Introduction

Invasive meningococcal disease (IMD) is a serious infection caused by the Gram-negative bacterium Neisseria meningitidis [1]. Some age groups are disproportionately affected by IMD, with major peaks of IMD incidence occurring in infants and in adolescents and young adults [2,3,4]. Adolescents and young adults typically exhibit lifestyles that are thought to promote meningococcal transmission, such as being exposed to smoke; frequent attendance at pubs, bars, and nightclubs; living in close quarters; and intimate kissing with multiple partners [5, 6]. IMD rates are markedly elevated among students in universities relative to other settings [2, 7], and outbreaks or clusters of disease within the university setting can occur [8,9,10]. Overall incidence of IMD is generally low but varies by country/region [2, 3]. Nevertheless, outbreaks are unpredictable [11], and sporadic individual cases continue to occur in both industrialized and non-industrialized countries [12].

Neisseria meningitidis is categorized into 12 serogroups according to the biochemical composition of the bacterial capsular polysaccharide [13]. However, only five serogroups (A, B, C, W, and Y) are responsible for the majority of disease worldwide [14]; vaccines for the prevention of IMD caused by each of these serogroups are available. Currently licensed meningococcal serogroup A, C, W, Y (MenACWY) conjugate vaccines include MenACWY-CRM197 (Menveo®; GlaxoSmithKline, Rixensart, Belgium), which is conjugated to the diphtheria protein cross-reactive material 197 (CRM197) [15]; MenACWY-D (Menactra®; Sanofi Pasteur, Swiftwater, PA, USA), which is conjugated to diphtheria toxoid (D) [16]; and MenACWY-TT (Nimenrix®; Pfizer Inc, Sandwich, UK), which is conjugated to tetanus toxoid (TT) [17]. Available monovalent meningococcal serogroup C (MenC) vaccines include MenC-CRM197 (Menjugate®; GlaxoSmithKline Vaccines Srl, Siena, Italy) [18] and MenC-TT (NeisVac-C™; Pfizer Ltd, Kent, UK) [19], which use CRM197 and TT, respectively, as carrier proteins. In addition, PsA-TT (MenAfriVac™; Serum Institute of India, Pune, India) is a meningococcal serogroup A (MenA) conjugate vaccine using TT as a carrier protein that was developed specifically to combat MenA disease in Africa [20]. Hib-MenC-TT (Menitorix®; GlaxoSmithKline, Rixensart, Belgium) is a combination vaccine that includes MenC in addition to Haemophilus influenzae type b (Hib) [21]. The use of these polysaccharide conjugate meningococcal vaccines has collectively reduced the burden of meningococcal disease worldwide [22, 23].

Due to the poor immunogenicity of serogroup B capsular polysaccharide [24,25,26], two subcapsular antigen vaccines for the prevention of meningococcal serogroup B (MenB) disease have recently been developed: MenB-FHbp (Trumenba®, bivalent rLP2086; Pfizer Inc, Philadelphia, PA, USA) [27] and MenB-4C (Bexsero®, 4CMenB; GlaxoSmithKline Vaccines Srl, Siena, Italy) [28]. MenB-FHbp is composed of two recombinant lipidated factor H binding proteins (FHbp), one variant each from subfamilies A and B. MenB-4C contains neisserial adhesin A, neisserial heparin-binding antigen, and a nonlipidated FHbp variant from subfamily B, in addition to outer membrane vesicles [28]. Vaccines for the prevention of MenB disease may provide some cross-protection against strains from other serogroups, including meningococcal serogroup X (MenX) [29, 30], which emerged recently in Africa [31].

Based on the rapid and severe clinical presentation of IMD, relative ease of transmission via respiratory secretions, and unpredictability of IMD incidence and epidemiology, protection can best be achieved by initiating proactive rather than reactive vaccination strategies [32]. Herd protection (i.e., protection of unvaccinated individuals) can be an important component of vaccination-mediated disease control, which occurs by limiting bacterial acquisition and thus transmission from vaccinated to unvaccinated individuals; this phenomenon has been particularly evident for certain MenC vaccination programs (i.e., in the Netherlands, United Kingdom, and Australia) [33,34,35]. Evidence also exists of reduced meningococcal carriage associated with MenA vaccine use in Africa [36]. Optimized vaccination strategies require continual adaptation to include available vaccines and thus ensure protection against emerging disease-causing strains.

This article details recent changes in IMD epidemiology, the associated shifts in meningococcal vaccination recommendations, and data from clinical studies of MenACWY-TT, the most recently approved MenACWY vaccine [17]. Other MenACWY conjugate vaccines that were licensed earlier (MenACWY-D and MenACWY-CRM197) [15, 16] are also briefly summarized; their use has been previously described in detail [37]. Additionally, although many regions have multiple MenACWY vaccines licensed, some vaccination programs only use MenACWY-TT [38,39,40]. 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.

Recent Changes in Meningococcal Epidemiology and Vaccination Recommendations

Global shifts in meningococcal epidemiology coupled with a growing body of data regarding MenACWY vaccines have prompted changes in meningococcal vaccine recommendations in various countries (Table 1) [38, 39, 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69]. Epidemiologic shifts and any associated changes in recommendations are summarized for select countries below.

Table 1 Incidence of IMD by country and serogroup and associated new vaccination recommendations
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The United Kingdom

The United Kingdom has been experiencing a pronounced increase in meningococcal serogroup W (MenW) disease since 2010 [70], with the number of reported MenW cases in England increasing more than tenfold from 2009–2010 (22 cases) to 2016–2017 (225 cases) [41]. Adults ≥ 45 years old were the primary age group initially affected, but over time, MenW IMD increased in all age groups. Genetic analysis demonstrated that a majority of the MenW isolates responsible for the initial rapid increase belonged to a single clone of clonal complex 11 (cc11) [70].

Due to this rapid increase in MenW IMD, in September 2015 MenACWY vaccination (MenACWY-CRM197 or MenACWY-TT) replaced the previous recommendation for monovalent MenC vaccination for adolescents [42]. The new vaccination program was directed at adolescents in school year 9, with the strategy of reducing transmission by targeting the age group preceding that in which meningococcal carriage rates begin to drastically increase [42, 71]. Public Health England reported vaccination coverage rates of 71.4–83.6% by August 2017 [72]. The program also included catch-up vaccination for students 14–18 years of age as well as those < 25 years of age who were entering university [42]. MenACWY vaccination coverage in England among students who left school in 2015–2016 was 36.6% by June 2016 [73]. During the first year of the program, the number of MenW cases in school leavers decreased by 69%, with 6 confirmed cases (all unvaccinated) versus 19.4 predicted cases [73].

France

MenW disease has increased in France, beginning in 2015, and accounted for 9% of all IMD notifications in 2016, with an incidence rate of 0.07 per 100,000 [43]. Compared with cases from other serogroups, older individuals had a higher incidence of MenW IMD and exhibited a higher case-fatality rate. As in the United Kingdom [70], multilocus sequence typing revealed that the MenW cases responsible for the upsurge in France were dominated by cc11; this was in contrast to endemic MenW disease caused largely by cc22 [43]. The increase in MenW IMD in France includes a 2017 outbreak among French university students that involved two cases and one death [8]. To date, France continues to recommend only MenC vaccination to infants and toddlers [45]. Of note, the vaccine schedule in France was modified in 2016 to include a MenC dose at 5 months of age, in addition to a second dose at 12 months of age, due to the persistent burden of MenC disease [45, 74].

Italy

Meningococcal epidemiology in Italy has demonstrated recent trends that differ from those of many other countries. In 2011, serogroups B, C, W, and Y accounted for 49.3% (75/152), 12.5% (19/152), 2.6% (4/152), and 10.5% (16/152) of cases, respectively [44]. By 2015, MenC accounted for 30.5% (57/187) of cases [44]; this increase reflected an outbreak that began in the Tuscany region in which 61 MenC cases were reported during 2015–2016 [67]. Genomic analysis indicated that the invasive strain belonged to cc11 [67]. In response, the Regional Health Authority of Tuscany offered MenACWY as a single dose to adolescents 11–19 years of age; the vaccine was also available to individuals 20–44 years of age residing in affected regions [66]. MenACWY was integrated into Italy’s national immunization program (NIP) in 2017 as a single dose given to adolescents 12–14 years of age; although the national recommendation is that toddlers continue to receive a single MenC dose, several regions (e.g., Veneto, Emilia-Romagna, and Puglia) now recommend MenACWY in this age group [45, 46, 75,76,77].

The Netherlands

Children in the Netherlands have been routinely vaccinated against MenC since 2002, leading to a sustained reduction in MenC incidence [47]. However, starting at the end of 2015, MenW incidence drastically increased, accounting for approximately one-third of all IMD cases in 2016 at an incidence rate of 0.29 per 100,000. Incidence was highest in those ≥ 65 years of age, followed by those 15–24 years of age and then those < 5 years of age. In response to this increase, beginning in 2018, MenACWY vaccination (using MenACWY-TT) targeting toddlers 14 months of age and adolescents 13–14 years of age was added to the NIP [40, 47, 48].

Australia

In Australia, MenC vaccine was introduced in 2003, resulting in a significant reduction in MenC IMD [23]. MenB then predominated until 2015 despite a substantial decline in the number of MenB cases over that time [51]. However, MenW cases increased over eightfold from 2014 (17 cases) to 2017 (140 cases), with MenW becoming the predominant serogroup in 2016; similar to other countries, the increase was largely attributed to cc11 [51]. An increase in meningococcal serogroup Y (MenY) notifications has also occurred since 2011 [51]. Similar to the high fatality rates observed in cases of MenW disease in France [43], MenW cases in Australia in 2017 had a higher case-fatality rate (11.4%) than MenB (5.9%), MenY (4.1%), or MenC cases (7.1%) [51]. Several states instituted school-based programs using MenACWY for adolescents approximately 15–19 years of age in response to the increasing number of MenW cases [78]. Additionally, a MenW outbreak originating in central Australia and affecting a number of other states prompted several regions to initiate temporary MenACWY vaccination programs [78]. As in the United Kingdom and the Netherlands, the Australian government recently integrated MenACWY into the NIP in response to increasing MenW incidence, with a program targeting toddlers 12 months of age (who were previously recommended to receive MenC) [38]. The program started on July 1, 2018, and specifies use of MenACWY-TT [68, 79]. More recently, the Australian government announced that MenACWY will be added to the NIP in April 2019 under a school-based program targeting adolescents 14–16 years of age; catch-up vaccination will also be available for those 15–19 years of age [80].

Canada

The proportion of IMD caused by MenW in Canada dramatically increased to 18.8% (15/80) in 2016, nearly triple that reported in 2015 (6.8%, 6/88) [52]. Genomic analysis tied the recent increase in MenW disease to the rise of cc11, whereas MenW disease before 2014 was generally caused by cc22 isolates. Interestingly, MenW cases caused by cc11 occurred predominantly in older individuals (median age, 53.5 years) compared with cc22 cases (median age, 23.5 years). Canadian children generally receive a MenC vaccine at 12 months of age, with some provinces administering additional doses in infancy, whereas adolescents receive one dose of either MenC or MenACWY, depending on the province [81]. In September 2016, British Columbia changed its vaccination recommendations for younger adolescents from MenC to MenACWY [56]. The next year, the Okanagan region in British Columbia experienced a MenW outbreak in older adolescents (15–19 years of age), prompting a temporary MenACWY vaccination program in this age group as well [82].

Argentina

Increases in MenW IMD occurred earlier in Argentina than in other countries. MenW accounted for just 6.3% (4/64) of all IMD isolates across all age groups in 2006 [58]; this increased to 49.3% (66/134) by 2010 [59] and remained steady through 2014 (49.0%; 73/149) [60]. In 2014, the highest proportions of MenW occurred in infants and toddlers (47.1–66.7%) and adults ≥ 30 years of age (75–90%). Consistent with observations from other countries, the increase in MenW was shown to be associated with cc11 strains [83]. In a 3-year prospective surveillance study conducted from 2012 to 2015 at six pediatric hospitals in Argentina, 42.9% (36/84) of the N. meningitidis isolates serogrouped were MenW [84]. In this study, a significant association between MenW and age < 1 year was observed (odds ratio 3.18; 95% CI 1.14–8.99), with 66.7% (24/36) of MenW cases occurring in this age group. In 2016, the Ministry of Health in Argentina released new recommendations in which MenACWY-CRM197 would be administered at 3, 5, and 15 months of age, with an additional dose at 11 years of age [61]. These recommendations were included in the 2017 Argentina vaccination calendar [62].

Chile

The increase of MenW IMD in Chile occurred somewhat differently than in Argentina. In 2006, only 4.5% (3/67) of cases were caused by MenW [58], increasing to 10.7% (6/56) in 2010 [59]. MenW disease incidence drastically increased thereafter, accounting for nearly three-quarters (73.1%; 87/119) of IMD in Chile in 2014 [60]. Proportions were high in most age groups in 2014, especially infants (65.8%) and individuals aged ≥ 5 years (75–100%). By 2017, MenW had decreased to 58.8% (47/80) of isolates [63]. Similar to other global observations, a recently published study found that, among 119 IMD isolates collected in Chile, all MenW isolates (66%) were identified as cc11 [85]. As a result of increasing MenW prevalence, the Chilean Ministry of Health initiated a MenACWY vaccination program in 2012 targeting children aged ≥ 9 months to < 5 years, and a single MenACWY-TT dose at 12 months of age was added to the NIP in 2014 [39, 64, 69]. In the years that followed, the number of cases substantially decreased in the age groups targeted for vaccination, but no herd protection was observed, likely due to the age group vaccinated [39].

MenACWY-D and MenACWY-CRM197 Vaccines

Of the three currently available MenACWY conjugate vaccines, MenACWY-D [16] and MenACWY-CRM197 [15] were approved earlier, whereas MenACWY-TT [17] is the most recently licensed. Safety and immunogenicity of all three vaccines have been evaluated throughout a large part of the human lifespan (i.e., in infants, toddlers, children, adolescents, and adults) [15,16,17, 86], but the availability of each vaccine varies across different regions of the world [87]. In the United States, MenACWY-D and MenACWY-CRM197 are available, but MenACWY-TT is not currently approved [87, 88]. In contrast, MenACWY-D is not currently licensed in the European Union, where MenACWY-CRM197 and MenACWY-TT are used instead [17, 89, 90]. Additionally, the ages for which the vaccines are licensed can vary both between vaccines and between countries for a particular vaccine.

MenACWY-D

MenACWY-D is available in several countries, including some of those experiencing recent MenW disease increases, such as Australia, Canada, Argentina, and Chile [89]. Ages for which the vaccine is approved differ by country. For instance, in Canada, it is approved for use in individuals 9 months to 55 years of age [91]. For children 9–23 months of age, the manufacturer recommends that MenACWY-D be administered in two doses given at least 3 months apart. In individuals 2–55 years of age, MenACWY-D is administered as a single dose. In the United States, if 4 years have passed since the previous vaccination dose, a single booster dose may be administered to individuals 15–55 years of age who are at continued risk for meningococcal disease [16]. The immunogenicity of MenACWY-D has been described previously, with reports of ≥ 86.4% of subjects 1 year of age having serum bactericidal assays using human complement (hSBA) titers ≥ 1:8 for each of the four serogroups 1 month after a second dose [91]. Additionally, ≥ 96.2% of children 2–10 years of age had SBA titers ≥ 1:8 across the four vaccine serogroups 28 days after vaccination. Commonly reported reactions following MenACWY-D administration include injection site tenderness or pain and irritability in children and injection site pain, headache, and fatigue in adults.

MenACWY-CRM197

Similar to MenACWY-D, MenACWY-CRM197 is approved in many countries experiencing recent MenW disease increases, including the United Kingdom, France, Netherlands, Australia, Canada, Argentina, and Chile, among others [90]. In the European Union, MenACWY-CRM197 is approved for individuals 2 years and older, who are given a single dose [92]. In the United States, on the other hand, the vaccine is approved from 2 months of age, with recommended dosing for infants varying by age at initiation [15]. A booster dose can be given according to recommendations in both regions [15, 92]. In children 2–10 years of age, ≥ 68% had hSBA titers ≥ 1:8 across the four serogroups at 1 month after a single dose; percentages were ≥ 75% in adolescents 11–18 years of age and ≥ 69% in adults 19–55 years of age [92]. Commonly reported reactions after MenACWY-CRM197 dosing include pain, firmness, and erythema at the injection site and sleepiness, headache, irritability, and generally feeling unwell in children; and pain, firmness, and erythema at the injection site and nausea, headache, myalgia, and generally feeling unwell in adolescents and adults.

Review of Recent MenACWY-TT Studies

The recommendations for MenACWY vaccination in most of the reviewed countries include the most recently approved quadrivalent vaccine, MenACWY-TT [17, 39, 40, 42, 93]. MenACWY-TT is licensed throughout a large part of the lifespan (i.e., 6 weeks of age and older) [17, 86]. Several studies conducted in infants, toddlers, children, and adolescents have supported the expanded recommendations for MenACWY-TT vaccine use; these are summarized below and in Table 2 [94,95,96,97,98,99,100,101,102,103,104,105,106,107].

Table 2 Clinical studies of MenACWY-TT in infants, toddlers, and adolescents
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Infant Studies

In a noninferiority study conducted in Europe, 2095 infants were randomized to receive MenACWY-TT at 2, 3, 4, and 12 months of age; MenACWY-TT at 2, 4, and 12 months of age; MenC-CRM197 at 2, 4, and 12 months of age; or MenC-TT at 2, 4, and 12 months of age [94]. All subjects received other routine vaccinations as recommended. Immunogenicity was assessed 1 month after the primary infant series. A 2- or 3-dose primary series of MenACWY-TT was shown to be noninferior to a 2-dose primary series of MenC-CRM197 or MenC-TT in terms of the immune response to MenC. One month after primary vaccination, ≥ 93.1% of subjects had titers ≥ 1:8 in serum bactericidal assays using rabbit complement (rSBA) for the four serogroups, whereas ≥ 88.5% had titers ≥ 1:8 in assays using hSBA. Although proportions of subjects with titers ≥ 1:8 decreased by 12 months of age, immune responses to booster doses were robust, with ≥ 99.1% of subjects having rSBA or hSBA titers ≥ 1:8 a month after booster vaccination. MenACWY-TT vaccination was also demonstrated to be safe and tolerable.

In another study, MenACWY-TT was administered to 750 infants in a 2:1:1 randomization ratio with dosing at 2, 4, 6, and 15–18 months of age; 6 and 15–18 months of age; or 15–18 months of age [95]. All infants also received additional routine vaccinations. Efficacy and safety measures were reported. Among those receiving a 3-dose primary series at 2, 4, and 6 months of age, ≥ 99.4% of subjects had rSBA titers ≥ 1:8 for each of the vaccine serogroups at 1 month after the third dose. Among subjects receiving 1 dose at 6 months and those receiving one dose at 15–18 months, ≥ 93.9% and ≥ 96.3%, respectively, had rSBA titers ≥ 1:8 for each of the four serogroups 1 month after vaccination. For groups that received a booster dose at 15–18 months of age, ≥ 99.3% of subjects had rSBA titers ≥ 1:8 for each of the four serogroups at 1 month after booster vaccination. Proportions of subjects reporting local reactions, systemic events, adverse events (AEs), and serious AEs (SAEs) were similar across groups after primary and booster vaccinations. None of the SAEs were considered vaccine-related.

Toddler Studies

In a study conducted in 1000 toddlers aged 12–19 months in Finland, subjects were randomized 3:3:1:1 to 1 of 4 treatment groups [i.e., MenACWY-TT + measles, mumps, rubella, and varicella (MMRV) vaccine; MenACWY-TT alone; MMRV alone, or MenC-CRM197] [96]. One dose of MenACWY-TT was shown to be noninferior to MenC-CRM197 for immunogenicity against serogroup C and was also immunogenic against serogroups A, W, and Y. Forty-two days after vaccination with a single dose of MenACWY-TT, ≥ 99.7% of subjects had rSBA titers ≥ 1:8 against each vaccine serogroup; ≥ 99.4% also had titers ≥ 1:128 against serogroups A, W, and Y. Among subjects in the MenACWY-TT + MMRV and MMRV groups, all seroconverted against measles and rubella; 87.7% and 83.6%, respectively, had seroconverted against mumps; and 97.9% and 94.6% had seroconverted against varicella by 42 days postvaccination. Noninferiority was demonstrated for concomitant versus individual administration. Fever and rash occurred at a similar frequency in the MenACWY-TT + MMRV and MMRV groups; these frequencies were higher than those observed in the MenACWY-TT and MenC-CRM197 groups. Safety profiles were otherwise comparable across groups.

A phase 3 study was conducted in 802 toddlers 12–14 months of age in Australia, Canada, Czech Republic, Panama, South Africa, and Turkey, with subjects randomized to receive one dose of MenACWY-TT, two doses of MenACWY-TT at 2 months apart, one dose of MenACWY-TT coadministered with 13-valent pneumococcal conjugate vaccine (PCV13), or one dose of PCV13 followed by one dose of MenACWY-TT administered 2 months later [97]. At 1 month postvaccination, ≥ 92.8% of toddlers vaccinated with MenACWY-TT had rSBA titers ≥ 1:8 for the four serogroups, and geometric mean titers (GMTs) increased substantially compared with titers before vaccination. Responses were robust and slightly higher after two doses compared with one dose. Coadministration of MenACWY-TT and PCV13 did not alter the safety or immunogenicity profile of MenACWY-TT.

Child Studies

In a phase 2 study, 309 children aged 2–10 years in Finland were randomized 3:1 to receive one dose of MenACWY-TT or a licensed meningococcal MenACWY polysaccharide vaccine (Men-PS) [98]. The study assessed vaccine response rates, which were defined as a postvaccination rSBA titer ≥ 1:32 for seronegative children (rSBA titer < 1:8 at prevaccination) and ≥ fourfold increase in rSBA titer from prevaccination to postvaccination for seropositive children (rSBA titer ≥ 1:8 at prevaccination). At 1 month postvaccination, MenACWY-TT was noninferior to Men-PS with rSBA response rates ≥ 94.3% in the MenACWY-TT group and ≥ 81.2% in the Men-PS group. Exploratory analyses demonstrated that response rates and rSBA GMTs were higher among MenACWY-TT than Men-PS recipients, and a higher percentage of subjects had rSBA titers ≥ 1:128 for serogroup C in the MenACWY-TT group versus the Men-PS group. In the MenACWY-TT and Men-PS groups, pain was the most frequent solicited local symptom in children aged 2–5 years (45.1% and 71.8%, respectively) and 6–10 years (71.8% and 82.1%, respectively); redness and swelling were more common in the MenACWY-TT groups [98].

A follow-up study evaluated the persistence of serum bactericidal antibodies in these subjects up to 5 years after receiving MenACWY-TT or Men-PS [99]. At year 5, the proportion of subjects in the MenACWY-TT group (n = 98) with rSBA titers ≥ 1:8 for serogroups A, C, W and Y were 90.8%, 90.8%, 78.6%, and 78.6%, respectively; in the Men-PS group (n = 13), these proportions were 15.4%, 100%, 0.0%, and 7.7%, respectively. Exploratory analyses indicated that differences between the vaccine groups were significant for serogroups A, W, and Y. As individuals with rSBA-MenC titers < 1:8 at any time during the study were revaccinated with a MenC conjugate vaccine and withdrawn from further analyses, interpretation of serogroup C antibody persistence in the remaining subjects was difficult.

Adolescent and Young Adult Studies

A study of 93 British adolescents 16–19 years of age who had been previously vaccinated with MenC-TT or MenC-CRM197 at 3.5–5.9 years of age compared immunogenicity and safety of MenACWY-TT with MenACWY-CRM197 [100]. Of the 92 participants with available data, nearly all had protective rSBA titers (i.e., ≥ 1:8) for all serogroups at 1 month after booster in both groups, with the exception being for serogroup Y in one subject boosted with MenACWY-CRM197. The highest titers were measured in subjects primed with MenC-TT and boosted with MenACWY-TT. A high proportion of subjects in both MenACWY booster groups had protective titers through 9 months after booster. Both vaccines were well tolerated, although redness and muscle pain were comparatively more common among MenACWY-CRM197 recipients, and tiredness was more common among MenACWY-TT recipients. No vaccine-related SAEs occurred in either group.

A similar study assessed MenACWY-TT boosting in 501 Dutch adolescents aged 10, 12, and 15 years who had previously received the MenC vaccine at 14 months to 3 years of age [102]. All children had been primed with MenC-TT, and booster vaccinations used either MenACWY-TT or MenC-TT. One month after booster dosing, all participants except one had rSBA titers ≥ 1:8 for serogroup C; however, noninferiority for MenACWY-TT compared with MenC-TT could not be demonstrated for the subjects in the 10- and 15-year-old age groups. rSBA GMTs significantly declined in all age groups by 1 year after booster dosing, and noninferiority could not be demonstrated for any age group; however, all but two participants maintained rSBA titers ≥ 1:8. Importantly, the decline in protective antibodies was fastest in the 10-year-old age group, which may be important in determining optimal ages for vaccination.

Results from this study for serogroups A, W, and Y were reported in a separate publication and indicated that GMTs significantly increased at 1 month after MenACWY-TT vaccination [101]. MenW and MenY GMTs were higher in the 15-year-old age group compared with the 10-year-old age group, and MenA and MenY GMTs were higher in the 12-year-old age group compared with the 10-year-old age group; 100% of subjects in the 12- and 15-year-old age groups and ≥ 94.5% in the 10-year-old age group achieved rSBA titers ≥ 1:8 for all three serogroups. At 1 year after booster, 95.1% of subjects maintained rSBA titers ≥ 1:8 against all three serogroups, and MenW GMTs in the 10-year-old age group were significantly lower than in the other age groups, again suggesting that vaccination after earlier adolescence might maximize effectiveness.

The safety and immunogenicity of MenACWY-TT were compared with that of MenACWY-D in Canadian and US adolescents and young adults in a phase 2 clinical study [103]. Subjects were randomized to receive a single dose of MenACWY-TT (1 of 2 lots, with lot A and lot B having 68% and 92% O-acetylation of the MenA polysaccharide, respectively) or MenACWY-D. Vaccine response was defined as an hSBA titer ≥ 1:8 in initially seronegative subjects or a fourfold increase in titer in subjects who were initially seropositive. At 1 month after vaccination, vaccine response rates for the four serogroups ranged from 51.2 to 77.2% in subjects vaccinated with MenACWY-TT lot A, 51.0–82.5% in subjects vaccinated with MenACWY-TT lot B, and 39.0–76.3% in subjects vaccinated with MenACWY-D. The primary study objective, noninferiority of MenACWY-TT (lot A) compared to MenACWY-D with respect to hSBA responses against each serogroup, was demonstrated. Local and systemic events were comparable among the three vaccine groups, and the frequency of SAEs was similar in MenACWY-TT and MenACWY-D vaccinated subjects.

The persistence of the bactericidal antibody response was compared in US subjects who had been randomized 3:1 to receive one dose of MenACWY-TT or MenACWY-D at 10–25 years of age [105]. Five years postvaccination, the proportions of subjects with hSBA titers ≥ 1:8 against serogroups A, C, W, and Y were 48.9%, 92.9%, 87.0%, and 94.4%, respectively, in the MenACWY-TT group and 44.4%, 79.5%, 84.1%, and 90.9% in the MenACWY-D group. In the MenACWY-TT group, serogroup C, W, and Y hSBA GMTs remained above prevaccination levels at 5 years; in the MenACWY-D group, serogroup W and Y GMTs remained elevated. Exploratory analyses suggested that serogroup C and Y GMTs and the percentage of subjects with titers ≥ 1:8 against serogroup C were higher in the MenACWY-TT group compared with the MenACWY-D group. No vaccination-related SAEs were reported during the 5 years of this study.

A study carried out in the Philippines and Saudi Arabia evaluated bactericidal antibody persistence and safety of MenACWY-TT in healthy adolescents and adults aged 11–55 years at the time of vaccination [104]. Of the 500 subjects who were randomized 3:1 to receive one dose of MenACWY-TT or Men-PS, 404 vaccinated subjects returned at year 5: 299 subjects in the MenACWY-TT group (including n = 208 subjects aged 11–17 years) and 105 subjects in the Men-PS group (including n = 76 subjects aged 11–17 years). In the total year 5 cohort, the percentages of subjects with rSBA titers ≥ 1:8 for serogroups A, C, W, and Y in the MenACWY-TT group were 90.0%, 79.3%, 71.6%, and 84.3%, respectively; corresponding values in the Men-PS group were 74.3%, 71.2%, 24.8%, and 44.8%, respectively. Exploratory analyses indicated that the percentages of subjects with rSBA titers ≥ 1:8 for serogroups A, W, and Y were significantly higher in the MenACWY-TT group than the Men-PS group at year 5. In both vaccine groups, rSBA antibody responses of the adolescent age group were consistent with those of the total population. No SAEs related to vaccination were reported during the 5-year study period.

Two recent studies addressed concomitant administration of MenACWY-TT with other vaccines commonly recommended to adolescents [106, 107]. In reviewing these studies, it is important to note that vaccination rates among adolescents are often low [73, 108, 109], and concomitant vaccination is an established strategy for increasing vaccine uptake [110, 111]. The first study compared concomitant administration of MenACWY-TT and tetanus, diphtheria, and acellular pertussis vaccine (Tdap; Boostrix®; GlaxoSmithKline, Rixensart, Belgium) [112] with sequential administration of the two vaccines in 691 adolescents aged 11–25 years from Korea, Germany, and the Dominican Republic. One month after vaccination, prespecified noninferiority criteria were met in the coadministration group for all four meningococcal serogroups (using rSBA GMTs) as well as for antibodies targeting diphtheria and tetanus but not for antibodies targeting pertussis antigens. Overall, 96.9–100% of subjects had anti-meningococcal rSBA titers or anti-Tdap antibody concentrations meeting or exceeding assay cutoffs for all serogroups and antigens tested. Coadministration did not increase frequencies of local reactions, systemic events, or unsolicited AEs, and none of the three SAEs reported across groups were considered vaccine-related.

An additional study in 1300 female subjects aged 9–25 years in Estonia, Thailand, and the Dominican Republic investigated concomitant administration of MenACWY-TT with 2-valent human papillomavirus (HPV2; Cervarix™; GlaxoSmithKline, Rixensart, Belgium) [113] and Tdap vaccines [107]. Concomitant vaccination of MenACWY-TT and HPV2 with one another or with Tdap in addition was noninferior to individual administration of either vaccine. Across groups, ≥ 97.3% of subjects had rSBA titers ≥ 1:8 or ≥ 1:128 against each of the meningococcal serogroups, and ≥ 99.6% of subjects in each group had anti-HPV antibodies meeting or exceeding prespecified thresholds. Similar to the study assessing concomitant administration with Tdap, coadministration of all three vaccines met noninferiority criteria for diphtheria and tetanus but not pertussis antigens compared with coadministration of Tdap with HPV2 only; however, ≥ 98.0% of subjects in each group had pertussis antigen antibodies above the assay cutoff. Safety and tolerability of all vaccines were not affected by concomitant administration.

Discussion

Vaccination is the best method for preventing IMD [37]. Coupled with the broad distribution of A, C, W, and Y IMD serogroups worldwide and the potential for sporadic and unpredictable outbreaks, multivalent meningococcal vaccines provide the best prophylactic coverage against IMD. Several countries (United Kingdom, France, the Netherlands, Australia, and Chile) that included monovalent MenC in their national meningococcal vaccination recommendations have experienced recent notable increases in IMD due to MenW [41, 43, 47, 51, 59]. Recent global increases in MenW disease and resulting changes in vaccination programs are of critical importance and have been chronicled elsewhere in addition to the current review [114]. Increases were sometimes quite dramatic, such as the tenfold increase in MenW IMD in the United Kingdom that occurred from 2009–2010 to 2016–2017 [41]. In association with increased incidence, the United Kingdom, the Netherlands, Australia, and Chile, as well as other countries and regions, have opted to update meningococcal vaccination recommendations to replace monovalent MenC vaccine with quadrivalent MenACWY vaccines [38, 42, 69, 75,76,77, 115,116,117]. To similarly address recent changes in IMD epidemiology, Italy changed its vaccination recommendations to include an adolescent MenACWY vaccine dose to address a MenC outbreak that occurred in 2015–2016 [44,45,46, 67]. In some cases, the effects of MenACWY vaccination are already evident (e.g., United Kingdom, which had a 69% decrease in the number of MenW cases in the first year of an emergency MenACWY vaccination program targeting matriculated high school students/college entrants) [73]. Epidemiologic surveillance over the coming years is expected to provide valuable insight into the protection afforded by broader serogroup coverage.

Currently, three conjugate quadrivalent vaccine formulations—MenACWY-CRM197, MenACWY-D, and MenACWY-TT—are in use globally [15,16,17]. Of these, MenACWY-TT is the most recently approved, with initial authorization in the European Union in 2012 [17] and approval in more than 40 other countries [88]. The TT carrier protein contained in the MenACWY-TT formulation provides good thermal stability and a large surface area for polysaccharide conjugation [118]. In addition, higher antibody titers postdosing have been reported with the TT protein than with the CRM protein [119,120,121]. The immunogenicity and safety profile of MenACWY-TT has been established in clinical studies and supports use across all age groups [17]. The European Medicines Agency license for MenACWY-TT currently specifies that infants 6 weeks to < 6 months of age should be given two doses separated by 2 months, followed by a booster dose at 12 months of age with at least 2 months since the previous primary dose [17]. Infants from 6 months to < 12 months of age should be given one dose, followed by a booster dose at 12 months of age or at least 2 months after the first dose. Toddlers from 12 months of age, children, adolescents, and adults are given a single dose; previously vaccinated individuals who are 12 months or older may be given a booster MenACWY-TT dose if previously vaccinated with a conjugated or plain polysaccharide meningococcal vaccine.

The available MenACWY conjugate vaccines induce protection against four of the five major disease-causing serogroups, the greatest number in a single vaccine. However, these vaccines will not prevent serogroup B infections, which are a predominant cause of IMD in many countries [23]. An adjunct vaccination strategy with recently introduced MenB vaccines should therefore be considered to provide protection against this serogroup. An innovative approach of combining these vaccines into a pentavalent entity is currently under evaluation. Two studies conducted in adolescents and young adults evaluated a pentavalent MenABCWY vaccine based on MenACWY-CRM197 and MenB-4C compared with individual administration of both vaccines [122, 123]. Immune responses after two doses of the MenABCWY vaccine were high for all serogroups in both studies [122, 123], and an extension study also supported prime-boost strategies in those vaccinated with currently licensed MenB-4C or MenACWY-CRM197 vaccines [124]. Another MenABCWY vaccine based on MenB-FHbp for the serogroup B component is currently under clinical evaluation [125].

The addition of subcapsular antigens to capsular polysaccharide-based multivalent vaccines could also augment protection against non-MenB isolates (cross-protection), as shown by the high proportions of MenB-FHbp recipients with hSBA titers ≥ 1:8 against strains from serogroups C, W, X, and Y [30]. For MenB-4C, two studies suggested that sera from vaccinated subjects were capable of killing MenW and MenX strains [29, 126].

Although direct protection is an important component of meningococcal vaccination strategies, reducing meningococcal carriage and transmission can also be crucial for reducing IMD on a population level. In addition to inducing protective antibodies, meningococcal conjugate vaccines have the ability to reduce acquisition of nasopharyngeal carriage in those vaccinated and thus reduce subsequent transmission to the unvaccinated [127]. Protection of unvaccinated individuals (herd protection) has been observed with MenC conjugate vaccination in the United Kingdom, where decreases in IMD incidence were first evident in vaccinated individuals, followed by unvaccinated children and older adults [34]. Similar findings were observed with the use of MenC vaccine in the Netherlands, where MenC IMD decreased rapidly in all age groups, although only children and adolescents ≤ 18 years of age were vaccinated [33]; such outcomes were also observed in Australia [35]. As mentioned previously, data also indicate reduced carriage following MenA vaccination in Africa [36]. Supportive data are still needed to address the potential of MenACWY vaccines to induce herd protection.

Conclusion

In summary, global shifts in IMD epidemiology, particularly the increased incidence of MenW IMD, have resulted in reactive vaccination recommendations in several countries. Quadrivalent conjugate vaccines cover the greatest number of serogroups among available vaccines, and reductions in MenW IMD are already evident in the United Kingdom, where MenACWY vaccination has been incorporated into the immunization program [73]. As IMD occurs unpredictably, proactive vaccination strategies providing broad protection against disease-causing serogroups are advisable. MenACWY-TT, the most recently approved quadrivalent vaccine, administered as a primary infant series or as a single dose in toddlers and adolescents, provides broad seroprotection coupled with a favorable safety profile.