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W135 in Africa: origins, problems and perspectives
Travel Medicine and Infectious Disease (2003) 1, 19–28
www.elsevierhealth.com/journals/tmid
W135 in Africa: origins, problems and perspectives Dominic Kelly, Andrew J. Pollard* Department of Paediatrics, Oxford Vaccine Group, University of Oxford, John Radcliffe Hospital, Level 4, Oxford OX3 9DU, UK Received 3 February 2002; accepted 6 February 2003
KEYWORDS Neisseria meningitidis; Meningitis; Meningitis belt; Epidemiology; Vaccine; Africa; Clonal complex
Summary Serogroup A meningococci have been the major cause of epidemic meningococcal disease in Africa throughout the last 100 years. The reasons for this unusual pattern of behaviour have remained unclear and there remain significant debates and logistic difficulties around the appropriate use of plain A/C polysaccharide vaccination to control African meningococcal disease. Since the Hajj pilgrimage of 2000 serogroup W135 organisms (of the ST-11 clonal complex) have emerged as a further significant cause of epidemic meningococcal disease in Africa. Whilst advances in molecular biological and genetic techniques have yielded increasing insights into meningococcal epidemiology there remain many unanswered questions about the reason for the emergence of a serogroup W135 clone capable of epidemic behaviour and in particular its relation to past use of group A/C polysaccharide. The high cost and short supply of quadrivalent (A,C,Y, W135) vaccine to protect against W135 disease has added to what was already the significant burden of controlling serogroup A meningococcal disease. The ability of virulent meningococcal clones to acquire new capsule types raises further concerns about the future nature of meningococcal disease in Africa and the strategies of vaccination use and development necessary to contain it. Q 2003 Elsevier Science Ltd. All rights reserved.
Introduction Epidemic meningococcal disease in Africa has for many years been predominantly due to serogroup A meningococci. A high incidence of endemic meningococcal disease coupled with regular epidemics of devastating proportions has defined an area of subSaharan Africa known as the ‘meningitis belt’. This encompasses a region stretching from West Africa through Mali, Upper Volta, Niger and the Sudan to Eritrea in the Horn of Africa.2,3 Epidemics of meningococcal disease have been a consistent *Corresponding author. Tel./fax: þ 44-1856-857420. E-mail address: [email protected]
feature of this area for at least 100 years. In the natural world patterns that initially seem unchanging on the brief time scale of human observation are often shown to be dynamic with more prolonged observation or further insight. The recent occurrence of epidemics of serogroup W135 disease, first following the Hajj pilgrimage of 20004 and 20015 and more recently in Burkina Faso in 20026 has caused just such a change in perspective. The epidemiology of Neisseria meningitidis in Africa over the last two decades combined with the high rate of genetic change of the bacterium7 had previously hinted at the possibility of just such an occurrence. A continent beset by many hardships and struggling to cope with the burden of
1477-8939/03/$ - see front matter Q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1477-8939(03)00019-X
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meningococcal disease already present is now faced with a more serious situation. Logistic and financial constraints mean there is limited access to effective control measures for epidemics caused by serogroup W135 meningococci.8 This new manifestation of meningococcal disease also raises important issues about the control of meningococcal disease in the future and the possibility of the emergence of other clones for which vaccination is less effective or unavailable.
Microbiology N meningitidis is a gram-negative diplococcus enveloped by a polysaccharide capsule essential for pathogenicity. Differences in polysaccharide chemical structure define 12 capsule types A, B, C, H, I, K, L, W135, X, Y, Z, 29E(Z).9 Serogroup B and C are homopolymers of sialic acid differentiated by their respective methods of linkage between the sialic acid monomers. Serogroup W135 and Y are heteropolymers of sialic acid and galactose or
Figure 1
glucose respectively. Serogroup A is composed solely of N-acetyl mannosamine-1-phosphate.10 There is no antigenic cross-reactivity between capsules. Meningococci of serogroups A, B and C have been responsible for greater than 90% of invasive meningococcal infections worldwide.11 Serogroups W135, Y and X are among the more frequent serogroups isolated from the remaining cases of invasive disease. The capsule is thought to have multiple effects on the process of transmission and pathogenesis. Though it has been shown to hinder epithelial invasion it has antiphagocytic and anticomplement properties that confer protection against the host immune response. In addition it may aid transmission by preventing desiccation. The differences in capsule structure may be important in explaining the variations in epidemiology and virulence between serogroups. Within each serogroup the meningococcus exhibits a high degree of genetic diversity. Genetic variation arises from a combination of spontaneous mutation and horizontal genetic exchange of DNA due to the natural transformability of meningococci
Surface structures of Neisseria meningitidis.
W135 in Africa: origins, problems and perspectives
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(the ability to acquire exogenous DNA from other bacteria including other commensal Neisseria species such as N. Lactamica12). One study has suggested that the rate of recombination in a set of meningococcal ‘house-keeping’ genes is at least 80 times that of spontaneous mutation. The genetic material shared in this way between bacteria includes genes encoding metabolic enzymes, IgA protease, membrane proteins and enzymes controlling synthesis of the polysaccharide capsule. A variety of methods have been used to differentiate the genetic variants of meningococci within a serogroup. An understanding of these methods is crucial to appreciating the epidemiology of N meningitidis and the debate over the origin of epidemic serogroup W135 disease. Meningococci may be subdivided by their possession of particular major outer membrane proteins (Fig. 1). Most commonly used are Por B and Por A (serotype and serosubtype respectively). Similar methods can be applied to the lipopolysaccharide (immunotype).13 However whilst important for immediate public health issues and vaccine development these methods have proven unsatisfactory for epidemiological use on a broader scale. The molecules being on the surface are likely to be under selection pressure and they index too small a fraction of the bacterium’s genetic material to be revealing about overall relatedness between isolates.14 The recent ability to analyse more comprehensively the genetic variation between organisms using both direct and indirect methods has provided new insight into their epidemiology. Multilocus enzyme electrophoresis (MLEE) identifies natural variation in several essential metabolic enzymes.15 These enzymes are known as house-keeping genes and in coding essential and relatively conserved parts of normal cellular metabolism they experience neutral evolutionary selection pressure making them suitable for looking at lineage relationships over long periods of time.14 Organisms are grouped by their possession of similar clusters of enzymes to yield an electrophoretic type or ET (e.g. ET-15 or ET-37). There are now methods for more direct analysis of the meningococcal genome itself. Pulsed field gel electrophoresis (PFGE) of restriction fragments of the whole bacterial genome yields band patterns that can be compared between organisms.16 Most recently the sequencing of specific regions of genes coding for the ‘housekeeping’ enzymes has been described—multilocus sequence typing (MLST). Following MLST and in a similar fashion to the results of MLEE (but now using the variation in the genes themselves rather than the proteins they produce) the organisms are grouped by their possession of similar clusters of
alleles. This yields the sequence type or ST.17 The resulting data is more readily comparable between laboratories than MLEE. ST still correlates closely with ET because both techniques involve analysis of the genetic code and protein output respectively of the same group of enzymes. However, a variety of serotypes, serosubtypes or PFGE patterns may be associated with a particular ST. Organisms with the same ST may even belong to different serogroups (e.g. ST-11 can be either serogroup B, C or W135).Other molecular approaches to meningococcal identification are still being assessed.11 Groups of related STs are known as a clonal complex. The complex is named after the most genetically typical and persistent organism17 (e.g. ST-8 clonal complex includes ST-66 and ST-487). Such a complex is postulated to have derived from a single ancestral bacterium and subsequently u ˙ndergone only a limited amount of genetic change. Groups of related ET were previously described as subgroups, clusters or complexes18 but are basically clonal complexes and synonymous with a particular ST (e.g. ST-11 organisms are ET-37). While there are a large number of different STs the majority of isolates in any one area and particularly those causing disease are from a restricted range of clonal complexes. In the 20th century disease causing isolates have belonged almost entirely to STs 1, 4, 5, 8, 11, 32 and 44. The concept of clonal complexes has proved to be have significant epidemiological use. Surveillance or analysis of stored isolates can demonstrate the spread of a particular clonal complex across the globe.19 In addition specific complexes appear to be associated with particular patterns of disease and virulence. ET-5 (ST-32) appears to cause prolonged outbreaks of hyper-endemic disease.20 ST-5 and ST7 in association with group A capsule cause epidemic disease particularly in Africa.21 ST11 has been associated with sporadic outbreaks and is thought to be hypervirulent.22 At any one time a clonal complex is typically associated with a particular capsule type (e.g. ET-37 associated with serogroup C in 90% of cases globally in the 1960s – 1980s23). However the existence of meningococci of the same clonal complex but of different serogroup is indirect evidence for the ability of a single organism to switch capsule types. In Oregon a rise in serogroup B related disease since 1993 was due to the ET-5 complex. Since 1994 Group C ET-5 strains have also been identified and have been shown to arise from allelic exchange of a capsule determining gene.10 Capsule switching has also been observed in contacts of an individual with disease.[24] This has significant implications for vaccine strategies based on a limited number of
22
serogroups where a bacterium of a clonal complex may retain its virulence after changing its polysaccharide capsule type.
Epidemiology The epidemiology and vaccinology of N meningitidis has classically focused on the serogroup. Group A meningococci appear to have been responsible for the majority of epidemics of meningococcal disease in the last 100 years. In Europe these epidemics were particularly associated with the World Wars presumably because of the large-scale population movements associated with troops and refugees. Serogroup A epidemics have been less frequent since the 1950s but still occurred (e.g. in Finland in the 1970s25). Serogroup A Asian epidemics are well described.26 In Africa epidemics of serogroup A meningococcal disease occur periodically every 5 – 10 years across the subSaharan area known as the ‘meningitis belt’.1 Geographically contiguous, this area is further defined by its coincidence with the 300 – 1100 mm annual rainfall isohyets south from the Sahara.3 Such epidemics are limited to the dry seasons and end abruptly with the onset of rains. They are striking for the high attack rate (as high as one in ten in some communities) and their vast scale. In Nigeria in 1996 over 80 000 cases were reported. In non-epidemic periods there is a hyperendemic state with incidences of 10 –50/100 000/year. The reasons for the periodicity are unclear but may involve climatic variables, waning population immunity (by elapsed time since exposure and the arrival of new exposure naive cohorts in the form of young children) and the interaction with other pathogens. Variations in the amount of transmission may be less important than factors altering pathogenicity as transmission has been shown to occur throughout both seasons.1 The last 20 years has brought an increasing recognition of the importance of pathogen variation in contributing to the epidemics. Serogroup A epidemics in both Africa and Asia have been caused by a limited number of clonal complexes.18 ST-5 organisms originating in China in the 1980s spread through Nepal to east Asia and were finally disseminated globally via the 1987 Hajj pilgrimage in Mecca.21 The introduction of ST5 organisms to Africa resulted in a wave of epidemics over several years. There has probably been a long history of the meningococcus arriving on the continent in this way.1 Since 1995 a further clone ST-7 has been steadily replacing ST-5 as a cause of epidemics in Africa.21 Some authors have
D. Kelly, A.J. Pollard
speculated on the importance of this replacement and a lack of protective cross immunity between clonal complexes even with the same serogroup as a causal factor in the new waves of epidemic disease.21 Serogroup B and C meningococci are associated with sporadic disease and minor outbreaks. They have been responsible for outbreaks within communities that are relatively confined and living in high density such as army barracks.27 Though not associated with the large-scale epidemics of group A it is increasingly recognized that particular clones of B and C have caused a rise in case numbers to hyperendemic levels lasting several years in some countries (e.g. ST-5 in Oregon, USA20 and ST-11 in Canada.22) Serogroup B and C meningococci both cause disease in Africa. In this setting serogroup C has on rare occasions been associated with epidemic behaviour.28,29 Serogroup W135 meningococci were first identified in the 1960s causing outbreaks of meningococcal disease in the US army.30 They remained an infrequently occurring serogroup causing sporadic cases of invasive meningococcal disease including some reports of pneumonia in the elderly.31 Serogroup W135 constituted 2.6 – 4% of reported N meningitidis in the UK, France and the USA during the 1990s.4 Following the Hajj pilgrimage to Mecca in 2000 there was an outbreak of serogroup W135 disease in Saudi Arabia followed by cases amongst pilgrims returning to their home countries.4 Over 300 cases were reported in 14 countries.32 Cases occurred in the contact of pilgrims and in those with no identifiable association with the Hajj suggesting ongoing transmission within the pilgrims’ of home countries’. A rare meningococcal serogroup W135 strain was identified as the cause (serotype 2a subtype P1.2, 1.5).5 This was the first recorded epidemic caused by serogroup W135 meningococci and was associated with ST-11 (ET-37) clonal complex.11 This complex, recognized as being hypervirulent, had been mainly associated with serogroup C meningococci prior to the Hajj.22 Capsule switching is well described and has been documented following transmission of meningococci from a patient with disease to contacts.24 However, serogroup W135 strains almost identical to the ST-11 (ET-37) clone of the 2000 Hajj outbreak have been circulating for over 30 years making it unlikely that the clone arose by capsule switching at the 2000 Hajj.11 Determining when the clone arose would require more extensive investigation of past isolates from around the globe. The Hajj of 2000 appears to have facilitated the spread of a virulent clone by allowing crowded conditions favourable to transmission in a large group of people from all
W135 in Africa: origins, problems and perspectives
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around the globe. The reasons for the change in behaviour of the clone are unclear. An almost identical Hajj associated outbreak with the same serogroup W135 strain followed in 2001.5 Following this, pilgrims to the 2002 Hajj were required to have had the quadrivalent plain polysaccharide vaccine covering serogroups A, C, W135 and Y as a condition of their visa. This replaced a requirement for the bivalent A/C polysaccharide vaccine which had been mandatory since the Hajj related serogroup A outbreaks in 1987. It is interesting to note that serogroup W135 disease following the Hajj has been noted previously in Saudi Arabia.33 However, no further identification is available on these isolates. Since the Hajj related outbreak of 2000 epidemic serogroup W135 disease has appeared in Africa.6 Serogroup W135 meningococci were first described in Africa in 1980.34 Prior to this the situation is less clear. A study of purulent meningitis in Dakar between 1970 and 1979 has no mention of serogroup W135 disease.35 It is unclear whether it was not detected because it was not looked for or because it was not there. Table 1 documents subsequent reports of serogroup W135 meningococcal isolation. It is clear that serogroup W135 meningococci have been consistently isolated in studies of carriage and disease in Africa since 1980. These have been predominantly ET-37 during the last decade. The studies of disease however are either unsystematic samples from a larger population of cases or else hospital based and not clearly related to a population size. It is thus difficult to discern trends in the absolute incidence of disease due to
a particular serogroup by comparing studies. A change in the proportion contributed by serogroup W135 may be due to a decrease in incidence of disease caused by other serogroups as well as a change in serogroup W135 disease. Carriage studies may be more revealing from this perspective as they are collected from a known population. Unfortunately studies of meningococcal carriage in Africa are few. Prior to the 2000 Hajj pilgrimage serogroup W135 meningococci had not been associated with large-scale epidemics despite the fact that the majority of isolates from the 1990s belonged to the same clonal complex as the strain causing the 2000 outbreak.11 Following the Hajj of 2000 and the subsequent globally widespread outbreaks caused by the serogroup W135 clone there have been further reports of serogroup W135 disease in Africa. In epidemics in Burkina Faso and Niger in 2001 serogroup W135 was recorded in almost 40% of isolates, most of the others being serogroup A.41 As the samples were collected in an unsystematic fashion towards the end of the epidemics it was unclear as to whether they represented endemic disease following a large scale A/C vaccination campaign or whether serogroup W135 had been a significant contributor to the epidemic. In January 2002 an epidemic of meningococcal disease began in Burkina Faso. By the time it was abating in May over 12 000 cases of disease and almost 1500 deaths had been reported. Over 90% were caused by serogroup W135.4 This leaves little doubt regarding the epidemic behaviour of this clone and already in the first weeks of 2003 further cases of meningococcal disease are
Table 1 Isolations of serogroup W135 meningococci from Africa reported in the literature. Year
Region
Study type (ep ¼ epidemic, en ¼ endemic)
198036 198134
Upper Volta Senegal Niger Senegal Niger Gambia Africa Gambia Mali Gambia Cameroon
Carriage (en) Disease (en) Disease (ep) Disease (en) Disease (post-ep) Disease (post-ep) Disease (ep) Disease (en) Disease (ep) Carriage Disease (en)
198234 1983 –8537 1989 –9438 1990 –9528 199428 199639 1998 –9940 1999 –00 2000 –01 200141
200243
Electrophoretic type
ET-37 ET-37 ET-37 ET-37 ET-37
Burkina Faso Niger Cent Afr Rep42 Burkina Faso
Disease (ep)
Disease (ep)
W135 isolates/total isolates (%) or % with carriage 1.3% 3/25 (12) 1/221 (0.5) 0/51 7/42 (17) (7) 2/125 (2) 6/10 (60) 2/12 (17) 5.3% 1/8 (13) 4/23 (17) 4/17 (24) 12/32 (38) 12/31 (39) 3 isolates 147/160 (92)
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being reported from Burkina Faso though their serogroup is as yet unreported. The increasing occurrence of epidemic meningitis beyond the traditional meningitis belt lends further cause for concern as to the eventual impact of this form of serogroup W135 disease.3
Vaccination Vaccines based on the polysaccharide capsule can induce protective immunity to meningococcal disease caused by the serogroup possessing that polysaccharide.44 Widespread antibiotic resistance in meningococci isolated from US military recruits led to the development of an effective serogroup C polysaccharide vaccine in the late 1960s. This was followed by bivalent serogroup A/C meningococcal polysaccharide vaccine in 1978 and a quadrivalent polysaccharide vaccine against serogroups A, C, Y and W135 in 1982.45 Serogroup B polysaccharide is poorly immunogenic.46 In Africa, within potential epidemic regions, surveillance of cases of meningococcal disease will trigger a population based mass-vaccination response when an absolute number or rate of increase of cases reaches a threshold level. The threshold level varies with the epidemiological context.47 There is ongoing debate about whether this is the most effective use of the vaccine or whether combined approaches with preventative vaccination would be more effective.48 Epidemic response may be slow if surveillance is poor and there is limited infrastructure for the logistical support of mass vaccination campaigns. Preventative strategies are hindered by the poor response of infants to plain polysaccharides and the lack of prolonged protection available from polysaccharide vaccines that do not induce a T cell dependent memory response.9 Glycoconjugate vaccines which induce long term immunity would avoid the need for repeated epidemic control measures and are discussed below. The emergence of epidemic serogroup W135 disease has highlighted a weak spot in the armamentarium against the meningococcus. The quadrivalent (A/C/Y/W135) vaccine is more expensive than the bivalent (A/C) version that has been widely used for epidemic control, it is in short supply43 and is of unknown efficacy. Although the serogroup W135 component can be shown to be immunogenic49,50 the small numbers of cases of disease attributable to this serogroup have precluded any trial of efficacy. Limited effectiveness data can be inferred from use of the quadrivalent vaccine in the US and UK. US military data suggests there have been ‘few
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documented cases caused by serogroups that were represented in…vaccines’.45 In the UK following the recommendation by the Department of Health that pilgrims have the quadrivalent vaccine in 2001 there were no cases in those who had received the vaccine.5 However, the proportion of all pilgrims who had received vaccination could only be estimated indirectly at ‘less than 47%’. The most recent UK data since the quadrivalent vaccine has become an entry requirement for pilgrims travelling to Saudi Arabia for the Hajj is that the number of cases has fallen from 45 in 2000 and 38 in 2001 to 6 in 2002.51 There remains no effectiveness information from the areas at risk of epidemic serogroup W135 disease. In view of the emerging W135 epidemic in Burkina Faso during 2002/2003 the WHO, GlaxoSmithKline and the Bill and Melinda Gates foundation have rapidly developed and made available a trivalent (A/C/W135) polysaccharide vaccine. Though three million doses are to be provided at a cost much less than that of the quadrivalent vaccine the effectiveness remains unknown [WHO. Partnership moves in record time to provide vaccine against meningitis as epidemic emerges in Africa]. (http://www.who.int/mediacentre/releases/2003/pr9/en) The disadvantages of polysaccharide vaccines have been addressed through the development of vaccines utilising the polysaccharides conjugated to a protein carrier (glycoconjugate vaccines). For serogroup C disease this approach has been successful in achieving immunogenicity in infants, inducing memory responses and thus increasing the duration of protective immunity and affecting carriage.9 Trials of quadrivalent conjugate vaccines are now in progress in several countries.52,53 At present it is clear that these vaccines will be too costly for the countries at risk of epidemic disease. The development of monovalent serogroup A glycoconjugate vaccines is supported by the ‘meningitis vaccine project’ but does not address the issue on nonserogroup A disease.54 Concerns about the effects of limited serogroup coverage are discussed below.
Epidemic W135—origins Why should a clone that has been circulating in Africa for at least 8 years in non-epidemic form develop the capacity to cause large outbreaks? Epidemic serogroup W135 disease may have been present previously in Africa. Concurrent and larger serogroup A epidemics promoted by similar environmental and demographic factors to
W135 in Africa: origins, problems and perspectives
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serogroup W135 disease may have been obscuring a lower level of serogroup W135 disease. In Mali in 1994 17% of isolates were W135.28 Difficulties in interpreting the relative proportions of isolates particularly in differing vaccination scenarios make it hard to be certain of the significance of this information. Given the degree to which N meningitidis is subject to genetic transformation, has the organism changed significantly? Studies of serogroup W135 isolates from over 30 years have shown only minor differences between isolates from 1970 Scotland and Canada and the 2000 Hajj (e.g. 1 band on PFGE and 1 enzyme on MLEE). However it is possible that minor changes in genes encoding virulence factors important in transmission, colonisation or survival have occurred.11 Such changes have been clearly shown occurring during the spread of serogroup A meningococci—some associated with (though not necessarily causally related) to new pandemic waves of disease.19 Polysaccharide A/C vaccine has been widely used in Africa over the last 20 years. It has also been a requirement for the Hajj pilgrimage since 1987. Not all potentially pathogenic meningococci are covered by the vaccine and it is unclear how such vaccines affect the overall population biology of the bacterium. Concern exists that other clones may replace those removed by vaccination or that a pathogenic clone may through recombinatorial events acquire variant capsule types and retain its virulence thus subverting the original purpose of vaccination.55 The almost complete elimination of group C carriage following the introduction of serogroup C meningococcal conjugate vaccination in the UK has not been followed by an increase in carriage of other serogroups.56 However the overall rate of meningococcal disease has not declined by as much as would be expected, because of an increase in serogroup B disease.57 Point prevalence carriage studies may fail to reflect the complexities of carriage dynamics which may have an effect on disease incidence. Studies of pentavalent glycoprotein pneumococcal conjugate in The Gambia suggested that the vaccine’s effect in terms of carriage was countered by colonisation with non-vaccine serotypes.58 Similar concerns about meningococcal serogroup replacement were highlighted following a polysaccharide A/C vaccination campaign in The Gambia. Following the campaign there was a meningococcal carriage rate of 5% of which all except one isolate were serogroup W135 (27/28 isolates).39 Changes in serogroup and clonal complex prevalence are also noted over time in the absence of
vaccination for reasons as yet not understood.45, 59 The ability of vaccines to precipitate this process and particularly to select for variant serogroups of already virulent clones is not known. Underlying all the concerns regarding capsular replacement in relation to polysaccharide A/C vaccination is the presumption that polysaccharide vaccination affects carriage of meningococci. Previous studies have shown that any effect of polysaccharide on carriage is limited to several weeks though dramatic effects are seen following immunisation of closed communities, such as during military training.60 – 62 If plain polysaccharide A/C vaccination is implicated in the emerging epidemic behaviour of the serogroup W135 ST-11 clone it is surprising, given the short duration of the effect on carriage, that it has taken 12 years (from the vaccine coming into routine use for the Hajj and longer since its regular use in Africa) to precipitate the change in epidemiological behaviour. However it may be that temporary elimination of the serogroup A/C meningococci could allow a foothold for serogroup W135 meningococci from which they were more difficult to dislodge once established. Persistent use of A/C vaccine might lead to slowly increasing levels of W135 exacerbated by the large amounts of transmission and dissemination occurring at international gatherings (e.g. Hajj) and with population movements caused by famine and conflict. The reasons for such an abrupt emergence of the clones behaviour would still be unexplained. Of further concern in the long term is the possibility of hypervirulent lineages (such as ST11) undergoing capsule switching to generate virulent clones not covered by existing vaccines. Limited outbreaks of serogroup X meningococci in Ghana and Nigeria63 for which there is no current vaccine remind us of the importance of monitoring the situation closely in this region. Serogroup B ST-11 isolates have previously been described.23 This serogroup has proved so far intractable to vaccine attempts and the prospect of epidemic serogroup B disease is discomforting.54
The future The emergence of epidemic serogroup W135 meningococcal disease at the Hajj of 2000 and subsequently in Africa was unexpected. This is despite several concerns over the previous years
26
about the appearance of isolates from cases of disease and carriage. Strategies for serogroup A control were already only partially effective because of logistics, the difficulties of timely epidemic prediction and the relatively short lived immunity of the available vaccines coupled with their lack of effect on long term carriage. The available quadrivalent polysaccharide vaccine covering W135 disease has all of the problems described above associated with it. In addition its production has been previously on a small scale with difficulties of supply even before the problems of distribution to rural African communities is considered. In the short term widespread polysaccharide vaccination with a serogroup A and W135 containing vaccine may control epidemic meningococcal disease. In the medium term the availability of a conjugate vaccine covering the relevant serotypes (A,C, W135) may produce dramatic effect if this can ever be made affordable. However, the lessons emerging from the current difficulties suggest that introduction of multivalent conjugate vaccines into routine immunisation schedules in the affected region should be a high priority. The most clearly demonstrated virulence factor for the meningococcus is the polysaccharide capsule. Whilst the aim of a vaccine against a more universally possessed epitope remains the ideal, the inherent genetic heterogeneity of the meningococcus makes this a distant goal. Thus in terms of current vaccine development a more comprehensive and immunogenic anti-polysaccharide capsule vaccine remains a realistic objective. The danger of a half-hearted solution through providing a vaccine against limited serogroups and of limited efficacy on carriage may paradoxically be the same or worse than no solution at all. We have the technology today to provide a sustainable solution to the epidemic meningitis problem in Africa through an infant programme with one of the ACYW conjugate vaccines that are currently in trials. In this context, it is unthinkable that thousands may die in the meningitis belt of Africa during 2003, despite these vaccines being available. However, even if production of these effective vaccines could meet the potential demand this year, it is unlikely that current predictions of vaccine cost could be met outside of industrialised nations. The spectre of an epidemic group B strain for which there would be no options for vaccination has been raised by the current behaviour of W135. Heightened surveillance and efforts to develop a serogroup B vaccine must also continue in earnest.
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Conflicts of interest AJP conducts clinical trials of meningococcal vaccines on behalf of the University of Oxford sponsored by several vaccine manufacturers.
References 1. Greenwood B. Meningococcal meningitis in Africa. Manson lecture. Trans R Soc Topics Med Hyg 1999;93:341—353. 2. Lapeyssonie L. La meningite cerebro-spinale en Afrique. Bull WHO 1963;281(Suppl. 1):3—114. 3. Molesworth AM, Thomson MC, Conno SJ, et al. Where is the meningitis belt? Defining an area at risk of epidemic meningitis in Africa. Trans R Soc Trop Ed Hyg 2002;96(3): 242—249. 4. Aguilera J, Perrocheau A, Meffre C, Hahne S. Outbreak of serogroup w135 meningococcal disease after the Haj pilgrimage, Europe, 2000. Emerg Infect Dis 2002;8:761—767. 5. Hahne SJ, Gray SJ, Aguilera J-F, Crowcroft NS, Nichols T, Kaczmarski EB, Ramsay M. W135 meningococcal disease in England and Wales associated with Hajj 2000 and 2001. Lancet 2002;359:582—583. 6. WHO, Meningococcal disease, serogroup W135, Burkina Faso: preliminary report 2002. Wkly Epidemiol Rec 2002; 77:152—155. 7. Feil EJ, Maiden MCJ, Actman M, Spratt BG. The relative contributions of recombination and mutation to the divergence of clones of Neisseria meningitidis. Mol Biol Evol 1999;16:1496—1502. 8. Chongaile CN. Meningitis in Africa—tackling W135. Lancet 2002;360:2054—2055. 9. Pollard AJ, Levin M. Vaccines for the prevention of meningococcal disease. Pediatr Infect Dis J 2000;19: 333—345. 10. Swartley JS, Marfin AA, Edupuganti S, Liu L-J, Cieslak P, Perkins B, Wenger JD, Stephens DS. Capsule switching of Neisseria meningitidis. Proc Natl Acad Sci USA 1997;94: 271—276. 11. Mayer L, Reeves MW, Al-Hamdan N, Sacchi CT, Taha M, et al. Outbreak of W135 meningococcal disease in 2000: not emergence of a new W135 strain but clonal expansion within the electrophoretic type-37 complex. J Infect Dis 2002;185: 1596—1605. 12. Linz B, Schenker M, Peixan Z, Achtman M. Frequent interspecific genetic exchange between commensal neisseriae and Neisseria meningitidis. Mol Microbiol 2000;36(5): 1049—1061. 13. Frasch CE, Zollinger WD, Poolman JT. Serotpye antigens of Neisseria meningitidis and a proposed scheme for the designation of serotypes. Rev Infect Dis 1985;7:504—510. 14. Caugant DA. Population genetics and molecular epidemiology of Neisseria meningitidis. APMIS 1998;106:505—525. 15. Selander RK, Caugant DA, Ochman H, Musser JM, Gilmour MN, Wittam TS. Methods of multilocus enzyme electrophoresis for bacterial population genetics and systematics. Appl Environ Microbiol 1986;51:837—884. 16. Bygraves JA, Maiden MCJ. Analysis of the clonal relationships between strains of Neisseria meningitidis by pulsed field gel electrophoresis. J Gen Microbiol 1992;138:523—531. 17. Maiden MCJ, Bygraves JA, Feil E, Morelli G, Russel JE, Urwin R, et al. Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic organisms. Proc Natl Acad Sci USA 1998;95:3140—3145.
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18. Achtman M. Global epidemiology. In: Cartwright K, editor. Meningococcal disease, 1st ed. Chichester: Wiley; 1995. p. 159—175. 19. Zhu P, van der Ende A, Falush D, Brieske N, Morelli G, et al. Fit genotypes and escape variants of subgroup III Neisseria manigitidis during three pandemics of epidemic meningitis. Proc Natl Acad Sci USA 2001;98:5234—5239. 20. Diermayer M, Hedberg K, Hoesly F, Fischer M, Perkins B, Reeves M, Fleming D. Epidemic serogroup B meningococcal disease in Oregon: the evolving epidemiology of the ET-5 strain. JAMA 1999;281:1541—1543. 21. Nicolas P, Decousset L, Riglet V, Castelli RS, Blanchet G. Clonal expansion of sequence type (ST)-5 and the emergence of ST-7 in serogroup A meningococci, Africa. Emerg Infect Dis 2001;7:849—854. 22. Pollard AJ, Scheifele D. Meningococcal disease and vaccination in North America. J Paediatr Child Health 2001;37: 520—527. 23. Wang JF, Caugant DA, Morelli G, Koumare B, Achtman M. Antigenic and epidemiological properties of the ET-37 complex of Neisseria meningitidis. J Infect Dis 1993;167: 1320—1329. 24. Vogel U, Claus H, Frosch M. Rapid serogroup switching in Neisseria meningitidis. N Engl J Med 2000;342:219—20. 25. Peltola H, Jonsdottir K, Lystad A, Sievers CJ, Kallings I. Meningococcal disease in Scandinavia. BMJ 1982;284: 1618—1621. 26. Wang J, Caugant DA, Li X, et al. Clonal and antigenic analysis of serogroup A Neisseria meningitidis with particular reference to epidemiological features of epidemic meningitis in China. Infect Immun 1992;60:5267—5282. 27. Cartwright K. Meningococcal carriage and disease. In: Cartwright K, editor. Meningococcal disease, 1st ed. Chicester: Wiley; 1995. p. 115—145. 28. Kwara A, Adegbola RA, Corrah PT, Weber M, Achtman M, Morelli G, Caugant DA, Greenwood BM. Meningitis caused by a serogroup W135 clone of the ET-37 complex of Neisseria meningitidis in West Africa. Trop Med Int Child Health 1998; 3:742—746. 29. World Health Organisation, Outbreaks. Wkly Epidemiol Rec 2000;75:117—118. 30. Evans JR, Artenstein MS, Hunter DH. Prevalence of meningococcal serogroups and description of three new groups. Am J Epidemiol 1968;87:643—646. 31. Brandstetter RD, Blair RJ, Roberts RB. Neisseria meningitidis serogroup W135 disease in adults. JAMA 1981;246: 2060—2061. 32. World Health Organisation, Outbreaks. Wkly Epidemiol Rec 2000;75:180. 33. Yousouf M, Nadeem A. Fatal meningococcaemia due to group W135 amongst Hajj pilgrims: implications for future vaccination policy. Ann Trop Med Parasitol 1995;89:321—322. 34. Denis L, Rey JL, Amadou A, Saliou P, Prince-David M, M’Boup S, et al. Emergence of meningococcal meningitis caused by W135 serogroup in Africa. Lancet 1982;ii:1335—1336. 35. Cadoz M, Denis F, Mar ID. An epidemiological study of purulent meningitis cases admitted to hospital in Dakar: 1970—79. Bull World Health Org 1981;59:575—584. 36. Riou JY, Saliou P, Guibourdenche M, Chalvignac MA. Etude bacteriologique de 358 souches de Neisseria et branhamella isolees en Haute Volta. Med Mal Infect 1980;10: 430—436. 37. Greenwood BM, Smith AW, Hassan-King M, Bijlmer HA, Shenton FC, Hughes AS, Nunn PP, Jack AD, Gowers PR. The efficacy of meningococcal polysaccharide vaccine in preventing group A meningococcal disease in The Gambia, West Africa. Trans R Soc Trop Med Hyg 1986;80:1006—7.
38. Guibourdenche M, Hoiby EA, Riou J-Y, Varaine F, Joguet C, Caugant DA. Epidemics of serogroup A Neisseria meningitidis of subgroup III in Africa, 1989—94. Epidemiol Infect 1996; 116:115—120. 39. MacLennan JM, Urwin R, Obaro S, Griffiths D, Greenwood B, Maiden MCJ. Carriage of serogroup W-135, ET-37 meningococci in The Gambia: implications for immunisation policy? Lancet 2000;356:1078. 40. Fonkoua M-C, Taha M-K, Nicolas P, Cunin P, Alonso J-M, et al. Recent increase in meningitis caused Neisseria meningitidis serogroups A and W135, Yaounde, Cameroon. Emerg Inf Dis 2002;8:327—329. 41. Taha M-K, Parent du Chatelet I, Schlumberger M, Sanou I, Djibou S, de Chabalier F, Alonso J-M. Neisseria meningitidis serogroups W135 and A were equally prevalent among meningitis cases occurring at the end of the 2001 epidemics in Burkina Faso and Niger. J Clin Microbiol 2002;40: 1083—1084. 42. World Health Organisation, Epidemics of meningococcal disease, African meningitis belt. Wkly Epidemiol Rec 2001; 37:218—288. 43. Decosas J, Koama J-BT. Chronicle of an outbreak foretold: meningococcal meningitis W135 in Burkina Faso. Lancet Infect Dis 2002;2:763—765. 44. Jodar L, Feavers IM, Salisbury D, Granoff DM. Development of vaccines against meningococcal disease. Lancet 2002; 359:1499—1508. 45. Brundage JF, Ryan MAK, Feighner BH, Erdtmann FJ. Meningococcal disease among United States military service members in relation to routine uses of vaccines with different serogroup-specific components, 1964—1998. Clin Infect Dis 2002;35:1376—1381. 46. Morley SL, Pollard AJ. Vaccine prevention of meningococcal disease, coming soon? Vaccine 2001;20:666—687. 47. Lewis R, Nathan N, Diarra L, Belanger F, Paquet C. Timely detection of meningococcal meningitis epidemics in Africa. Lancet 2001;358:287—293. 48. Correspondence, Meningococcal immunisation in Ghana. Lancet 2000;355:2252—2253. 49. Griffiss JM, Brandt BL, Broud DD. Human immune response to various doses of Y and W135 meningococcal polysaccharide vaccines. Infect Immun 1982;37:205—208. 50. Peltola H, Safary A, Kayhty H, Karanko V, Andre F. Evaluation of two tetravalent (ACYW135) meningococcal vaccines in infants and small children: A clinical study comparing immunogenicity of O-acetyl-negative and O-acetyl-positive group C polysaccharides. Pediatrics 1985;76:91—96. 51. News, Vaccine campaign reduces illness in travellers. BMJ 2000;356:120. 52. Rennels M, King Jr J, Ryall R, et al. Dose escalation, safety and immunogenicity study of a tetravalent meningococcal polysaccharide diphtheria conjugate vaccine in toddlers. Paediatr Infect Dis J 2002;21:978—979. 53. Campbell JD, Edelman King Jr JC, Papa T, Ryall R, Rennels MB. Safety, reactogenicity and immunogenicity of a tetravalent meningococcal polysaccharide—diphtheria toxoid conjugate vaccine given to healthy adults. J Infect Dis 2002;186:1848—1851. 54. Pollard AJ, Maiden MCJ. Epidemic meningococcal disease in sub-Saharan Africa—towards a sustainable solution? Lancet Infect Dis 2003;3:69—70. 55. Maiden MJC, Spratt BG. Meningococcal conjugate vaccines: new opportunities and new challenges. Lancet 1999;354: 615—616. 56. Baker P, Borrow R, Miller E. Impact of meningococcal C conjugate vaccination in the UK. J Med Microbiol 2002;51: 717—722.
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57. Trotter CL, Ramsay ME, Kaczmarski EB. Meningococcal serogroup C conjugate vaccination in England and Wales: coverage and initial impact of the campaign. Commun Dis Public Health 2002;5:220—225. 58. Obaro SK, Adegbola RA, Banya WA, Greenwood BM. Carriage of pneumococci after pneumococcal vaccination. Lancet 1996;348:271—272. 59. Rosenstein NE, Perkins BA, Stephens DS, Lefkowitz L, Cartter ML, Danila R, et al. The changing epidemiology of meningococcal disease in the United States 1992—1996. J Infect Dis 1999;180:1894—1901. 60. Gotschlich EC, Goldschneider I, Artenstein MS. Human immunity to meningococcus. V. The effect of immunization
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with meningococcal group C polysaccharide on the carrier state. J Exp Med 1969;129:1385—1395. 61. Artenstein MS, Gold R, Zimmerly JG, Wyle FA, Schneider H, Harkins C. Prevention of meningococcal disease by group C polysaccharide vaccine. N Engl J Med 1970;282: 417—420. 62. Sivonen A. Effect of Neisseria meningitidis group A polysaccharide vaccine on nasopharyngeal carrier rates. J Infect 1981;3:266—272. 63. Gagneux S, Wirth T, Hodgson A, Ehrhard I, Morelli G, Kriz P, Genton B, Smith T, Binka F, Pluschke G, Achtman M. Clonal groupings in serogroup X Neisseria meningitidis. Emerg Infect Dis 2002;8.
www.elsevierhealth.com/journals/tmid
W135 in Africa: origins, problems and perspectives Dominic Kelly, Andrew J. Pollard* Department of Paediatrics, Oxford Vaccine Group, University of Oxford, John Radcliffe Hospital, Level 4, Oxford OX3 9DU, UK Received 3 February 2002; accepted 6 February 2003
KEYWORDS Neisseria meningitidis; Meningitis; Meningitis belt; Epidemiology; Vaccine; Africa; Clonal complex
Summary Serogroup A meningococci have been the major cause of epidemic meningococcal disease in Africa throughout the last 100 years. The reasons for this unusual pattern of behaviour have remained unclear and there remain significant debates and logistic difficulties around the appropriate use of plain A/C polysaccharide vaccination to control African meningococcal disease. Since the Hajj pilgrimage of 2000 serogroup W135 organisms (of the ST-11 clonal complex) have emerged as a further significant cause of epidemic meningococcal disease in Africa. Whilst advances in molecular biological and genetic techniques have yielded increasing insights into meningococcal epidemiology there remain many unanswered questions about the reason for the emergence of a serogroup W135 clone capable of epidemic behaviour and in particular its relation to past use of group A/C polysaccharide. The high cost and short supply of quadrivalent (A,C,Y, W135) vaccine to protect against W135 disease has added to what was already the significant burden of controlling serogroup A meningococcal disease. The ability of virulent meningococcal clones to acquire new capsule types raises further concerns about the future nature of meningococcal disease in Africa and the strategies of vaccination use and development necessary to contain it. Q 2003 Elsevier Science Ltd. All rights reserved.
Introduction Epidemic meningococcal disease in Africa has for many years been predominantly due to serogroup A meningococci. A high incidence of endemic meningococcal disease coupled with regular epidemics of devastating proportions has defined an area of subSaharan Africa known as the ‘meningitis belt’. This encompasses a region stretching from West Africa through Mali, Upper Volta, Niger and the Sudan to Eritrea in the Horn of Africa.2,3 Epidemics of meningococcal disease have been a consistent *Corresponding author. Tel./fax: þ 44-1856-857420. E-mail address: [email protected]
feature of this area for at least 100 years. In the natural world patterns that initially seem unchanging on the brief time scale of human observation are often shown to be dynamic with more prolonged observation or further insight. The recent occurrence of epidemics of serogroup W135 disease, first following the Hajj pilgrimage of 20004 and 20015 and more recently in Burkina Faso in 20026 has caused just such a change in perspective. The epidemiology of Neisseria meningitidis in Africa over the last two decades combined with the high rate of genetic change of the bacterium7 had previously hinted at the possibility of just such an occurrence. A continent beset by many hardships and struggling to cope with the burden of
1477-8939/03/$ - see front matter Q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1477-8939(03)00019-X
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meningococcal disease already present is now faced with a more serious situation. Logistic and financial constraints mean there is limited access to effective control measures for epidemics caused by serogroup W135 meningococci.8 This new manifestation of meningococcal disease also raises important issues about the control of meningococcal disease in the future and the possibility of the emergence of other clones for which vaccination is less effective or unavailable.
Microbiology N meningitidis is a gram-negative diplococcus enveloped by a polysaccharide capsule essential for pathogenicity. Differences in polysaccharide chemical structure define 12 capsule types A, B, C, H, I, K, L, W135, X, Y, Z, 29E(Z).9 Serogroup B and C are homopolymers of sialic acid differentiated by their respective methods of linkage between the sialic acid monomers. Serogroup W135 and Y are heteropolymers of sialic acid and galactose or
Figure 1
glucose respectively. Serogroup A is composed solely of N-acetyl mannosamine-1-phosphate.10 There is no antigenic cross-reactivity between capsules. Meningococci of serogroups A, B and C have been responsible for greater than 90% of invasive meningococcal infections worldwide.11 Serogroups W135, Y and X are among the more frequent serogroups isolated from the remaining cases of invasive disease. The capsule is thought to have multiple effects on the process of transmission and pathogenesis. Though it has been shown to hinder epithelial invasion it has antiphagocytic and anticomplement properties that confer protection against the host immune response. In addition it may aid transmission by preventing desiccation. The differences in capsule structure may be important in explaining the variations in epidemiology and virulence between serogroups. Within each serogroup the meningococcus exhibits a high degree of genetic diversity. Genetic variation arises from a combination of spontaneous mutation and horizontal genetic exchange of DNA due to the natural transformability of meningococci
Surface structures of Neisseria meningitidis.
W135 in Africa: origins, problems and perspectives
21
(the ability to acquire exogenous DNA from other bacteria including other commensal Neisseria species such as N. Lactamica12). One study has suggested that the rate of recombination in a set of meningococcal ‘house-keeping’ genes is at least 80 times that of spontaneous mutation. The genetic material shared in this way between bacteria includes genes encoding metabolic enzymes, IgA protease, membrane proteins and enzymes controlling synthesis of the polysaccharide capsule. A variety of methods have been used to differentiate the genetic variants of meningococci within a serogroup. An understanding of these methods is crucial to appreciating the epidemiology of N meningitidis and the debate over the origin of epidemic serogroup W135 disease. Meningococci may be subdivided by their possession of particular major outer membrane proteins (Fig. 1). Most commonly used are Por B and Por A (serotype and serosubtype respectively). Similar methods can be applied to the lipopolysaccharide (immunotype).13 However whilst important for immediate public health issues and vaccine development these methods have proven unsatisfactory for epidemiological use on a broader scale. The molecules being on the surface are likely to be under selection pressure and they index too small a fraction of the bacterium’s genetic material to be revealing about overall relatedness between isolates.14 The recent ability to analyse more comprehensively the genetic variation between organisms using both direct and indirect methods has provided new insight into their epidemiology. Multilocus enzyme electrophoresis (MLEE) identifies natural variation in several essential metabolic enzymes.15 These enzymes are known as house-keeping genes and in coding essential and relatively conserved parts of normal cellular metabolism they experience neutral evolutionary selection pressure making them suitable for looking at lineage relationships over long periods of time.14 Organisms are grouped by their possession of similar clusters of enzymes to yield an electrophoretic type or ET (e.g. ET-15 or ET-37). There are now methods for more direct analysis of the meningococcal genome itself. Pulsed field gel electrophoresis (PFGE) of restriction fragments of the whole bacterial genome yields band patterns that can be compared between organisms.16 Most recently the sequencing of specific regions of genes coding for the ‘housekeeping’ enzymes has been described—multilocus sequence typing (MLST). Following MLST and in a similar fashion to the results of MLEE (but now using the variation in the genes themselves rather than the proteins they produce) the organisms are grouped by their possession of similar clusters of
alleles. This yields the sequence type or ST.17 The resulting data is more readily comparable between laboratories than MLEE. ST still correlates closely with ET because both techniques involve analysis of the genetic code and protein output respectively of the same group of enzymes. However, a variety of serotypes, serosubtypes or PFGE patterns may be associated with a particular ST. Organisms with the same ST may even belong to different serogroups (e.g. ST-11 can be either serogroup B, C or W135).Other molecular approaches to meningococcal identification are still being assessed.11 Groups of related STs are known as a clonal complex. The complex is named after the most genetically typical and persistent organism17 (e.g. ST-8 clonal complex includes ST-66 and ST-487). Such a complex is postulated to have derived from a single ancestral bacterium and subsequently u ˙ndergone only a limited amount of genetic change. Groups of related ET were previously described as subgroups, clusters or complexes18 but are basically clonal complexes and synonymous with a particular ST (e.g. ST-11 organisms are ET-37). While there are a large number of different STs the majority of isolates in any one area and particularly those causing disease are from a restricted range of clonal complexes. In the 20th century disease causing isolates have belonged almost entirely to STs 1, 4, 5, 8, 11, 32 and 44. The concept of clonal complexes has proved to be have significant epidemiological use. Surveillance or analysis of stored isolates can demonstrate the spread of a particular clonal complex across the globe.19 In addition specific complexes appear to be associated with particular patterns of disease and virulence. ET-5 (ST-32) appears to cause prolonged outbreaks of hyper-endemic disease.20 ST-5 and ST7 in association with group A capsule cause epidemic disease particularly in Africa.21 ST11 has been associated with sporadic outbreaks and is thought to be hypervirulent.22 At any one time a clonal complex is typically associated with a particular capsule type (e.g. ET-37 associated with serogroup C in 90% of cases globally in the 1960s – 1980s23). However the existence of meningococci of the same clonal complex but of different serogroup is indirect evidence for the ability of a single organism to switch capsule types. In Oregon a rise in serogroup B related disease since 1993 was due to the ET-5 complex. Since 1994 Group C ET-5 strains have also been identified and have been shown to arise from allelic exchange of a capsule determining gene.10 Capsule switching has also been observed in contacts of an individual with disease.[24] This has significant implications for vaccine strategies based on a limited number of
22
serogroups where a bacterium of a clonal complex may retain its virulence after changing its polysaccharide capsule type.
Epidemiology The epidemiology and vaccinology of N meningitidis has classically focused on the serogroup. Group A meningococci appear to have been responsible for the majority of epidemics of meningococcal disease in the last 100 years. In Europe these epidemics were particularly associated with the World Wars presumably because of the large-scale population movements associated with troops and refugees. Serogroup A epidemics have been less frequent since the 1950s but still occurred (e.g. in Finland in the 1970s25). Serogroup A Asian epidemics are well described.26 In Africa epidemics of serogroup A meningococcal disease occur periodically every 5 – 10 years across the subSaharan area known as the ‘meningitis belt’.1 Geographically contiguous, this area is further defined by its coincidence with the 300 – 1100 mm annual rainfall isohyets south from the Sahara.3 Such epidemics are limited to the dry seasons and end abruptly with the onset of rains. They are striking for the high attack rate (as high as one in ten in some communities) and their vast scale. In Nigeria in 1996 over 80 000 cases were reported. In non-epidemic periods there is a hyperendemic state with incidences of 10 –50/100 000/year. The reasons for the periodicity are unclear but may involve climatic variables, waning population immunity (by elapsed time since exposure and the arrival of new exposure naive cohorts in the form of young children) and the interaction with other pathogens. Variations in the amount of transmission may be less important than factors altering pathogenicity as transmission has been shown to occur throughout both seasons.1 The last 20 years has brought an increasing recognition of the importance of pathogen variation in contributing to the epidemics. Serogroup A epidemics in both Africa and Asia have been caused by a limited number of clonal complexes.18 ST-5 organisms originating in China in the 1980s spread through Nepal to east Asia and were finally disseminated globally via the 1987 Hajj pilgrimage in Mecca.21 The introduction of ST5 organisms to Africa resulted in a wave of epidemics over several years. There has probably been a long history of the meningococcus arriving on the continent in this way.1 Since 1995 a further clone ST-7 has been steadily replacing ST-5 as a cause of epidemics in Africa.21 Some authors have
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speculated on the importance of this replacement and a lack of protective cross immunity between clonal complexes even with the same serogroup as a causal factor in the new waves of epidemic disease.21 Serogroup B and C meningococci are associated with sporadic disease and minor outbreaks. They have been responsible for outbreaks within communities that are relatively confined and living in high density such as army barracks.27 Though not associated with the large-scale epidemics of group A it is increasingly recognized that particular clones of B and C have caused a rise in case numbers to hyperendemic levels lasting several years in some countries (e.g. ST-5 in Oregon, USA20 and ST-11 in Canada.22) Serogroup B and C meningococci both cause disease in Africa. In this setting serogroup C has on rare occasions been associated with epidemic behaviour.28,29 Serogroup W135 meningococci were first identified in the 1960s causing outbreaks of meningococcal disease in the US army.30 They remained an infrequently occurring serogroup causing sporadic cases of invasive meningococcal disease including some reports of pneumonia in the elderly.31 Serogroup W135 constituted 2.6 – 4% of reported N meningitidis in the UK, France and the USA during the 1990s.4 Following the Hajj pilgrimage to Mecca in 2000 there was an outbreak of serogroup W135 disease in Saudi Arabia followed by cases amongst pilgrims returning to their home countries.4 Over 300 cases were reported in 14 countries.32 Cases occurred in the contact of pilgrims and in those with no identifiable association with the Hajj suggesting ongoing transmission within the pilgrims’ of home countries’. A rare meningococcal serogroup W135 strain was identified as the cause (serotype 2a subtype P1.2, 1.5).5 This was the first recorded epidemic caused by serogroup W135 meningococci and was associated with ST-11 (ET-37) clonal complex.11 This complex, recognized as being hypervirulent, had been mainly associated with serogroup C meningococci prior to the Hajj.22 Capsule switching is well described and has been documented following transmission of meningococci from a patient with disease to contacts.24 However, serogroup W135 strains almost identical to the ST-11 (ET-37) clone of the 2000 Hajj outbreak have been circulating for over 30 years making it unlikely that the clone arose by capsule switching at the 2000 Hajj.11 Determining when the clone arose would require more extensive investigation of past isolates from around the globe. The Hajj of 2000 appears to have facilitated the spread of a virulent clone by allowing crowded conditions favourable to transmission in a large group of people from all
W135 in Africa: origins, problems and perspectives
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around the globe. The reasons for the change in behaviour of the clone are unclear. An almost identical Hajj associated outbreak with the same serogroup W135 strain followed in 2001.5 Following this, pilgrims to the 2002 Hajj were required to have had the quadrivalent plain polysaccharide vaccine covering serogroups A, C, W135 and Y as a condition of their visa. This replaced a requirement for the bivalent A/C polysaccharide vaccine which had been mandatory since the Hajj related serogroup A outbreaks in 1987. It is interesting to note that serogroup W135 disease following the Hajj has been noted previously in Saudi Arabia.33 However, no further identification is available on these isolates. Since the Hajj related outbreak of 2000 epidemic serogroup W135 disease has appeared in Africa.6 Serogroup W135 meningococci were first described in Africa in 1980.34 Prior to this the situation is less clear. A study of purulent meningitis in Dakar between 1970 and 1979 has no mention of serogroup W135 disease.35 It is unclear whether it was not detected because it was not looked for or because it was not there. Table 1 documents subsequent reports of serogroup W135 meningococcal isolation. It is clear that serogroup W135 meningococci have been consistently isolated in studies of carriage and disease in Africa since 1980. These have been predominantly ET-37 during the last decade. The studies of disease however are either unsystematic samples from a larger population of cases or else hospital based and not clearly related to a population size. It is thus difficult to discern trends in the absolute incidence of disease due to
a particular serogroup by comparing studies. A change in the proportion contributed by serogroup W135 may be due to a decrease in incidence of disease caused by other serogroups as well as a change in serogroup W135 disease. Carriage studies may be more revealing from this perspective as they are collected from a known population. Unfortunately studies of meningococcal carriage in Africa are few. Prior to the 2000 Hajj pilgrimage serogroup W135 meningococci had not been associated with large-scale epidemics despite the fact that the majority of isolates from the 1990s belonged to the same clonal complex as the strain causing the 2000 outbreak.11 Following the Hajj of 2000 and the subsequent globally widespread outbreaks caused by the serogroup W135 clone there have been further reports of serogroup W135 disease in Africa. In epidemics in Burkina Faso and Niger in 2001 serogroup W135 was recorded in almost 40% of isolates, most of the others being serogroup A.41 As the samples were collected in an unsystematic fashion towards the end of the epidemics it was unclear as to whether they represented endemic disease following a large scale A/C vaccination campaign or whether serogroup W135 had been a significant contributor to the epidemic. In January 2002 an epidemic of meningococcal disease began in Burkina Faso. By the time it was abating in May over 12 000 cases of disease and almost 1500 deaths had been reported. Over 90% were caused by serogroup W135.4 This leaves little doubt regarding the epidemic behaviour of this clone and already in the first weeks of 2003 further cases of meningococcal disease are
Table 1 Isolations of serogroup W135 meningococci from Africa reported in the literature. Year
Region
Study type (ep ¼ epidemic, en ¼ endemic)
198036 198134
Upper Volta Senegal Niger Senegal Niger Gambia Africa Gambia Mali Gambia Cameroon
Carriage (en) Disease (en) Disease (ep) Disease (en) Disease (post-ep) Disease (post-ep) Disease (ep) Disease (en) Disease (ep) Carriage Disease (en)
198234 1983 –8537 1989 –9438 1990 –9528 199428 199639 1998 –9940 1999 –00 2000 –01 200141
200243
Electrophoretic type
ET-37 ET-37 ET-37 ET-37 ET-37
Burkina Faso Niger Cent Afr Rep42 Burkina Faso
Disease (ep)
Disease (ep)
W135 isolates/total isolates (%) or % with carriage 1.3% 3/25 (12) 1/221 (0.5) 0/51 7/42 (17) (7) 2/125 (2) 6/10 (60) 2/12 (17) 5.3% 1/8 (13) 4/23 (17) 4/17 (24) 12/32 (38) 12/31 (39) 3 isolates 147/160 (92)
24
being reported from Burkina Faso though their serogroup is as yet unreported. The increasing occurrence of epidemic meningitis beyond the traditional meningitis belt lends further cause for concern as to the eventual impact of this form of serogroup W135 disease.3
Vaccination Vaccines based on the polysaccharide capsule can induce protective immunity to meningococcal disease caused by the serogroup possessing that polysaccharide.44 Widespread antibiotic resistance in meningococci isolated from US military recruits led to the development of an effective serogroup C polysaccharide vaccine in the late 1960s. This was followed by bivalent serogroup A/C meningococcal polysaccharide vaccine in 1978 and a quadrivalent polysaccharide vaccine against serogroups A, C, Y and W135 in 1982.45 Serogroup B polysaccharide is poorly immunogenic.46 In Africa, within potential epidemic regions, surveillance of cases of meningococcal disease will trigger a population based mass-vaccination response when an absolute number or rate of increase of cases reaches a threshold level. The threshold level varies with the epidemiological context.47 There is ongoing debate about whether this is the most effective use of the vaccine or whether combined approaches with preventative vaccination would be more effective.48 Epidemic response may be slow if surveillance is poor and there is limited infrastructure for the logistical support of mass vaccination campaigns. Preventative strategies are hindered by the poor response of infants to plain polysaccharides and the lack of prolonged protection available from polysaccharide vaccines that do not induce a T cell dependent memory response.9 Glycoconjugate vaccines which induce long term immunity would avoid the need for repeated epidemic control measures and are discussed below. The emergence of epidemic serogroup W135 disease has highlighted a weak spot in the armamentarium against the meningococcus. The quadrivalent (A/C/Y/W135) vaccine is more expensive than the bivalent (A/C) version that has been widely used for epidemic control, it is in short supply43 and is of unknown efficacy. Although the serogroup W135 component can be shown to be immunogenic49,50 the small numbers of cases of disease attributable to this serogroup have precluded any trial of efficacy. Limited effectiveness data can be inferred from use of the quadrivalent vaccine in the US and UK. US military data suggests there have been ‘few
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documented cases caused by serogroups that were represented in…vaccines’.45 In the UK following the recommendation by the Department of Health that pilgrims have the quadrivalent vaccine in 2001 there were no cases in those who had received the vaccine.5 However, the proportion of all pilgrims who had received vaccination could only be estimated indirectly at ‘less than 47%’. The most recent UK data since the quadrivalent vaccine has become an entry requirement for pilgrims travelling to Saudi Arabia for the Hajj is that the number of cases has fallen from 45 in 2000 and 38 in 2001 to 6 in 2002.51 There remains no effectiveness information from the areas at risk of epidemic serogroup W135 disease. In view of the emerging W135 epidemic in Burkina Faso during 2002/2003 the WHO, GlaxoSmithKline and the Bill and Melinda Gates foundation have rapidly developed and made available a trivalent (A/C/W135) polysaccharide vaccine. Though three million doses are to be provided at a cost much less than that of the quadrivalent vaccine the effectiveness remains unknown [WHO. Partnership moves in record time to provide vaccine against meningitis as epidemic emerges in Africa]. (http://www.who.int/mediacentre/releases/2003/pr9/en) The disadvantages of polysaccharide vaccines have been addressed through the development of vaccines utilising the polysaccharides conjugated to a protein carrier (glycoconjugate vaccines). For serogroup C disease this approach has been successful in achieving immunogenicity in infants, inducing memory responses and thus increasing the duration of protective immunity and affecting carriage.9 Trials of quadrivalent conjugate vaccines are now in progress in several countries.52,53 At present it is clear that these vaccines will be too costly for the countries at risk of epidemic disease. The development of monovalent serogroup A glycoconjugate vaccines is supported by the ‘meningitis vaccine project’ but does not address the issue on nonserogroup A disease.54 Concerns about the effects of limited serogroup coverage are discussed below.
Epidemic W135—origins Why should a clone that has been circulating in Africa for at least 8 years in non-epidemic form develop the capacity to cause large outbreaks? Epidemic serogroup W135 disease may have been present previously in Africa. Concurrent and larger serogroup A epidemics promoted by similar environmental and demographic factors to
W135 in Africa: origins, problems and perspectives
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serogroup W135 disease may have been obscuring a lower level of serogroup W135 disease. In Mali in 1994 17% of isolates were W135.28 Difficulties in interpreting the relative proportions of isolates particularly in differing vaccination scenarios make it hard to be certain of the significance of this information. Given the degree to which N meningitidis is subject to genetic transformation, has the organism changed significantly? Studies of serogroup W135 isolates from over 30 years have shown only minor differences between isolates from 1970 Scotland and Canada and the 2000 Hajj (e.g. 1 band on PFGE and 1 enzyme on MLEE). However it is possible that minor changes in genes encoding virulence factors important in transmission, colonisation or survival have occurred.11 Such changes have been clearly shown occurring during the spread of serogroup A meningococci—some associated with (though not necessarily causally related) to new pandemic waves of disease.19 Polysaccharide A/C vaccine has been widely used in Africa over the last 20 years. It has also been a requirement for the Hajj pilgrimage since 1987. Not all potentially pathogenic meningococci are covered by the vaccine and it is unclear how such vaccines affect the overall population biology of the bacterium. Concern exists that other clones may replace those removed by vaccination or that a pathogenic clone may through recombinatorial events acquire variant capsule types and retain its virulence thus subverting the original purpose of vaccination.55 The almost complete elimination of group C carriage following the introduction of serogroup C meningococcal conjugate vaccination in the UK has not been followed by an increase in carriage of other serogroups.56 However the overall rate of meningococcal disease has not declined by as much as would be expected, because of an increase in serogroup B disease.57 Point prevalence carriage studies may fail to reflect the complexities of carriage dynamics which may have an effect on disease incidence. Studies of pentavalent glycoprotein pneumococcal conjugate in The Gambia suggested that the vaccine’s effect in terms of carriage was countered by colonisation with non-vaccine serotypes.58 Similar concerns about meningococcal serogroup replacement were highlighted following a polysaccharide A/C vaccination campaign in The Gambia. Following the campaign there was a meningococcal carriage rate of 5% of which all except one isolate were serogroup W135 (27/28 isolates).39 Changes in serogroup and clonal complex prevalence are also noted over time in the absence of
vaccination for reasons as yet not understood.45, 59 The ability of vaccines to precipitate this process and particularly to select for variant serogroups of already virulent clones is not known. Underlying all the concerns regarding capsular replacement in relation to polysaccharide A/C vaccination is the presumption that polysaccharide vaccination affects carriage of meningococci. Previous studies have shown that any effect of polysaccharide on carriage is limited to several weeks though dramatic effects are seen following immunisation of closed communities, such as during military training.60 – 62 If plain polysaccharide A/C vaccination is implicated in the emerging epidemic behaviour of the serogroup W135 ST-11 clone it is surprising, given the short duration of the effect on carriage, that it has taken 12 years (from the vaccine coming into routine use for the Hajj and longer since its regular use in Africa) to precipitate the change in epidemiological behaviour. However it may be that temporary elimination of the serogroup A/C meningococci could allow a foothold for serogroup W135 meningococci from which they were more difficult to dislodge once established. Persistent use of A/C vaccine might lead to slowly increasing levels of W135 exacerbated by the large amounts of transmission and dissemination occurring at international gatherings (e.g. Hajj) and with population movements caused by famine and conflict. The reasons for such an abrupt emergence of the clones behaviour would still be unexplained. Of further concern in the long term is the possibility of hypervirulent lineages (such as ST11) undergoing capsule switching to generate virulent clones not covered by existing vaccines. Limited outbreaks of serogroup X meningococci in Ghana and Nigeria63 for which there is no current vaccine remind us of the importance of monitoring the situation closely in this region. Serogroup B ST-11 isolates have previously been described.23 This serogroup has proved so far intractable to vaccine attempts and the prospect of epidemic serogroup B disease is discomforting.54
The future The emergence of epidemic serogroup W135 meningococcal disease at the Hajj of 2000 and subsequently in Africa was unexpected. This is despite several concerns over the previous years
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about the appearance of isolates from cases of disease and carriage. Strategies for serogroup A control were already only partially effective because of logistics, the difficulties of timely epidemic prediction and the relatively short lived immunity of the available vaccines coupled with their lack of effect on long term carriage. The available quadrivalent polysaccharide vaccine covering W135 disease has all of the problems described above associated with it. In addition its production has been previously on a small scale with difficulties of supply even before the problems of distribution to rural African communities is considered. In the short term widespread polysaccharide vaccination with a serogroup A and W135 containing vaccine may control epidemic meningococcal disease. In the medium term the availability of a conjugate vaccine covering the relevant serotypes (A,C, W135) may produce dramatic effect if this can ever be made affordable. However, the lessons emerging from the current difficulties suggest that introduction of multivalent conjugate vaccines into routine immunisation schedules in the affected region should be a high priority. The most clearly demonstrated virulence factor for the meningococcus is the polysaccharide capsule. Whilst the aim of a vaccine against a more universally possessed epitope remains the ideal, the inherent genetic heterogeneity of the meningococcus makes this a distant goal. Thus in terms of current vaccine development a more comprehensive and immunogenic anti-polysaccharide capsule vaccine remains a realistic objective. The danger of a half-hearted solution through providing a vaccine against limited serogroups and of limited efficacy on carriage may paradoxically be the same or worse than no solution at all. We have the technology today to provide a sustainable solution to the epidemic meningitis problem in Africa through an infant programme with one of the ACYW conjugate vaccines that are currently in trials. In this context, it is unthinkable that thousands may die in the meningitis belt of Africa during 2003, despite these vaccines being available. However, even if production of these effective vaccines could meet the potential demand this year, it is unlikely that current predictions of vaccine cost could be met outside of industrialised nations. The spectre of an epidemic group B strain for which there would be no options for vaccination has been raised by the current behaviour of W135. Heightened surveillance and efforts to develop a serogroup B vaccine must also continue in earnest.
D. Kelly, A.J. Pollard
Conflicts of interest AJP conducts clinical trials of meningococcal vaccines on behalf of the University of Oxford sponsored by several vaccine manufacturers.
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