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Meningococcal disease

Bacterial Infections Introduction Meningococcal disease Staphylococcal infection Group A Streptococcus Group B Streptococcus References

Overview

Among the elderly and adult persons, meningitis is often the consequence of infections with bacteria such as Listeria monocytogenes, particularly in pregnant women, and Cryptococcus neoformans, which has become a prevalent pathogen in immunocompromised patients. Staphylococcus aureus has been implied in community-acquired meningitis outbreaks. Other bacterial pathogens such as Mycobacterium tuberculosis, Treponema pallidum and Borrelia burgdorferi may also cause aseptic meningitis. Escherichia coli and group B streptococci are a frequent cause of meningitis in neonates. Viruses also cause meningitis, most particularly enteroviruses and coxsackieviruses and, less frequently, herpes simplex viruses and cytomegalovirus.

But most cases of meningitis occurring beyond the neonatal period are due to three bacterial species, Haemophilus influenzae type B (Hib), Streptococcus pneumoniae and Neisseiria meningitidis. The incidence of Streptococcus is greatest in small infants and children less than 2 years old, that of Haemophilus in children from 6 months to 2 years of age, and that of Neisseria in children, adolescents and young adults from 1 to 29 years of age. These bacteria are characterized by their propensity to colonize the nasopharynx in a harmless way, from where they can invade the host and cause silent bacteremia or overt infection, including otitis media, pneumonia or meningitis. Most cases are acquired by person-to-person contact through aerosol droplets or contacts with respiratory secretions from the asymptomatic carriers.

The introduction of H influenzae type b (Hib) conjugate vaccine in routine immunization programs has nearly eliminated invasive Hib disease from many countries, leaving S pneumoniae and N meningitidis as the commonest causes of meningitis worldwide. In a few surveys done in sub-Saharan Africa, Streptococcus accounted for about 20% to 30% of the cases of meningitis whereas N meningitidis was responsible for 60% to 65% of cases. This is without taking into account the progressive implementation of the conjugated polysaccharide vaccines against pneumococcus, whose effect is seen in a decreased rate of invasive pneumococcal disease including meningitis in children and adults [1]. The first national immunization program against pneumococcal disease using a 7-valent conjugate S pneumoniae vaccine was launched on April 2009 in Rwanda with the aim of vaccinating all Rwandan children younger than 1 year of age on a routine basis. With the progressive generalization of such a public health measure, it is likely that N meningitidis (meningococcus) will eventually remain as the only major agent of meningitis worldwide.

Disease burden

Approximately half of the cases of meningococcal disease are acute bacterial meningitis, other syndromes including pneumonia, septic arthritis and meningococcemia ('purpura fulminans'). A rash is present in the majority of cases consisting of typical petechiae on the chest, upper arms and axillae. Bacterial meningitis remains a major threat to global health, accounting for an estimated annual 500 000 cases worldwide with at least 50 000 deaths and as many cases of neurological disability [2]. In developing countries such as The Gambia, an estimated 2% of all children will die of meningitis before they reach 5 years of age [3]. Even with sophisticated care units and antibiotic therapy, case fatality rates remain at 5% to 10% in industrialized countries and can reach up to 20% in developing countries. Between 10% and 20% of survivors develop permanent neurological sequelae such as epilepsy, mental retardation or sensorineural deafness.

Up to 5% to 10% of a population may be asymptomatic carriers of N meningitidis, which is a harmless commensal of the nasopharyngeal mucosa. The bacterium is transmitted by person-to-person contact through aerosol droplets or contact with respiratory secretions from asymptomatic carriers. Only a limited fraction of those who become infected will develop a clinical disease with infection of the meninges. There are approximately 3000 cases of meningococcal disease reported in the USA and 7 700 in Western Europe each year [4]. The incidence in the USA tends to range from 0.5 to 1.5 cases per 100 000 population per year [2] . Among known risk factors are concomitant upper respiratory infections, HIV infection, crowding, active and passive smoking and lower socioeconomic status.

Meningoccus serogroups that are responsible for severe meningitis belong to only 5 groups: MenA, B, C, Y and W135. A meningitis epidemic outbreak due to group X was also recently reported. Group A meningococci are characterized by their propensity to cause large scale epidemics in developing countries, as best illustrated by the epidemics of meningitis which occur in irregular cycles in the countries of the African 'meningitis belt' where they usually last for a few years, peaking in March-April at the end of the dry season and dying out during the intervening rainy season [5]. They are responsible for about 3 000 to 10 000 deaths annually according to the intensity of the epidemic. Extensive population travel such as the Hajj pilgrimage to Saudi Arabia facilitates the spread of the epidemic from country to country. The seasonality of the epidemics is linked to external environmental factors, especially the impact of Harmattan, a strong wind during the dry season blowing dust and sand particles from the Sahara [6].

MenA strains also are responsible for pandemic waves, such as that which started in China in the 1960s and spread to Russia and Scandinavian countries and eventually reached Brazil in the 1970s [7]. In the early 1980s, a second MenA pandemic wave began in China, spread through Nepal, and reached Saudi Arabia, causing an epidemic in August 1987 during the Hajj pilgrimage to Mecca with 1 841 reported cases. Pilgrims returning from Mecca introduced the strain throughout Africa where epidemics were recorded in 1988 in Chad and Sudan, in 1989 in Morocco and subsequently in most other African countries [8]. A third pandemic wave began in China in 1993, causing large epidemics in Mongolia in 1994 and Moscow in 1996. It eventually reached Africa, showing high virulence, with approximately 150 000 cases and 20 000 deaths reported in 1996-1997, and a case fatality rate of more than 10%, in spite of appropriate antibiotic treatment. The epidemic spread to many countries, including countries south of the meningitis belt such as Rwanda, Burundi, Kenya and Tanzania, finally reaching Zambia and the Central African Republic [9]. The emergence of MenW135 strains in Saudi Arabia in 2000 then in Burkina Faso in 2002 added even more complexity to the picture.

Group B meningococcus (MenB) is the most important cause of endemic meningitis in industrialized countries, accounting for 30% to 40% of the cases in North America and for up to 80% in some European countries such as Norway, The Netherlands, Germany and Denmark, with most of the remaining cases been due to group C strains. The latter are particularly prevalent in the United Kingdom, Ireland, Canada, Greece and Spain. In all countries, the incidence of group B and C disease is highest in winter in infants less than one year-old. In the USA, where MenB, C and Y occur in roughly equal proportions, an estimated 3000 cases are reported every year with a case fatality rate of 12% [10] .

MenB also can cause severe, persistent epidemics, which begin slowly but may persist for 10 years or longer, as seen in the past in Norway; in Cuba, Brazil and areas of Chile; and currently in New Zealand. Persons of Pacific Islands origin and the Maoris experienced very high rates of disease, with incidences as high as 45.6 and 20.6 per 100 000 population, respectively, reaching 611 and 247 per 100 000 in <1 year old infants [11] . The global incidence of MenB disease has been estimated at between 20 000 and 80 000 cases per year, accounting for 2 000-8 000 deaths annually.

Meningococcal disease is distinct from other Gram negative bacterial infections by its propensity to release in the circulation endotoxin (lipooligosaccharide)-rich outer membrane vesicles that cause rapidly progressing cutaneous hemorrhage and skin necrosis, disseminated intravascular coagulation and shock [12] . Many meningococcal strains have reduced susceptibility to penicillins, but high levels of resistance are rarely found. Still, the antibiotic of choice for treatment of meningococcal meningitis in outbreaks in developing countries is oily chloramphenicol.

Bacteriology

N. meningitidis is a Gram-negative encapsulated diplococcus. At least 13 different serogroups have been defined on the basis of the immunochemistry of the capsular PS, but serogroups A, B, C, Y, and W135 account for almost all cases of disease. Meningococci are further classified into serotypes and subtypes on the basis of the immunologic reactivity of their PorB and PorA outer membrane proteins, respectively. Approaches such as multilocus enzyme electrophoresis, now replaced by multilocus sequence typing (MLST) [13] [14] , have been used to monitor the global epidemiology of meningococcal disease and classify isolates as related sequence types (STs) designated as 'clone-complexes' [15] . The complete nucleotide sequence of the genome of isolates from serogroups A, B and C has been determined. Meningococci achieve high genetic complexity characterized by changes through horizontal gene transfer, gene conversion, phase variation, capsular switching and other antigenic variations such as clonal replacement [16] .

Studies of the genetics of meningococcus indicate that most cases of invasive disease are caused by bacteria from a limited number of clone-complexes corresponding to hypervirulent lineages, whereas carriage isolates belong to many different lineages, many of which have never been associated with disease [17] . Thus the group A strains responsible for the two pandemics during the second half of the 20th century were from the lineage known as subgroup III/ST-5 complex, whereas the group B strains from the Norway epidemics belonged to the ET-5/ST-32 complex, and those responsible for the New Zealand epidemic to lineage III/ST-41/44 complex. The great majority of group A strains isolated from the meningitis belt countries between 1987 and 2003 belonged to the ST-5 complex whereas the ST-11 complex was associated to serogroup W135.

Important meningococcal virulence factors have been identified including factor H-binding protein (fHbp). Recruitment of factor H by fHbp contributes to the ability of N meningitidis to avoid innate immune responses by preventing complement-mediated lysis in human plasma [18] [19] , thus deregulating complement levels and rendering host cells in the vascular compartment more susceptible to complement-mediated damage, which would contribute to the hemorrhagic rash seen in meningococcal sepsis.

Vaccines

Vaccines against groups A, C, Y and W135 include monovalent or plurivalent polysaccharide (PS) vaccines and conjugate vaccines [20] , some of which have already been combined with routinely administered vaccines to fit within the EPI regimen [21] . Meningococcus group A is well known for its ability to cause large scale epidemics of meningococcal disease in the sub-Saharan "African meningitis belt" [5] [22] where epidemic waves of meningitis occur on an almost yearly basis. As described below, an affordable monovalent MenA conjugate vaccine is in advanced development by the Serum Institute of India, Ltd, with support from the Meningitis Project, a partnership between WHO and PATH, to be made available to countries of the African meningitis belt [23] .

Group B meningococcus, on the other hand, is the only meningococcal serogroup whose infection cannot be prevented by a PS vaccine. MenB vaccines based on bacterial outer membrane vesicles (OMVs) or proteins such as PorA, PorB or NspA have been used with success to fight epidemics in Norway, Cuba or more recently New Zealand, but these vaccines are narrowly strain-specific. Newer vaccines based on broadly cross-reacting "genome-derived neisserial antigens "(GNA) identified by "reverse vaccinology" [24] [25] are at an early stage of development and will be described below.

Vaccines against groups A, C, Y, and W135 meningococci

Groups A, C Y and W135 meningococcal diseases can readily be prevented by vaccines based on high molecular weight capsular PS [26] , which were licensed in the late 1960s. Monovalent MenA or MenC and bivalent MenA/C PS vaccines are available and have been used for years for vaccination of children more than 2 years of age and adults. The recent emergence of serogroup W135 prompted the development of a trivalent A/C/W135 vaccine (GSK) and of a tetravalent A/C/Y/W135 vaccine (Sanofi Pasteur). PS vaccines, however, do not induce T cell-dependent immunity, are poorly immunogenic in infants and children less than 2 years old, who are the major group at risk for these infections [27] , and fail to elicit immunological memory. Moreover, studies of MenA and MenC PS vaccines as well as those of the 23-valent pneumococcal PS vaccine in adults and children have shown that a state of immune tolerance, or hyporesponsiveness, can develop to repeated PS vaccine exposures [28] .

Extrapolating from the experience gained with Hib vaccines, a series of conjugate meningococcal vaccines were developed using diphtheria or tetanus toxoid as a carrier. Thus, MenC conjugate vaccines were introduced in 1999 into the UK as an addition to routine infant immunization at 2, 3 and 4 months of age combined with a catch-up campaign among 1-18 years old children and adolescents. The vaccine program had a tremendous impact on the incidence of the disease, resulting in a more than 90% decrease in the number of deaths and clinical cases and a 66% decrease in asymptomatic carriage [29] [30] and also decreasing by 70% the number of cases in non-vaccinated people, a substantial benefit due to induction of herd immunity [31] [32] . The vaccine, which is now administered in two IM injections 2 months apart followed by a booster injection at 12-15 months, has been included into the routine infant vaccination programs in the UK, the Netherlands and Canada, showing 87% to 98% efficacy in various studies [33] . Vaccination of adolescents was also highly immunogenic [34] .

Multivalent conjugate vaccines have since been developed, including a tetravalent (MCV4) MenA/C/Y/W135 conjugate vaccine (Sanofi Pasteur) which has been licensed in the USA and in Canada for 2-55 years old children and adults and was shown to elicit significantly higher and more persistent serum bactericidal antibody responses than the PS vaccine [35] , as well as a combined Hib/MenC conjugate vaccine [36] and a heptavalent DTPw-HBV/Hib-MenA/C conjugate vaccine (GSK) [37] .

The Meningitis Vaccine Project (Men A)

Epidemic group A meningococcal meningitis continues to be a major problem in countries of the sub-Saharan meningitis belt, where the use of PS MenA vaccines have not been very successful, in part because of high price. The Meningitis Vaccine Project (MVP), which was started in 2001 as a partnership between the WHO and PATH, after the terrible epidemic in 1996-97 when more than 250 000 African people fell ill and the death toll soared well above 25 000, is developing with the support of the Bill and Melinda Gates Foundation a MenA conjugate vaccine that will be made available at a cost of US $0.40 to the countries in the African meningitis belt [38] . The vaccine is been produced by the Serum Institute of India, Ltd, in Pune, using tetanus toxoid as a carrier, MenA polysaccharide provided by SynCoBio Partners in Amsterdam and a coupling technology provided by the US Food and Drug Administration [39] . The vaccine has successfully been tested in a Phase I trial in India then a Phase II trial on 600 healthy toddlers aged 12 to 23 months in The Gambia and Mali, inducing 4-fold increases in anti-MenA bactericidal antibody titers in 73% to 85% of vaccine recipients, with GMTs much higher than those elicited by non-conjugated PS vaccines [40] [41] . A Phase II/III clinical trial is undergoing in 2-29 year-olds in several sites in India and Africa, including sites in Bamako and in Dakar, while a study of different dose schedules in infants is taking place in Ghana. MVP plans to license the vaccine if possible starting end of 2009 to be used in single-dose mass vaccination campaigns in 1-29 years olds in the countries of the African belt, a target population of about 250 million people.

Vaccines against group B meningococci

Group B N meningitidis, which is responsible for about 50% of cases of meningococcal disease worldwide, is the only serogroup against which capsular PS vaccines cannot be developed, due to antigenic mimicry with PS in human neurologic tissues [2] [42] . Consequently, vaccine research against MenB has focused on outer membrane protein (OMP) antigens such as PorA, PorB or FetA. The PorA vaccines that were developed in Norway (The Norway Institute of Public Health and Chiron-Novartis), in Cuba (The Finlay Institute and GSK) or in The Netherlands (RIVM and GSK) were successfully used to fight the MenB epidemics in these countries. The Norwegian MenB outer membrane vesicle (OMV) vaccine, MenvacTM, showed good immunogenicity as judged from the fact that 65% of vaccinees had a protective bactericidal antibody titer after three doses. Ten months later, however, this proportion had declined to 28%, but a fourth dose induced a rise of antibodies to protective titers in 93% of subjects [43] . Similarly, a vaccine containing the PorA and Por B proteins from the New Zealand strain NZ together with LPS was developed by Chiron-Novartis and the University of Auckland and shown in a series of clinical trials to elicit strain-specific bactericidal antibodies in 70% of infants and 90% of teen-agers. The vaccine, MenZBTM [44] [45] , has now been introduced nationwide in the under 20 years-old population of New Zealand [46] [47] [48] .

Similarly also, the Cuban meningococcal vaccine VA-MENINGOC-BCTM is based on a combination of MenB OMV that contain membrane proteins such as PorA, PorB, Opal, Opt, NspA and others, added with purified capsular PS from a MenC strain. The vaccine, which showed 83% efficacy in a Phase III trial on 106 251 10-16 years old schoolchildren, was introduced as a nationwide vaccination campaign in 1989-90 on 3 million infants, children and adolescents aged 3 months to 24 years. It is currently administered in a routine 2-dose vaccination schedule at 3 months and 5 months of age, which resulted in a sharp and sustained decline in the incidence of the disease [49] . The vaccine has also been extensively tested in several other countries including Brazil, Columbia, Chile, Iceland, Ukraine and Russia [50] [51] [52] .

OMV vaccines elicit strain-specific complement-mediated bactericidal activity directed against the strain used to prepare the vaccine and against strains with narrowly related PorA molecules. An alternative has been to use recombinant membrane proteins or improved OMV preparations [53] . A hexavalent PorA-based candidate vaccine was thus developed by the Netherlands Vaccine Institute using OMVs prepared from two N meningitiidis strains that had been engineered to each express three different PorA antigens [54] [55] [56] . The vaccine was successfully evaluated in adults and children but showed only modest immunogenicity in infants [57] . A nine-valent vaccine has now been prepared using three N meningitidis strains engineered to express three different Por A molecules each.

An attempt was made at using OMVs from N lactamica that shares a number of antigens with N meningitidis but lacks an antigenically-related PorA molecule [58] [59] . This vaccine however was found not to induce bactericidal antibodies, although it did protect animals from a lethal challenge with MenB.

Truly successful development of a broad specificity MenB vaccine is expected to come from a "reverse vaccinology" approach, or 'genome mining', i.e. starting from the whole genome sequence of the bacterium and attempting to identify genes of potential interest [24] [25] [60] [61] [62] [63] . Thus, starting from a library of 600 candidate MenB genes, 350 genes were cloned and expressed and the resulting gene products were tested for the induction of bactericidal antibodies in mice. This labour-intensive approach successfully allowed the identification of 28 novel MenB proteins referred to as "genome-derived Neisserial antigens" (GNAs) which appear to be well conserved among the various MenB strains studied and seem to be the target of bactericidal antibodies [64] [65] [66] . Among the most promising candidate vaccine antigens are GNA1870 [67] [68] , GNA2132, a lipoprotein related to transferrin-binding protein [69] and NadA protein [70] [71] . GNA 1870, a surface exposed lipoprotein which recently was renamed factor H-binding protein (fHbp) to reflect the fact that it binds factor H, an important component of complement regulation, can be found as three variants, variant 1 accounting for 83% of the strains [18] [72] [73] . The feasibility of engineering a recombinant chimeric protein expressing critical epitopes from all three variant groups has been demonstrated [74] . The 5 Component Vaccine against Meningococcus B (5CVMB), a MenB subunit vaccine containing 5 GNA antigens including fHbp, induced bactericidal antibodies against 78% of a panel of 85 meningococcal strains and is being developed by Novartis [75] . The theoretical coverage of the 5CVMB antigens and the feasibility to use them in a broad-range MenB vaccine are promising [76] .

The introduction of conjugated vaccines into pediatric vaccination schedules has led to a drastic decrease in the incidence of invasive diseases caused by Hib, N meningitidis serogroup C or pneumococcus, a major public health success. These vaccines as well as the conjugate vaccines which target MenA, Y or W135 offer the potential for safe and effective control of the corresponding bacterial diseases. A definitive solution to the prevention of meningococcal disease worldwide will not however be possible until a serogroup B meningococcal vaccine is also available [16] [77].

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