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).     

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.     

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 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.     

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.     

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.     

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.     

Safety and immunogenicity of a meningococcal (Groups A, C, Y, W-135) polysaccharide diphtheria toxoid conjugate vaccine in healthy children aged 2 to 10 years in Chile

Immune responses to meningococcal conjugate (Menactra; MCV-4) and plain polysaccharide (Menomune-A/C/Y/W-135; PSV-4) vaccines against serogroups A, C, Y, and W-135 were assessed in 220 of 1037 Chilean children aged 2 to 10 years participating in a comparative safety trial. Both vaccines were generally well tolerated. Geometric mean serum bactericidal antibody (SBA) titers 28 days postvaccination were comparable in both groups for all four serogroups. Seroconversion was evident in > 97% of MCV-4 and > 90% of PSV-4 vaccinees who tested seronegative at baseline. Menactra safely induced broad and robust immune responses against serogroups A, C, Y and W-135 in this population.     

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 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 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.     

A new vaccine concept: polysaccharide conjugate vaccines]

Polysaccharide-based vaccines such as the vaccines against Neisseiria meningitidis group A and C or Streptococcus pneumoniae have proved their efficacy in children and adults. Nevertheless they induce B cell mediated immunological response and therefore fail to protect infants. In the eighties appeared a new concept of Polysaccharide based vaccine for infants: Polysaccharide conjugate vaccines. Coupling polysaccharide to carrier protein transforms the T-independent antigen into T-dependant antigen. The first conjugate vaccines for the prevention of infections caused by Haemophilus influenzae type b were a success, with a 95% efficacy. A worldwide vaccination program might lead to the eradication of that bacterial disease. New vaccines are currently under development, the next conjugate vaccine should be one against Streptococcus pneumoniae. First published clinical data are very promising and confirmed the potential of the polysaccharide conjugate vaccine approach against bacterial infections.     

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.     

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。     

Serogroup C meningococcal conjugate vaccines: new preparations. Effective from age two months

(1) Two unconjugated polyoside vaccines are available in France for the prevention of meningococcal infections: Vaccine meningococcique A+C from Pasteur Vaccines (against serogroups A and C) and Menomune from Aventis Pasteur MSD (against serogroups A, C, Y and W-135). Neither vaccine is effective in children under the age of two years. (2) 2002 saw the arrival of two conjugated vaccines directed solely against serogroup C meningococci and designed to protect infants from two months of age. Meningitec, marketed by Wyeth-Lederlé, is adsorbed to aluminium phosphate. The other conjugate vaccine is adsorbed to aluminium hydroxide and marketed under two names: Meninvact (Aventis Pasteur MSD) and Menjugate (Socopharm). (3) Immunogenicity studies have shown three advantages of conjugate vaccines over polyoside vaccines, namely a serologic response from as early as two months of age; a higher antibody titre 6 months after vaccination; and a larger increase in the antibody titre after booster injections. (4) Two-year follow-up data on a mass vaccination campaign launched in the United Kingdom in 1999 with Meningitec and Menjugate show that both vaccines have short-term efficacy in infants, children and adolescents. There was about an 80% fall in the number of invasive infections due to group C meningococci among vaccines, no such fall among unvaccinated subjects of the same age, and no major increase in the incidence of infections due to other serogroups. The number of deaths due to documented meningococcal infection showed a similar fall. (5) Most known adverse effects of these conjugate vaccines are mild and similar to those of other standard vaccines. They do not appear to be more frequent than with standard vaccines. Severe allergic reactions have occasionally been observed. A few deaths have followed vaccination with these products but appear to have been coincidental. There is no evidence that the two conjugate vaccines differ in terms of adverse effects. (6) Meningitec (suspension for injection) is more convenient to use than Meninvact and Menjugate (powders for injection). (7) Unlike the other companies concerned, Aventis Pasteur MSD failed to provide us with any documentation on their vaccine. (8) In practice, when specific vaccination against serogroup C meningococci is required (for case contacts or in areas of high incidence), Meningitec is currently the vaccine of choice. If Meningitec stocks are inadequate to deal with an outbreak, the second-line choice is Menjugate.     

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.     

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.