Abstract
Meningococcal disease is one of the most feared and serious infections in the young and its prevention by vaccination is an important goal. The high degree of antigenic variability of the organism makes the meningococcus a challenging target for vaccine prevention.
Meningococcal polysaccharide vaccines against serogroup A and C are efficacious and have been widely used, often in combination with serogroup Y and W135 components. Their relative lack of immunogenicity in young children and infants can be overcome by conjugation to a protein carrier. The effectiveness of serogroup C glycoconjugate vaccines in children of all ages has been demonstrated and they have now been introduced into routine vaccination schedules. Conjugate vaccines against other serogroups, including A, Y, and W135 will soon be available and it is hoped they may emulate this success.
Prevention of serogroup B disease has proven more elusive. Several serogroup B vaccines based on outer membrane vesicles have been shown to be immunogenic and reasonably effective in adults and older children, but the protection offered by them is chiefly strain-specific. Multivalent recombinant PorA vaccines have been developed to broaden the protective effect, but no efficacy data are available as yet. Intensive efforts have been directed at other outer membrane protein vaccine candidates and lipopolysaccharide, and some of these have been shown to offer protection in experimental animal models. Nonpathogenic Neisseriae spp. such as Neisseria lactamica are also possible vaccine candidates. Previously unknown proteins have been identified from in silico analysis of the meningococcal genome and their vaccine potential explored. However, none of these has yet been presented as the ‘universal’ protective antigen and work in this field continues to be held back by our limited knowledge concerning the mechanisms of natural protection against serogroup B meningococci.
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Neisseria meningitidis is a leading infectious cause of death in previously healthy children in many countries of the developed world — largely as a result of the disappearance of many infectious diseases in children over the past century. Despite ranking highly in mortality statistics in wealthy nations, meningococcal disease is rare in absolute terms. However, in resource-poor countries, particularly in Sub-Saharan Africa, this organism claims thousands of lives during regular cycles of epidemic disease.
Attempts to control meningococcal disease by immunization started soon after the discovery of the causative organism, N. meningitidis (previously known as Diplococcus intracellularis) in 1887. It has only been during the last 30 years, however, that vaccine intervention has been widely available to control a subset of meningococci. Intensive research has been directed at comprehensive protection from meningococcal disease during the last decade and there is hope that vaccine prevention of all types of meningococcal disease may become possible.
In this article we describe the clinical presentation and epidemiology of meningococcal disease and prevention through vaccination.
1. Meningococcal Disease
1.1 Classification of Meningococci
Like other Gram-negative bacteria, N. meningitidis is surrounded by a peptidoglycan layer that separates the cytoplasmic membrane from the outer membrane. The outer membrane is surrounded by a polysaccharide capsule,[1] which is an important virulence factor, as it interferes with complement binding and opsonophagocytosis. Differences in the chemical structure of the polysaccharide allow classification of the organism into at least 13 serogroups. Only five of these are commonly pathogenic (A, B, C, Y, W135). Meningococci are further subdivided into serotypes and serosubtypes on the basis of class 2/3 (Porin B; PorB) and class 1 (PorA) outer membrane proteins (OMPs), respectively. Finally, the seroreactivity of the lipopolysaccharide component of the outer membrane determines the immunotype.
More recently, bacterial typing methodologies based on molecular techniques have been widely employed and are better suited for describing the relatedness of meningococci within clonal complexes than serologic techniques that use variable surface structures for classification. Multi-locus enzyme electrophoresis involves the study of cytoplasmic proteins and multi-locus sequence typing is used to describe the similarities or differences in conserved bacterial housekeeping genes.[2–4]
1.2 From Colonization to Clinical Disease
In most cases, N. meningitidis is a commensal organism, infecting the human nasopharynx harmlessly while inducing an immune response.[5,6] Nasopharyngeal carriage rates vary considerably with age. A large survey in the UK found rates of 2.1% in children aged <4 years, compared with 24.5% in teenagers.[7] Carriage studies relying on cultures of nasopharyngeal or throat swabs probably underestimate true carriage rates,[8] since much higher rates of colonization are suggested by studies that employ more sensitive methodologies,[9] including the identification of the meningococcal antigen from tonsillar tissues.[10]
Close contacts of individuals with meningococcal disease have higher carriage rates[11] than the general population and secondary cases of invasive disease account for 1–2% of all meningococcal cases.[12] Antibacterial chemoprophylaxis is widely used to prevent secondary cases but cannot be expected to impact on the wider epidemiology in endemic settings where most carriers are not contacts of any known case.[13] Chemoprophylaxis is, therefore, insufficient for the wider control of meningococcal disease.
Invasion is thought to usually occur soon after colonization with a new meningococcal strain, but most carriers will develop an immune response during colonization and carriage of the organism is terminated.[5] However, even prolonged colonization, which may be characteristic of some meningococci, does not necessarily protect every individual against subsequent colonization or even invasion.[14]
Bacterial adhesion to the nasopharyngeal mucosa is facilitated by pili and various OMPs, notably Opa.[15] This may be followed by endothelial endocytosis and invasion into the bloodstream.[16,17] The inherent invasive potential of meningococci varies between clones but is further influenced by host and environmental determinants.[18] Host immunity mediated by specific or cross-reactive antibodies may halt disease progression following invasion; complement-mediated bacteriolysis is the most important mechanism. In the absence of host immunity, the infection can progress and clinical consequences can range from occult bacteremia[19,20] to purpura fulminans. Localised infections are well described and include pharyngitis, conjunctivitis, septic arthritis, and pneumonia.[21–24] Chronic meningococcemia may occur,[25] but the typical picture of meningococcal disease is of rapidly progressive sepsis, with or without meningitis.[23,26] In most cases, this is associated with a characteristic petechial rash.[26]
The overall mortality of meningococcal disease ranges from 5% to 12%.[23,24,27,28] It is higher in patients with sepsis than in patients with meningitis and highest in the most severe form of meningococcal sepsis, purpura fulminans. Recent data suggest that aggressive management may reduce mortality, even in the most severe cases, to <5%.[29–31] Mortality has recently been noted to be higher in teenagers and in individuals with serogroup C infections.[32–34] This increased mortality is associated with a higher likelihood of disease caused by ST11-complex strains. For survivors of meningococcal disease, the risk of sequelae is around 15%.[23] The most common long-term complications are amputations because of limb ischemia, skin necrosis requiring skin grafts, and neurologic impairment (deafness, seizures). A number of experimental treatment modalities have been described,[35] but there are limited data to support the use of any of these beyond specialised intensive care management.[36]
1.3 Risk Factors
The gulf between the widespread carriage of N. meningitidis and the relatively low disease rate in most populations suggests that individual susceptibility may play an important role in determining the outcome following bacterial colonization. Although most meningococcal disease occurs in patients without overt risk factors, certain groups are known to be at increased risk.
Individuals with complement deficiencies are prone to recurrent episodes of meningococcal disease; often these episodes are caused by less common serogroups.[37–39] Deficiencies of mannose binding protein[40] and properdin,[41] as well as hypogammaglobulinemia,[42] have all been recognized as risk factors — the latter reflecting the importance of antibodies for complement-mediated bacteriolysis. The expanding number of genetic polymorphisms relating to proteins that have been linked with meningococcal disease susceptibility or severity has been the subject of recent detailed reviews.[43] Hyposplenism also may increase susceptibility, although data are scarce.[44] Poor socioeconomic status, crowding,[45,46] exposure to tobacco smoke,[47] and the presence of intercurrent infections are further important risk-modifying factors.
1.4 Epidemiology
The complex epidemiology of meningococcal disease highlights the difficulties involved in the control of this disease. The present situation in Europe and North America is principally characterized by endemic disease. Hyperendemicity and outbreaks are nonetheless associated with the emergence or introduction of new hyperinvasive clones.[12] Despite the intense media interest generated by outbreaks, the fraction of disease associated with local outbreaks is small (2%).[48] Epidemic disease has in recent years mainly been observed in parts of Africa and Asia (see later this section).
Disease incidence is similar in the US and Europe (1–6 per 100 000[27,33] ), although there is great variability between European countries.[27,49] The prevalence of different serogroups varies with age: in one US study, median ages of patients with disease were 6, 17, 24, and 33 years for serogroups B, C, Y, and W135, respectively.[33] The overall incidence is highest during the first 2 years of life. It peaks at around 6 months of age, when maternally derived immunity has waned, but acquired immunity has not yet been established. A second incidence peak is seen in teenage years[33] in most populations. The average age of cases shifts from infancy to higher age groups (older children and teenagers) during epidemics.[50,51]
In Europe, serogroup B predominates as the cause of endemic disease, while the proportion of endemic disease caused by serogroup C varies between 20% and 45%.[27,49] However, a number of countries have seen rises in serogroup C cases in recent years, mostly associated with the ST11 complex meningococci. A marked increase of group C disease in the 1990s was recognized in the UK,[52] partly due to the use of active surveillance methods and the availability of polymerase chain reaction methodology for case ascertainment. Other European regions (Spain, Belgium, France) have also seen high rates of group C disease in recent years, some of which were contained by large-scale vaccination campaigns with group C polysaccharide[53] or polysaccharide conjugate vaccines.[52,54–56]
Similarly, the dynamic nature of meningococcal epidemiology is recognized in North America[57] where the overall incidence is 1 per 100 000,[33] but much higher disease rates have been observed regionally in association with outbreaks of group C disease caused by hypervirulent clones of the ST11 complex.[12] serogroup B has also caused outbreaks in recent years. In Oregon, a sustained 13-fold increase in the age-specific incidence rate in teenagers was associated with the appearance of the ST-32 complex.[51] Serogroup Y disease, on the other hand, was rare 10 years ago, but has since attained prominence, accounting for 32% of all meningococcal disease in US surveillance studies since the mid-1990s.[33,58]
Serogroup W135 was observed in families of pilgrims returning to London, Singapore, and the US from the Hajj pilgrimage to Mecca in Saudi Arabia.[59–64] Although carriage rates in family members of returning pilgrims are increased,[61,62] these strains do not appear to have caused significant outbreaks more widely.[59] To prevent the spread of new clones and serogroups, the widespread use of antibacterials (especially ciprofloxacin) to eradicate carriage in travelers returning from Saudi Arabia has recently been advocated.[62,65] While apparently effective in reducing transmission, the wider implications regarding the promotion of antimicrobial resistance should cause concern. Vaccination with quadrivalent polysaccharide vaccines that protect against A, C, Y, and W135 meningococci is now a visa requirement for travelers into Saudi Arabia.[59,64] Whereas this can be expected to protect the vaccinated individual against invasive disease, it may have only a limited effect on carriage.[60,66] In one study, 15% of pilgrims returning to Singapore were carriers. All had previously been vaccinated.[62] Epidemic disease caused by W135 bacteria of the same clonal complex as that involved in the Hajj outbreaks, ST11, has recently also been observed in African epidemics.[67,68]
Serogroup A disease has in recent decades been predominantly confined to Asia and Sub-Saharan Africa (the meningitis belt) where epidemics occur with attack rates as high as 500 per 100 000 and thousands of deaths occur.[69] An epidemic in West Africa in 1996 is estimated to have caused 250 000 cases and 25 000 deaths.[70] However, hyperendemic disease caused by serogroup A was observed in Finland and Russia as recently as 30 years ago, and in New Zealand in the 1980s, and several pandemics have been described that originated in China. A recent study warns of the possible emergence of serogroup A in Greece.[20] The global control of meningococcal disease will not be possible without vaccines which protect against the five commonly invasive serogroups.
2. Immunity Against Neisseria meningitidis
The importance of bactericidal antibodies against the polysaccharide capsule of N. meningitidis was recognized by Gotschlich and coworkers[71,72] as being the cornerstone of humoral immunity towards the meningococcus. This provided the basis for the development of efficacious polysaccharide vaccines. Having unravelled the chemical structure of the polysaccharide capsule and developed a purification method, researchers at the Walter Reed Army Institute, Rockville, MD, published a series of studies on the seroepidemiology of meningococcal disease in military recruits.[1,5,71–73] They described an inverse relationship between disease susceptibility towards serogroup A, B, and C and a functional in vitro assay, the serum bactericidal assay (SBA), and further established a titer of ≥1 : 4 as being highly predictive of protective immunity.
To facilitate standardization, a modified SBA has more recently been developed for the study of serogroup C immunity and has found wide application.[74] It differs from the original assay by the use of rabbit (r) rather than human (h) complement. An rSBA titer of 1 : 8 has been described as the nearest equivalent of the hSBA titer of 1 : 4 indicative of protective immunity. Although the validity of this cut-off has been disputed,[75] there is increasing seroepidemiologic and experimental evidence to support the rSBA threshold of ≥1 : 8 as a surrogate marker of protection at an individual[74] as well as a population level.[76]
3. Polysaccharide Vaccination Against Meningococcal Disease
3.1 Vaccination Against Meningococci of Group A, C, Y, W135
Gotschlich and coworkers[72,73] showed that a hSBA of ≥1 : 4 could successfully be induced by vaccines based on purified meningococcal group A and group C capsular polysaccharides. This was a major breakthrough over earlier attempts to vaccinate using killed whole cell vaccines, which had been associated with unacceptable endotoxin-related side effects, or earlier capsular polysaccharide vaccines which were nonimmunogenic, probably as a result of the degradation of the polysaccharide in the manufacturing process. Further studies soon confirmed these vaccines to be highly efficacious in reducing the risk of infection not only in the confined settings of army barracks,[77–80] but also in open communities.[53,81,82]
As a result, polysaccharide vaccines against serogroup A and serogroup C meningococci have since been widely used in epidemics, for outbreak control, or as secondary prophylaxis for close contacts of index cases, with a good safety record.[83] They have further been recommended for young adults sharing crowded accommodation (e.g. military recruits,[79,84] university students[85] ) as well as for travelers to countries with hyperendemic or epidemic disease patterns related to one of the serogroups.[59] Quadrivalent polysaccharide combination vaccines against these serogroups are commercially available, as are bivalent products against serogroups A and C only. Vaccine efficacy rates of 80–90% against group C disease in adults and older children have been observed, whereas efficacy against group A disease is in the range of 95%.[86] These estimates are based on short observation and longer term efficacy rates are probably much lower. There are no data regarding the efficacy of the serogroup Y and W135 components.
A moderate potential to induce herd immunity via a reduction of carriage has been described.[53,73,81,87,88] However, the duration of herd immunity is invariably limited, as indeed is the duration of serologic and clinical protection in the individual or the community. Overall vaccine efficacy against serogroup C was 65% in a Canadian efficacy study during the first 2 years, but had become undetectable 3 years after the vaccination campaign.[82] In another study, only 4–10% of children aged <5 years retained any serum bactericidal activity 1 year after vaccination.[89]
Polysaccharide vaccine responses in young children against encapsulated bacteria are characterised by poor or absent immune responses and immunologic memory. This also holds true for serogroup C polysaccharide meningococcal vaccines. Reduced IgG responses are found in children aged <2 years.[90,91] Moreover, even the presence of IgG antibodies does not necessarily render the infants’ serum bactericidal, probably as a result of deficient antigen-binding properties.[92] In keeping with these observations, serogroup C polysaccharide meningococcal vaccines lack efficacy in young children. A recent Canadian study described vaccine efficacy to be absent in children aged <2 years, compared with 41% in older children (although the confidence intervals crossed zero in the under 10 years of age group) and 75% in teenagers.[82]
In contrast, responses towards serogroup A vaccines are maintained even in young children.[93,94] Infants mount an antibody response following serogroup A polysaccharide vaccination and second doses elicit booster responses suggestive of immunologic memory. Supported by a Finnish efficacy study in young children indicating protection in those over 3 months of age,[81] a schedule of two doses during infancy has therefore been suggested as suitable for children from early infancy. Regular boosters throughout childhood might be able to sustain protective IgG levels during the age of greatest risk.[90] On these grounds, it has also been argued that routine vaccination with serogroup A polysaccharide vaccines in parts of Africa would have the potential to prevent serogroup A epidemics.[95] The feasibility and cost effectiveness of this approach has been a subject of some debate.[96,97]
Several shortcomings are nonetheless associated with the use of polysaccharide vaccines. The reduced immunogenicity in young children and infants hampers immunization of those at greatest risk. Even antibody levels against the more immunogenic serogroup A polysaccharide in infants return to baseline within 1 year of vaccine administration.[98] To maintain immunity, repeat doses of these vaccines would be required, but the efficacy of such a schedule is unknown. Of concern, it has been observed that re-vaccination with serogroup A or C polysaccharide vaccines leads to a diminution of antibody responses to subsequent doses in adults as well as children.[93,99–104] Specific IgG levels and SBA titers still rise in these individuals, but typically less vigorously than in individuals of the same age group who have never before received the vaccine. This phenomenon has been called hypo-responsiveness,[100,102,105] suppression,[95] or refractoriness,[106] and although of uncertain clinical significance, it is seen by many as discouraging the repeated use of polysaccharide vaccines in children. Its occurrence is not limited to children, however, which also causes uncertainty about the most appropriate schedule for periodic re-vaccination of the risk-groups, mentioned in section 1.3.
3.2 Meningococcal Glycoconjugate Vaccines
The limitations in section 3.1 were the driving force behind the development of protein-polysaccharide conjugate meningococcal vaccines using the same technology as that employed for the efficacious Haemophilus influenzae type b (Hib) vaccines.[107–109] The principle behind this approach lies in the covalent conjugation of the polysaccharide moiety to a carrier protein, thus eliciting a T-cell-dependent immune response that can induce immunity in infants and generate immunologic memory.
Conjugate vaccines against serogroup A and C meningococci were developed first and found to be immunogenic in adults and infants.[110–113] In adults, IgG and SBA responses to a single dose were not significantly different to that with polysaccharide vaccines,[110] but in those of a young age, the immunogenicity of the conjugated serogroup C antigen was clearly superior to that of the plain polysaccharide vaccine.[111,112] However, even in adults, the antibodies induced by the conjugate group C vaccines are of higher avidity (i.e. increased overall antigen-binding strength of antibodies) and functional activity (killing of bacteria) than those induced by the polysaccharide vaccine.[113]
A more complex picture evolves regarding the immunogenicity of serogroup A conjugates. Owing to the high immunogenicity of the group A polysaccharide, IgG responses to group A antigen after two doses of the conjugate vaccine in infants were not significantly higher than after two doses of the plain polysaccharide vaccine.[111,112] The different quality of the response to the conjugate vaccine is nonetheless illustrated by the fact that the SBA results were 20-fold higher in conjugate recipients.[111]
Regarding the induction of memory, data for serogroups A and C differ again. Memory has conventionally been assessed by the administration of a plain polysaccharide booster to children who had been ‘primed’ with conjugate vaccines. Most studies administered the booster to individuals at around 1 year of age, when polysaccharide responses are usually minimal (see section 3.1). Serogroup C booster responses have consistently been excellent,[99,100,114–116] indicative of immunologic memory.
Memory responses for serogroup A conjugates have been less consistent. A study in the Gambia failed to demonstrate immunologic memory in individuals 2 years of age following a three-dose schedule in infancy.[100] Further follow-up of this cohort confirmed that at 5 years of age, only those individuals who had received an additional group A conjugate vaccine dose at 2 years of age had meaningful immunologic memory. In those who had not received a conjugate booster, IgG levels rose but not SBA titers.[102] In contrast, a study in Niger, in which three conjugate doses in monthly intervals were also given, showed vigorous responses to a polysaccharide booster administered at 1 year of age.[117] The reasons for this discrepancy are unclear. The two vaccines were based on different carrier proteins — the Niger study tested a diphtheria-conjugate, whereas the Gambian study used the mutant diphtheria toxoid CRM197 as a carrier. Possibly more importantly, it has been suggested that the size of the oligosaccharide molecules in the Gambian study vaccine may have been suboptimal.[104]
Whereas no efficacy data are available for group A conjugate vaccines so far, the efficacy of group C conjugate vaccines has since been proven by their large scale use in the UK (see section 3.3), where a steady rise of meningococcal disease incidence was observed during the mid-1990s.[52] Absolute numbers rose from 1132 in 1994 to 2418 cases in 1998, while the proportion caused by serogroup C increased from 26% to 34%.
3.3 Serogroup C Conjugates — the UK Experience
The ability of meningococcal C conjugate vaccines to induce ‘protective’ serum bactericidal antibody titers in more than 90% of individuals of all ages has been a consistent feature of the prelicensure immunogenicity studies performed.[99,100,114,115,118–122] Whereas a single dose is sufficient in toddlers and adolescents,[121] two to three doses are required to achieve this in infants. The proportion of individuals with SBA results ≥1 : 8 decreases to around 50–85% within 1 year of vaccination,[114,115,118,121] but this percentage promptly rises to almost 100% upon administration of a polysaccharide vaccine booster.[114,115,121]
At the time of licensure in the UK, none of the three meningococcal group C conjugate vaccines had undergone efficacy trials. Nonetheless, in light of favorable safety and immunogenicity data on the one hand and epidemiologic pressures on the other hand, the UK Department of Health supported universal vaccination of infants and children with group C meningococcal glycoconjugate vaccines. An immunization program which started in November of 1999 resulted in 80% of children and adolescents below 18 years of age vaccinated within 1 year.[52] Three doses in monthly intervals were administered to infants from 2 months of age along with their routine vaccinations. From 1 year of age onwards, only a single dose was given. Infants between 6 and 12 months of age received two doses. Booster doses have not been part of the routine schedule.
Nine months into the campaign, the earliest estimates indicated 97% short-term efficacy in teenagers and 92% in toddlers, albeit with wide confidence intervals. More recent figures based on the screening method vary between 89% and 94% for all age groups.[56,123,124] An effectiveness study in teenagers based on a case-control design recently confirmed these results — vaccine efficacy was estimated to be 93%.[125] The annual number of deaths attributable to confirmed serogroup C infection in the age cohort of <20 years had fallen from 67 in 1999 to 5 in 2001,[56] while in the unvaccinated population over 20 years of age, no decrease was observed. The campaign was therefore extended to include young adults between 20 and 24 years of age.[126]
The three meningococcal group C conjugate vaccines licensed in the UK (table I) all contain the same amount of meningococcal polysaccharide antigen (10μg), which is less than that contained in most polysaccharide vaccines (50μg). Two products utilize the mutant diphtheria toxoid CRM197 as a protein carrier, whereas in the third product tetanus toxoid is used. The latter appears to be the most immunogenic,[121] but it is not yet known how this might affect long-term protection.
In view of the bimodal incidence curve of meningococcal disease with a second peak in teenage years, the duration for which bactericidal responses are maintained is of particular importance. Recent data from the UK suggest that memory responses can be detected at 4 years of age following vaccination with a CRM197 conjugate — interestingly even in children without evidence of bactericidal activity after a first dose.[127] Whether immunity persists into the second decade when the second incidence peak occurs is not yet known, but enhanced surveillance mechanisms are in place to monitor this.
One concern prior to the widespread use of conjugate group C vaccines had been the potential rise of nonserogroup C meningococcal disease,[128] which could result from replacement colonization or from capsule switching.[66,129,130] Isolated reports have raised concerns over possible serogroup replacement in the wake of meningococcal polysaccharide vaccination campaigns.[131,132] Sensitive systems for the detection of such developments are in place in the UK,[133] but no increase of serogroup B disease has been observed in vaccinated age cohorts.[56] Molecular typing by multi-locus sequence typing has equally not revealed evidence of capsular switching of virulent clones.[56,124] Furthermore, carriage data obtained 1 year after the launch of the meningococcal serogroup C conjugate vaccine program in the UK did not show an increase in serogroup B carriage (or any other serogroup) in teenagers, despite a 66% reduction in carriage of group C meningococci.[134]
The marked reduction in carriage observed in these studies suggests the possibility that the serogroup C conjugate vaccine does induce herd immunity. Early estimates in toddlers and children in the UK appear to confirm a reduction of disease cases in unvaccinated children.[56,123] The duration of these effects is still unclear and longer monitoring periods will be required to distinguish these from the similar, but short-lived effects observed following meningococcal polysaccharide vaccination (see section 3.1).
Postmarketing surveillance in the UK has shown the widespread use of meningococcal group C conjugate vaccines to be ‘safe’ and efficacious.[135] Safety and adverse event data have been collated from clinical trials of meningococcal group C and A/C conjugate vaccines, in addition to accumulated data from spon-taneous reporting on 12 million doses distributed in the UK during 1999–2000. Mild reactions have been reported at similar rates to those for other glycoconjugate vaccines: local reactions (redness, tenderness and swelling at the injection site) in up to 50% of vaccinees, irritability in up to 80% of infants, and fever >38°C in up to 9% of infants when administered with other vaccines.[99,100,110,112,114,116,118,119,122,136–139] Headaches and malaise occurred in up to 10% of older children and adults.[116,120] The frequencies of rare adverse events are based on spontaneous reporting rates from the UK and have been calculated using the number of reports received as the numerator and the total number of doses distributed as the denominator. Severe reactions were very uncommon and included:
-
systemic allergic reactions (lymphadenopathy, anaphylaxis, hypersensitivity reactions including bronchospasm, facial edema, and angioedema) in <0.01% of patients;
-
neurologic responses (dizziness, convulsions including febrile convulsions, fainting, hypesthesia, paresthesia, and hypotonia) in <0.01%;
-
nausea or vomiting in <0.01%;
-
rash, urticaria or pruritus in 0.01%;
-
arthralgia in <0.01%.[140]
A number of other countries have now included meningococcal group C conjugate vaccines into their routine schedule. In some countries, this is by way of a three-dose schedule in infancy (e.g. Republic of Ireland, Spain), while others have opted for a single dose at 1 year of age (e.g. The Netherlands, Australia, and some provinces in Canada). It has recently been suggested that, while the most effective approach may be to give three doses in infancy, giving a single dose at 12 months could be more cost effective for some countries.[141] Any such cost-effectiveness analyses may be altered by the findings of a recent study using a meningococcal polysaccharide-tetanus conjugate in the UK that has clearly demonstrated the immunogenicity of schedules using reduced numbers of doses of this vaccine in infants.[142]
The future will probably see conjugate vaccines in new combinations and it is likely that they will in time replace existing polysaccharide vaccines, provided general affordability is shown (table II). Combination conjugate vaccines against serogroup A, C, Y, and W135 meningococci are already undergoing phase II trials and should have considerable potential to reduce meningococcal disease rates worldwide,[143,144] if they can be made widely available. Combinations of conjugate meningococcal vaccines with Hib or pneumococcal vaccines might also be an attractive, and potentially more cost-effective, public health measure.[145]
4. Vaccines Against Serogroup B Meningococci
Effective prevention of meningococcal disease caused by serogroup A, C, Y, and W135 may be within reach, but the global battle against N. meningitidis cannot be won without a breakthrough in the development of vaccines against serogroup B. This poses a much greater challenge, immunologically as well as logistically.
4.1 Difficulties in the Development of Group B Vaccines
In contrast to serogroup A and C disease, the serologic equivalent of protection against group B meningococci is uncertain.[146] The correlation between SBA results and IgG levels has been found to be poor,[147] especially in young children.[148–150] Although weak correlations between SBA and efficacy of vaccines directed against serogroup B strains were found by some investigators,[148,150–152] others found no correlation.[153] Mechanisms other than bactericidal antibodies are probably relevant for protective immunity against group B meningococci. The standardization of group B bactericidal assays is also more problematic as rabbit serum is unsuitable as a complement source.[154]
It is obvious that these factors hamper the prediction of efficacy from immunogenicity data, which facilitated the licensure of meningococcal C glycoconjugate vaccines. The licensure of group B candidate vaccines therefore requires data from prospective efficacy trials. Given the low incidence of serogroup B disease in most countries, very large prospective trials would be required. As these would need to include a sizeable proportion of the birth cohorts of many European countries, the choice of the most suitable candidate for such trials requires careful consideration.
4.2 Group B Polysaccharide Vaccines
Past attempts to protect against serogroup B meningococci have been blighted by the poor immunogenicity of its defining polysaccharide antigen. Being structurally homologous with the neural cell adhesion molecule expressed on foetal neural tissue, it is not surprising that, as a self-antigen, the serogroup B capsular polysaccharide is poorly immunogenic.[155] As these molecules are most highly expressed during embryonic development, there is particular concern that the induction of antibodies might imply a theoretical risk of teratogenicity.
Conjugation of the polysaccharide to a carrier protein has nonetheless been attempted. As a result, immunogenicity was increased and bactericidal antibodies were induced in animals.[156,157] However, ongoing concerns about the safety of such vaccines are likely to preclude their wider use in human trials.
Since the generation of a polysaccharide-based vaccine would provide the most broadly protective approach to vaccine design, attempts to overcome these problems have continued through chemical modification of the group B polysaccharide [a homopolymer of α(2→8) N-acetyl neuraminic acid].[158,159] Jennings et al.[158] replaced the N-acetyl group of the polysaccharide with an N-propionyl group and conjugated the resultant polysaccharide to a tetanus-toxoid carrier.[158] Although this vaccine induces antibodies in mice and nonhuman primates,[160] these antibodies have been found to bind to polysialylated human embryonic brain glycopeptides,[161] raising similar safety concerns as with the original polysaccharide-conjugate approach. Further attempts are being made to identify suitable meningococcal epitopes by analyzing subgroups of antibodies induced by propionylated vaccines that are bactericidal but do not bind to self-antigens.[161]
4.3 Outer Membrane Vesicle Vaccines
In view of the difficulties encountered with polysaccharide-based vaccines, other approaches for vaccine design have been investigated. Proteins are immunogenic in infants and the meningococcal outer membrane is rich in these. Antibodies directed against a range of OMPs have been found to possess bactericidal activity in vitro but their relative importance for defense against group B meningococci is more difficult to establish. The challenge is to identify proteins that are: (i) surface exposed and immunogenic; (ii) induce bactericidal antibodies; (iii) are conserved across various strains; and (iv) are consistently expressed.
The release of blebs (vesicles) of outer membrane during growth is a feature common to Gram-negative organisms that has been successfully exploited in vaccine development. Meningococcal bacteria shed these in large numbers and vaccines based on outer membrane vesicles (OMV), containing OMPs as well as lipopolysaccharides, are somewhat efficacious in older children and teenagers.
Three such OMV vaccines underwent clinical efficacy trials (see table III). A Cuban vaccine, developed by the Finlay Institute, Cuba was based on a single strain (B:4:P19,15) responsible for an epidemic in Cuba. It also contains serogroup C polysaccharide antigen, both in order to improve solubility and to broaden coverage. Efficacy in teenagers in the confined setting of residential schools was 83%.[162] It has since been in routine use in Cuba for children from 3 months of age onward and is licensed in several Latin American countries. However, this high efficacy rate was not observed when the vaccine was widely used in Brazil some years later.[151,163] Two case-control studies were conducted in the metropolitan areas of Sao Paolo[151] and Rio de Janeiro.[163] As previously in Cuba, a two-dose schedule had been followed. Although protective efficacy was 70% in older children and teenagers, it was only around 40% in young children and absent in children aged <2 years — the Sao Paolo study even reported negative efficacy rates. This was consistent with serologic results showing 43% of children aged between 2 and 5 years had a hSBA of >1 : 4, compared with just 13% of children aged <2 years.[150]
Only 44% of bacterial isolates in Brazil matched the vaccine strain.[151] The limited protection induced by these vaccines is therefore thought to be a consequence of serosubtype-restricted immunity rather than resulting from insufficient immunogenicity. An immunogenicity study conducted in Chile confirmed the absence of bactericidal responses to heterologous strains in infants,[165] whereas against homologous strains, 56% of infants had a >4-fold increase in bactericidal antibody titer after two vaccine doses. This increased to 90% after three doses,[165] which raises the question whether an additional dose might result in improved protective efficacy in infants, for example, in the setting of an outbreak caused by an homologous strain.
The National Institute for Public Health in Norway has produced an OMV vaccine based on a strain isolated from an early case during an epidemic. In a cluster-randomized prospective trial, its efficacy in teenagers over a 29-month period was found to be 57%.[164] Later reports related that efficacy had been 87% during the first 10 months but had fallen to 30% after 2 years.[152] This was matched by a fall in the proportion of individuals with a hSBA of ≥1 : 4 from 97% to 42%, which suggests some correlation of SBA with efficacy. An additional dose was given to a group of 311 volunteers 10 months after the second dose, to which impressive booster responses (higher than after the second dose) were observed. Thus, the efficacy might be improved by a three-dose schedule.[166] This may also make the response more cross-protective, which could further increase efficacy.[166] However, although improved cross-protection is observed in adults after three doses, the same does not necessarily apply to infants.
Bactericidal antibodies induced by OMVs are principally directed against the class I antigen, PorA, (as indeed are those acquired by natural infection[147] ) and to a lesser degree against other antigens including the class 5 antigen, Opc.[165–167] The marked antigenic heterogeneity of PorA profoundly limits any cross-protection offered by OMV vaccines based on a single strain. This provided the rationale for the Dutch Institute for Environmental Health and Vaccines’ approach of including six different PorA proteins in two trivalent recombinant OMVs, combined in a vaccine.[168] Epidemiologic evidence during the early 1990s indicated the potential for this vaccine to cover between 50% and 80% of strains in various countries,[27,169,170] although as many as 20 serosubtypes might be required to provide cover against 80% of sporadic serogroup B cases in the US.[169] No efficacy data are available for this vaccine, but immunogenicity was measured as the proportion of individuals with at least a 4-fold increase of bactericidal antibody titers against six isogenic strains.[170,171] Following a two-dose primary schedule, a booster was given 5–9 months later to assess memory responses. In toddlers and schoolchildren, the proportion of responders in both age groups showed remarkable serosubtype specific variation, ranging from 16% to 100% following the booster dose.[171] A separate study in infants used a three-dose primary vaccination schedule, followed by a booster at 1 year of age. The same serosubtype-dependent immunogenicity was observed, with only 19–49% of infants having at least a 4-fold increase in bactericidal titer. However, memory responses at 1 year of age in 78–95% of infants[170] and avidity maturation was demonstrated.[172] It remains unclear whether this vaccine would offer any hope of broad protection in this age group.
The effectiveness of OMV vaccines is apparently limited by reduced immunogenicity in infants as well as suboptimal cross-protection. The remarkable antigenic variability of the target antigens continues to pose a challenge and the emergence of pathogenic meningococci that are deficient in important OMPs included in these vaccines has also been described.[173] Efforts are underway to overcome these limitations; vaccine developers have joined forces with major vaccine manufacturers. Through such a partnership a monovalent OMV vaccine is currently being introduced in New Zealand, based on the outbreak strain causing hyperendemic disease in that country.
4.4 N. lactamica
Another interesting approach centres on the use of the closely related commensal species N. lactamica as a vaccine. N. lactamica is unencapsulated and nonpathogenic, and nasopharyngeal carriage peaks before the age of 4 years. This coincides with a decline in the incidence of meningococcal disease, despite meningococcal carriage rates in the same age group being very low.[7,174] Most carriers of N. lactamica have bactericidal antibodies against meningococci[174] and meningococcal incidence has been found to be lower in communities with high N. lactamica colonization rates.[174,175]
The two species N. lactamica and N. meningitidis share numerous membrane proteins with cross-reactive antigenicity.[176–180] Recently, the injection of killed whole cells of N. lactamica or its OMPs has been shown to protect mice against a lethal challenge with N. meningitidis of various strains.[181] Interestingly, this occurred despite the absence of serum bactericidal activity, which suggests that other mechanisms (such as opsonophagocytosis) may be the predominant protective mechanism in this model. This may also be the case in human immunity to serogroup B meningococci, but whether this protective effect can be fully replicated in human vaccinees remains unclear. It has also been cautioned that the cross-reactivity between OMPs of these two species could be a double-edged sword: if OMP-based vaccines against meningococci reduce immunizing colonization with nonmeningococcal Neisseria spp., the protective effect of the vaccine would have to be weighed against the reduction in natural boosting through colonization with the commensal.[176]
4.5 Transferrin Binding Protein
Much interest has focused on the role of bacterial iron acquisition mechanisms which fulfil an essential role in meningococcal metabolism.[182] Meningococci have evolved several proteins involved in scavenging iron from the host,[183] among them the lactoferrin receptor (LbpA/LbpB),[184–186] the ferric binding protein (FbpA),[187,188] and the transferrin binding protein (TbpA/B).[189,190]
Of these, TbpB has potential as a candidate vaccine. It is better surface exposed than TbpA, although the latter is more highly conserved between strains. Opsonins against TbpA plus B complexes are found in the serum of patients during convalescence after meningococcal disease.[191] Both have been shown to induce bactericidal antibodies in animals, but TbpB is more immunogenic[192] and antibodies directed against it bind to a range of meningococcal strains.[189,193–195] It has, therefore, been introduced into human phase I trials. Early results have been disappointing, with the majority of vaccinees showing <4-fold rises in bactericidal titers. TbpA, on the other hand, provided increased survival rates in animals and better cross-protection against an experimental lethal meningococcal infection when compared with TbpB, despite poorer bactericidal serum responses.[192] This seems to demonstrate the limited reliability of bactericidal assays for the prediction of protection in this model. The combination of TbpA and TbpB in the same vaccine may offer advantages.[192]
4.6 Neisserial Surface Protein A
One meningococcal surface protein of unknown function, Neisserial surface protein A (NspA), has been shown to be immunogenic while being more highly conserved than Tbp or PorA. More than 99% of 250 meningococcal strains reacted with a mouse monoclonal antibody directed at NspA, and passive and active protection was demonstrated in mice against experimental infection with meningococci of serogroups A, B, and C.[196] Focusing on serogroup B meningococcal strains, other researchers could not fully replicate these findings:[197] 35% of strains did not react with polyclonal anti-NspA antibodies despite the expression of NspA and were not susceptible to killing by serum, despite their protein sequences being 99–100% homologous.[197] It was found that these strains produced larger amounts of group B polysaccharide and the authors concluded that poor accessibility of NspA in some group B strains may be the main factor limiting its immunogenicity. Reduced serum bactericidal activity was shown to correspond to a lack of protection against experimental infection.[198]
4.7 Other Surface Proteins
Numerous additional surface proteins have been considered as vaccine candidates (table IV), including adhesion penetration protein (App),[199,200] ferric enterobactin receptor (FetA; FrpB),[188,201] FbpA,[187] opacity associated protein (OpA; class 5),[15,202] OpcA (Opc; class 5c),[203] Pilin,[204] PorB (class 2/3 protein),[205] and reduction modifiable protein (Rmp; class 4).[206,207] Like those discussed previously in sections 4.3–4.6, some of these proteins may well be considered as components of a serogroup B meningococcal vaccine but none are likely to provide a broadly cross-protective vaccine on their own. They may become important components of a multi-component or new generation vesicle vaccine.
4.8 Genomic Approaches
The goal of identifying a universal conserved antigen has been fuelled by the recently completed genetic sequencing of serogroup A and B strains.[208,209] Having added numerous previously unknown proteins to an expanding list of vaccine candidates[210] this process has been dubbed reverse vaccinology.[211] The identification of vaccine candidates starts in silico by computer analysis of DNA fragments. It is based on the identification of open reading frames encoding proteins and the prediction of their properties. The antigens are then expressed in Escherichia coli and their potential to induce bactericidal antibodies is tested in mice. Several candidates have been identified in this way.[212] However, because of the organism’s uniquely high potential for phase variation and genetic re-arrangements,[213] the expression of some proteins is highly variable, making their capacity to induce antibodies that are bactericidal in vivo hard to predict. Recent approaches have therefore included the transcriptome (RNA) analysis of meningococcal bacteria incubated in different conditions, simulating the different stages of invasion.[214]
4.9 Lipopolysaccharide
The range of novel antigens is not restricted to proteins. Lipopolysaccharide is outer membrane bound and a key pathogenicity factor. Its inner core is highly conserved between strains and has been chosen for protein conjugation. Murine antibodies directed against it possess cross-reactive bactericidal activity.[215] However, it has recently been shown that protection of mice against an experimental infectious challenge depends on the relative prevalence of sialylated, nonsialylated, and/or truncated lipopoly-saccharide glycoforms[216] leading to a complete lack of protection against certain strains.
5. Conclusion
Meningococcal disease remains of great public health importance despite the availability of vaccines that protect against serogroup C disease from early infancy. Quadrivalent conjugate vaccines will be in the marketplace within a matter of years. They offer the possibility for control of all non-B meningococcal disease and can be employed in response to local epidemiologic patterns. Prevention of serogroup B disease presents a major challenge to vaccine developers but the commercial and public health benefits of development of a successful B vaccine will undoubtedly continue to fuel research efforts to produce a vaccine against this evasive pathogen.
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Acknowledgements
The authors have undertaken clinical trials sponsored by several major meningococcal vaccine manufacturers on behalf of the University of Oxford and St George’s Vaccine Institute and have received assistance for travel to attend scientific meetings from these sponsors.
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Rüggeberg, J.U., Pollard, A.J. Meningococcal Vaccines. Pediatr-Drugs 6, 251–266 (2004). https://doi.org/10.2165/00148581-200406040-00004
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DOI: https://doi.org/10.2165/00148581-200406040-00004