Meningococcal vaccines: to eradicate the disease, not the bacterium

Neisseria meningitidis is exclusively a human-adapted bacterium, most frequently found in asymptomatic carriage that promotes natural immunity. However, it is also the causative agent of severe invasive infections, such as septicaemia and/or meningitis that may lead to life-threatening septic shock. Vaccination with capsular polysaccharidic antigens (either plain or conjugated) induces serogroup specific protective antibodies. Meningococcal capsular polysaccharide vaccines are only available against serogroups A, C, Y and W135. There is no available capsular vaccine against serogroup B. Future strategies to develop meningococcal vaccine should be global strategies aimed to design a "universal vaccine" effective against meningococcal disease due to any strain, regardless its phenotype and genotype. However, these global strategies may be hindered by the high diversity of meningococcal isolates and their changing epidemiology. Alternatively, targeted or local vaccine strategies may be developed against specific isolates and can help particularly in controlling outbreaks while preserving benefits from carriage.     

Development of new vaccines against meningococcal disease

Meningococcal diseases continue to have a major public health impact in many countries. Five major groups of Neisseria meningitidis (A, B, C, Y and W135) are responsible for most meningoccocal diseases. Plain polysaccharides vaccines for Nelsseria meningitidis groups A, C, Y and W-135 have been in use for approximately 20 years, both to prevent invasive disease in high-risk population and to control disease outbreaks. However, these conventional meningococcal vaccines induce a relatively short-lasting T-cell independent immune response, are not effective in children under two years of age and can induce hyporesponsiveness. New meningococcal group C conjugate vaccines have since been developed, which offer solid advantages over the currently licensed plain polysaccharide vaccines. There is still no vaccine available against the serogroup B, which is a major cause of invasive disease. This report summarises the different approaches to the development of vaccines against the pathogenic meningococci.     

Serogroup B meningococcal vaccines

Neisseria meningitidis causes severe, often fatal septicemia and meningitis. Polysaccharide vaccines that offer protection against infection with meningococcal serogroups A, C, Y and W-135 are effective in older children and adults, and have been widely used. New polysaccharide-conjugate vaccines against one or more of these serogroups are now in use or under accelerated development; however, a broadly protective vaccine against infection by serogroup B N meningitidis is not yet available. Serogroup B contributes significantly to the burden of meningococcal disease in many industrialized countries where both epidemic and endemic serogroup B infections occur. Vaccines effective against specific strains responsible for serogroup B epidemic disease have been developed, but the development of a safe serogroup B vaccine that is cross protective against multiple strains and is effective in infants and young children is a challenge. In spite of these difficulties, promising approaches stemming from a better understanding of meningococcal pathogenesis and of the genetics of serogroup B N meningitidis continue to evolve. Progress toward an effective serogroup B vaccine, an important addition for meningococcal disease prevention, is the focus of this review. The epidemiology and pathogenesis of meningococcal disease are detailed, along with discussion of the challenges faced in the development of efficacious serogroup B vaccines.     

Meningococcal vaccines

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.     

Meningococcal glycoconjugate vaccines

Neisseria meningitidis is a major cause of invasive bacterial infections worldwide. For this reason, efforts to control the disease have been directed at optimizing meningococcal vaccines and implementing appropriate vaccination policies. In the past, plain polysaccharide vaccines containing purified capsular polysaccharides A, C, Y and W135 were developed, but failed to protect infants, who are at greatest risk. Experience with the conjugate Haemophilus vaccine suggested that this approach might well empower meningococcal vaccines. Thus, a very efficacious vaccine against serogroup C Neisseria meningitis was optimized and has been widely used in developed nations since 1999. On the basis of epidemiological changes in the circulation of pathogenic serogroups in the United States, a quadrivalent conjugate vaccine against A, C, Y and W135 serogroups (Menactra?) has been developed and was approved by the U.S. FDA (Food and Drug Administration) in 2005. Recently, another tetravalent conjugate meningococcal vaccine (Menveo?) has been licensed and made available in the United States of America and in the European Union. Finally, in response to large epidemics caused by serogroup A meningococcus in Africa, a new, safe, immunogenic and affordable vaccine has been developed. This review highlights the evolution of conjugate meningococcal vaccines in general and discusses how this kind of vaccine can contribute to preventing meningococcal disease.     

Meningococcal vaccines

Neisseria meningitidis is one of the leading infectious causes of death in children under five years old in industrialized countries, and most cases can be attributed to five disease-causing serogroups: A, B, C, Y and W135. Meningococcal vaccine development began in the 1930s with killed whole-cell and exotoxin vaccines, but widespread use of polysaccharide vaccines did not begin until the 1970s. Serogroup A, C, Y and W135 polysaccharides are all included in vaccines for travellers, other high risk groups and control of outbreaks, but have limited immunogenicity and effficacy in childhood. Protein-polysaccharide conjugate vaccines overcome this problem and offer the possibility of protection in early childhoodfrom serogroup A, C, Y and W135. An effective serogroup B vaccine remains elusive and the greatest challengefor vaccine developers.     

脑膜炎球菌疫苗的研究和开发现状

流行性脑脊髓膜炎(流脑)是一个世界性公共卫生问题,发病率和死亡率都较高.此文从细菌遗传学特征、流脑的流行趋势、疫苗供应现状、可供选择的候选疫苗及其筛选方法等方面讨论了脑膜炎球菌疫苗(特别是B群脑膜炎球菌疫苗)的研究和开发现状.     

Meningococcal disease in international travel: vaccine strategies

International travel and migration facilitate the rapid intercontinental spread of meningococcal disease. Serogroup A, and to a lesser extent serogroup C, have been responsible for pandemics in the past (mainly in Africa), but in recent years there was an international outbreak due to W135 related to the Hajj pilgrimage. The high carriage rates, persistence and transmissibility, in combination with the high case fatality rate of the Hajj-associated W135 outbreak clone, certainly raise considerable concern about the public health consequences of widespread dissemination of this organism and the potential for future epidemics. Indeed, the now evolving W135 epidemic in Africa mandates that the bivalent meningococcal vaccine should be replaced by the tetravalent meningococcal vaccine, covering A, C, Y and W135 serogroups. The currently available polysaccharide tetravalent meningococcal vaccine, albeit associated with high seroconversion and efficacy rates, has several shortcomings: it is not immunogenic in young children, duration of protective immunity is short, and it has minimal or no effect on nasopharyngeal carriage and therefore transmission of the organism. Immunogenicity of polysaccharide vaccines can be improved by chemical conjugation to a protein carrier, thereby eliciting a T-cell-dependent antibody response. In contrast to polysaccharide vaccines, conjugate vaccines are immunogenic in young infants, induce long-term protection, and reduce nasopharyngeal carriage. The tetravalent conjugate vaccine will be a leap forward in the control of meningococcal epidemics in affected countries. It will also boost the uptake of meningococcal vaccines in travelers, because the duration of protection is longer and it eliminates the problem of immune hyporesponsiveness of serogroup C with repeated dosing. The small risk of travel-associated disease for the general traveler and the unpredictable nature of epidemics make it difficult to provide evidence-based vaccine recommendations. The current recommendation is to vaccinate all Hajj pilgrims, travelers to areas with current outbreaks, travelers to the sub-Saharan meningitis belt, and high-risk individuals (i.e., those with immunodeficiencies).     

The New Zealand Meningococcal Vaccine Strategy: a tailor-made vaccine to combat a devastating epidemic

The New Zealand Meningococcal Vaccine Strategy aims to end the devastating 14-year epidemic of B:4:P1.7b,4 group B meningococcal disease in New Zealand through a mass immunisation programme to all under 20 year olds using a tailor-made vaccine (MeNZB). This paper describes the scientific rationale, development, and key components of the New Zealand Meningococcal Vaccine Strategy. A summary of the efficacy and safety data of existing outer membrane vesicle group B meningococcal vaccines is included as these data critically support the Strategy.     

Meningococcal vaccines

Neisseria meningitidis is a major world-wide cause of meningitis. N. meningitidis related diseases have become more pronounced in the last decade and changes in meningococcal-associated disease have opened new opportunities for prevention and vaccine development. Although multivalent vaccines have been developed against the N. meningitidis serogroups A, C, W-135, and Y, four of the most common serogroups, the diversity of N. meningitidis has increased the number of challenges for the development of an effective vaccine against all currently identified strains. Without the development of a vaccine against serogroup B, it will be difficult to effectively prevent global meningococcal disease. This review provides a background on N. meningitidis biology and focuses on the current status of meningococcal research and vaccine development. In addition, the efficacy of the currently marketed N. meningitidis vaccines will be discussed.     

New therapies and vaccines for bacterial meningitis

Acute bacterial meningitis remains an important cause of morbidity and mortality worldwide. There have recently been major advances in the prevention of the major causes of bacterial meningitis following improvements in vaccinology. The success of immunisation against Haemophilus influenzae type b infection is being mirrored with serogroup C conjugated meningococcal vaccine and pneumococcal conjugate vaccine. However, there remain major challenges, notably, serogroup B meningococcal infection and shifts in epidemiology caused by vaccine introduction. In addition, much of the world’s population is unvaccinated. Therefore, improvements in management of acute bacterial meningitis are vital. In this review we attempt to summarise important advances in both prevention and treatment of acute bacterial meningitis.     

New therapies and vaccines for bacterial meningitis

Acute bacterial meningitis remains an important cause of morbidity and mortality worldwide. There have recently been major advances in the prevention of the major causes of bacterial meningitis following improvements in vaccinology. The success of immunisation against Haemophilus influenzae type b infection is being mirrored with serogroup C conjugated meningococcal vaccine and pneumococcal conjugate vaccine. However, there remain major challenges, notably, serogroup B meningococcal infection and shifts in epidemiology caused by vaccine introduction. In addition, much of the world's population is unvaccinated. Therefore, improvements in management of acute bacterial meningitis are vital. In this review we attempt to summarise important advances in both prevention and treatment of acute bacterial meningitis.     

Prevention of group B meningococcal disease by vaccination: a difficult task

New Zealand has embarked on an immunisation program to reduce the incidence of disease caused by serogroup B Neisseria meningitidis. Similar immunisation programs in Norway and South America have shown good efficacy in older vaccinees (ie, persons receiving vaccinations), but variable efficacy in younger vaccinees. Protective efficacy correlates well with the ability of the vaccine to stimulate a fourfold rise in serum bactericidal antibodies. Unfortunately, second and third doses of serogroup B N. meningitidis vaccines do not boost serum bactericidal antibody titres to very high levels; consequently protective efficacy wanes within a few years of immunisation. The overall outcome of the immunisation program will reflect both the immunogenicity of the vaccine and the uptake of the vaccine by the target population. The especially high incidence of meningococcal disease in Pacific and Maori children means that particular efforts will need to be made to reach these groups.     

Modeling future changes to the meningococcal serogroup C conjugate (MCC) vaccine program in England and Wales

The UK meningococcal serogroup C conjugate (MCC) vaccine program has successfully controlled serogroup C disease, due to high vaccine effectiveness and substantial herd immunity. However, children immunised at 2, 3 and 4 months of age receive only short-term direct protection and may be at risk of disease 15 months after vaccination. To investigate this we applied a mathematical model to predict the future epidemiology of serogroup C disease, with and without changes to the immunization schedule. Only a few cases of serogroup C disease were predicted to occur over the next few years because of persisting herd immunity, even without a change to the vaccine schedule. The inclusion of a booster dose is likely to improve the impact of the MCC program and reducing the number of doses in infancy will improve cost-effectiveness and create space in the schedule for the addition of other vaccines.     

Meningococcal disease and travel

Meningococcal disease continues to be a worldwide problem. This review examines the impact meningococcal disease has on international travel and vice versa the impact international travel has on the intercontinental spread of meningococci. The risk of meningococcal disease to the endemic population differs from that of travellers. The best documented risk of meningococcal disease among travellers has been in Hajj pilgrims for Mecca and Madina in Saudi Arabia. In response to the recent Hajj associated outbreak of W135 meningococcal disease, quadrivalent meningococcal vaccine (against serogroups A/C/Y/W135) became a visa requirement. In view of increasing worldwide reports of Y and W135 meningococcal disease, there should be a switch in recommendation from the bivalent (against A& C) to the quadrivalent vaccine for all travellers.     

Young-adult carriers of Neisseria meningitidis in Puglia (Italy): will the pattern of circulating meningococci change following the introduction of meningococcal serogroup C conjugate vaccines?

Studies of meningococcal carriage are essential in improving knowledge of the epidemiology of meningococcal disease. The aim of this study is to ascertain the carrier rate and the serogroups of Neisseria Meningitidis circulating in a sample of students from the University of Bari. The population consisted of university students from the University of Bari - School of Medicine, who were invited to take a nasopharyngeal swab. The swabs were plated on selective plate medium; cultural and MLST tests were performed. Of 583 university students 12 carriers were identified (2%). 9 isolates proved auto-agglutinable. The other strains belonged to serogroups B, W135 and Y. Auto-agglutinable strains belonged to different clonal complexes, of which ST-53 was the most common. Only one strain, that belonged to ST-23/cluster A3 clonal complex, could cause meningococcal disease. No type C serogroup strain was detected and this could be directly related to immunization policies that provided meningococcal serogroup C conjugate vaccines for newborns and adolescents. The changing pattern of circulating serogroups of Neisseria meningitidis in healthy carriers could support a new immunization strategy which could provide quadrivalent meningococcal conjugate vaccines to pre-adolescents and adults.     

基于B群脑膜炎奈瑟球菌候选抗原进行疫苗开发的研究进展

流行性脑脊髓膜炎（流脑）是一种由脑膜炎奈瑟球菌引发的严重呼吸道传染病。随着脑膜炎球菌多糖疫苗和多糖-蛋白质结合疫苗的应用,大部分于人群中广泛流行的致病性脑膜炎奈瑟球菌（血清A、C、W135、Y群）已得到了有效控制。然而,这也导致B群脑膜炎奈瑟球菌引发的流脑的占比增多。此文综述了目前已发现的B群脑膜炎球菌疫苗候选抗原,以及基于这些抗原已经获批和正在研发的B群脑膜炎球菌疫苗,以期帮助研究人员进行新型B群脑膜炎球菌疫苗的研发。     

Review of the cost effectiveness of immunisation strategies for the control of epidemic meningococcal meningitis

Outbreaks of meningococcal disease have caused devastation worldwide. Effective vaccines have not been used routinely, due to perceived limitations of the duration of effectiveness as well as immunogenicity when administered during infancy. Given the sporadic nature of outbreaks, the optimal use of these vaccines to control both short-term epidemic and endemic meningococcal disease has been the subject of much debate. Seven economic studies on the use of polysaccharide vaccination strategies help to highlight the relevant epidemiological and economic issues surrounding the decisions for their use. Five of these studies were based in Africa, the region where annual incidence rates can be several orders of magnitude greater than the rest of the world. These studies demonstrated that vaccination against meningococcal disease during outbreak situations is suboptimal given the inability to rapidly immunise populations in a timely fashion in resource-poor areas. However, depending on the disease incidence and the ability to deliver vaccines, the polysaccharide vaccine can be cost effective for preventive strategies when given prior to the start of outbreaks, either through presumptive vaccination or through a modified routine delivery strategy. Economic analyses of mass immunisation campaigns and modelled routine vaccination suggest that routine use of meningococcal vaccines for preventive strategies could be within the range of cost-effective public health interventions in those regions of the world where meningococcal disease is endemic. This includes the meningococcal belt of Africa, the Sahelian region.