If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Several methods are currently used to predict vaccine coverage across meningococcal serogroup B strains.
•
MEASURE was developed for MenB-FHbp, MATS, gMATS and BAST for 4CMenB.
•
These methods provide large-scale, rapid and reproducible predictions of vaccine coverage.
•
gMATS and BAST may be applicable in the future to other Neisseria serogroups/species.
•
Real-world evidence will be instrumental to define the predictive value of these methods.
Summary
Serogroup B meningococci (MenB) remain a prominent cause of invasive meningococcal disease (IMD). The protein-based multicomponent 4CMenB and the bivalent MenB-FHbp are the only currently available vaccines against MenB-caused IMD. Efficacy studies are not possible, due to the low incidence of IMD. Therefore, the vaccines’ immunogenicity has been evaluated against several target strains chosen to quantify complement-mediated killing induced by each vaccine component in the serum bactericidal antibody assay. However, due to the wide genetic diversity and different expression levels of vaccine antigens across MenB strains, vaccine performance may differ from one strain to another. Here, we review the methods used to predict MenB strain coverage for 4CMenB and MenB-FHbp. Phenotypic assays such as the meningococcal antigen typing system (MATS, 4CMenB-specific) and the flow cytometric meningococcal antigen surface expression assay (MEASURE; MenB-FHbp-specific) were developed. Genomic approaches are also available, such as genetic MATS (gMATS) and the Bexsero antigen sequence type (BAST) scheme, both 4CMenB-specific. All methods allow tentative predictions of coverage across MenB strains, including that afforded by each vaccine antigen, and are rapid and reproducible. Real-world data on vaccine effectiveness are needed to confirm predictions obtained by these methods.A Video Abstract linked to this article can be found on Figshare: https://doi.org/10.6084/m9.figshare.13234340.
Invasive meningococcal disease (IMD) is a serious condition caused by Neisseria meningitidis. The incidence of IMD fluctuates considerably from one region to another and over time, while remaining relatively low worldwide. In the last two decades, 0.01 to 3.6 cases/100,000 persons were estimated globally.
The Global Meningococcal Initiative meeting on prevention of meningococcal disease worldwide: epidemiology, surveillance, hypervirulent strains, antibiotic resistance and high-risk populations.
While effective antibiotics against N. meningitidis are currently available, there is growing evidence of an increase in antimicrobial resistance worldwide.
The Global Meningococcal Initiative meeting on prevention of meningococcal disease worldwide: epidemiology, surveillance, hypervirulent strains, antibiotic resistance and high-risk populations.
Considering all these elements, IMD continues to be an important health concern.
Twelve meningococcal serogroups (Men) are identified, with six of them (MenA, MenB, MenC, MenX, MenY, and MenW) responsible for nearly all IMD worldwide.
The prevalence of these serogroups varies with geographical and socio-economic status and over time. Implementation of MenACWY vaccination has drastically decreased the occurrence of IMD caused by MenA, MenC, MenW and MenY in the Americas, Australia, Africa, and European countries. MenB is now one of the major causes of IMD in these regions, albeit with an evidenced trend of decreasing incidence.
The Global Meningococcal Initiative meeting on prevention of meningococcal disease worldwide: epidemiology, surveillance, hypervirulent strains, antibiotic resistance and high-risk populations.
Mono- or polyvalent meningococcal vaccines against MenA, MenC, MenW and MenY have been available for many years, with polysaccharide-protein conjugate vaccines preferred over polysaccharide due to their ability to induce better booster response, long-term immunological memory and herd protection.
The development of vaccines against MenB has been more challenging due to the poor immunogenicity of the MenB capsular polysaccharide. This prompted the design of protein vaccines, based on meningococcal surface-exposed proteins able to induce bactericidal antibodies across the diversified MenB strains.
Two MenB vaccines are now licensed for use in several countries worldwide. The multicomponent vaccine 4CMenB (Bexsero, GSK) contains four antigenic constituents: factor H binding protein (fHbp) variant 1 presented as a fusion protein with GNA2091 accessory protein, neisserial heparin binding antigen (NHBA) fused with accessory protein GNA1030, Neisseria adhesin A (NadA), and outer membrane vesicles (OMV) obtained from the N. meningitidis epidemic strain NZ98/254, expressing porin A (PorA) serosubtype P1.4. The second vaccine, MenB-FHbp (rLP2086; Trumenba, Pfizer) contains lipidated fHbp of the subfamilies B (corresponding to variant 1) and A (variants 2 and 3). In most countries, 4CMenB vaccine is approved for use in individuals from 2 months of age and older; the MenB-FHbp vaccine is approved in individuals 10 years of age and older. In the United States (US), both MenB vaccines are indicated for individuals 10–25 years old. Both vaccines have been found to be immunogenic and well tolerated in the age groups for which their use has been approved.
Government of Andorra. Decret del 10-02-2016 pel qual s'aprova la modificacio del Decret del 3 de febrer del 2016 d'actualitzacio del calendari de vacunacions del Pla de vacunacions sistematiques obligatories. Butlleti Oficila del Principat d'Andorra. Num.12, 2016. http://www.bopa.ad/bopa/028012/Documents/GD20160212_13_47_42.pdf. [last accessed July 4, 2020].
Czech Republic. Law of 21April2020amending Act No. 258/2000 Coll., on the protection of public health and amending certain related laws, as amended, and other related laws. https://www.epravo.cz/_dataPublic/sbirky/2020/sb0073-2020.pdf. [last accessed July 10, 2020].
Portugal and Malta plan to introduce 4CMenB in 2020, while regional introduction is underway in other countries such as Spain (e.g., the Castile y Leon region
Orden SAN/386/2019, de 15 de abril, por la que se modifica el Calendario Oficial de Vacunaciones Sistematicas a lo largo de la vida de las personas para la Comunidad de Castilla y Leon. Boletin Oficial de Castilla y Leon. 2019;78:20762–2075.
In Australia, government-funded MenB vaccination is also offered to Aboriginal and Torres Strait Islander children and for people of all ages with high-risk medical conditions, starting with July 2020.
In the UK, the first country to introduce a vaccine against MenB in the national infant vaccination program, a 2 + 1 schedule is used, with administrations at 2, 4, and 12 months of age. At three years since introduction, a 75% reduction in MenB IMD cases in infants was reported, corresponding to an incidence rate ratio between observed and expected cases of 0.25 (95% confidence interval: 0.19–0.36). Protection is believed to be afforded at least until the end of the third year of life.
Assessing protective efficacy against meningococci through strain coverage
Vaccine efficacy is defined as the percentage reduction in disease incidence in a vaccinated versus a non-vaccinated population, under optimal conditions, such as a randomized clinical trial. However, this is not feasible for IMD, for which the incidence is very low and evaluation of vaccine efficacy would require the enrolment of very large, impractical numbers of individuals. Consequently, the licensure of meningococcal vaccines was not based on vaccine efficacy assessments and relied on immunogenicity results. Immunogenicity data were generated by assays which detect antibody-dependent lysis of reference meningococcal isolates in the presence of external sources of complement. Since the structure of the capsular polysaccharide is highly conserved within the meningococcal serogroups, polysaccharide-based vaccines which show adequate immune responses against reference strains are very likely to provide protection against all strains belonging to the same serogroups. Indeed, a titre of ≥1:4 in serum bactericidal antibody (SBA) assays using human complement (hSBA) was found to indicate protection against MenC-caused IMD;
this threshold has been extended and used for the licensure of polysaccharide-protein conjugate vaccines against other meningococcal serogroups. The availability of this established correlate of protection allows prediction of efficacy against MenACWY strains based on the immune responses to reference strains. However, evaluation of protein-based vaccines remains more challenging because MenB vaccines target proteins that show high variation in their sequence and/or levels of expression. Since protection against a certain meningococcal strain is only possible if that strain expresses antigens cross-reactive with those contained in the vaccine, evaluation of the protection afforded must therefore account for the wide genetic diversity of MenB strains, which impacts the level of expression of (surface) antigens through gene regulation, phase variation and sequence diversity.
Addressing this issue lead to novel, specific methods predicting SBA activity against genetically diverse strains, accounting for each and all vaccine components. These methods allow conservative estimates of protection, based on prediction of strain coverage, defined as the proportion of disease-causing meningococcal isolates killed by post-vaccination immune sera in hSBA, in a specific region and period of time. These methods are in general accepted by regulatory authorities and constitute an innovative solution for the evaluation of MenB vaccines. However, the best practice to demonstrate vaccine effectiveness remains evaluation in real-life settings, which can only be performed following implementation of MenB vaccination in national immunization programs.
Here we review the methods used to evaluate the protective coverage of current MenB vaccines across circulating IMD-causing MenB strains. A plain language summary on our findings is provided in Fig. 1.
However, Goldschneider et al. were the first to propose a correlate of protection in 1969, by testing SBA activity in sera collected from infants and adults using a hSBA against MenA, MenB and MenC strains.
An increase in SBA activity against MenC strains was found to be associated in most cases with the appearance of immunoglobulin (Ig) G and IgM antibodies against the infecting strain. Of note, while the mounting of hSBA titres ≥1:4 was considered as protective, titres <1:4 were not necessarily indicative of susceptibility to disease.
This complement-mediated bactericidal killing assay became the gold-standard for evaluating successful immunization and protection against meningococci. Since variations in the assay protocol can severely impact the results, the assay conditions must be defined and validated, in alignment with guidelines developed by a panel of experts from the World Health Organization (WHO) in 1976.
World Health Organisation. WHO Expert Committee on Biological Standardization Requirements for meningococcal polysaccharide vaccine (requirements for biological substances No. 23).
The limited availability of human complement to assess SBA was recognized very early in the development of meningococcal vaccines and alternative sources were sought. In the assessment of polysaccharide vaccines against MenA and MenC, baby-rabbit complement
Standardization and a multilaboratory comparison of Neisseria meningitidis serogroup A and C serum bactericidal assays. The multilaboratory study group.
was considered an acceptable alternative. After assessment of the SBA assay using baby-rabbit serum as complement (rSBA), the WHO recommended the following immunogenicity-related criterion for licensure of meningococcal polysaccharide vaccines: ≥4-fold rise (increase of ≥2 dilutions) in SBA titres in ≥90% of the immunized adult individuals, when tested against target strains.
World Health Organisation. WHO Expert Committee on Biological Standardization Requirements for meningococcal polysaccharide vaccine (requirements for biological substances No. 23).
Later on, it was noted that higher rSBA than hSBA titres against MenC strains were observed for the majority of sera, and rSBA titres of ≥1:8 or ≥1:128 were proposed as threshold of protection.
Correlation between serum bactericidal activity against Neisseria meningitidis serogroups A, C, W-135 and Y measured using human versus rabbit serum as the complement source.
The rSBA was subsequently used in the licensure process of meningococcal vaccines in the US and the UK. The WHO later recommended that hSBA/rSBA titres of ≥1:4/≥1:8 be used as thresholds of protection against disease in the clinical development and licensure of MenA vaccines as well.
While for MenACWY vaccines both sources are used, human complement is considered the only acceptable source of complement for evaluation of MenB vaccines.
Indeed, the choice of complement profoundly impacts the assay results for MenB strains; for instance, it has been shown that IgM antibodies against the MenB capsular polysaccharide are bactericidal in the presence of rabbit, but not human complement.
Characterization of fHbp, nhba (gna2132), nadA, porA, and sequence type in group B meningococcal case isolates collected in England and Wales during January 2008 and potential coverage of an investigational group B meningococcal vaccine.
analysing the immune response of vaccination against each separate MenB strain by hSBA is not feasible. Therefore, during the clinical development of MenB vaccines, immune responses were evaluated against antigen-specific reference strains. For 4CMenB, four strains, chosen to allow testing of SBA directed against each of the four major vaccine antigens, were used most often, especially in phase 3 trials: 44/76-SL for fHbp, 5/99 for NadA, NZ98/254 for PorA, and M10713 for NHBA. The latter only became available in the later stages of the clinical development program and up until that point, an enzyme-linked immunosorbent assay (ELISA) was used for the assessment of immune response.
For MenB-FHbp, four primary test strains were used, harbouring fHbp subfamilies A (PMB80 and PMB2001) and B (PMB2948 and PMB2707). These strains, heterologous to the fHbp variants included in the vaccine, were selected based on several criteria, such as their representativeness of fHbp diversity in US and European IMD-causing MenB strains and a low-to-medium surface expression of fHbp.
Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial.
Immunogenicity and safety of a multicomponent meningococcal serogroup B vaccine and a quadrivalent meningococcal CRM197 conjugate vaccine against serogroups A, C, W-135, and Y in adults who are at increased risk for occupational exposure to meningococcal isolates.
Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study.
Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials.
A phase 3, randomized, active-controlled study to assess the safety and tolerability of meningococcal serogroup B vaccine bivalent rLP2086 in healthy adolescents and young adults.
demonstrate the vaccines’ ability to induce SBA killing against reference strains and to potentially provide protection against other MenB strains expressing antigens similar to the vaccine components. However, in view of the great diversity and the temporal changes observed worldwide for MenB strains, the use of a limited set of reference strains is insufficient to derive protection against other strains. However, testing against a large number of strains by hSBA would require a large amount of sera from vaccinated individuals, which is especially challenging in the case of infants and children. Moreover, several sources of complement are needed as distinct strains may behave differently with complement sources. Thus, some strains can be complement-sensitive to multiple human complement sources, although the reason behind this is not fully understood. Lipooligosaccharide expression (immunotype and degree of sylilation) and lack of PorA expression have previously been found to impact SBA activity.
In addition, the measured SBA may be influenced by the serendipitous presence of naturally-acquired antibodies to the tested strain in the human sera used as complement source that even if non-bactericidal alone can synergize with those present in the tested samples and contribute to complement activation. The polymorphism of human factor H (a key regulator of the alternative complement pathway),
are several other factors impacting the behaviour of strains with different complement sources.
Another drawback for the use of hSBA in evaluating the strain coverage of MenB vaccines is the limited availability of suitable human complement. The complement should be collected from healthy individuals who did not acquire antibodies against meningococcal strains through immunization or naturally-acquired immunity. To address these limitations, the use of endogenous complement as source was recently proposed and used to estimate strain coverage of a vaccine containing 4CMenB components across a panel of 110 IMD-causing MenB isolates circulating in the US.
Breadth of coverage against a panel of 110 invasive disease isolates, immunogenicity and safety for 2 and 3 doses of an investigational MenABCWY vaccine in US adolescents – results from a randomized, controlled, observer-blind phase II study.
Methods for prediction of MenB vaccines strain coverage
MATS
The meningococcal antigen typing system (MATS) was developed in 2010 to estimate coverage of MenB strains by 4CMenB. The method is 4CMenB-specific and combines three antigen-specific sandwich ELISAs that measure both immunological cross-reactivity and quantity of the antigens for fHbp, NadA and NHBA, with genotyping and phenotyping information for PorA (Fig. 2, Text Box 1).
Fig. 2Schematic representations of methods currently used to assess immunogenicity and predict MenB strain coverage for protein-based MenB vaccine. Note: *A titre of , in serum bactericidal antibody (SBA) assays using human complement (hSBA) was found to indicate protection against MenC-caused invasive meningococcal disease
and this threshold has been extended and used for the licensure of vaccines against other meningococcal serogroups. ** Identify antigen-encoding genes predicted to be positive in MATS.
Briefly, the overall vaccine coverage is estimated by assessing ELISA reactivity for fHbp, NHBA and NadA present in the lysate of MenB strains and genotype of PorA for the presence of the variable region 2 P1.4 that matches the PorA serosubtype of the vaccine's OMV component. A MATS-positive strain is a strain predicted to be covered by antibodies directed against at least one of the four antigens contained in 4CMenB. In MATS, ELISA reactivity of each strain is compared to that of three reference MenB strains, specific to each of the fHbp, NadA and NHBA antigens. The difference in reactivity is calculated as the relative potency (RP) of each strain. A strain is considered as covered if the RP is higher than a positive bactericidal threshold (PBT),
PBT values correspond to a 80% probability that the strain is killed in hSBA by pooled sera from 4CMenB-immunized infants when the strain is covered by only one antigen and a 96% probability of killing for MenB isolates positive for two or more antigens.
The assay has been used to predict 4CMenB coverage for more than 3000 strains in several countries. Coverage estimates varied worldwide from 66% to 91%
It is important to note that the MATS ELISAs use polyclonal antibodies for both the capture and detection of fHbp, NHBA, and NadA, providing an enhanced determination of the immunological and cross-reactive properties of a given antigen. However, MATS does not account for a potential synergistic effect for two or more vaccine components, nor for OMV components other than PorA, which leads to an underestimation of strain coverage compared to assessment by hSBA. This was shown by comparing MATS predictions with hSBA results in a panel of 40 MenB strains, selected from a set of 535 isolates collected from England and Wales from July 2007 to June 2008. The selection method ensured that the 40-strain panel was representative of the large set of circulating isolates in terms of MATS phenotypes and strain genotyping profile.
Bactericidal antibody against a representative epidemiological meningococcal serogroup B panel confirms that MATS underestimates 4CMenB vaccine strain coverage.
MATS was found to be a conservative predictor of strain coverage by 4CMenB in infants and adolescents, with a predicted strain coverage of 70%, whereas hSBA results showed a coverage of 88% for the same strain panel. Therefore, MATS has an 78% accuracy and 96% positive predictive value when compared with hSBA.
Bactericidal antibody against a representative epidemiological meningococcal serogroup B panel confirms that MATS underestimates 4CMenB vaccine strain coverage.
It was suggested that MATS might also underestimate the contribution of NadA to 4CMenB strain coverage, which was found to be very low (≤2.5%) across MenB strains collected worldwide.
Meningococcal serogroup B strain coverage of the multicomponent 4CMenB vaccine with corresponding regional distribution and clinical characteristics in England, Wales, and Northern Ireland, 2007-08 and 2014-15: a qualitative and quantitative assessment.
Rajam G., Stella M., Kim E., Paulos S., Boccadifuoco G., Serino L., et al. Meningococcal antigen typing system (MATS)-based Neisseria meningitidis serogroup B coverage prediction for the MenB-4C vaccine in the United States. mSphere. 2017;2. 10.1128/mSphere.00261-17.
. This might be due to differences between in vitro and in vivo NadA expression. A study evaluating transcription regulation of the nadA gene in MenB strains showed that while some strains exhibit low levels of NadA expression (undetectable by MATS) in vitro, infection in vivo might upregulate NadA expression and therefore results in efficient killing by 4CMenB-induced anti-NadA antibodies in the infant rat model.
Transcriptional regulation of the nadA gene in Neisseria meningitidis impacts the prediction of coverage of a multicomponent meningococcal serogroup B vaccine.
In addition, due to the constant evolution of MenB strains, the sequence and level of expression of 4CMenB components in disease-causing isolates is likely to vary over time, thus MATS prediction must be re-evaluated periodically to ensure it reflects the current epidemiological trend. For instance, a phase variation in the nadA gene was found to affect expression of NadA in meningococcal strains circulating in the UK between 2010 and 2016. This impacted MATS estimates since strains with low expression levels are not predicted as covered by this method.
MATS is specific to antigen components in the 4CMenB, and therefore cannot be used for the assessments of other vaccines. Furthermore, MATS is a phenotypic method that requires cultured isolates and cannot be used for non-culture polymerase chain reaction (PCR)-confirmed IMD cases.
MEASURE
The flow cytometric meningococcal antigen surface expression (MEASURE) assay was developed in 2010 for assessment of strain coverage by MenB-FHbp.
Development of a meningococcal antigen surface expression (MEASURE) assay for the phenotypic characterization of fHBP expression by Neisseria meningitidis.
in: Proceedings of the eleventh EMGM meeting, Ljubljana, Slovenia2011: 18-20
Predicting the susceptibility of meningococcal serogroup B isolates to bactericidal antibodies elicited by bivalent rLP2086, a novel prophylactic vaccine.
Briefly, a monoclonal antibody MN86-994-11 was identified as highly specific for fHbp across diverse MenB isolates expressing fHbp subfamily A or B. MN86-994-11 was used for the detection of surface-expressed fHbp by flow cytometry, and a mean fluorescence intensity of 1000 was found to correspond to approximately 30 pg of surface-expressed fHbp/μg of total cell protein. This value was correlated with 91.2% probability of the isolate to be killed in hSBA by MenB-FHbp immune sera, thus providing a cut-off for predicting susceptibility to bactericidal killing (Fig. 2, Text Box 1).
Predicting the susceptibility of meningococcal serogroup B isolates to bactericidal antibodies elicited by bivalent rLP2086, a novel prophylactic vaccine.
While providing a rapid and reproducible estimation of the MenB-FHbp strain coverage, MEASURE also has several limitations. First, strain susceptibility to bactericidal killing was determined for MenB-FHbp only, and the method is not applicable to other vaccines. Moreover, in contrast to MATS, MEASURE was developed to measure surface expression of fHbp variants in meningococcal strains, but does not assess antigenic diversity, and so it does not account for antigenic cross-reactivity between fHbp (sub)families/variants. The use of this specific monoclonal antibody allows for detection of a single conformational epitope conserved across different variants. Similar to MATS, MEASURE cannot predict the percentage of individuals with SBA activity following vaccination, and cannot be used for non-culture PCR-confirmed IMD cases.
gMATS
Culture-confirmed IMD isolates are not always available, mainly due to early antibiotic treatment, and in some countries (e.g. Italy or the UK) more than 50% of cases are confirmed by PCR only.
Therefore, an alternative method was developed, using antigen genotyping to predict vaccine coverage and thus enabling the testing of the complete range of epidemiologically-representative MenB strain panels. Genetic MATS (gMATS) was defined by assessing the level of correlation between MATS coverage estimates and antigen genotyping for each of the four antigenic components of 4CMenB.
Thus, gMATS complements MATS predictions with data generated by genotyping (Text Box 1).
In gMATS, genes encoding fHbp and NHBA are PCR-amplified and sequenced, or their sequences are extracted from the whole genome sequence (WGS) when available. Antigen-specific predicted strain coverage by gMATS is defined by identifying peptide IDs significantly associated with MATS coverage/non-coverage for that antigen. For fHbp and NHBA, only peptide IDs present in ≥5 isolates were considered for the analysis. Peptide IDs for which the percentage of MATS-covered strains is >60% or <40% are considered predictors of coverage or non-coverage, respectively, while peptide IDs not meeting either of the two criteria are designated as “unpredictable”. In total, 16 fHbp peptides and nine NHBA peptides were identified as predictors of coverage. The presence/absence of the nadA gene can be scored, but this does not allow to predict coverage as NadA is believed to be artificially under-expressed in strains when grown for MATS analysis. Therefore, NadA is always considered as not contributing to coverage in gMATS. Coverage for PorA is defined as in MATS (PorA variable region 2 match with peptide 4) (Table 1). A strain is considered as gMATS-covered if the sequence of the antigen-encoding gene corresponds to peptides predicted as “covered” on the basis of MATS, gMATS-not covered if the sequence of the antigen-encoding gene corresponds to peptides predicted as “not-covered” on the basis of MATS, and unpredictable in the remaining cases. Finally, when predicting strain coverages, half of the unpredictable gMATS strains were assumed to be covered, as 49% of them were found to be MATS-positive.
Strain coverage for 4CMenB by gMATS was evaluated in a panel of 3481 invasive MenB isolates from 13 countries and was concordant with MATS results; 84.5%, 81.5%, 100% and 100% of strains could be predicted as fHbp, NHBA, NadA and PorA-MATS covered by gMATS, leading to an overall estimate of 81.3%. gMATS vaccine strain coverage predictions ranged from 57% to 87% across 13 countries and were similar with those predicted by MATS (Fig. 3).
Similarly to MATS, gMATS underestimates strain coverage as assessed by killing in hSBA and does not account for cooperative effects between the antigens, nor for the contribution of the NadA antigen or minor OMV components of 4CMenB. Another limitation of gMATS is that coverage cannot be predicted for new alleles of the fhbp and nhba genes, for which MATS data are not available. However, the assay presents the major advantage of not requiring bacterial isolates and is therefore not limited to culture-positive cases
The Bexsero Antigen Sequence Type (BAST) scheme is a WGS-based scheme established and implemented in the Neisseria PubMLST database (http://pubmlst.org/neisseria).
Temporal changes in BEXSERO antigen sequence type associated with genetic lineages of Neisseria meningitidis over a 15-year period in Western Australia.
Temporal changes in BEXSERO antigen sequence type associated with genetic lineages of Neisseria meningitidis over a 15-year period in Western Australia.
(Text Box 1). Coverage is estimated by examining antigen peptide sequences present in both the vaccine and an epidemiological dataset and genotype-phenotype modelling. However, the method presents some inherent limitation in predicting coverage, mainly due to the fact that the dataset of MATS data on fHbp subvariants and NHBA peptides was quite limited when the assay was developed (2011) and therefore all fHbp subvariants and NHBA peptides described later are considered as “unknown” in BAST. This is particularly true for NHBA, as strains are predicted to be covered by NHBA only when the encoding gene is an exact match for the peptide contained in the vaccine, resulting in a significant underestimation of coverage prediction by BAST. Exact match for PorA VR1 7.2 is also assessed, despite the fact that the epitope is non-immunogenic. Peptides/variants considered as covered in BAST are reported in Table 1.
BAST strain coverage predictions are available for isolates collected from the UK and Ireland during 2010–2014, for which coverages of 22.8–30.8% and 66.1% were predicted by BAST exact matches and by genotype-phenotype modelling, respectively.
Temporal changes in BEXSERO antigen sequence type associated with genetic lineages of Neisseria meningitidis over a 15-year period in Western Australia.
In addition, the European meningococcal strain collection genome library (EMSC-GL) for the epidemiological year 2011–2012 was characterized with the BAST scheme. The EMSC-GL comprised 799 meningococcal strains causing IMD, submitted by 16 European countries, of which 65.7% were MenB. Predicted BAST strain coverages varied from 0 to 97.1% across countries, for an overall estimate of 52.4%.
In a recent study in Poland, across 662 typed isolates, 292 BAST profiles were identified and strain coverage due to exact match was estimated at 39.7%, while the gMATS prediction was 86.6%.
Of note, the gMATS coverage was similar to the 83.3% coverage predicted by extrapolation of MATS data for a subset of strains collected during 2010–2011.
As for MATS and gMATS predictions, the difference in reported estimates of strain coverage obtained with the BAST scheme (that scores exact matching with the four major vaccine antigens) reflects changes over time and across geographical areas in the epidemiology of MenB-caused IMD. This method enables constant surveillance of 4CMenB antigens in the circulating strains, without requiring a live isolate, therefore covering non-culture cases. Moreover, it allows comparisons (albeit limited) with strain coverages for other vaccines. For instance, in the EMSC-GL study, a strain coverage of 3.4% was predicted for the bivalent MenB-FHbp, based on exact peptide matches for the vaccine's fHbp variants in the tested isolates, for which SBA data were available; no overlap of coverage was observed between the two vaccines within the European genomic library.
However, as is the case for gMATS, BAST is limited by the continuous evolution of MenB isolates, generating new STs, new alleles or combination of alleles encoding the four vaccine antigens. In addition, cross-protection or phenotypic expression data on which BAST relies are very limited, it is important to correlate this analysis with other functional assays. For these reasons, the accuracy of BAST is lower than for gMATS. However, the BAST scheme can also be enhanced in the future to include new STs expressing vaccine antigens or to allow predictions adjusted for cross-protection or synergistic effects between vaccine components. For instance, a novel OMV typing (OMVT) scheme was recently developed. Based on WGS, unique OMVTs were identified and grouped in a relatively small number of OMVT clusters, for which a non-overlapping associations with BASTs was shown.
This association further supports the presumption that immune and/or metabolic selection is the driving force behind the presence of a stable, structured population of IMD-causing strains, and allows for the improvement of current WGS-based methods to evaluate strain coverage.
From prediction to observation: remaining challenges in assessing true vaccine effectiveness
MenB vaccines are used either in national vaccination programs (in the UK, Ireland, Italy, Lithuania, Andorra and San Marino) or as outbreak control (in Canada, the US, and France). Prediction of coverage of the diverse and continuously-evolving MenB strains is crucial for both vaccination strategies. Currently, phenotypic assays such as hSBA, MATS and MEASURE, or genomic approaches such as gMATS and BAST are available for prediction of strain coverage.
All these methods predict relatively high strain coverages for both licensed MenB vaccines (4CMenB and MenB-FHbp), for different regions worldwide. However, their results need to be validated against long-term, real-life vaccine effectiveness data. These data continue to accumulate for 4CMenB, following its implementation in the UK national immunization program and from a large vaccination campaign in a Canadian region. Immunization in individuals ≤20 years of age in the Saguenay-Lac-Saint-Jean region of Quebec, was estimated to reduce the MenB-IMD risk with 86% (95% confidence interval:−2–98) (unadjusted value: 96%) and to result in a vaccine effectiveness of 79% (95% confidence interval: −231–99) over a period of four years.
Impact of a mass vaccination campaign against serogroup B meningococcal disease in the Saguenay-Lac-Saint-Jean region of Quebec four years after its launch.
These estimates in age groups directly targeted for vaccination are supportive of the 75% reduction in MenB IMD cases in infants observed in the UK, over three years from vaccine introduction.
A study estimating the effect of meningococcal vaccines on herd protection against N. meningitidis in UK university students showed that 4CMenB and MenACWY vaccines induced carriage reduction for a subset of Neisseria strains, at 4–12 months after vaccination.
Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial.
Recently-concluded studies conducted in Australia indicated that vaccination of adolescents with 4CMenB did not impact (oro)pharyngeal carriage of MenB.
Meningococcal serogroup B strain coverage of the multicomponent 4CMenB vaccine with corresponding regional distribution and clinical characteristics in England, Wales, and Northern Ireland, 2007-08 and 2014-15: a qualitative and quantitative assessment.
However, vaccine effectiveness estimates from these countries seem to indicate a greater coverage for 4CMenB than that predicted by either method (Table 2). Moreover, MATS and similar/complementing methods have limitations which do not allow them to fully predict vaccine effectiveness, nor indeed to accurately predict strain coverage. Inherently, MATS is a conservative predictor of 4CMenB's breadth of coverage, but can be complemented with gMATS to provide more accurate estimates, even for non-cultivable strains. In addition, phenotypic data on the expression of vaccine antigens may still be needed to allow the updating of genomic methods such as gMATS and BAST.
Table 2Predicted strain coverage and observed impact in real-world settings for 4CMenB.
Bactericidal antibody against a representative epidemiological meningococcal serogroup B panel confirms that MATS underestimates 4CMenB vaccine strain coverage.
Impact of a mass vaccination campaign against serogroup B meningococcal disease in the Saguenay-Lac-Saint-Jean region of Quebec four years after its launch.
UK, United Kingdom; hSBA, serum bactericidal assay using human complement; CI, confidence interval; MATS; meningococcal antigen typing system; gMATS, genetic MATS; NA, not available. Note: * Impact was defined as percentage reduction in MenB-caused invasive meningococcal disease incidence from pre-vaccine introduction (UK)/ pre-vaccination campaign (Canada).
While all these methods have been developed to predict coverage against MenB strains, they can potentially be extended to other serogroups as well. Non-MenB strains also express antigens contained in the protein vaccines and there is growing evidence that 4CMenB may provide cross-protection against other meningococcal serogroups. For instance, pooled sera from infants and adolescents immunized with 4CMenB exhibited SBA activity against non-MenB strains. In a panel of 147 MenC, MenW, and MenY clinical isolates collected from three European countries and Brazil, 74.1% of strains were killed in hSBA by sera from 4CMenB-immunized infants.
4CMenB, a multicomponent meningococcal vaccine developed for serogroup B meningococci elicits cross-reactive immunity also against serogroups C, W and Y.
in: Proceedings of the thirty-seventh annual meeting of the European society for paediatric infectious diseases (ESPID), Ljubljana, Slovenia2019: 12-17
Sera derived from adolescents vaccinated with two doses of 4CMenB demonstrated killing in hSBA against four strains, which were representative of the current MenA epidemiology, selected from 1046 MenA isolates collected from different countries between 2000 and 2016.
Sera from adolescents and infants receiving one and three doses of 4CMenB, respectively, displayed bactericidal activity against all six tested invasive MenW isolates, causing meningitis or septicaemia in patients from England and Wales during 2011–2012.
MenB-FHbp-immune adolescent sera also demonstrated SBA activity against six non-MenB strains (one MenA, MenC, MenY and MenX and two MenW), although the conclusion is limited by the fact that the strains were selected for testing based on fHbp prevalence.
The bivalent factor H binding protein meningococcal serogroup B vaccine elicits bactericidal antibodies against representative non-serogroup B meningococci.
So far, MATS has not been successfully applied to other serogroups, since PBTs have only been established for MenB strains. However, non-MenB meningococci seem to be less genetically diverse, therefore potentially requiring a lower number of strains to evaluate the contribution of each 4CMenB antigen to coverage.
Meningococcal antigen typing system development and application to the evaluation of effectiveness of meningococcal B vaccine and possible use for other purposes.
Similarly, gMATS and BAST may be adaptable enough to be applied to other Neisseria serogroups or species.
While not without limitations, current methods afford large-scale, robust and rapid prediction of MenB strain coverage by protein-based MenB vaccines. However, prediction of true vaccine performance remains challenging and the gold standard is represented by real-world effectiveness studies in a population once the vaccines are broadly implemented. In addition, continuous monitoring of MenB strain diversity remains paramount to anticipate temporal and regional variations in strain coverage and adjust the composition of current vaccines to match them, if necessary.
Trademark statement
Bexsero is a trademark owned by or licensed to the GSK group of companies. Trumenba is a trademark of Pfizer Inc.
Author contribution
All authors participated in the development and the review of the manuscript and approved the final submitted version.
Declaration of Competing Interest
AB, MMG, MP and RBB are employees of the GSK group of companies and hold shares as part of their employee remuneration. MKT reports grants from the GSK group of companies and Pfizer during the conduct of the work; grants from Sanofi, outside the submitted work. In addition, MKT has a patent (NZ630133A) issued with the GSK group of companies. RB has performed contract research on behalf of Public Health England for the GSK group of companies, Pfizer and Sanofi.
Acknowledgments
The authors would like to thank Eva Hong and Ala-Eddine Deghmane (Institut Pasteur, National Reference center for Meningococci and Haemophilus influenzae) for their helpful discussion on MATS assay. The authors also thank the Modis platform for writing support, editorial assistance and manuscript coordination, on behalf of GSK. Petronela M. Petrar provided medical writing support and Divya Kesters coordinated the manuscript development and provided editorial support. This work was sponsored by GlaxoSmithKline Biologicals SA, which funded all costs associated with the development and the publishing of the present manuscript.
References
Acevedo R.
Bai X.
Borrow R.
Caugant D.A.
Carlos J.
Ceyhan M.
et al.
The Global Meningococcal Initiative meeting on prevention of meningococcal disease worldwide: epidemiology, surveillance, hypervirulent strains, antibiotic resistance and high-risk populations.
Government of Andorra. Decret del 10-02-2016 pel qual s'aprova la modificacio del Decret del 3 de febrer del 2016 d'actualitzacio del calendari de vacunacions del Pla de vacunacions sistematiques obligatories. Butlleti Oficila del Principat d'Andorra. Num.12, 2016. http://www.bopa.ad/bopa/028012/Documents/GD20160212_13_47_42.pdf. [last accessed July 4, 2020].
Czech Republic. Law of 21April2020amending Act No. 258/2000 Coll., on the protection of public health and amending certain related laws, as amended, and other related laws. https://www.epravo.cz/_dataPublic/sbirky/2020/sb0073-2020.pdf. [last accessed July 10, 2020].
Orden SAN/386/2019, de 15 de abril, por la que se modifica el Calendario Oficial de Vacunaciones Sistematicas a lo largo de la vida de las personas para la Comunidad de Castilla y Leon. Boletin Oficial de Castilla y Leon. 2019;78:20762–2075.
Standardization and a multilaboratory comparison of Neisseria meningitidis serogroup A and C serum bactericidal assays. The multilaboratory study group.
Correlation between serum bactericidal activity against Neisseria meningitidis serogroups A, C, W-135 and Y measured using human versus rabbit serum as the complement source.
Neisseria meningitidis group B correlates of protection and assay standardization.
in: Proceedings of the international meeting report Emory University, Atlanta, Georgia, United States24. 2006: 5093-5107https://doi.org/10.1016/j.vaccine.2006.03.091 (16-17 March 2005. Vaccine)
Characterization of fHbp, nhba (gna2132), nadA, porA, and sequence type in group B meningococcal case isolates collected in England and Wales during January 2008 and potential coverage of an investigational group B meningococcal vaccine.
Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial.
Immunogenicity and safety of a multicomponent meningococcal serogroup B vaccine and a quadrivalent meningococcal CRM197 conjugate vaccine against serogroups A, C, W-135, and Y in adults who are at increased risk for occupational exposure to meningococcal isolates.
Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study.
Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials.
A phase 3, randomized, active-controlled study to assess the safety and tolerability of meningococcal serogroup B vaccine bivalent rLP2086 in healthy adolescents and young adults.
Breadth of coverage against a panel of 110 invasive disease isolates, immunogenicity and safety for 2 and 3 doses of an investigational MenABCWY vaccine in US adolescents – results from a randomized, controlled, observer-blind phase II study.
in: Proceedings of the thirteenth emgm meeting of the european meningococcal disease society, Amsterdam, Netherlands2015: 60-61 (Sept 14–17(abstr P37))
Bactericidal antibody against a representative epidemiological meningococcal serogroup B panel confirms that MATS underestimates 4CMenB vaccine strain coverage.
Meningococcal serogroup B strain coverage of the multicomponent 4CMenB vaccine with corresponding regional distribution and clinical characteristics in England, Wales, and Northern Ireland, 2007-08 and 2014-15: a qualitative and quantitative assessment.
Rajam G., Stella M., Kim E., Paulos S., Boccadifuoco G., Serino L., et al. Meningococcal antigen typing system (MATS)-based Neisseria meningitidis serogroup B coverage prediction for the MenB-4C vaccine in the United States. mSphere. 2017;2. 10.1128/mSphere.00261-17.
Transcriptional regulation of the nadA gene in Neisseria meningitidis impacts the prediction of coverage of a multicomponent meningococcal serogroup B vaccine.
Development of a meningococcal antigen surface expression (MEASURE) assay for the phenotypic characterization of fHBP expression by Neisseria meningitidis.
in: Proceedings of the eleventh EMGM meeting, Ljubljana, Slovenia2011: 18-20
Predicting the susceptibility of meningococcal serogroup B isolates to bactericidal antibodies elicited by bivalent rLP2086, a novel prophylactic vaccine.
Temporal changes in BEXSERO antigen sequence type associated with genetic lineages of Neisseria meningitidis over a 15-year period in Western Australia.
Impact of a mass vaccination campaign against serogroup B meningococcal disease in the Saguenay-Lac-Saint-Jean region of Quebec four years after its launch.
Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial.
4CMenB, a multicomponent meningococcal vaccine developed for serogroup B meningococci elicits cross-reactive immunity also against serogroups C, W and Y.
in: Proceedings of the thirty-seventh annual meeting of the European society for paediatric infectious diseases (ESPID), Ljubljana, Slovenia2019: 12-17 (May)
The bivalent factor H binding protein meningococcal serogroup B vaccine elicits bactericidal antibodies against representative non-serogroup B meningococci.
Meningococcal antigen typing system development and application to the evaluation of effectiveness of meningococcal B vaccine and possible use for other purposes.
30515-6&id=gr1.jpg){kind=link}
30515-6&id=gr2.jpg){kind=link}
30515-6&id=gr3.jpg){kind=link}
30515-6&id=gr4.jpg){kind=link}