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Predicted strain coverage of a meningococcal multicomponent vaccine (4CMenB) in Europe: a qualitative and quantitative assessment

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Summary

Background

A novel multicomponent vaccine against meningococcal capsular group B (MenB) disease contains four major components: factor-H-binding protein, neisserial heparin binding antigen, neisserial adhesin A, and outer-membrane vesicles derived from the strain NZ98/254. Because the public health effect of the vaccine, 4CMenB (Novartis Vaccines and Diagnostics, Siena, Italy), is unclear, we assessed the predicted strain coverage in Europe.

Methods

We assessed invasive MenB strains isolated mainly in the most recent full epidemiological year in England and Wales, France, Germany, Italy, and Norway. Meningococcal antigen typing system (MATS) results were linked to multilocus sequence typing and antigen sequence data. To investigate whether generalisation of coverage applied to the rest of Europe, we also assessed isolates from the Czech Republic and Spain.

Findings

1052 strains collected from July, 2007, to June, 2008, were assessed from England and Wales, France, Germany, Italy, and Norway. All MenB strains contained at least one gene encoding a major antigen in the vaccine. MATS predicted that 78% of all MenB strains would be killed by postvaccination sera (95% CI 63–90, range of point estimates 73–87% in individual country panels). Half of all strains and 64% of covered strains could be targeted by bactericidal antibodies against more than one vaccine antigen. Results for the 108 isolates from the Czech Republic and 300 from Spain were consistent with those for the other countries.

Interpretation

MATS analysis showed that a multicomponent vaccine could protect against a substantial proportion of invasive MenB strains isolated in Europe. Monitoring of antigen expression, however, will be needed in the future.

Funding

Novartis Vaccines and Diagnostics.

Introduction

The prevention of invasive disease caused by capsular group B meningococci (MenB) is a long-recognised unmet medical need in many countries, despite vaccines against capsular groups A, C, W, and Y being available.1, 2 A major obstacle to the development of a MenB vaccine is that the polysaccharide capsule is not immunogenic, as it is for other capsular groups, which makes the use of other antigens necessary.1, 2

Meningococcal surface proteins have inherent variability that derives from many mechanisms, including recombination and phase variation.3 The potential effect of a protein-based vaccine on circulating MenB bacteria, therefore, depends on the extent to which the MenB antigens cross react with those present in the vaccine, and the degree of expression of each antigen on the cell surface. Protein-based MenB vaccine antigens generally have high structural variability and low cell-surface expression, and are very different from polysaccharides, which have low structural variability and very high expression.

Established typing methods for meningococci, such as multilocus sequence typing (MLST) and typing of variations in the PorA, PorB, and FetA outer-membrane proteins, can define relations between different lineages and strains.4 Additional measures to account for the components of new protein-based vaccines, which are not included in the current routine typing schemes, will be needed to assess public health effects.

Clinical efficacy studies to support the licensing of vaccines are the best way of showing benefit, but are not possible for Neisseria meningitidis, owing to low and sporadic incidence. Meningococcal glycoconjugate vaccines have been licensed on the basis of immunogenicity and safety data without formal efficacy studies.5 Assessment of meningococcal vaccines relies on the use of serological markers of protection. A titre of at least 4 in the serum bactericidal antibody assay with human complement is the only accepted correlate of protection.5 Nevertheless, notable logistical difficulties are associated with the use of this assay for MenB vaccines. Strain diversity could be addressed by testing of panels of individual circulating MenB strains in the serum bactericidal antibody assay, but a large volume of serum would be needed, which presents ethical difficulties in paediatric studies. Additionally, the serum bactericidal antibody assay with human complement is difficult to standardise across strains and complement sources. Therefore, its use in empiric testing of large strain panels is impractical, and alternative means of measuring surface-based antigens are necessary.5, 6

Any predictive method to assess vaccine-strain coverage must be responsive to the quantity of antigens and to their cross-reactivity with the vaccine in question. The novel multicomponent protein-based vaccine against MenB, 4CMenB (Bexsero), has been developed by Novartis Vaccines and Diagnostics, Siena, Italy. The meningococcal antigen typing system (MATS) uses polyclonal antibodies against three of its components—factor-H-binding protein, neisserial heparin-binding antigen, and neisserial adhesin A—to detect antigens in an ELISA, to predict postvaccination reponses in the serum bactericidal antibody assay with human complement.6 MATS uses whole-cell lysates and, therefore, does not distinguish between intracellular and surface-bound antigens. However, there is no indication of a lack of correlation between the total amount of antigen, as detected by MATS, and the fraction expressed on the cell surface, which is relevant for the serum bactericidal activity of antibodies. To assess the immunodominant contribution of the outer-membrane-vesicles from the New Zealand outbreak strain NZ98/254, which possess PorA P1.4, MATS also assesses the PorA variable region 2 of the target bacteria.7 Strains that meet a minimum threshold of reactivity to factor-H-binding protein, neisserial heparin-binding antigen, or neisserial adhesin A in the MATS ELISA, or that possess the PorA P1.4 variant are expected to be covered by the multicomponent vaccine. The baseline relation between MATS and the serum bactericidal antibody assay with human complement was established in pooled sera obtained from infants who received three doses of the primary series of 4CMenB and a booster dose at age 12 months.6

In this study we aimed to estimate potential coverage of 4CMenB in Europe by assessment of isolates from many countries. Here we report the first application of MATS to a large-scale epidemiological survey.

Section snippets

Strain selection and classification

We surveyed countries that account for most of the invasive meningococcal disease in Europe, as reported to the European Centre for Disease Prevention and Control in 2006–08,8 and in the European Union Invasive Bacterial Infections Surveillance Network report of 2006.9 All invasive MenB isolates submitted to the reference laboratories in the period July, 2007, to June, 2008, in England and Wales, France, Germany, Italy, and Norway were assessed. This period represented the most recent year with

Results

Good assay accuracy, precision, and reproducibility had been previously established across the participating laboratories in an interlaboratory standardisation study.12 1052 strains were assessed that represented the major clonal complexes and PorA subtypes of endemic European MenB strains (appendix). Clonal complexes 32, 41/44, and 269 accounted for most of the strains, and clonal complex 213 accounted for 4–10% of strains in some countries (table 1). The overall distributions of the most

Discussion

We assessed the predicted coverage of the multicomponent vaccine 4CMenB in five European countries that account for roughly two-thirds of invasive MenB disease reported in Europe in any given year. Although some variation was seen between countries, the vaccine was predicted to cover most circulating MenB strains in Europe overall and in the individual countries assessed. Our analysis took into account seasonal variation and provides a fixed point for future comparisons, and the laboratories

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