Meningococcal B vaccine (4CMenB): the journey from research to real world experience

ABSTRACT

Introduction: Neisseria meningitidis serogroup B (MenB) is the most common cause of bacterial meningitis in many industrialized countries and occurs at any age. The highest incidence is in infants aged <1 year, followed by children and adolescents. Four-component MenB vaccine (4CMenB, Bexsero) is the only MenB vaccine authorized for use in all age-groups. Experience with 4CMenB is growing as it is implemented in different countries/age-groups encompassing university students, children, adolescents, and infant mass vaccination programs.

Areas covered: An update of recently available data describing the mechanism of immunogenicity of 4CMenB and real-world evidence of vaccine effectiveness and disease impact. We discuss the appropriate age for vaccination to maximize population impacts.

Expert commentary: Invasive meningococcal disease is uncommon and sufficiently powered efficacy studies were not feasible during 4CMenB development. Additionally, several thousand genetically diverse invasive MenB strains circulate globally, varying widely in surface protein expression. This posed significant challenges in predicting clinical protection with MenB vaccines. Five years of 4CMenB use post-licensure confirm the clinical benefit of vaccination as predicted during development. Preliminary evidence suggests an extended impact on other meningococcal serogroups and Neisseria gonorrhoeae.

KEYWORDS:

• 4CMenB
• effectiveness
• infants; adolescents
• impact
• meningococcal serogroup B
• Neisseria meningitidis
• Neisseria gonorrhoeae
• vaccine

1. Introduction

Neisseria meningitidis serogroup B (MenB) is the most common cause of bacterial meningitis in many industrialized countries, and infants less than 1 year of age are most frequently affected. While the burden of illness due to meningococcal serogroups such as serogroup C (MenC) in Europe and Australia, and serogroup A in the meningitis belt has reduced dramatically in countries that employ meningococcal conjugate vaccines in routine childhood vaccination schedules, invasive meningococcal disease (IMD) due to MenB has continued unchecked. In 2012 in Europe, 68% of confirmed IMD cases were caused by MenB, with an overall case fatality of approximately 7%, compared to 14% for MenC and 8% for MenY [1]. In 2016, 35% of all confirmed IMD in the United States (US) was due to MenB [2], and in 2015, 62% of cases in Australia were due to MenB [3].

The incidence of MenB in infants usually vastly exceeds the incidence in other age groups: for example, the incidence was 11-fold higher in <1 year olds (11.5 cases per 100,000) than in 15–24 year-olds in Europe (1.1 cases per 100,000) (2012), and was almost 6-fold higher in <1 year olds (0.67 cases per 100,000) than in 16–23 year-olds (0.12 cases per 100,000) in the US (2016) [1,2].

4CMenB is a four-component vaccine that contains three main Neisseria protein antigens discovered by mining the genome of N. meningitidis with the so-called ‘reverse vaccinology’ approach [4]. They are Neisseria adhesin A (NadA), Neisserial Heparin Binding Antigen (NHBA), and variant 1 of factor H binding protein (fHbp). The three protein antigens were selected on the basis of their ability to induce serum bactericidal antibodies (SBA) to homologous and heterologous MenB strains [5]. fHbp is a lipoprotein expressed on the surface of the bacterium that binds human complement regulator factor H; thus allowing the bacterium to escape complement killing and to grow in human blood. There are three noncross reactive variants of fHbp named variants 1, 2, and 3 that have also been described as subfamilies; subfamily B containing variant 1, and subfamily A containing variants 2 and 3. NadA is a surface exposed protein that binds human epithelial cells, monocytes and macrophages, and is involved in bacterial adhesion and invasion of human epithelial cells. NHBA is a lipoprotein also exposed on the bacterial surface which binds heparin, improving the survival of bacteria in blood, and mediates adhesion to epithelial cells. fHbp and NHBA antigens were fused respectively to two accessory antigens known as Genome-derived Neisseria Antigen (GNA) 2091 and GNA 1030, which were selected for their ability to induce bactericidal antibodies and/or to induce protection in an adult mouse model [4].

The fourth component of 4CMenB is the OMV derived from a MenB outbreak strain (B:4:P1.7–2.4) from New Zealand and included in 4CMenB to provide protection against strains expressing the serosubtype P1.4 of PorA [6,7] (Table 1). The inclusion of four components in the final vaccine aimed at inducing high levels of SBA capable of providing broad protection against the majority of IMD caused by MenB, and to induce antibodies able to block important steps contributing to meningococcal virulence.

Table 1. Antigen components of 4CMenB and rLP2086 and rationale for their selection.

Vaccine	Antigen	Sequence variant	Rationale
4CMenB	50 µg fHbp fused to accessory protein GNA2091	fHbp (Family B) Variant 1.1	Recombinant fHbp induced SBA against a broad range of variant 1 strains and passive protection against homologous and heterologous meningococcal challenge in animal models [74]. GNA 2091 is an accessory antigen shown to convey protection in animal models [4].
	50 µg NHBA fused to accessory protein GNA 1030	NHBA Peptide 2	NHBA induces SBA against strains carrying different peptides [75], and antibodies against NHBA are protective in animal models against homologous and heterologous N. meningitidis strains [76]. Antibodies to fHbp, OMV and NHBA also work synergistically to induce SBA [22]. GNA 1030 is an accessory antigen that induces bactericidal antibodies and conveys protection in animal models [4].
	50 µg NadA	Variant 3	NadA is highly immunogenic and induces cross-reactive SBA responses against strains carrying the nadA gene [77,78] Anti-NadA-specific antibodies in sera from immunized infants passively protected infant rats by bacteremia in a challenge model [79].
	25 µg OMV	NZ98/254 PorA 1.4	OMV is highly effective in inducing SBA and is the same OMV used to curtail a MenB epidemic in New Zealand [7]. Inclusion of the OMV component induced a specific protective response against P1.4 homologous strains [6], and improved immunogenicity against heterologous strains by contributing with minor antigens
rLP2086	60 µg fHbp	A05 (Variant 3.45)	Recombinant lipidated fHbp induced SBA against a strains expressing a threshold level of fHbp, and passive protection against homologous and heterologous meningococcal challenge in animal models [74]. A combination of two genetically different fHbp subfamilies induces strain coverage dependent on fHbp sequence diversity and expression level
	60 µg fHbp	B01 (Variant 1.55)

fHbp = factor H binding protein, GNA = Genome-derived Neisseria Antigens, NadA = Neisseria adhesin A, NHBA = Neisserial Heparin Binding Antigen, OMV = outer membrane vesicle, PorA = porin A, SBA = serum bactericidal antibodies, IMD = invasive meningococcal disease, MenB = meningococcus serogroup B

4CMenB (Bexsero, GSK), was first authorized in the European Union (EU) in 2013 and in the United States in 2015. 4CMenB is licensed in Europe, and other countries including Canada, Australia, Brazil, Argentina, for use in infants from 2 months of age as a three-dose schedule plus booster and from 3 months of age as a two-dose schedule plus booster [8], and as a two-dose schedule from 2 years and above. In the United States, it is licensed for 10–25 year-olds as a two-dose schedule with a minimum interval of 1 month between doses. 4CMenB is currently recommended in infant universal mass immunization (UMV) programs in the United Kingdom (UK), Ireland, and Italy [9–12].

The second MenB vaccine, rLP2086 (Trumenba, Pfizer), was authorized in the United States in October 2014 and in the EU in 2017. rLP2086 is licensed for use as a two- or three-dose schedule in 10–25 year-olds in the United States and in individuals aged 10 years and older in the EU. rLP2086 contains two fHbp variants (variants 1 and 3 or subfamilies A and B) in a lipidated form (Table 1).

Because IMD is uncommon, it was not feasible to conduct sufficiently powered studies to demonstrate vaccine efficacy prior to licensure. Therefore, 4CMenB and rLP2086 were both authorized on the basis of immunogenicity demonstrated in clinical trials in terms of the percentage of subjects who achieved threshold levels considered protective in SBA assay using human serum as complement source (hSBA). An hSBA titer of at least 1:4 is widely accepted as a surrogate marker of protection against meningococcal disease [13]. However, several thousand genetically diverse invasive MenB strains circulate globally, and these vary widely in their surface protein expression. Establishing the breadth of coverage of these new vaccines across the potential range of invasive strains proved difficult, and relied on SBA and novel in vitro assays such as the Meningococcal Antigen Typing System (MATS).

At present, the published data are not sufficient to enable evaluation of the full impact of rLP2086 vaccination. For 4CMenB, the journey to understand MenB vaccine efficacy started some 20 years ago when the genome sequence of MenB was decoded (Figure 1). Since then, our understanding of MenB vaccine efficacy, in particular of 4CMenB, has advanced extensively. Effectiveness in preventing IMD at a population level has been demonstrated [14], and the wider population impacts of vaccination continue to be explored (Figure 1). In addition to direct protection of vaccinated persons, additional benefits could include reductions in carriage of MenB or other serogroups that share antigens in common with the vaccine, and potentially cross-species impacts on diseases such as gonorrhea.

Figure 1. 4CMenB: the journey from early research to real world experience.

MATS = Meningococcal Antigen Typing System, hSBA = serum bactericidal antibodies using human complement, IMD = invasive meningococcal disease. Figure references: 1 = [26], 2 = [80], 3 = [81], 4 = [14].

Since authorization, new data include effectiveness estimates against MenB from the UK infant UMV program, and data suggestive of possible protection against serogroup W (MenW) [14,15] and cross-protection against Neisseria gonorrhoeae infection have become available [16,17]. Additionally, data from in vitro studies with human monoclonal antibodies induced by 4CMenB provide first indications of the mechanism of 4CMenB immunogenicity, and the synergistic effect of the antibodies induced by the vaccine antigens. Here we provide an update of the mechanism of action of 4CMenB that support the antigen make-up of the vaccine, and real-world evidence of vaccine effectiveness and impact. We also discuss the appropriate age for vaccination to maximize population impacts. A summary contextualizing the results and potential clinical relevance and impact is displayed in the Focus on the Patient Section (Figure 2).

Figure 2. Focus on the patient section.

2. Mechanistic insights into 4CMenB action

Meningococcal vaccines work by inducing complement-mediated killing of bacteria through antibodies directed against specific surface structures. However, conservation at the amino acid level and a threshold density of the target antigen is required for efficient complement activation [18]. For the OMV component of 4CMenB, efficacy is linked to bactericidal antibodies directed mainly against the homologous PorA, which is highly abundant on the surface of the bacterium, but varies quite remarkably in terms of primary sequence among different isolates [19]. For strains in which expression of the target antigens is low, or when their sequences are highly diverse compared to the forms present in the vaccine, multiple targets may be needed for antibody binding to reach sufficient antibody density on the bacterial surface to trigger the activation of complement [20].

A recent study by Giuliani et al [21], showed that fHbp, NadA, and NHBA in 4CMenB each contain multiple protective epitopes. Antibodies targeting the different epitopes work synergistically, enhancing the bactericidal response to each antigen. For example, monoclonal antibodies to fHbp that individually did not induce SBA with human complement, elicited strong SBA responses when combined with monoclonal antibodies targeting different epitopes on the same protein. In addition, it has been reported that antigens like fHbp and NHBA may work in synergy to elicit bactericidal killing of strains that would be resistant to antibodies raised against each of the two, separately [22]. These findings show that the presence of multiple epitopes and multiple antigen targets in the same vaccine promotes a robust bactericidal response, even when a single target is not sufficient, thereby substantiating the inclusion of multiple antigens in 4CMenB. A model for this phenomenon is proposed in Figure 3. As the majority of invasive MenB strains contain genes for more than one 4CMenB component, it is likely that the antibodies to each antigen, in addition to working on their own, contribute to a synergistic bactericidal response when combined. This is particularly important when the level of expression of an antigen is not high enough to guarantee an adequate density of the target on the bacterial surface. In the particular case of fHbp, it is well known that the level of antigen expression varies markedly between strains, and can be particularly low in strains expressing some peculiar var2 and var3 subvariants [23–25]. In these cases, the amount of antibodies directed to this target might not reach the threshold for achieving effective complement activation and bacterial killing. However, this gap could be partially filled by the presence of antibodies directed against other antigens (e.g. NHBA), which, although per se not sufficient for complement activation, could help to reach the threshold in cooperation with antibodies against fHbp, thus ultimately contributing to bacterial killing and protection.

Figure 3. Synergy of C1q engagement by (a) monoclonal antibodies binding to two different antigens on the bacterial surface or (b) two monoclonal antibodies binding to the same antigen.

So far, MATS has been used to predict the coverage of IMD-causing meningococcal strains in different countries. MATS measures the phenotypic expression and cross-reactivity of each of the three main antigens, fHbp, NadA, and NHBA on individual MenB strains. Combined with conventional genotyping for PorA, MATS provides an estimation of whether a given isolate would be susceptible to bactericidal killing by antibodies induced by 4CMenB. Since MATS provides an estimation of the contribution of each antigen independently, the cooperation of antibodies recognizing different antigens is not measured, providing a mechanistic explanation for the observed underestimation of 4CMenB protection. The underestimation of protection predicted by MATS was shown in the United Kingdom where the MATS predicted coverage was 73% on circulating clinical strains, while the bactericidal assay showed coverage of 88% of the strains [26]. Similarly, a recent study conducted in Spain reported that strains predicted not to be covered by MATS were killed when tested in hSBA with human sera [27]. Finally, the overall underestimation has been confirmed by real effectiveness of 82.9% from the use of 4CMenB in the UMV program in the United Kingdom [14].

3. Recent evidence of 4CMenB vaccine effectiveness

3.1. Canada

In 2003, an outbreak of a MenB ST269 clone began in Quebec which primarily affected children and adolescents [28]. The outbreak peaked in the Saguenay-Lac-Saint-Jean region where the incidence of MenB IMD reached 6.2/100,000 [29]. A short-term mass vaccination campaign with 4CMenB commenced in 2014, targeting all individuals aged 2 months to 20 years living in the Saguenay-Lac-Saint-Jean region. Eighty-two percent of the target population (49,000 individuals) received at least one vaccine dose [29]. No cases of MenB IMD were reported in vaccinated individuals between 2015 and 2016, from an incidence of MenB IMD in the target population of 11.4 per 100,000 in 2006–2014. No cases occurred in 10,000 unvaccinated individuals in the target population, and there were no cases among 2700 unvaccinated infants born in 2015 after the campaign had finished, which is suggestive of herd protection. During this period, in the entire region there were only two cases of IMD in nonvaccinated adults. The adjusted risk of disease in Saguenay-Lac-Saint-Jean was significantly decreased: relative risk 0.22 (95% confidence interval [CI] 0.05–0.92, p = 0.04). No safety concerns were raised during the campaign [30].

3.2. United Kingdom

Routine meningococcal UMV was pioneered in the United Kingdom with the introduction of the first infant MenC vaccination campaign in 1999 in response to a prolonged clonal MenC outbreak [31]. During the MenC campaign individuals from two months to 18 years of age were vaccinated with the conjugate vaccine. After the initial success of the infant and catch-up campaign, the MenC schedule received several adjustments and now comprises one dose in the second year of life and a second dose given as quadrivalent serogroups A, C, W, Y conjugate vaccine (MenACWY) at 14 years of age.

UMV with 4CMenB was introduced into the infant vaccination schedule in September 2015, and the UK authorities elected to use a reduced 2-dose priming schedule at 2 and 4 months of age, with booster at age 12 months [11]. One year after the introduction of infant UMV, the number of IMD cases in vaccine-eligible infants decreased from an average of 74 in the previous four years, to 37 in 2015–16 [14]. The overall effectiveness of two doses of 4CMenB against MenB IMD was calculated to be 82.9% (95% CI 24.1–95.2). Recent data showed that during the second year the vaccine impact was consistent with estimates reported for first year, suggesting similar ongoing efficacy in year 2 [32]. Effectiveness data from the UK substantiate prelicensure estimates and provide re-assurance that 4CMenB is highly effective in preventing MenB IMD.

3.3. University outbreaks in the United States

4CMenB has been used in six MenB IMD outbreaks in university campuses since 2013 [33]. In outbreaks that occurred in 2014 (University of California, Santa Barbara and Princeton University New Jersey) and in 2016 (Santa Clara University, California) [33–36], no cases of MenB have occurred in vaccinated students following the campaigns [36].

A seroprevalence study conducted in vaccinated students at Princeton University showed that 87% and 100% of vaccinated students had positive hSBA against reference strains for fHbp and NadA, respectively, while 66.1% of vaccinated students had hSBA titers ≥1:4 against the outbreak strain [37]. Nevertheless, no MenB IMD occurred in vaccinated students. This study confirms the findings of Goldschneider et al., published in 1969 [38], who showed that hSBA underestimates protection, and that while a positive result on hSBA assay indicates protection against IMD, a negative hSBA result is not an indication of susceptibility [39]. Indeed, whole blood from persons vaccinated with 4CMenB can kill meningococci even if negative in hSBA [40].

4. Evidence for cross-protection

4.1. Can 4CMenB offer protection against meningococci beyond MenB?

The antigens contained in 4CMenB are common to meningococcal serogroups other than MenB to a varying degree [41]. Thus it is expected that 4CMenB may induce some level of cross-protection against non-B serogroups. For example, the NadA and NHBA antigens are conserved also in the hypervirulent MenW ST11 strain responsible for a growing number of MenW cases in many countries including the United Kingdom, Australia, Chile, and Argentina [15,42,43]. Conversely, most MenW ST11 strains express fHbp as variant 2 or 3, therefore while cross-protection from fHbp variant 1 present in 4CMenB cannot be anticipated, cross-protection might be afforded through NadA and NHBA. Studies using sera from 4CMenB-vaccinated persons support this hypothesis, showing bactericidal activity against MenW clinical isolates from England and Wales, Germany, France, and Brazil, and serogroup X isolates from Africa [15,44,45]. Of note, MATS has not been developed to estimate coverage of non-B strains.

The UK commenced an emergency vaccination program using MenACWY at the same time (2015) when the UMV infant vaccination program with 4CMenB began [46]. The target groups for MenACWY vaccination were adolescents 13–14 years of age, with a catch-up phase for 14–18 year olds, and university entrants. In the first year after the vaccination program only 36.6% coverage of the target population was achieved. Yet the number of MenW IMD cases increased in all age groups except the target age group aged 15–19 years (31% reduction in cases), and interestingly, in infants <1 year of age (35% reduction in cases) [46]. The authors of this study concluded that the observed decrease in MenW cases in infants was consistent with the bactericidal activity elicited by 4CMenB against the MenW strains.

Although these data are suggestive of cross-protection by 4CMenB against other serogroups, large, well-designed studies are needed to provide conclusive evidence of cross-protection. Such studies will be difficult to perform in view of the low numbers of IMD cases caused by ACWY serogroups, and because of the confounding effects of concurrent meningococcal ACWY conjugate vaccination.

4.2. Can 4CMenB prevent N. gonorrhoeae infection?

4.2.1. Background and disease burden

N. gonorrhoeae causes infections of the genital tract with potentially severe long term consequences including infertility and chronic pelvic pain and is transmitted through sexual contact. N. gonorrhoeae also causes conjunctivitis, pharyngitis, pelvic inflammatory disease, and occasionally disseminated disease or meningitis [47]. Antimicrobial resistance among clinical isolates is a growing concern [48]. The World Health Organization estimated that today there are more than 78 million cases of gonorrhea worldwide, affecting almost 1% of the global population [49]. N. gonorrhoeae infections are thus a major public health concern.

N. meningitidis and N. gonorrhoeae share 80–90% sequence homology at the genome level [50]. In a study that examined 111 N. gonorrhoeae isolates from 28 countries, genes for fHbp, nhba, gna1030, and gna2091 were present in all isolates, whereas nadA was not identified in any isolate [51]. NHBA, GNA 1030, and GNA 2091 were highly conserved across N. gonorrhoeae strains, while fHbp was present as variant 3 and shown to be nonlipidated and not surface exposed in gonococci [52]. Compared to a reference MenB strain, amino acid sequence identity was 60.9% for gonococcal fHbp and 90.2% for NHBA. Expression of these proteins was variable [51].

4.2.2 Evidence supporting cross-protection against N. gonorrhoeae

No clinical trials have been conducted to evaluate the effect of 4CMenB vaccination on N. gonorrhoeae infection. A modeling study predicted that assumed effectiveness of 4CMenB against gonorrhea of as low as 20% could prevent more than 83,000 infections per birth cohort in the United States, with substantial cost savings [53]. Population-based surveillance in regions where 4CMenB has been widely used suggests that 4CMenB may show some cross-protection in the real-world setting [16,54].

A retrospective cohort study was conducted in the Saguenay-Lac-Saint-Jean region in Canada, where 49,000 individuals 2 months to 20 year of age received 4CMenB [16]. Notifications of gonorrhea to the public health authority were compared for the prevaccination period (Jan 2006–June 2014) and the post-vaccination period (July 2014–June 2017). There were 231 notifications from 2006 until June 2017 in those aged 14 years and older. The number of gonorrhea cases decreased in 14–20 year-olds during the postvaccination period, but increased in those ≥21 years, although this trend was not significant; vaccine effectiveness against gonococcal infection in 14–20 year-old was 59% (95% CI −22–84, p = 0.1) [16].

Other evidence comes from the 2004 to 2008 New Zealand campaign to control a prolonged MenB epidemic [54]. The MenZB OMV vaccine – the same OMV component in 4CMenB – was given to individuals <20 years of age and 81% of the target group (approximately 1 million individuals) received vaccination. A retrospective case control study estimated vaccine effectiveness in preventing gonorrhea among 14,730 vaccinees aged 15–30 years-recruited from sexual health clinics [17]. Cases were gonorrhea positive and controls were chlamydia positive. Vaccine effectiveness among fully vaccinated 15–30 year-olds was 31% (95% CI 21–39, p < 0.0001).

The statistically significant finding of 31% effectiveness of MenB OMV in preventing gonorrhea is very encouraging, particularly considering that additional potentially cross-protective antigens are present in 4CMenB. The evidence to date suggests that the degree of cross-protection could contribute to the overall population impact of 4CMenB vaccination programs.

4.3. Impact on meningococcal carriage

In a study conducted in UK adolescents, 4CMenB vaccination was associated with a significant decrease (26.6%, 95% CI 10.5–39.9) in the carriage of other capsular groups (BCWY, mainly serogroup Y), during the first year after vaccination. A trend in reduction in carriage of MenB strains was also detected, although not statistically significant, possibly because of the low level of carriage during the study [55]. Carriage of MenB and carriage acquisition did not decrease after three doses of rLP2086 in a limited number of adolescents in the United States who were vaccinated as part of a MenB outbreak control program [56]. In a recently published study, neither 4CMenB nor rLP2016 had an impact on carriage, although the study was probably too small to provide meaningful results [57].

A large randomized control trial to assess the impact of 4CMenB on pharyngeal meningococcal carriage in adolescents is currently underway in Australia (www.clinicaltrials.gov NCT03089086) [58].

4.4. What is the appropriate age for MenB vaccination? arguments for 4CMenB in infant UMV programs

While MenB infections occur in all age groups, the highest incidence is overwhelmingly in infants. Of all notified MenB IMD cases in Europe (2012), Australia (2015) and the US (2016), between 31.5% and 72% were in children less than 5 years of age, and 9% to 21% were in children aged less than 1 year [1–3].

Experience with meningococcal conjugate vaccines has shown that rapid disease control is achieved with infant UMV combined with a catch-up program in older age groups to rapidly induce herd protection effects [31,59]. For conjugate vaccines, booster doses during adolescence are required to prevent waning immunity [59].

Adolescents play a pivotal role as carriers of meningococci and are the main source of transmission. Adolescent vaccination against meningococcal disease is considered key to interrupting carriage and transmission, thereby influencing the epidemiology of IMD in all age groups [59]. However, results from a modeling study suggest that whilst adolescent-only vaccination programs against IMD can help to prevent disease in adolescents themselves, such strategies are not immediately effective in reducing disease in infants [60]. In the United States, adolescent-only vaccination was pursued commencing in 2005 using a single dose of MenACWY in 11–18 year olds, with a booster dose added in 2010 due to concerns around waning immunity [61]. Uptake of the vaccine was slow but steady, with coverage of one dose reaching 40% in 2008 and 82% by 2016 [62]. Adolescents are traditionally difficult to access for vaccination because they are infrequent users of healthcare services and so have fewer opportunities to receive vaccination from a healthcare provider [63].

For MenB vaccines, in the absence of solid carriage data for 4CMenB or for rLP2086, it is not known whether an adolescent-only strategy using MenB vaccines would have the desired effect on carriage and transmission to infants. If vaccination does interrupt transmission, the choice of an adolescent-only or combined adolescent plus infant strategy could influence the vaccine impact. A modeling study of 4CMenB vaccination in the United Kingdom has suggested that an adolescent-only vaccination strategy is the most favorable from a cost-effectiveness viewpoint, providing direct protection to the target population in whom a peak in IMD occurs. However, if vaccination interrupts transmission it would take 20 years for this strategy to substantially reduce the number of IMD cases [60] (Figure 4). In this model, most cases were prevented using a combined infant-adolescent vaccination strategy [60].

Figure 4. Effect of alternate vaccination strategies on annual disease cases.

VEC = vaccine efficacy against carriage, SC = strain coverage, CU = one-off catch up vaccination. Routine vaccination infant at 2, 3, 4, and 12 months of age (blue line) and adolescent vaccination at age 13 years (2 doses) (dashed yellow line). Combined strategy refers to routine vaccination infant at 2, 3, 4, and 12 months (3 + 1 doses) and adolescent at 13 years (2 doses). This could be switched after 10 years to routine infant at 2, 4, and 12 months (2 + 1 doses) and adolescent at 13 years (2 doses) (dashed green line). Reproduced from [60]: "Re-evaluating cost effectiveness of universal meningitis vaccination (Bexsero) in England: modelling study." Hannah Christensen, Caroline L Trotter, Matthew Hickman, W John Edmunds, 2014;349:g5725. With permission from BMJ Publishing Group Ltd.

4.4.1. The pivotal role of infant vaccination

There are very few vaccines for which the target group for vaccination is not the population most affected by disease. ‘Cocooning’ of newborn infants by administering pertussis vaccines to their contacts, and maternal immunization are examples of such policies, both of which provide almost immediate, short-term benefits to the vulnerable infant. While adolescent-only vaccination is likely to reduce MenB IMD in this age group, benefits to infants, in whom the disease burden is the highest, are unlikely to be realized for decades [60]. Direct protection of infants through infant UMV is the only way to achieve rapid and early prevention of disease in the age group most at risk. The track record of infant UMV vaccination programs in achieving rapid and high coverage of new antigens is excellent, especially when the new antigens can be incorporated to the routine vaccination schedule and coadministered with other vaccines [64]. If an effect of 4CMenB on nasopharyngeal carriage of meningococci can be demonstrated, then infant UMV would ideally be combined with an adolescent dose to maximize potential herd effects, interrupt transmission and reap the potential benefits of cross-protection. While this is the most costly option in the available model, the potential benefits of cross-protection and an extended impact on sexually transmitted disease (namely gonorrhea) have not been accounted for, and could markedly improve the cost-effectiveness of 4CMenB vaccination.

4.4.2. Evidence supporting 4CMenB vaccination in infants

4CMenB is the only MenB vaccine approved for use in individuals starting from 2 months of age (although this indication is not in place worldwide). Immunogenicity and safety data supporting licensure of 4CMenB in infants have been recently reviewed [65]. Prelicensure studies established immunogenicity and a clinically acceptable safety profile in more than 5800 infants using three-dose primary vaccination plus booster, with or without co-administration with other routinely administered vaccines [6,66–70]. 4CMenB was evaluated in commonly used schedules as three-dose priming with booster or reduced two-dose priming with booster. A pivotal study conducted in over 2600 infants in Europe showed that three doses of 4CMenB induced hSBA titers ≥1:4 in 84%–100% of participants against strains expressing antigens contained in the vaccine [69]. One month after a booster dose at 12 months of age the percentage with hSBA titers ≥1:4 increased to between 95% and 100% [69]. More recently, immunogenicity of a two-dose 3.5 and 5 month schedule and a 2.5, 3.5, and 5 month schedule with booster has been demonstrated [71]. One month after two priming doses, 98–100% of infants had hSBA titers ≥1:4 against fHbp, NadA and PorA reference strains, and 49–59% had hSBA titers ≥1:4 against the NHBA reference strain.

4CMenB may be co-administered with diphtheria, tetanus, acellular pertussis, Haemophilus influenzae type b, inactivated poliomyelitis, hepatitis B, heptavalent pneumococcal conjugate, meningococcal C conjugate, rotavirus, measles, mumps, rubella, and varicella vaccines [72]. The available data suggested that the overall responses to 4CMenB and the coadministered vaccines were not impacted by concomitant administration [6,66–69,73].

4CMenB was associated with local and systemic reactions in infants that were short-lived and largely of mild-to-moderate severity. Local and systemic reactions including fever were more frequent when 4CMenB was coadministered with other routinely administered vaccines [67,69], but these symptoms were significantly reduced when paracetamol was administered at the time of vaccination [68]. There was no evidence that the administration of prophylactic paracetamol influenced the immune response to vaccination, and paracetamol administration is recommended by the UK and Australian authorities when 4CMenB is administered to infants.

The United Kingdom implemented the world’s first infant UMV program with 4CMenB and has achieved rapid disease control in the target population with effectiveness already demonstrated during the first year of the program which continued as predicted during the second year [14,32]. For the infant UMV programs in Ireland from 2016 and Italy more time is needed to assess effectiveness or impact [9,10].

5. Expert commentary

Our understanding of the mechanism of protection, impact and effectiveness of 4CMenB is rapidly progressing. Prior to large-scale use, predictions of the likely impact of vaccination were challenging because of the microbial population diversity of clinical MenB isolates and the absence of previous experience with meningococcal vaccine containing new non-capsular polysaccharide antigens. Additionally, the rarity of the disease did not allow efficacy trials to be performed, and tools were not available to predict vaccine coverage. Experience with 4CMenB is growing exponentially as it is implemented in different parts of the globe and in diverse age groups, encompassing university students in the United States, individuals aged 2 months to 20 years in one region in Canada, and infant UMV programs in the United Kingdom, Ireland, and Italy. Reassuringly, predictions of effectiveness based on immunogenicity have been borne out and may be conservative. Estimates of effectiveness from the field clearly suggest that predictive methods like MATS underestimate the real degree of protection afforded by 4CMenB.

The UK infant UMV program using a reduced two-dose schedule with booster has provided rigorous examination of the safety and effectiveness of the vaccine. Accumulating evidence suggests 4CMenB is an effective tool in preventing deaths and disease due to MenB IMD. The incidence of IMD peaks in infants and in adolescents, and based on the available evidence, the most effective way to protect these highest risk age-groups is through direct vaccination. As yet it is unclear whether vaccination of adolescents delivers indirect protection of infants, and even if it does, an adolescent-only program will take a long time to offer adequate protection to this age group. A combined infant-adolescent program currently represents the preferred solution for achieving rapid control of MenB IMD.

While immunization programs are ongoing, new aspects of the mechanism of antibody-mediated protection of 4CMenB have been unraveled. For 4CMenB, the presence of multiple epitopes on each vaccine antigen and the synergistic behavior of the antibodies highlight the potential of this multicomponent formulation. Recent evidence suggesting potential impacts of 4CMenB vaccine on non-B serogroups and on N. gonorrhoeae are very promising, and warrant further exploration.

6. Five-year view

Five years after approval, the available data suggest that population impact of 4CMenB vaccination is set to exceed expectations. In the next five years, we will learn much more about the impacts of 4CMenB on carriage, IMD caused by non-B serogroups, and gonorrhea. Even modest impacts in these areas would represent substantial added benefits to 4CMenB vaccination. These data will be used to inform cost-effectiveness analyses and guide decisions on the optimal strategies to achieve maximum impact, and could change the way the vaccine is used in the longer term.

Key issues

• Recent evidence shows that the antibodies induced by 4CMenB can act synergistically to enhance the bactericidal response, suggesting that prelicensure estimates of strain coverage and vaccine effectiveness may be conservative.

• 4CMenB is the only MenB vaccine authorized for use in infants. High immunogenicity and acceptable safety profile were demonstrated in prelicensure studies. Two years of experience in the United Kingdom in which more than 1.5 million infants have received 4CMenB, attest to the tolerability of the vaccine. Vaccine effectiveness against MenB IMD was 82.9% reinforcing the concept that current estimates of coverage obtained by MATS underestimate real protection.

• Exploratory analyses and retrospective population-based studies are suggestive of possible impacts of 4CMenB on MenW IMD and on gonorrhea, although these data are yet to be substantiated.

• Five years after approval, the available data suggest that population impact of 4CMenB vaccination is set to exceed expectations.

Authors’ Contribution

All authors participated in the development and the review of the manuscript and approved the final submitted version. The corresponding author had final responsibility to submit for publication. Drafts were developed by a professional publication writer according to the recommendations, documentation, and outline provided by the lead author.

Declaration of interest

All authors are full time employees of the GSK group of companies. All authors hold shares in the GSK group of companies as part of their employee remuneration. 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 materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Trademarks

Bexsero is a trademark of the GSK group of companies. Trumenba is a trademark of Pfizer Inc.

Additional information

Funding

GlaxoSmithKline Biologicals SA funded all costs associated with the development and the publishing of the present manuscript.