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 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 carriage among local inhabitants during the pilgrimage 2000-2001

The first international outbreak of Neisseria meningitidis serogroup W135 occurred in 2000, in direct association with the annual Hajj in Saudi Arabia. In anticipation of the following Hajj, we conducted a survey of oropharyngeal carriage rates of N. meningitidis both pre- and post-pilgrimage in the King Khalid National Guard Hospital (KKNGH) employees preparing to attend the Hajj. These KKNGH employees were native to the Mecca-Jeddah area. Pre-Hajj throat cultures were obtained 1 week prior to Hajj, and post-Hajj cultures within 10 days after completing the Hajj pilgrimage. A total of 327 throat culture samples were collected from 218 persons. Overall meningococcal carriage rate was found to be 4.7%. Serogroup W135 accounted for 40% of all recovered pre-Hajj strains of N. meningitidis. Only one post-Hajj sample was positive for N. meningitidis W135. This high rate of colonization with N. meningitidis serogroup W135 indicates this strain predominates amongst the population indigenous to the Mecca-Jeddah area. This 'nidus' of N. meningitidis W135 is a potential reservoir for future outbreaks. More worrying, there is real risk of future W135 endemicity in this vulnerable local population. These preliminary findings warrant larger surveillance studies examining both transmission and carrier rate acquisition of N. meningitidis in the Mecca-Jeddah area. These vital data are needed to curb further epidemic outbreaks during future Hajj pilgrimages.     

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.     

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。     

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 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.     

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.     

火箭免疫电泳法定量检测4价脑膜炎球菌多糖疫苗中C群脑膜炎球菌多糖含量的方法学验证

目的 验证用火箭免疫电泳法(rocket immunoelectrophoresis,R1E)检测4价脑膜炎球菌多糖疫苗(tetravalent serogroup A／C／W135／Y meningDcoccal polysaccharide vaccine,MPV4)中C群多糖含量的可靠性。方法 以系列浓度的C群多糖溶液为标准,采用RlE对MPV4中C群多糖含量迸行重复测定。结果 最佳线性范围为30～86 mg／L,相关系数(r)均大于0.985;MPV4与C群多糖参比品的剂量反应曲线之间具有良好的平行性;在精密度试验中,试验内CV为6.08％～8.07％,试验间Cy为7.24％～9.19％;A、W135和Y群多糖及乳糖不引起非特异性免疫反应。结论 本法的线性、精密度和专属性均符合验证要求,可作为定量检测MPV4中C群多糖含量的方法。     

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.     

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.     

Safety and immunogenicity of a tetravalent meningococcal serogroups A, C, W-135 and Y conjugate vaccine in adolescents and adults

The highest incidence of invasive meningococcal disease is in young children, with a second peak in adolescents/young adults. All five major disease-causing serogroups (A, B, C, W-135 and Y) have been described in Asia. Immunogenicity and safety of the investigational meningococcal ACWY-tetanus toxoid conjugate vaccine (ACWY-TT, GlaxoSmithKline Biologicals) was evaluated in healthy, meningococcal conjugate vaccine-na?ve adolescents in the Philippines, India and Taiwan. 1025 adolescents were randomized (3:1) to receive one dose of ACWY-TT or tetravalent ACWY polysaccharide vaccine (Mencevax?, Men-PS). Serum bactericidal activity using rabbit complement (rSBA) was measured. Local and systemic adverse reactions were recorded for 4 days. Safety data were pooled with results from a second, similarly designed study in adults for evaluation of grade 3 systemic events. The pre-specified immunogenicity criterion for non-inferiority to Men-PS was met. One month post-vaccination, ≥85.4%-97.1% had a vaccine response (post-titre ≥1:8 in initially seronegative and ≥4-fold increase in seropositive), versus 78.0%-96.6% after Men-PS, against each vaccine serogroup. Exploratory comparisons showed statistically significantly higher post-vaccination rSBA geometric mean titres against all serogroups following ACWY-TT versus Men-PS. Exploratory analysis showed no statistically significant differences between groups in grade 3 general symptoms; however, the statistical criterion for non-inferiority between pooled treatment groups in terms of the ratio of incidences of grade 3 general symptoms was not demonstrated. No SAEs were related to vaccination. ACWY-TT was immunogenic in Asian adolescents with a reactogenicity profile that was clinically acceptable and similar to that of licensed Men-PS. The results of this study indicate that ACWY-TT could be used as a third conjugate vaccine in the protection of adolescents against meningococcal disease.     

Bacterial meningitis: the impact of vaccination

Acute bacterial meningitis remains an important cause of morbidity and mortality in children. Children <2 years of age are particularly susceptible to infection with encapsulated bacteria due to their immature response to polysaccharide antigens. Conjugate vaccines, which induce T cell memory, can provide immunological protection for these children. The Haemophilus influenzae type b (Hib) conjugate vaccine was the first such vaccine to become available. The efficacy of the vaccine has been quoted as being 98%. Its introduction was followed by a dramatic decrease in the incidence of all invasive Hib disease, including meningitis. This reduction was in part due to the ability of these vaccines to reduce nasopharyngeal carriage of the organism and thereby induce herd immunity. Different Hib vaccines use a variety of protein carriers and differ in their immunogenicity and efficacy. The most suitable vaccine needs to be determined according to the local epidemiology of Hib disease. Commercial combination vaccines may lead to lower antibody levels. A recent increase in the incidence of Hib disease in the UK highlights the importance of continued surveillance and the need for booster vaccinations to ensure continued protection. Conjugate vaccines to Streptococcus pneumoniae and Neisseria meningitidis have been developed. The introduction of a pneumococcal conjugate vaccine in the US has led to a decrease in the rate of infection by nearly 60% in children <5 years of age. A reduction in pneumococcal carriage may also modify disease epidemiology. The UK introduced the conjugate meningococcal C vaccine into its infant schedule with a corresponding reduction in N. meningitidis group C disease. A recent decrease in the effectiveness of the vaccine, however, suggests a booster may be necessary in the future. Our present understanding of the immunology of conjugate vaccines is far from complete. Developed countries have introduced conjugate vaccines into their immunisation schedules to prevent bacterial meningitis; however, their high cost precludes their use in many developing countries. Progress needs to be made in order to get these highly effective vaccines to those areas that need them.     

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.     

Meningococcal vaccine development: a novel approach

Neisseria meningitidis is a major world-wide cause of meningitis. Effective capsular polysaccharide (CPS) vaccines that elicit CPS-specific bactericidal (BC) antibodies were previously developed and licensed to protect against meningococcal disease. However, due to their T-cell independent character, CPS vaccines are useless in infants and do not provide immunological memory or long-lasting protection in adults. CPS-protein conjugate vaccines are being developed to improve and broaden vaccine efficacy by creating T-cell dependent antigens. However, group B meningococci (GBM) are responsible for nearly half of meningococcal disease and possess a CPS, composed of polysialic acid, that is poorly immunogenic. N-propionyl (NPr) modification of the GBM polysaccharide (GBMP) has enhanced its immunogenicity, but BC antibodies are not induced at high levels, even when conjugated to conventional protein carriers, unless adjuvants stronger than aluminium hydroxide are used. We have chosen to couple the NPr-GBMP by reductive amination to a recombinant GBM class 3 porin (rPorB), which we have shown to modulate the immune response in animals towards the production of CPS-specific BC antibodies. We have also combined this conjugate with similar CPS-rPorB conjugates for groups A and C meningococci to form a trivalent A/B/C conjugate vaccine. This trivalent meningococcal vaccine has been shown to be safe and highly immunogenic in mice and non human primates, generating CPS-specific BC antibodies for each of the 3 major serogroups, which should provide world-wide protection against meningococcal disease.     

W135 meningococcal carriage in association with the Hajj pilgrimage 2001: the Singapore experience

An international outbreak among pilgrims returning from the Hajj (pilgrimage to Mecca) and their close contacts was caused by W135 Neisseria meningitidis. In Singapore, this strain is a new emerging problem, clearly associated with this outbreak. We investigated the extent of transmission of N. meningitidis in Hajj pilgrims and their contacts, in order to provide evidence for developing a rational public health policy. We found a high acquisition rate of W135 N. meningitidis in Singaporean pilgrims during the Hajj with substantial transmission to their household contacts. These findings would support a policy of eradication of pharyngeal carriage in returning pilgrims to prevent introduction and dissemination of meningococci.     

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.     

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.