The changing and dynamic epidemiology of meningococcal disease

The epidemiology of invasive meningococcal disease continues to change rapidly, even in the three years since the first Meningococcal Exchange Meeting in 2008. Control of disease caused by serogroup C has been achieved in countries that have implemented meningococcal C or quadrivalent meningococcal ACWY conjugate vaccines. Initiation of mass immunization programs with meningococcal A conjugate vaccines across the meningitis belt of Africa may lead to the interruption of cyclical meningococcal epidemics. A meningococcal B vaccination program in New Zealand has led to a decreased incidence of high rates of endemic serogroup B disease. Increases in serogroup Y disease have been observed in certain Nordic countries which, if they persist, may require consideration of use of a multiple serogroup vaccine. The imminent availability of recombinant broadly protective serogroup B vaccines may provide the tools for further control of invasive meningococcal disease in areas where serogroup B disease predominates. Continued surveillance of meningococcal disease is essential; ongoing global efforts to improve the completeness of reporting are required.     

The concept of "tailor-made", protein-based, outer membrane vesicle vaccines against meningococcal disease

Protein-based, outer membrane vesicle (OMV) vaccines have previously proven to be efficacious against serogroup B meningococcal disease in Norway and Cuba. Currently, a public health intervention is going on in order to control a serogroup B epidemic in New Zealand. The scale-up and standardization of vaccine production required for controlling the New Zealand epidemic has allowed the establishment of large-scale GMP manufacturing for OMV vaccines. The outcome of this will be licensing of the vaccine in New Zealand and possibly other countries. The availability of licensed OMV vaccines raises the question of whether such vaccines may provide the opportunity to control other outbreaks and epidemics. For instance, such a vaccine could control a localised outbreak of group B meningococci in Normandy, France. "Tailor-made" vaccines, focusing on the sub-capsular antigens may also be considered for use in sub-Saharan Africa for the prevention of the recurrent outbreaks by serogroups A and W135 meningococci. This assumption is based on the epidemiological observation that meningococcal outbreaks in Africa are clonal and are strikingly stable regarding their phenotypic characteristics.     

Vaccine prevention of meningococcal disease, coming soon?

The past century has seen the use of a number of vaccines for prevention and control of meningococcal disease with varied success. The use of polysaccharide vaccines for the control of outbreaks of serogroup C infections in teenagers and young adults and epidemic serogroup A disease has been established for 30 years and an effective protein-polysaccharide conjugate vaccine against serogroup C was introduced into the UK infant immunisation schedule in 2000. The next generation of these glycoconjugate vaccines will be on the shelf soon, eventually offering the prospect of eradication of serogroups A, C, Y and W135 through routine infant immunisation. Despite these exciting prospects, serogroup B meningococci still account for a majority of infections in industrialised nations but development of safe, immunogenic and effective serogroup B meningococcal vaccines has been an elusive goal. Outer membrane vesicle vaccines for B disease are already used in some countries, and will likely be used more widely in the next few years, but efficacy for endemic disease in children has so far been disappointing. However, the innovations arising from the availability of the meningococcal genome sequence, public and scientific interest in the disease and recent pharmaceutical company investment in development of serogroup B vaccines may have started the countdown to the end of meningococcal infection in children.     

Impact of vaccination during an epidemic of serogroup C meningococcal disease in Salvador, Brazil

To combat rising incidence of serogroup C meningococcal disease in the city of Salvador, Brazil, the Bahia state immunization program initiated routine childhood immunization with meningococcal C conjugate vaccine (MenC) in February 2010, followed by mass MenC vaccination of city residents 10-24 years of age from May through August 2010. We analyzed trends in incidence of reported cases of meningococcal disease and serogroup distribution among meningococcal isolates identified in hospital-based surveillance in Salvador from January 2000 to December 2011 and estimated vaccine effectiveness using the screening method. Annual incidence of serogroup C meningococcal disease increased from 0.1 cases per 100,000 population during 2000-2006 to 2.3 in 2009 and 4.1 in 2010, before falling to 2.0 per 100,000 in 2011. Estimated coverage of mass vaccination reached 80%, 67% and 41% among 10-14, 15-19 and 20-24 year olds, respectively. Incidence in 2011 was significantly lower than average rates in 2008-2009 among children <5 years, but reductions among 10-24 year olds were not significant. Among 10-24 year olds, a single dose of MenC vaccine was 100% effective (95% confidence interval, 79-100%) against serogroup C meningococcal disease. Low coverage in the population targeted for mass vaccination may have limited impact on ongoing transmission of serogroup C meningococcal disease despite high vaccine effectiveness.     

Effectiveness of a single dose of the quadrivalent meningococcal conjugate vaccine,MenACWY-CRM,in the Korean Armed Forces

Conjugate vaccines are widely used to overcome the disadvantages of polysaccharide vaccines in the prevention of meningococcal disease. However, limited studies have examined the clinical effectiveness of single-dose meningococcal quadrivalent conjugate vaccines in adults. We assessed the effectiveness of the meningococcal vaccination program in the Republic of Korea Armed Forces, since 2013. Following vaccination program implementation, meningococcal disease cases decreased from 0.52/100,000 to 0.06/100,000 and the number of deaths declined from four to zero. Two meningococcal cases that developed post-implementation were identified as serotype B and X. The effectiveness of single-dose conjugate vaccination in recruits, expressed as the incidence rate ratio, was 0.88 during a 19–23-month observation period. These results indicate that meningococcal infections can be prevented by single-dose administration of the quadrivalent conjugate vaccine in at-risk groups, such as soldiers, travelers, and students in dormitories. Continuous investigation is needed to determine serogroup change, including B serogroups.     

Surveillance for meningococcal disease and strategies for use of conjugate meningococcal vaccines in the United States

BACKGROUND: Neisseria meningitidis is a leading cause of bacterial meningitis in US; new capsular type-specific conjugate vaccines offer an opportunity for improved control of meningococcal disease. We evaluated the relative burdens of invasive meningococcal disease in US and examined the projected impact of various meningococcal conjugate vaccination strategies on rates of meningococcal disease. METHODS: Meningococcal disease incidence rates were determined from active, population-based surveillance in selected US areas. Models were created to determine impact of vaccination of infants, toddlers, adolescents or college students with meningococcal conjugate vaccines, with assumptions for vaccine coverage, efficacy and duration of protection. Although we examined possible conjugate vaccine formulations including serogroups A, C, Y and W-135, the final vaccine impact analysis excluded serogroups A and W-135. Outcome measures were cumulative meningococcal disease incidence, and incidence 10 years after initiating vaccination among 0-22-year-olds. RESULTS: In models of serogroup C+Y meningococcal conjugate vaccination of infants, toddlers and adolescents, the cumulative incidence of meningococcal disease was reduced by 54, 48 and 25%, respectively; the toddler strategy had the greatest impact per dose. After 10 years of routine meningococcal conjugate vaccination, meningococcal disease could be reduced by 50% and deaths by 64%. CONCLUSIONS: Use of meningococcal conjugate vaccine could markedly reduce meningococcal disease incidence. Our data, along with vaccine formulation and vaccination program considerations, will be important in determining the optimal choice of vaccination strategy.     

The Meningitis Vaccine Project

Epidemic meningococcal meningitis is an important public health problem in sub-Saharan Africa. Current control measures rely on reactive immunizations with polysaccharide (PS) vaccines that do not induce herd immunity and are of limited effectiveness in those under 2 years of age. Conversely, polysaccharide conjugate vaccines are effective in infants and have consistently shown an important effect on decreasing carriage, two characteristics that facilitate disease control. In 2001 the Meningitis Vaccine Project (MVP) was created as a partnership between PATH and the World Health Organization (WHO) with the goal of eliminating meningococcal epidemics in Africa through the development, licensure, introduction, and widespread use of conjugate meningococcal vaccines. Since group A Neisseria meningitidis (N. meningitidis) is the dominant pathogen causing epidemic meningitis in Africa MVP is developing an affordable (US$ 0.40 per dose) meningococcal A (Men A) conjugate vaccine through an innovative international partnership that saw transfer of a conjugation and fermentation technology to a developing country vaccine manufacturer. A Phase 1 study of the vaccine in India has shown that the product is safe and immunogenic. Phase 2 studies have begun in Africa, and a large demonstration study of the conjugate vaccine is envisioned for 2008-2009. After extensive consultations with African public health officials a vaccine introduction plan has been developed that includes introduction of the Men A conjugate vaccine into standard Expanded Programme on Immunization (EPI) schedules but also emphasizes mass vaccination of 1-29 years old to induce herd immunity, a strategy that has been shown to be highly effective when the meningococcal C (Men C) conjugate vaccine was introduced in several European countries. The MVP model is a clear example of the usefulness of a "push mechanism" to finance the development of a needed vaccine for the developing world.     

The challenge of post-implementation surveillance for novel meningococcal vaccines

Novel serogroup B meningococcal vaccines are currently in late stage development and may be used in mass immunisation campaigns over the coming years. This represents an exciting development in the prevention of childhood meningitis, however monitoring the impact of these vaccines on meningococcal disease epidemiology will provide significant challenges. Although designed to prevent serogroup B meningococcal disease the vaccine antigens are not serogroup specific, creating the potential for multiple definitions of vaccine effectiveness and vaccine failure.     

Considerations for controlling invasive meningococcal disease in high income countries

The development of conjugate vaccines has enabled the prevention and control of Neisseria meningitidis caused by serogroups A, C, W-135 and Y. Vaccines that provide protection against a broad number of serogroup B strains likely will be available soon to enable greater control of meningococcal disease in high income countries. We present an argument for adequate post-marketing surveillance to monitor epidemiological shifts and to provide a context for the safety and reactogenicity of serogroup B vaccines, including the newer recombinant vaccines. We also offer a series of recommendations to address possible concerns about vaccine safety.     

Impact of systematic vaccination with the antimeningococcal C conjugated vaccine in a health area in Andalusia

BACKGROUND: A retrospective longitudinal study of population incidence was made to assess the effectiveness of meningococcal serogroup C conjugate vaccine, after its mass introduction in children in the geographic area of a health district, measuring its population impact, and we have studied the state of the meningococcal disease. METHODS: Vaccine coverage in children born between 1991 and 2001, and rates of incidence in declared cases of meningococcal disease in seven epidemiological seasons (1997/98 to 2003/04) were calculated. The impact of vaccination against serogroup C meningitis was assessed comparing the average annual rates of previous and later seasons to the vaccination campaigns in population younger and older than 10, using the Fisher exact test. RESULTS: In all the study period, 109 cases of meningococcal disease were declared, of which 50 were of serogroup C meningococcal disease. Starting from 2000/2001 season the incidence of serogroup C disease decreased in the population below 10. In this age group, the annual average rate of post-vaccine seasons decreases in respect to pre-vaccine (from 8.2 to 2.0 per 100,000 inhabitants) showing a statistically significant difference. In the population above 10 years, this incidence reduction was not observed. In the study period, no case of vaccine failure was declared. CONCLUSIONS: The absence of vaccine failure and the impact observed on the incidence of serogroup C meningococcal disease in children under 10 suggests the effectiveness of this new conjugate vaccine, together with suitable vaccination conditions (vaccination schedule, high catch-up, etc.) which are developing in our health district.     

Invasive meningococcal disease and travel

The epidemiology of invasive meningococcal disease varies geographically and in time and the risk of acquiring the disease varies regionally, as well as with living conditions and behavior. An area, in which meningococcal disease outbreaks have frequently occurred, is the "African meningitis belt", where epidemics of meningococcal disease with a peak incidence as high as 100-800/100,000 population/year have been reported. Another risk factor is mass gatherings including the Islamic pilgrimage to Makkah (Mecca), where outbreaks of meningococcal disease have repeatedly occurred. The latest outbreaks occurred during the Hajj pilgrimages of 2000 and 2001, when a shift from serogroup A disease to serogroup W135 occurred. Vaccination against serogroups A, C, W-135 and Y with novel conjugate vaccines may help protect individuals and reduce the spread of bacterial carriage and disease. Individuals who should be vaccinated include travelers to epidemic or hyperendemic areas (as identified by international health authorities), travelers for Umra or Hajj (Hajj pilgrims), travelers to high risk countries or regions (African meningitis belt) during the dry season or countries in sub-Saharan Africa outside the meningitis belt (where outbreak of meningitis has been reported in the preceding 2-3 years), military recruits or deployed military personnel, immunocompromized travelers and high school and college students. This review presents the global epidemiology of meningococcal disease, and discusses prophylaxis options including meningococcal ACWY vaccines.     

Priorities for research on meningococcal disease and the impact of serogroup A vaccination in the African meningitis belt

For over 100 years, large epidemics of meningococcal meningitis have occurred every few years in areas of the African Sahel and sub-Sahel known as the African meningitis belt. Until recently, the main approach to the control of these epidemics has been reactive vaccination with a polysaccharide vaccine after an outbreak has reached a defined threshold and provision of easy access to effective treatment but this approach has not prevented the occurrence of new epidemics. Meningococcal conjugate vaccines, which can prevent meningococcal carriage and thus interrupt transmission, may be more effective than polysaccharide vaccines at preventing epidemics. Because the majority of African epidemics have been caused by serogroup A meningococci, a serogroup A polysaccharide/tetanus toxoid protein conjugate vaccine (PsA–TT) has recently been developed. Results from an initial evaluation of the impact of this vaccine on meningococcal disease and meningococcal carriage in Burkina Faso have been encouraging.     

Prospects and challenges with introduction of a mono-valent meningococcal conjugate vaccine in Africa

Epidemic meningococcal meningitis is a priority disease for prevention and control in Africa. The current World Health Organization (WHO) approach to the control of meningitis epidemics is based on early detection of cases and emergency vaccination of the population at risk with meningococcal polysaccharide (PS) vaccines. But this is a tall order for the developing nations of Africa where experts operate from an ineffective health system. Although the widespread use of meningococal polysaccharide vaccines has had a major and much appreciated public health impact on the disease it has not prevented epidemics of this dreaded infection. The current partnership between WHO and the PATH aims to develop, evaluate and introduce an appropriate and affordable meningococcal conjugate vaccine that could potentially provide for a means of preventing epidemic meningitis caused by N. meningitidis group A. In this paper, we review the prospects and challenges facing the introduction of the mono-valent conjugate vaccine in Africa.     

中国脑膜炎球菌疫苗预防接种专家共识

中国上市的脑膜炎球菌疫苗包括脑膜炎球菌多糖疫苗、脑膜炎球菌多糖结合疫苗和联合疫苗,不同生产企业的脑膜炎球菌多糖结合疫苗的免疫程序有所不同,给实际接种工作带来困扰。本共识结合国内外研究最新进展,基于流行性脑脊髓膜炎流行特征、脑膜炎奈瑟菌菌群分布以及中国脑膜炎球菌疫苗免疫原性和安全性等研究证据,提出脑膜炎球菌疫苗预防接种建议,供预防接种人员和疾病预防控制机构人员参考使用。     

A review of vaccine research and development: meningococcal disease

This paper reviews the current status of research and development of vaccines against meningococcal disease due to Neisseria meningitidis, a major cause of severe meningitis and septicemia with epidemic potential. While five serogroups (A, B, C, Y, and W135) are responsible for most of the disease, Group A remains unique in its ability to cause large scale epidemics mainly in Africa but also in Asia. The majority of cases in Europe and America are due to Groups B and C. The successful experience with Hib and pneumococcal conjugate vaccines has paved the way for the development of polysaccharide conjugate vaccines for the prevention of meningococcal disease. Widespread vaccination with Group C conjugate vaccines now in use in several European countries indicates that these vaccines are immunogenic, induce immunological memory, reduce colonization and provide herd immunity to the general population. A monovalent group A conjugate vaccine being developed at an affordable price, offers hope for the elimination of large epidemics in African countries. Multivalent (A, C, Y, W) conjugate vaccines are being developed, and one has already been licensed. However, effective global prevention of meningococcal disease will not be achievable without the development of a vaccine against Group B meningitis, for which outer membrane protein vaccines are under development.     

Can we defeat meningococcal disease in low and middle income countries?

The development of multivalent conjugate and protein-based meningococcal vaccines may make global control of meningococcal disease possible. However, achieving control of meningococcal disease in low and middle income countries will be challenging. In low income countries whose vaccination programmes receive financial support from the Global Alliance for Vaccination and Immunisation, the main challenge is lack of sufficient epidemiological information to allow rational decisions on vaccine introduction to be made and, in these countries, enhanced surveillance is needed. In middle income countries, financial challenges predominate. These could be met by demonstration of the cost effectiveness of new meningococcal vaccines and through the introduction of a tiered-pricing system.     

The impact of pre-existing antibody on subsequent immune responses to meningococcal A-containing vaccines

Major epidemics of serogroup A meningococcal meningitis continue to affect the African meningitis belt. The development of an affordable conjugate vaccine against the disease became a priority for World Health Organization (WHO) in the late 1990s. Licensing of meningococcal vaccines has been based on serological correlates of protection alone, but such correlates might differ in different geographical regions. If high pre-vaccination antibody concentrations/titers impacts on the response to vaccination and possibly vaccine efficacy, is not clearly understood. We set out to define the pre-vaccination Meningococcal group A (Men A) antibody concentrations/titers in The Gambia and study their impact on the immunogenicity of Men A containing vaccines.     

Emergence of serogroup X meningococcal disease in Africa: Need for a vaccine

Neisseria meningitidis is responsible for the seasonal burden and recurrent epidemics of meningitis in an area of sub-Saharan Africa known as the meningitis belt. Historically, the majority of the cases in the meningitis belt are caused by serogroup A meningococci. Serogroup C meningococci were responsible for outbreaks in the meningitis belt in the 1980s, while serogroup W (formerly W-135) has emerged as a cause of epidemic meningitis since 2000. Serogroup X meningococci have previously been considered a rare cause of sporadic meningitis, but during 2006–2010, outbreaks of serogroup X meningitis occurred in Niger, Uganda, Kenya,Togo and Burkina Faso, the latter with at least 1300 cases of serogroup X meningitis among the 6732 reported annual cases. While serogroup X has not yet caused an epidemic wave of the scale of serogroup A in 1996–1997 or serogroup W in Burkina Faso during 2002, the existing reports suggest a similar seasonal hyperendemicity and capacity for localised epidemics. Serogroup X incidence appears to follow a pattern of highly localised clonal waves, and in affected districts, other meningococcal serogroups are usually absent from disease. Currently, no licensed vaccine is available against serogroup X meningococci. Following the introduction of a monovalent serogroup A conjugate vaccine (MenAfriVac^®) in the meningitis belt and the upcoming introduction of pneumococcal conjugate vaccines, vaccine-based prevention of serogroup X may become a public health need. The serogroup X polysaccharide capsule is the most likely target for vaccine development, but recent data also indicate a potential role for protein-based vaccines. A multivalent vaccine, preferably formulated as a conjugate vaccine and covering at least serogroups A, W, and X is needed, and the efforts for vaccine development should be intensified.     

Development and characterisation of outer membrane vesicle vaccines against serogroup A Neisseria meningitidis

Neisseria meningitidis bacteria of serogroup A are causing recurring meningitis epidemics on the African continent. An outer membrane vesicle (OMV) vaccine against serogroup A meningococci made from a subgroup III serogroup A meningococcal strain was previously shown to induce antibodies with serum bactericidal activity (SBA) in mice. We have here further investigated the properties of OMV vaccines made from five different subgroup III serogroup A meningococcal strains grown in a synthetic medium with low iron content. In addition to the major outer membrane proteins (PorA, PorB, RmpM, Opa and OpcA), small amounts of the NadA, TdfH, Omp85, FetA, FbpA and NspA outer membrane proteins, as well as lipooligosaccharides, were detected in the vaccines. The OMV vaccines were used to immunise mice. Anti-meningococcal IgG antibodies in the mouse sera were analysed by immunoblotting and by enzyme-linked immunosorbent assay against OMVs, and against live meningococcal cells in SBA and a flow-cytometric assay. The vaccines induced antibodies with high SBA and opsonophagocytic activity. The strongest IgG responses were directed against PorA. Significant SBA responses were also observed against a subgroup III strain, which did not express PorA, whereas no SBA was observed against a clone IV-1 serogroup A strain. An OMV vaccine from serogroup A meningococci may be an alternative to polysaccharide and conjugate polysaccharide vaccines for Africa.