactericidal activity against genetically diverse serogroup B strains, as well as MenB OMV (Table 1) [13, 31]. Because these MenB vaccines are based on proteins that are also harbored by other serogroups besides serogroup B, antibodies induced by both vaccines have demonstrated bactericidal activity against strains from other serogroups [32, 33].

In October 2023, a first-in-class pentavalent MenABCWY vaccine comprising components from MenACWY-TT (Men A, C, W, and Y capsular polysaccharides, each individually conjugated to TT) and MenB-fHbp was approved by the US Food and Drug Administration (Table 1) [14]. A phase 3 clinical study evaluating a similar MenABCWY vaccine based on MenACWY-CRM₁₉₇ (Men A, C, W, and Y capsular polysaccharides, each individually conjugated to CRM₁₉₇) and MenB-4C has completed, and additional investigational MenABCWY vaccines are in earlier stages of development [9, 34–38].

Epidemiology of Meningococcal Disease-Causing Serogroups: Changes in the Global Meningococcal Serogroup Landscape Over the Last 25 Years

Serogroup A

Meningococcal serogroup A epidemiology underwent major, sustained changes during the several decades before the COVID-19 pandemic. Serogroup A was responsible for all IMD outbreaks occurring in the Americas, Europe, the Middle East, Africa, Asia, and Oceania through the mid-twentieth century but largely disappeared from the Americas, Europe, and Oceania beginning in the 1990s [6, 8, 9]. Several serogroup A outbreaks occurred in India during 2005–2009 [6, 39]. In the African meningitis belt, serogroup A continued to predominate until > 200 million individuals (by 2014) 1–29 years of age received MenA-TT (MenA capsular polysaccharide conjugated to TT) as part of mass vaccination campaigns beginning in 2010 [4, 9, 40]. The percentage of IMD cases caused by serogroup A in countries within the African meningitis belt declined by more than 99% among fully vaccinated individuals [40], and outbreaks in Africa since 2012 have been attributed to other serogroups [6]. No serogroup A cases were reported in countries within the African meningitis belt during 2018‒2022 [41–45].

As of the latter half of the 2010s, endemic serogroup A disease persisted in substantial proportions (≥ 10% of groupable cases) in China and Russia and in very low proportions (< 1% of cases) in Germany, Italy, and Spain while remaining virtually undetected in other regions [4]. This status quo has continued in countries reporting serogroup-specific IMD data from the early 2020s, including England, France, Australia, and Chile [46–51].

Serogroup B

A systematic review of studies published during 2000‒2017 estimated that 48.5% of global IMD was caused by serogroup B [52]. Serogroup B was the predominant cause of IMD during 2010 to 2018 in many areas of the world, including the United States, Argentina, Europe, Israel, Australia, and New Zealand, and caused a large percentage of cases in many other regions, with the exception of the African meningitis belt [4, 53]. Although serogroup B disease comprised a substantial proportion of disease across all age groups during this period, it was often more concentrated among younger age groups (adolescents and young adults, and, often to an even greater degree, infants and young children) compared with older adults [4]. Serogroup B outbreaks occurred in New Zealand and Seine-Maritime in France during 1991–2007 and 2003–2006, respectively, both of which were contained with mass vaccination using OMV vaccines [9]. Later serogroup B outbreaks, including those in Saguenay-Lac-Saint-Jean in Quebec, Canada, during 2006–2013 and multiple US college campuses during 2011–2019 were successfully controlled using MenB protein vaccines [9]. Before the COVID-19 pandemic, serogroup B disease was generally declining as a result of secular trends, and, in some countries, routine use of effective MenB vaccines [9, 16, 54].

After the global reduction in cases of IMD associated with COVID-19 mitigation measures, a number of countries have experienced resurgence of serogroup B disease [55]. In England, IMD incidence declined from 0.98 per 100,000 during April 2019‒March 2020 (2019/20) to 0.16 per 100,000 during the following year but increased to 0.31 per 100,000 during 2021/22 and then 0.64 per 100,000 in 2022/23 [46]. These increases were driven almost entirely by serogroup B, for which incidence rose from 0.12 per 100,000 during 2020/21 to 0.58 per 100,000 during 2022/23, exceeding monthly pre-pandemic levels in December 2022 [46]. Additionally, the 2021/22 upsurge in England, which only recommends MenB vaccination for infants, was almost entirely attributed to individuals 18‒24 years of age, with smaller increases observed in infants [46, 56]. Increases in serogroup B disease in 2022/23, relative to the previous year, occurred among all age groups except infants, but most prominently in those 18‒24 years of age [46]. Similar increases in IMD in Ireland, from 10 cases in 2021 to 31 cases (provisional estimate) in 2022, primarily occurred among pediatric and young adult age groups (2021, 5 cases; 2022, 22 cases) and, when serogroup was identifiable, belonged exclusively to serogroup B [57–59]. In France, a steep decline in IMD during 2020/21 was followed by a rebound in 2022 caused by increases in serogroups B, W, and Y. France only has a recommendation for MenB vaccination for infants and the resurgence in serogroup B disease was most pronounced among individuals 15‒24 years of age, who experienced more cases in 2022 than in 2019 [47, 60]. Serogroup B gradually underwent an approximately 50% decrease in cases (196 to 102) in Australia from 2009 to 2019, but nevertheless predominated until being overtaken by serogroup W in 2016 and 2017; it then continued as the predominant serogroup from 2018 after implementation of MenACWY toddler and adolescent vaccination programs led to sharp declines in serogroup W IMD (Fig. 1a) [48, 61, 62]. IMD cases reached a trough of 74 during the COVID-19 pandemic in 2021 but then rebounded to 123 in 2022, driven entirely by a nearly 200% increase in serogroup B cases (35 to 102) [48]. Australia does not have a national recommendation for MenB vaccination of adolescents or adults, and, although age groups including individuals 0–4 and 15–24 years of age each comprised approximately one-third of serogroup B cases before the rebound, cases in 2022 among the youngest age group (n = 24) remained below the 2014‒2019 average (n =  ~ 36), whereas cases among those 15−24 years of age (n = 40) exceeded the 2014‒2019 average (n =  ~ 37; Fig. 1b) [48, 63]. In Chile, a decline in IMD from 69 cases in 2019 to 6 cases in 2020 was followed by a rebound (22, 29, and 61 cases during 2021, 2022, and 2023, respectively), which was also dominated by serogroup B (13, 20, 22, and 36 cases, respectively; comprehensive serogroup information by age group are not yet available) [49–51, 64].

Fig. 1.

Annual IMD cases in Australia during 2009–2022 [48]: a all IMD cases by serogroup, and b all serogroup B cases by age group. IMD invasive meningococcal disease

Collectively, age-specific serogroup B data in the post-pandemic period highlight the vulnerability of unvaccinated individuals to IMD resurgence and the resulting imperative for preventive vaccination. The most pronounced serogroup B rebounds in England, France, and Australia occurred among age groups lacking routine serogroup B vaccination recommendations in these countries [46–48, 56, 63, 65]; increases were particularly pronounced among adolescents and young adults, who are at increased risk of IMD and are considered the primary natural reservoirs and transmitters of meningococci [66]. By contrast, serogroup B cases among infants in England, for whom MenB vaccination is routinely recommended [56], increased to a much lesser degree and remained below pre-pandemic levels [46].

Serogroup C

Global spread of a serogroup C clone belonging to clonal complex (cc) 11 in the 1990s [67, 68] prompted implementation, beginning in 1999, of MenC conjugate vaccine programs throughout Europe, as well as other countries, including Canada, Brazil, and Australia; recommendations mainly targeted infants and toddlers [9, 69]. Although serogroup C prevalence declined in countries where MenC vaccination programs were introduced [54, 69], serogroup C was estimated to cause 21.7% of global IMD during the mid-1990s through mid-2010s [52] and remained present to varying degrees across global regions as of the late 2010s [4]. Analysis of serogroup distribution by age group in recent years indicated that serogroup C affected all age groups but in some countries comprised a relatively greater percentage of IMD among adolescents, young adults, and older adults compared with other age groups [4]. Of note, IMD outbreaks in the twenty-first century among men who have sex with men (MSM) in North America, Europe, and Australia have been caused largely by serogroup C strains belonging to the same hypervirulent cc11 lineage responsible for global increases in the 1990s [6, 70]. In the African meningitis belt, sharp declines in serogroup A disease associated with MenA-TT vaccination campaigns led to 32% of IMD during 2010–2019 and the majority of cases confirmed from cerebrospinal fluid (CSF) samples during 2017–2019 to be attributed to serogroup C, with spikes in percentages during these periods reflecting outbreaks [4, 11, 40–42]. Major serogroup C outbreaks in this region included a 2015 outbreak that comprised more than 15,000 cases across Niger and Nigeria and a similarly sized 2017 outbreak in Nigeria that led to more than 1100 deaths [6]. Before 2020, vaccination against serogroup C and other non-A serogroups in the African meningitis belt was primarily limited to outbreak response situations and typically used plain polysaccharide vaccines [6, 11, 41, 42, 45].

The 2020 season in the African meningitis belt experienced a marked decrease in IMD outbreaks; there were also far fewer confirmed cases from CSF samples (179 compared with 616 in 2019), although this may in part reflect limitations in surveillance rather than impacts of the COVID-19 pandemic [42, 43]. Confirmed cases rebounded to 641 and 530 in 2021 and 2022, respectively; most of these (483 and 461) were serogroup C cases in Niger that were associated with 2 separate epidemics, each comprising approximately 1350 cases [44, 45]. More recently, a meningitis outbreak in Nigeria spanning October 2022–April 2023 comprised 1686 suspected cases and 124 deaths; of samples that were positive for bacterial infection, 91% were caused by the N. meningitidis serogroup C [71]. Mass vaccination against non-A serogroups in the African meningitis belt has changed since the 2020 implementation of a “repurposing” strategy, wherein meningococcal vaccines with a short shelf life that remain in emergency stockpiles can be used in non-outbreak situations [43–45]. Additionally, use of meningococcal conjugate vaccines, rather than polysaccharide vaccines, has become more common during recent proactive and reactive mass vaccination programs in this region [43–45].

A number of countries (e.g., Ireland, France, England, Australia) experienced declines in serogroup C disease during the COVID-19 pandemic that did not appreciably increase in the context of post-pandemic rebounds observed for other serogroups [46–48, 57]. By contrast, a 3-year decline in IMD in the United States from 2019 (375 cases), to 2020 (235 cases), and to 2021 (209 cases) was largely attributed to decreases in other serogroups rather than serogroup C (85, 54, and 73 cases, respectively), leading serogroup C to predominate in 2021; 72–88% of serogroup C cases during these years occurred among individuals ≥ 24 years of age [72]. Provisional surveillance data indicate a major post-pandemic rebound in US cases, with 312 and 415 cases reported in 2022 and 2023, respectively, and preliminary serogroup distribution data indicate substantial contribution from serogroup C to IMD cases in 2022 but not 2023 [73, 74]. A serogroup C outbreak in Florida among MSM during December 2021–2023 [75] likely comprised a substantial proportion of serogroup C cases during 2022 in particular, with Florida reporting 27, 68, and 39 total (all serogroups) IMD cases in 2021, 2022, and 2023, respectively [73, 76].

Serogroup W

Although initially responsible for a very small percentage of cases in various global regions, serogroup W IMD first emerged as a cause of outbreaks in the year 2000 during the Hajj pilgrimage; the associated cc11 clone spread from pilgrims to their close contacts upon their return home [77]. In the mid-2000s, a new serogroup W cc11 sublineage emerged in South America and subsequently spread and further evolved to the UK 2009 and 2013 lineages [68, 78]. Increased levels of endemic disease and outbreaks due to serogroup W were reported during the pre-pandemic years in many regions, including the African meningitis belt, South America, Europe, and Oceania, with increases often more pronounced among older adults compared with younger age groups [4, 6, 77]. In the African meningitis belt in particular, serogroup W was the most common cause of IMD during 2010‒2019 before it was surpassed by serogroup C based on confirmed CSF samples; numbers of serogroup W cases in specific countries also fluctuated to reflect outbreaks, including a 2016 outbreak in Togo that comprised nearly 2000 cases [4, 6, 11, 41–45]. As mentioned for Australia, many countries introduced MenACWY vaccination programs during the 2010s, mostly targeting toddlers and adolescents and often constituting a switch from previous MenC programs [79], and available data for MenACWY-TT indicate resulting declines in serogroup W disease in some countries, including England, the Netherlands, Chile, and Australia [9, 48, 62].

Unlike in England and Australia, where declines in serogroup W disease during the COVID-19 pandemic persisted despite rebounds in serogroup B [46, 48], in 2022, serogroup W contributed substantially to the IMD rebound in France, where only MenC vaccine was used in routine immunizations [47, 80]. Increases were most evident among infants and adults ≥ 45 years of age, with cases among individuals 45‒65 years of age in 2022 exceeding those in 2019 [47]. In Chile, the IMD rebound that started in 2021 began to have substantial contribution from serogroup W in 2023 (2, 4, 4, and 16 cases in 2020, 2021, 2022, and 2023, respectively) [49–51, 64]. Serogroup W epidemiology across these countries in the post-pandemic period suggests that the MenACWY vaccination programs in England (for adolescents) and Australia (for adolescents and toddlers) may be providing herd protection, in contrast to the limited program in Chile (for toddlers and young children) and lack of such a program in France [56, 63, 65, 81]. Serogroup W also continued to cause significant disease in the African meningitis belt/extended meningitis belt after a brief decline in confirmed cases in 2020 [42–45]. In particular, a major outbreak in late 2021 comprising > 2500 cases and > 200 deaths in the Democratic Republic of Congo, which lacks routine vaccination programs against any meningococcal serogroup [82], was mostly attributed to serogroup W [44].

Serogroup Y

Although serogroup Y was historically considered less invasive compared with other serogroups, it emerged as a significant cause of disease throughout various global regions beginning in the 1990s [9, 78], accounting for an estimated 7.2% of global IMD during the mid-1990s through mid-2010s [52]. Prevalence of serogroup Y increased during 2010‒2018 in many global regions and remained stable in others, with 12% to 16% of IMD in the United States, Europe, and Australia attributed to serogroup Y in 2018 [4]. Of note, serogroup Y tends to cause a higher proportion of IMD among older adults compared with younger age groups [4]. Additionally, the general rise in antimicrobial resistance among meningococcal strains in the United States appears to be particularly pronounced for serogroup Y, and serogroup Y isolates resistant to multiple antimicrobial agents have been detected in many countries worldwide [9, 83]. In the United States, 22.8%, 51.2%, and 65.4% of serogroup Y IMD isolates available for characterization in 2019, 2020, and 2021, respectively, were resistant to penicillin and ciprofloxacin or penicillin only [72]. MenACWY vaccination programs have been demonstrably successful at reducing serogroup Y disease [9].

Changes in serogroup Y epidemiology during the COVID-19 pandemic and the following IMD rebound were broadly comparable with those for serogroup W epidemiology across France, England, and Australia [46–48]. In the 23 European countries that provide data to the ECDC, the collective IMD notification rate for serogroup Y remained below pre-pandemic levels as of 2022 [84]. However, the post-pandemic rebound was sharper than that of any other serogroup, resulting in serogroup Y becoming second only to serogroup B in reporting rate [84]. Serogroup Y increases in France in 2022 were concentrated among adolescents and young adults and adults ≥ 45 years of age, with cases exceeding 2019 levels for all of these age groups and higher among adolescents and young adults than in any year during 2015‒2021 [47]. Similar to those for serogroup W, these observations suggest that the presence or absence of preexisting MenACWY programs [56, 63, 65] influenced serogroup Y resurgence in the post-pandemic period. In the United States, preliminary serogroup distribution data for 2022 and 2023 indicate that the post-pandemic rebound is largely due to serogroup Y [74]. Rising IMD cases were particularly evident in Virginia (4, 16, and 26 in 2021, 2022, and 2023, respectively) [73, 76] and reflected a serogroup Y outbreak that began in mid-2022 and comprised 27 cases by August 2023; most cases were adults 30‒60 years of age [85]. The unvaccinated status of 26 cases [85] again highlights the importance of vaccination in preventing IMD in the post-pandemic period. The same strain responsible for the US outbreak (ST-1466) was responsible for an outbreak in Australia that began in mid-2023 [86]. The Australian outbreak comprised over 40 cases, with 30 confirmed as ST-1466; like the US outbreak, most cases were adults 30–60 years of age [86]. Notably, this strain has several unusual characteristics, such as frequently infecting the urogenital region, presenting clinically without meningitis, and having a relatively high case-fatality rate. Some of these characteristics overlap with those of disease caused by N. gonorrhea, potentially creating delayed or incorrect diagnoses [86] and further emphasizing the importance of vaccination as a preventative measure.

Other Serogroups

Serogroup X IMD cases have been sporadically reported in countries throughout the world since the 1960s [10, 78], and a systemic review estimated that 0.7% of global IMD was caused by serogroup X from the mid-1990s through the mid-2010s [52]. A more recent review of global IMD epidemiology found that serogroup X outside of the African meningitis belt during 2010 to 2019 remained limited to sporadic cases [4]. Serogroup X outbreaks have occurred in African meningitis belt countries, with the largest comprising 557 confirmed cases in Niger in 2006 and an estimated, but not confirmed, 1300 cases in Burkina Faso in 2010 [6, 10, 11]. Phylogenetic analyses have indicated that serogroup X isolates from the African meningitis belt stem from a single lineage within cc-181, while those from other regions predominantly belong to other clonal complexes and are more genetically diverse [87]. It is not clear why serogroup X cases occur only sporadically outside of the African meningitis belt, though there is some limited circumstantial evidence for the theory that serogroup X meningococcus is less virulent than other serogroups [87, 88]. Most cases of verified serogroup X IMD outside the African meningitis belt have occurred in immunocompromised individuals, and even when the individuals were healthy, the strains involved were sensitive to antibiotic treatment (including first-generation antibiotics such as penicillin) [87–89]. Past increases in serogroup X carriage and IMD have coincided with fading of certain strains of serogroup A, only to subside when new strains of serogroup A became prevalent [88]. Although mass MenA-TT vaccination in the African meningitis belt resulted in increased percentages of IMD caused by non-A serogroups, it does not seem to have precipitated an appreciable increase in the number of serogroup X cases, with those confirmed from CSF samples in the African meningitis belt exhibiting a steady decline of more than 90% from 2017 (333 samples) to 2022 (31 samples) [6, 11, 40–45]. In Niger and Ghana, serogroup X carriage led to increased endemic disease, but not to increased epidemics, while demonstrating a case-to-carrier ratio that was just 2.5% of that for serogroup A [88]. Thus, it is possible that the lower virulence of serogroup X strains and predominance of other serogroups outside the African meningitis belt limit the ability of serogroup X to cause large outbreaks, but within those serogroups there may be specific strains that are permissive for serogroup X IMD. Taken together, these data suggest the ability of serogroup X cc-181 to expand beyond the African meningitis belt will remain limited and that cases outside this area will remain sporadic.

Serogroup E IMD was first identified in the late 1960s and rarely causes disease; reported cases are usually immunocompromised individuals [78]. Although carriage surveys in Dutch young adults in 2018 and 2022 indicated a significant rise in serogroup E carriage prevalence in parallel with a significant decline in serogroup Y, the absence of serogroup E disease in 2022 suggests continued low invasive potential of serogroup E [90], which is consistent with the general lack of congruence between carriage and disease epidemiology [9].

Some meningococcal strains are unable to express capsules and are therefore termed nongroupable (NG) [9, 78]. Similar to serogroup E, NG strains also rarely cause invasive disease. However, an NG clade emerged in the 2010s in the United States and United Kingdom to cause outbreaks of meningococcal urethritis among heterosexual men, as well as occasional, sporadic cases of invasive disease [70, 91]. Phylogenetic analyses indicated that this clade descended from the serogroup C lineage associated with IMD outbreaks among MSM and also contains multiple gonococcal genes [70, 91]. Also, countries often report a high number of ungrouped cases, which are likely serogroup B, C, W, and Y cases that were not typed [4].

Implications of Trends in IMD Epidemiology for Future Vaccination Strategies

Since the start of the twenty-first century, IMD has been caused almost exclusively by serogroups A, B, C, W, and Y. Although outbreaks of serogroup X contributed to significant case numbers in the early 2000s in the African meningitis belt, its incidence dropped by 90% from 2017 to 2022. Disease caused by serogroup A has remained endemic in China and Russia in the latter half of the 2010s; however, its incidence in other countries and regions is very low. Serogroup B was the predominant cause of IMD in many areas of the world during the 2010s, typically affecting younger age groups. Despite declines in serogroup C disease in many countries as of the late 2010s, serogroup C still contributed to a substantial portion of IMD globally, affecting all age groups. In recent pre-COVID 19 pandemic years, both serogroup C and W have caused IMD outbreaks in many regions and countries. Throughout the 2010s, serogroup Y disease remained stable or increased in many regions and countries, with disease predominantly occurring in older adults. During the post-COVID-19 period, disease rebounds in various global regions have been attributed to serogroups B, C, W, and Y. Fluctuations in dominance between serogroups A, B, C, W, and Y are likely due to a combination of genetic mutations giving rise to hypervirulent clones, secular trends with unclear etiologies, and impact of vaccination programs [9].

Factors contributing to rebounds in IMD post-COVID-19 are uncertain. During the COVID-19 pandemic, there were substantial decreases in diseases typically spread by the respiratory route, thought to be due to implementation of non-pharmacological interventions such as social distancing and closures of schools and businesses [92]. Additionally, in 2020, routine vaccination rates fell worldwide as a result of vaccination programs being temporarily suspended and vaccine supply or administration issues [93, 94]. In 2021, a survey of 4962 parents from eight countries found that 50% reported delaying or forgoing meningococcal vaccinations [95]. Such disruption in vaccination during the COVID-19 pandemic could have left many individuals unprotected or partially protected, contributing to the post-pandemic rebounds in disease. It has also been speculated that low exposure to environmental pathogens resulting from lockdown measures, such as quarantining, may have resulted in a lack of immune stimulation in the population, causing an “immunity debt” that potentially left individuals, particularly the pediatric population, more susceptible to infection once restrictions were lifted [96]. It is likely that myriad factors are contributing to the rebounds seen in IMD after the COVID-19 pandemic and future studies are needed to clarify what factors contribute to the changing epidemiology of IMD.

Over the last several decades, implementation of meningococcal conjugate vaccination programs has been very effective at controlling serogroup-specific IMD. In response to increases in serogroup C disease during the 1990s, many countries introduced a monovalent MenC conjugate vaccine into their national immunization programs, resulting in significant and rapid reductions in MenC disease among vaccine eligible age groups [69]. Following the introduction of the monovalent MenA conjugate vaccine in the African meningitis belt region in 2010, there was a substantial decline in MenA disease [40]. In more recent years, the shift from serogroup C to serogroup W and Y disease in many countries led to recommendations for quadrivalent MenACWY conjugate vaccines [62]. In countries that implemented recommendations for a MenACWY vaccine, serogroup C disease remained low and there were substantial decreases in disease caused by serogroups W and Y [62]. In many cases, disease rebounds or outbreaks after pandemic-associated declines have been concentrated among unvaccinated individuals, particularly adolescents and young adults. These age groups are typically at elevated risk of IMD from the serogroup(s) associated with these recent rebounds or outbreaks. This trend is highlighted in England, where current vaccination recommendations include MenB vaccination for infants, MenB and MenC vaccinations for toddlers, and MenACWY vaccination for adolescents [56], and where IMD rebounds in 2021/22 and 2022/23 were caused almost exclusively by serogroup B cases in age groups other than infants [46]. By contrast, IMD resurgence in 2022 in France, where the current vaccination recommendations were limited to MenC for infants and toddlers and MenB for infants (as of 2022) [65], reflected increases in serogroups B, W, and Y across age groups that were most pronounced among adolescents and young adults, but also older age groups for serogroups W and Y in particular [47], consistent with the typical age-related distribution of these serogroups [4]. In Chile, routine recommendation of toddler MenACWY vaccination and lack of MenB vaccination recommendations [81] presumably facilitated a post-pandemic resurgence in serogroup B IMD [49–51].

Although widespread use of meningococcal conjugate vaccines, including MenACWY-TT [9, 62], demonstrably reduces IMD caused by these serogroups in unvaccinated age groups (likely via herd protection), it remains difficult to define specific target age groups and corresponding vaccine uptake rates that will provide effective herd protection. For example, notwithstanding the lack of available serogroup-specific US data for 2022 and 2023, the recent serogroup C and Y outbreaks in Florida and Virginia, respectively [75, 85], occurred despite ≥ 85.0% MenACWY uptake rates among US adolescents 13–17 years of age in these states in 2022 [97]. In contrast, MenACWY vaccination programs in toddlers and adolescents in Australia, which had respective uptake rates of 94.7% and 75.9% in 2022 [61], have thus far successfully prevented resurgence of these serogroups despite the rebound in serogroup B cases [48, 63]. In England, where MenB vaccination is only routinely recommended for infants, the resurgence of serogroup B disease after the pandemic occurred primarily in adolescents and adult age groups, suggesting a lack of indirect protection by the MenB vaccine [46].

The current analysis is limited by its reliance on comprehensive and robust IMD surveillance systems, which vary globally [16, 52]. Molecular surveillance for the African meningitis belt in particular is limited [11, 41–45], with outbreaks typically attributed to specific serogroups on the basis of extrapolation from a small percentage of samples with typing data [71, 98, 99]. Data from industrialized countries in the post-pandemic period may also be subject to incomplete characterization at this time (e.g., US data during 2022 and 2023) [73, 74, 76].

Taken together, findings from this review collectively highlight the importance of vaccination against serogroups prevalent in a given region. Since their licensure, quadrivalent MenACWY conjugate vaccines have been replacing monovalent MenC conjugate vaccines in many regional vaccination programs, with the effect of controlling serogroups C, W, and Y disease [13]. More recently, MenB protein-based vaccines have been incorporated into national immunization programs in many countries, typically recommended for infants, and demonstrated to be effective at reducing serogroup B disease among vaccinated age groups [100–102]. The MenACWXY vaccine recently prequalified by the WHO [12] may increase coverage of relevant serogroups in African meningitis belt countries, but is expected to provide little additional benefit compared with MenACWY vaccines in other global regions. In addition to the continued prevalence of serogroups C, W, and Y disease, global regions outside the African meningitis belt generally experience considerable disease burden from serogroup B, with available data in multiple countries highlighting post-pandemic IMD rebounds that are largely driven by serogroup B. Rather than using the MenACWXY vaccine, countries outside of the African meningitis belt would therefore be better served by comprehensive use of MenACWY and MenB vaccines, with the recently approved MenABCWY vaccine [14] yielding the potential to simplify meningococcal vaccination against these serogroups [103].

Author Contributions

Conceptualization: Steven Shen, Jamie Findlow; Literature Search and Data Analysis: Steven Shen; Drafting and/or Critically Revising: Steven Shen, Jamie Findlow, Paula Peyrani.

Funding

This work was supported by Pfizer Inc. The sponsor is also funding the journal’s Rapid Service fee.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Steven Shen, Jamie Findlow, and Paula Peyrani are employees of Pfizer and may hold stock or stock options.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.