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.     

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。     

Characterization of the key antigenic components and pre-clinical immune responses to a meningococcal disease vaccine based on Neisseria lactamica outer membrane vesicles

Serogroup B strains are now responsible for over 80% of meningococcal disease in the UK and no suitable vaccine is available that confers universal protection against all serogroup B strains. Neisseria lactamica shares many antigens with the meningococcus, except capsule and the surface protein PorA. Many of these antigens are thought to be responsible for providing cross-protective immunity to meningococcal disease. We have developed an N. lactamica vaccine using methods developed for meningococcal outer membrane vesicle (OMV) vaccines. The major antigenic components were identified by excision of 11 major protein bands from an SDS-PAGE gel, followed by mass spectrometric identification. These bands contained at least 22 proteins identified from an unassembled N. lactamica genome, 15 of which having orthologues in published pathogenic Neisseria genomes. Western blotting revealed that most of these bands were immunogenic, and antibodies to these proteins generally cross-reacted with N. meningitidis proteins. Sera from mice and rabbits immunized with either N. lactamica or N. meningitidis OMVs produced comparable cross-reactive ELISA titres against OMVs prepared from a panel of diverse meningococcal strains. Mice immunized with either N. meningitidis or N. lactamica OMVs showed no detectable serum bactericidal activity against the panel of target strains except N. meningitidis OMV sera against the homologous strain. Similarly, rabbit antisera to N. lactamica OMVs elicited little or no bactericidal antibodies against the panel of serogroup B meningococcal strains. However, such antisera did mediate opsonophagocytosis, suggestingthat this may did mediate opsonophagocytosis, suggesting that this may be a mechanism by which this vaccine protects in a mouse model of meningococcal bacteraemia.     

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.     

Prospects offered by genome studies for combating meningococcal disease by vaccination

Meningococcal disease was first recognised and Neisseria meningitidis isolated as the causative agent over 100 years ago, but despite more than a century of research, attempts to eliminate this distressing illness have so far been thwarted. The main problem lies in the fact that N. meningitidis usually exists as a harmless commensal inhabitant of the human nasopharynx, the pathogenic state being the exception rather than the norm. As man is its only host, the meningococcus is uniquely adapted to this ecological niche and has evolved an array of mechanisms for evading clearance by the human immune response. Progress has been made in combating the disease by developing vaccines that target specific pathogenic serogroups of meningococci. However, a fully comprehensive vaccine that protects against all pathogenic strains is still just beyond reach. The publication of the genome sequences of two meningococcal strains, one each from serogroups A and B and the imminent completion of a third illustrates the extent of the problems to be overcome, namely the vast array of genetic mechanisms for the generation of meningococcal diversity. Fortunately, genome studies also provide new hope for solutions to these problems in the potential for a greater understanding of meningococcal pathogenesis and possibilities for the identification of new vaccine candidates. This review describes some of the approaches that are currently being used to exploit the information from meningococcal genome sequences and seeks to identify future prospects for combating meningococcal disease.     

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: 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.     

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.     

Meningococcal vaccine against serogroups A, C, Y and W-135: new preparation. Encouraging immunogenicity studies

(1) Prevention of meningococcal meningitis is based on vaccination, and chemoprophylaxis in case contacts. The five main meningococcal serogroups known to be pathogenic for humans are A, B, C, Y and W-135. Their geographic distribution is variable. In France, two-thirds of cases are due to serogroup B, which is poorly immunogenic and for which there is no vaccine; the only licensed vaccine offers protection solely against serogroups A and C. (2) A meningococcal polysaccharide vaccine directed against serogroups A, C, Y and W-135 has been granted temporary authorization for use by pilgrims to Mecca and for case contacts. (3) The vaccine elicits antibodies against the four serogroups in most adults, at least in the short term. It is poorly immunogenic in children under two years of age, especially against serogroup C. (4) The preventive efficacy of the vaccine against meningitis due to serogroups Y and W-135 is not known, and few data are available on serogroups A and C. Protection has not been shown beyond two years after vaccination. At one year the vaccine provides about 95% protection against serogroup A and 65% against serogroup C. (5) Systemic and local reactions to vaccination with the four-valent vaccine appear to be acceptable. (6) In practice, for want of anything better, the four valent vaccine (A, C, Y and W-135) is better than the two-valent vaccine (A+C) for protecting pilgrims to Mecca and contacts of patients with serogroup A, C, Y or W-135 meningococcal infection.     

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.     

Meningococcal disease: the advances and challenges of meningococcal disease prevention

Vaccination as a means to prevent meningococcal disease caused by Neisseria meningitidis is critical given the abrupt onset and rapid progression of this disease. Five serogroups--A, B, C, W-135, and Y--are responsible for the majority of cases. In developed countries, infants have the greatest risk of disease, with a smaller secondary peak observed in late adolescence. Vaccines utilizing the polysaccharide capsule are poorly immunogenic in young children but can reduce the incidence of meningococcal carriage in high risk groups. In contrast, protein conjugate vaccines to polysaccharide capsules A, C, W-135, and Y have broadened the population protection from disease but their effect on meningococcal carriage and transmission is yet unknown except for monovalent meningococcal C conjugate that has been shown to reduce carriage. Challenges remain in providing direct protection to infants and protection against meningococcal B disease. To date, outer membrane vesicle vaccines have been used to control meningococcal B disease in epidemic settings and vaccine candidates against subcapsular antigens are in development, but a vaccine that confers long-lasting protection is unavailable.     

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.     

Strategies for development of universal vaccines against meningococcal serogroup B disease: the most promising options and the challenges evaluating them

A vaccine inducing protection against most of the circulating variants of serogroup B meningococcal strains is not yet available. A number of plausible options are currently under investigation. A conjugate vaccine based on a modified capsular polysaccharide might well work, but has safety concerns from molecular mimicry between group B sialic acid and human tissue. Recently, however, the group B capsule has been shown to contain de-N-acetyl sialic acid residues that do not cross react with normal host tissues and can then be the target of bactericidal antibodies. Potentially, this polysaccharide structure could form the basis of a safe and protective group B vaccine. Outer membrane vesicles (OMVs) from Neisseria lactamica avoid the immunodominant and highly strain specific immune response against the PorA protein, and are reported to elicit cross reactive protection in mice against lethality from challenge with meningococcal group B bacteria. However, the serum antibody responses lack bactericidal activity, and the mechanisms of protection are unknown. A number of universal, cross-reactive antigens have been identified through "reverse vaccinology" and successfully tested as recombinant protein vaccines. Promising results have also been demonstrated using OMV vaccines prepared from strains engineered for upregulation of conserved, cross-reactive antigens. This approach takes advantage of experience gained with conventional wild-type OMV vaccines and the large number of new antigens identified through sequencing the genome of N. meningitidis. Initial studies show that the traditional use of detergents to decrease toxicity by extraction of lipopolysaccharides (LPS) should, if possible, be omitted in order to avoid extraction of important lipoproteins. In the absence of detergent extraction, clinical OMV formulations with acceptable toxicity may still be achieved by constructing vaccine production strains with genetically detoxified LPS. Thus, a MenB vaccine might be designed based on non-cross-reactive capsular antigens, OMV vaccines from genetically modified strains, recombinant proteins or a combination of these approaches. Given all of the recent data available and experience gained, the possibility for development of a universal vaccine for prevention of group B meningococcal disease looks promising. For evaluation of vaccine formulations relying on cross-reactive proteins, selection of strains for representation of the global epidemiological situation will be of outmost importance. Defining criteria for establishing and revising such strain collections is currently ongoing and will be a key element in developing and evaluating new protein based vaccines in the time to come.     

History of Meningococcal Outbreaks in the United States: Implications for Vaccination and Disease Prevention

Invasive meningococcal disease caused by Neisseria meningitidis presents a significant public health concern. Meningococcal disease is rare but potentially fatal within 24 hours of onset of illness, and survivors may experience permanent sequelae. This review presents the epidemiology, incidence, and outbreak data for invasive meningococcal disease in the United States since 1970, and it highlights recent changes in vaccine recommendations to prevent meningococcal disease. Relevant publications were obtained by database searches for articles published between January 1970 and July 2015. The incidence of meningococcal disease has decreased in the United States since 1970, but serogroup B meningococcal disease is responsible for an increasing proportion of disease burden in young adults. Recent serogroup B outbreaks on college campuses warrant broader age‐based recommendations for meningococcal group B vaccines, similar to the currently recommended quadrivalent vaccine that protects against serogroups A, C, W, and Y. After the recent approval of two serogroup B vaccines, the Advisory Committee on Immunization Practices first updated its recommendations for routine meningococcal vaccination to cover at‐risk populations, including those at risk during serogroup B outbreaks, and later it issued a recommendation for those aged 16–23 years. Meningococcal disease outbreaks remain challenging to predict, making the optimal disease management strategy one of prevention through vaccination rather than containment. How the epidemiology of serogroup B disease and prevention of outbreaks will be affected by the new category B recommendation for serogroup B vaccines remains to be seen.     

Vaccines against polysaccharide antigens

Encapsulated bacteria such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae serogroup B (Hib) are a major cause of disease worldwide. Vaccine development against these organisms has targeted their capsular polysaccharides (CPS), as anti-capsular antibodies often protect against disease. The capsular polysaccharide vaccines that have been available against these organisms are neither immunogenic nor protective in young children and certain immunocompromised individuals. In general, polysaccharide (PS) antigens elicit a T-independent immune response, characterized by lack of memory, and poor immunogenicity at the extremes of life. Efforts to overcome the poor immunogenicity of CPS vaccines have led to development of conjugate vaccines. By conjugating CPS to carrier proteins it is possible to induce a T-dependent immune response against these antigens. Although conjugate vaccines have been successful against Hib disease, their applicability to multi-serotype/serogroup pathogens like the pneumococcus or the meningococcus is questioned. As a result, alternative vaccines including (1) surface proteins conserved across serotypes/serogroups, (2) peptides that mimic PS antigens and (3) DNA vaccines are presently under investigation. This review will highlight the potential and limitations of both CPS and CPS-conjugate vaccines against encapsulated bacteria as well as alternative strategies against PS antigens.     

广东省流行性脑脊髓膜炎流行菌群变化趋势分析

目的研究流行性脑脊髓膜炎（流脑）流行菌群的变迁趋势。方法对广东省1966—2009年分离的656株流脑菌株的血清群构成进行分析。结果656株流脑菌株中,A群占24％、B群占47％、C群占9％,其它群占20％。1966—2001年的447株流脑菌株中,A群占22％、B群占46％、C群占6％,其它群占26％;2002—2009年的209株流脑菌株中,A群占28％、B群占53％、c群占13％,其它群占6％。A群流脑病人来源菌株比例由85％下降至47％,B群流脑病人来源菌株比例由15％上升至28％,c群流脑病人来源菌株比例由0％上升至22％。健康人群鼻咽部携带C群流脑菌株的比例由7％上升至11％,A群由9％上升至24％,B群由53％上升至58％。结论广东省流脑病人及健康人群携带菌株中,C群、B群流脑菌株的比例呈上升趋势,流脑流行菌群正在发生从A群到C群、B群的变化。     

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).