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1 Peter Medawar Building for Pathogen Research and Department of Zoology, University of Oxford, OX1 3SY, UK
2 Division of Bacteriology, National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Herts EN6 3QG, UK
3 Department of Biology, Pennsylvania State University, University Park, PA 16802, USA
4 Meningococcal Reference Unit, Health Protection Agency, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WZ, UK
Correspondence
Martin C. J. Maiden
martin.maiden{at}zoo.ox.ac.uk
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Present address: Department of Medical Microbiology, University of Maastricht, Maastricht, The Netherlands.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). Serogroup B, the predominant cause of meningococcal disease in many countries (Caugant, 1998), is not, therefore, covered by routine immunization and the development of a conjugate vaccine against this polysaccharide is hampered by low immunogeniticy and perceived safety issues (Stein et al., 2006). Both these problems are a consequence of the identity of this molecule with host polysaccharides (Finne et al., 1983). Various approaches that use subcapsular antigens, both proteins and polysaccharides, have been proposed to provide what are best described as serogroup B substitute meningococcal vaccines (Jodar et al., 2002).
Any meningococcal vaccine must accommodate the extensive genetic and antigenic diversity of this common inhabitant of the human nasopharynx (Stephens, 2007). Two contrasting approaches have been employed: the identification of conserved antigens; or the generation of specific vaccines against certain types. The former includes the identification of candidate antigens from genome sequence data, so-called reverse vaccinology (Pizza et al., 2000), while the latter is exemplified by the use of outer-membrane vesicle (OMV) vaccines to disrupt outbreaks of serogroup B disease caused by a single meningococcal clone (Bjune et al., 1991; O'Hallahan et al., 2004; Sierra et al., 1991). In practice the identification of highly conserved antigens has proved difficult, probably because any surface component that is expressed at sufficient levels to be a vaccine target is naturally variable. There remains the possibility of either making specific vaccines that target particular meningococcal variants or producing multivalent formulations of antigens that achieve broad coverage (van den Dobbelsteen et al., 2007). Both these approaches require detailed information about the molecular epidemiology of the meningococcus (Perrett & Pollard, 2005).
Despite their high diversity, meningococcal populations are structured into lineages that are identified as clonal complexes (cc) by multilocus sequence typing (MLST) (Maiden et al., 1998). Only a minority of these, the so-called hyperinvasive lineages, are regularly associated with human disease (Caugant, 2001; Maiden et al., 1998; Yazdankhah et al., 2004). The prevalence of these lineages varies geographically and temporally but each complex tends to be associated with a particular repertoire of surface antigens (Urwin et al., 2004). Three strain-specific vaccines, based on OMV preparations, have been developed and deployed in response to particular outbreaks of meningococcal disease (Oster et al., 2005; Perkins et al., 1998). A more general approach is to identify combinations of meningococcal surface protein variants that will protect against all or at least a high proportion of meningococcal disease; however, the success of such vaccines will depend on the stability of association of antigen variants with invasive meningococci over time (Sacchi et al., 2000).
In the present work, molecular typing, based on the nucleotide sequence determination of meningococcal genes (Elias et al., 2006; Jolley et al., 2007), was employed to identify the variants of two major surface proteins, PorA and FetA, in England and Wales over 20 years prior to the introduction of meningococcal serogroup C conjugate (MCC) vaccines (Miller et al., 2001). These proteins are both typing targets and components that have been present in a number of strain-specific meningococcal vaccines (Jodar et al., 2002). In addition, the clonal complex and hence the hyperinvasive lineage was determined by MLST (Maiden et al., 1998). The data produced a highly discriminatory typing scheme but, notwithstanding a very high diversity of strain types, a relatively simple vaccine based on combinations of PorA and FetA variants could potentially protect against a majority of meningococcal disease over this extended period of time.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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MLST.
This was performed as described previously (Jolley et al., 2000). Briefly, the seven housekeeping loci used in the scheme were amplified by PCR and the amplicons purified by precipitation to remove unincorporated amplification primers and nucleotides. These were then used as templates for dideoxynucleotide sequence reactions using BigDye Terminators (ABI). The extension reactions were separated on an automated DNA analyser (ABI) and the sequences assembled with the Staden software package (Staden, 1996).
Antigen gene sequencing.
The nucleotide sequence determination of the regions of the porA gene that encode most of the antigenic variability of this protein, VR1 and VR2, was undertaken using previously published methods (Suker et al., 1994). The region of the FetA gene that encodes the principal variable region (VR) of this protein was similarly determined (Thompson et al., 2003). For both proteins the peptide sequences were deduced and assigned names using the published nomenclature schemes (Jolley et al., 2007; Russell et al., 2004; Thompson et al., 2003).
Data storage and analysis.
Data were stored on a customized isolate database available at http://pubmlst.org/neisseria/. The database automatically generated the strain types according to the recently proposed typing nomenclature (Jolley et al., 2007). This has the format serogroup : PorA type : FetA type : sequence type (clonal complex); for example B : P1.7-2,4 : F1-5 : ST-41 (cc41/44). Analysis was conducted with the PubMLST database tools (Jolley & Maiden, 2006; Jolley et al., 2004). The diversity index for strain types was calculated according to Simpson (1949) and modified for strain typing (Hunter & Gaston, 1988).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). The complete dataset, including geographical distribution of isolates, is available at http://pubmlst.org/neisseria.
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Each serogroup was mainly associated with particular clonal complexes in a given year, but this changed over time (Table 2). There were differences in the clonal complexes present in each of the three years, and the disappearance of serogroup A disease from the UK over the duration of the survey was due to the disappearance of members of the ST-1 complex. Serogroup A is mostly found in members of the ST-1, ST-4 and ST-5 complexes, which rarely express capsules of other serogroups, and their disappearance from most industrialized countries over the period of the survey is yet to be satisfactorily explained (Achtman, 1997). In contrast, the serogroups expressed by other clonal complexes changed during this period. For example, the percentage of isolates that were serogroup C increased from 20 % to 36 % but whereas most of these isolates belonged to ST-344 complex in 1975, the ST-11 complex was the major cause of serogroup C disease in 1995; members in this clonal complex predominantly expressed serogroup W-135 in 1975. In 1975 most serogroup B meningococcal disease was caused by ST-8 isolates; this was succeeded by members of the ST-32 complex in 1985 and members of the ST-41/44 complex in 1995 (Table 2).
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). The combined prevalence of the five most common variants was 68 % for PorA VR1, 48 % for PorA VR2, and 66 % for FetA VR. There were a limited number of combinations of the different VRs in the dataset with a tendency for non-overlapping structure (Gupta et al., 1996), although this was more marked with the two PorA VRs than with the PorA VRs and FetA VR (Fig. 1). The data permitted the design of a possible combination of PorA and FetA VRs for use in a vaccine, and the assessment of possible levels of coverage that such a vaccine might be able to attain, in the absence of immunological constraints (Fig. 2).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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, 2004). MLST has provided a very reliable means of identifying hyperinvasive meningococci (Brehony et al., 2007), but does not necessarily provide sufficient discrimination for the unambiguous identification of disease clusters representing outbreaks (Bygraves et al., 1999; Feavers et al., 1999). The addition of PorA and FetA VRs added discrimination and identified antigen variants in this sample of invasive meningococci (Jolley et al., 2007) and such ‘fine typing’ has been employed in the identification of outbreak clusters in Germany (Elias et al., 2006).
The levels of discrimination achieved in the current survey were high (Simpson's diversity index 0.94–0.99), comparable with the result achieved with PorA and FetA typing previously, 0.96 (Elias et al., 2006). They were also similar to the best levels of coverage and precision achieved with other methods, indicating that the nine-gene sequence typing scheme has sufficient discrimination for the reliable detection of outbreaks (Swaminathan et al., 1996). In addition, the clonal complex information identified hyperinvasive lineages, enabling the monitoring of trends in meningococcal disease over time and comparison with other datasets (Brehony et al., 2007). Furthermore, as the procedure is PCR based it is inherently suitable for application to clinical specimens (Taha et al., 2005), and finally, the typing data were also informative as to the antigenic variability of the meningococcus.
The lower estimate of diversity index from the 1975 dataset was probably due to the limitations in geographical sampling of disease isolates at this time. Most of the isolates present in the collections for the two later years were independent. However, as the 1975 sample was the complete set of isolates available from submissions to the PHLS, it is possible that epidemiologically related isolates were present, which could also explain the high proportion of ST-8 isolates; indeed it is perhaps more likely that outbreak isolates would have been submitted to the PHLS reference facilities at this time. Geographical source of isolation was available for all of the 1975 and 1995 isolates and for 93 of the 1985 isolates. Of the 48 locations that submitted isolates in 1975, 12 submitted four or more with the greatest (Manchester) submitting 20. By contrast, in the 1985 dataset 55 locations were represented, only two of which (London, eight and Manchester, four) were represented more than three times. Similarly, in the 1995 dataset of 67 locations, only London and Manchester (five isolates each) were represented by more than three isolates.
The data were consistent with previous studies that have indicated dynamic behaviour in meningococcal populations (Caugant, 2001; Harrison et al., 2006; Yazdankhah et al., 2004). Disease incidence rises and falls with the presence of hyperinvasive lineages in the carried population of meningococci. The antigens associated with particular clonal complexes consequently rise and fall over time, as predicted by models of pathogen strain structuring by immunological selection (Gupta & Maiden, 2001), although there appeared to be differences in the stability of the lineages with regard to different antigens. The ST-1 clonal complex is very strongly associated with particular antigenic variants, including capsule and subcapsular antigens (Suker et al., 1994; Urwin et al., 2004), and serogroup A disease disappeared from the UK with this clonal complex. Despite reintroduction since then, for example with ST-5 complex meningococci in the 1990s, serogroup A meningococci have not, to date, re-established themselves as a cause of disease in the UK (Jones & Sutcliffe, 1990). The sialic-acid-based capsules, corresponding to serogroups B, C, Y and W-135, have a more dynamic relationship with clonal complex. This may reflect the fact that horizontal gene exchange of only the gene occupying the siaD locus of the capsular region is required to alter the serogroup (Swartley et al., 1997; Vogel et al., 2000). A further difference is that the serogroup A capsule is thought to be more immunogenic (Gold et al., 1979).
The clonal complexes associated with capsules containing sialic acid (the ST-8, ST-32, ST-344 and ST-41/44 complexes) are, however, more limited in the repertoire of subcapsular antigens that they express, each being associated with particular variant families. In particular, there was a tendency of the VRs to occur in non-overlapping combinations (Fig. 1
), which, along with the dynamic behaviour noted above, is consistent with models of strain structuring based on herd immunity (Gupta & Maiden, 2001; Gupta et al., 1996). This also confirmed the observations made on a global dataset, where it was suggested that combinations of PorA VRs and FetA VRs might be an effective means of controlling meningococcal disease (Urwin et al., 2004). Simple vaccines based on combinations of these two components could achieve high coverage of circulating meningococci (Fig. 2). The implementation of such a vaccine may require epidemiological monitoring to ensure that it remains effective (Trotter et al., 2007).
Current approaches in the development of a comprehensive meningococcal vaccine can be divided into two distinct strategies: those seeking to enhance the immune response to conserved antigens and those based on highly immunogenic yet variable antigens. While not excluding the utility of vaccines based on conserved antigens, the observations reported here support the development of multivalent formulations consisting of variable antigens. The evidence of strain structuring indicates that such antigens are the principal targets of natural immunity. This is also consistent with clinical studies of OMV vaccines, which have repeatedly highlighted the importance of PorA for vaccine-induced immunity. In terms of clinical development, the most advanced multivalent vaccines consist of OMVs produced from genetically modified strains expressing multiple variants of PorA (van den Dobbelsteen et al., 2007). The present study provides a rational approach for deciding which variants should be included in this type of vaccine. It further suggests that ensuring the expression of appropriate variants of a second antigen, such as FetA, would be an effective way of broadening vaccine coverage.
In conclusion, meningococci isolated from cases of invasive disease are highly diverse at both housekeeping protein and antigen encoding loci; however, much of this diversity is transient, especially the minor variants of protein antigens. A more limited repertoire of antigen variants is persistent over time and these tend to be associated with particular invasive lineages. Combinations of subcapsular antigens reappear over time, sometimes associated with different lineages, perhaps in response to increases and decreases of herd immunity against particular strain types. This leads to the possibility that appropriately composed component vaccines may be able to protect human populations from meningococcal disease over periods of time sufficient to warrant their development and implementation.
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ACKNOWLEDGEMENTS |
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). The development of this site has been funded by the Wellcome Trust and European Union. Edited by: J. Parkhill
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REFERENCES |
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Received 8 November 2007;
revised 15 January 2008;
accepted 16 January 2008.
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), 1985 (
) and 1985 (
).