Conjugate vaccine introduction in the African meningitis belt: meeting surveillance objectives

The epidemiology of bacterial meningitis will change with introduction of meningococcal and pneumococcal conjugate vaccines in the African meningitis belt. The principal objectives of surveillance are to evaluate the impact of vaccination, to detect and investigate epidemics and provide material for research. The capacity of existing surveillance activities in the meningitis belt to meet these objectives varies due to infrastructural and financial constraints. Impact assessment of conjugate vaccine against meningococcal serogroup A will be limited to comparing incidence trends from a few surveillance sites with data obtained before vaccine introduction and to comparing trends in the incidence of suspected cases or localised epidemics in most other settings. The timeliness of detection of epidemics and identification of epidemic meningococcal serogroups could be improved in most countries by analysing suspected case data in health centre level resolution and by investigating outbreaks with mobile teams. For research and impact assessment of pneumococcal conjugate vaccines, several surveillance sites covering at least 0.5 million inhabitants should be maintained which undertake exhaustive case finding and systematic laboratory confirmation of meningitis and pneumonia. Molecular diagnostics will facilitate surveillance in remote areas, but the available techniques should be evaluated for diagnostic performance in the field and long‐term sustainability.     

Prevention of bacterial meningitis: an overview of Cochrane systematic reviews

Acute bacterial meningitis (ABM) is an acute inflammation of leptomeninges caused by bacteria, and has a case fatality rate of 10-30%. Prevention strategies, such as vaccination and prophylactic antibiotics, can prevent ABM and have substantial public health impact by reducing the disease burden associated with it. The aim of this paper is to summarize the main findings from Cochrane systematic reviews that have considered the evidence for measures to prevent ABM. We assessed the evidence available in the Cochrane Library. We found five Cochrane reviews focused on the prevention of ABM; three with use of vaccination and two with prophylactic antibiotics. Polysaccharide serogroup A vaccine is strongly protective for the first year, against serogroup A meningococcal meningitis in adults and children over 5 years of age. Meningococcal serogroup C conjugate (MCC) vaccine is safe and effective in infants. Haemophilus influenzae type b (Hib) vaccine is safe and effective against Hib-invasive disease at all ages. Ceftriaxone, rifampicin and ciprofloxacin are the most effective prophylactic antibiotics against Neisseria meningitidis. There is sufficient evidence to use polysaccharide serogroup A vaccine to prevent serogroup A meningococcal meningitis, MCC conjugate vaccines to prevent meningococcal C meningitis and Hib conjugate vaccine to prevent Hib infections. More studies are needed to evaluate the effects of Hib conjugate vaccine on mortality. Further, studies are required to compare the relative effectiveness of ceftriaxone, ciprofloxacin and rifampicin in chemoprophylaxis against meningococcal infection.     

CRM197-conjugated serogroup C meningococcal capsular polysaccharide, but not the native polysaccharide, induces persistent antigen-specific memory B cells

Neisseria meningitidis is one of the leading causes of bacterial meningitis and septicemia in children. Vaccines containing the purified polysaccharide capsule from the organism, a T cell-independent antigen, have been available for decades but do not appear to provide protection in infancy or immunologic memory as measured by antibody responses. By contrast, T cell-dependent serogroup C protein-polysaccharide conjugate vaccines protect against serogroup C meningococcal disease from infancy onward and prime for immunologic memory. We compared the magnitude and kinetics of plasma cell and memory B-cell responses to a meningococcal plain polysaccharide vaccine and a serogroup C glycoconjugate vaccine in adolescents previously primed with the conjugate vaccine. Plasma cell kinetics were similar for both vaccines, though the magnitude of the response was greater for the glycoconjugate. In contrast to the glycoconjugate vaccine, the plain polysaccharide vaccine did not induce a persistent immunoglobulin G (IgG) memory B-cell response. This is the first study to directly show that serogroup C meningococcal glycoconjugate vaccines induce persistent production of memory B cells and that plain polysaccharide vaccines do not, supporting the use of the conjugate vaccine for sustained population protection. Detection of peripheral blood memory B-cell responses after vaccination may be a useful signature of successful induction of immunologic memory during novel vaccine evaluation.     

Systematic review: Impact of meningococcal vaccination on pharyngeal carriage of meningococci

Objective To investigate the effect of meningococcal vaccines on pharyngeal carriage of meningococci. Methods Systematic review. MEDLINE and EMBASE were searched for relevant studies. Controlled trials and observational studies which used comparison groups or compared carriage rates before and after vaccination were included in the review. Results Twenty‐nine studies satisfied the inclusion criteria. Twenty‐five studies reported the effect of a polysaccharide vaccine, one the effect of a serogroup C conjugate vaccine and three the impact of serogroup B outer‐membrane vaccines on overall and/or serogroup‐specific meningococcal carriage rates. Ten studies of meningococcal polysaccharide vaccines found reduced serogroup‐specific carriage; seven of these focussed on high‐risk groups and had a short follow‐up period. Only one of five studies of civilian populations in Africa showed a significantly reduced carriage. Many studies had methodological shortcomings. The one study which assessed the effect of a meningococcal conjugate vaccine on carriage showed a significant impact. Three studies of serogroup B outer‐membrane protein vaccines showed no effect on carriage. Conclusions A few well‐designed trials of the impact of meningococcal vaccines on carriage have been undertaken. Such studies should be an essential component of the evaluation of new meningococcal vaccines, particularly those introduced to control epidemic meningococcal disease in Africa.     

Meningococcal disease and control in China: Findings and updates from the Global Meningococcal Initiative (GMI)

The Global Meningococcal Initiative (GMI) is a global expert group, including scientists, clinicians and public health officials from a wide range of specialities. The goal of the GMI is to prevent meningococcal disease worldwide through education, research, and co-operation. The Chinese GMI roundtable meeting was held in June 2017. The GMI met with local experts to gain insight into the meningococcal disease burden in China and current prevention and vaccination strategies in place. China experienced five epidemics of serogroup A meningococcal disease (MenA) between 1938 and 1977, with peak incidence of 403/100,000 recorded in 1967. MenA incidence rates have significantly declined following the universal introduction of the MenA polysaccharide vaccine in China in the 1980s. Further, surveillance data indicates changing meningococcal epidemiology in China with the emergence of new clones of serogroup B from serogroup C clonal complex (cc) 4821 due to capsular switching, and the international spread of serogroup W cc11. The importance of carriage and herd protection for controlling meningococcal disease was highlighted with the view to introduce conjugate vaccines and serogroup B vaccines into the national immunization schedule. Improved disease surveillance and standardized laboratory techniques across and within provinces will ensure optimal epidemiological monitoring.     

Meningococcal disease: risk for international travellers and vaccine strategies

International travel and migration facilitate the rapid intercontinental spread of meningococcal disease. Serogroup A and, less so serogroup C, have been responsible for epidemics in the past (mainly in Africa). In recent years, W135 has emerged (first in Saudi Arabia, then in West Africa) as a serogroup that requires attention. Serogroups X and Y are infrequent, but associated with slowly rising trends. There are significant variations in the incidence of meningococcal disease and the distribution of serogroups responsible for meningococcal disease, both geographically and with time. Vaccine strategies need to address this variation, and broad coverage against all serogroups for which vaccines are currently available should be offered to travellers. Tetravalent polysaccharide meningococcal vaccines are limited by their poor immunogenicity in small infants and by the lack of long-term protection. In contrast, the novel tetravalent conjugate vaccine that is currently only available in North America is immunogenic in young infants, induces long-term protection and reduces nasopharyngeal carriage. The tetravalent conjugate meningococcal 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 travellers because the duration of protection is longer and it eliminates the problem of immune hyporesponsiveness of serogroup C with repeated dosing. Current vaccine recommendations are to vaccinate all Hajj pilgrims, all travellers to areas with current outbreaks, travellers to the SubSaharan meningitis belt, and individuals with certain medical conditions.     

Impact of meningococcal serogroup C conjugate vaccines on carriage and herd immunity

BACKGROUND: In 1999, meningococcal serogroup C conjugate (MCC) vaccines were introduced in the United Kingdom for those under 19 years of age. The impact of this intervention on asymptomatic carriage of meningococci was investigated to establish whether serogroup replacement or protection by herd immunity occurred. METHODS: Multicenter surveys of carriage were conducted during vaccine introduction and on 2 successive years, resulting in a total of 48,309 samples, from which 8599 meningococci were isolated and characterized by genotyping and phenotyping. RESULTS: A reduction in serogroup C carriage (rate ratio, 0.19) was observed that lasted at least 2 years with no evidence of serogroup replacement. Vaccine efficacy against carriage was 75%, and vaccination had a disproportionate impact on the carriage of sequence type (ST)-11 complex serogroup C meningococci that (rate ratio, 0.06); these meningococci also exhibited high rates of capsule expression. CONCLUSIONS: The impact of vaccination with MCC vaccine on the prevalence of carriage of group C meningococci was consistent with herd immunity. The high impact on the carriage of ST-11 complex serogroup C could be attributed to high levels of capsule expression. High vaccine efficacy against disease in young children, who were not protected long-term by the schedule initially used, is attributed to the high vaccine efficacy against carriage in older age groups.     

Meningococcal disease in the Middle East and North Africa: an important public health consideration that requires further attention

This paper reviews the epidemiological data describing meningococcal disease in the Middle East and North Africa (MENA). While meningococcal disease remains an important cause of endemic and epidemic disease in many MENA countries, existing published epidemiological data appear limited, fragmented, and collected via disparate methodologies. Children aged 5 years and younger are predominantly affected, though outbreaks of the disease often affect older age groups. Whilst serogroup A remains a main cause of meningococcal disease in the region, cases of serogroup B, W-135, and Y have been increasingly reported over the last two decades in some countries. The Hajj pilgrimage is a key factor influencing outbreaks and transmission, and the use of vaccines has minimized the effects on the home countries of the pilgrims and has decreased global dissemination of disease. Wider use of available polyvalent meningococcal conjugate vaccines may provide broader protection against the range of serogroups causing disease or posing a threat in the region. In addition, strengthening regional surveillance systems and regularly publishing reports with reliable estimates of disease incidence, carriage, disease-related mortality, and sequelae may facilitate the development of appropriate interventions and public health strategies regarding meningococcal disease within the region.     

Meningococcal disease caused by Neisseria meningitidis: epidemiological, clinical, and preventive perspectives

Bacterial meningitis constitutes a significant global public health problem. In particular, Neisseria meningitidis continues to be a public health problem among human populations in both developed and developing countries. Meningococcal infection is present as an endemic and an epidemic disease. Meningococcal disease is manifested not only as meningitis, but also as meningococcemia. The latter is usually fulminant. The global persistence of N. meningitidis is due to the significant number of carriers and the dynamics of transmission and disease. Approximately 500 million people worldwide are carriers of the bacterium in their nasopharynx. Multiple factors have been identified that predispose to the transmissibility of N. meningitidis, including active or passive inhalation tobacco smoking, upper viral respiratory tract infections, drought seasons, and overcrowding. These factors explain the frequent occurrence of outbreaks in military barracks, schools, prisons, and dormitories. Some of the determinants of invasiveness of the bacteria include nasopharyngeal mucosal damage in colonized individuals, virulence of the strains, absence of bactericidal antibodies, and deficiencies of the complement system. During both endemic and epidemic scenarios of meningococcal disease, control measures should include treating the cases with appropriate antimicrobial therapy (penicillin, ceftriaxone, or chloramphenicol); providing chemoprophylactic drugs to contacts (rifampin or ciprofloxacin), and close observation of contacts. Nevertheless, the key to effective control and prevention of meningococcal disease is immunoprophylaxis. Available vaccines include the polysaccharide monovalent, bivalent (serogroups A, C), or tetravalent (A, C, Y, W-135 serogroups) vaccines; conjugate vaccine (serogroup C); and the combined vaccine with outer membrane proteins and polysaccharide (serogroups B, C). Due to a recent increase in case reporting of serogroup C N. meningitidis in Mexico, we have developed a national response strategy that includes availability of vaccines and medications for chemoprophylaxis. This review aims at providing health care workers with updated information regarding the epidemiological, clinical, and preventive aspects of meningococcal disease. The English version of this paper is available at: http://www.insp.mx/salud/index.html.     

Meningococcal carriage in the African meningitis belt

In the African meningitis belt, epidemics of meningococcal disease occur periodically, although unpredictably, every few years. These epidemics continue to cause havoc but new efforts to control the disease, through the use of conjugate vaccines, are being made. Conjugate vaccines are likely to reduce meningococcal carriage, thus generating herd immunity, but to understand their potential impact we need to know more about the epidemiology of meningococcal carriage in Africa. We review published studies of meningococcal carriage in the African meningitis belt. A wide range of carriage prevalences has been reported, from 3% to over 30%, and the serogroup distribution has been variable. Factors influencing carriage include age, contact with a case, and the epidemic/endemic situation; however, season and immunisation with polysaccharide vaccine have little effect. Since the dynamics of carriage within a population are complex, longitudinal carriage studies are of great value; however, few such studies have been done. Carefully designed carriage studies are needed to measure and interpret the impact of meningococcal group A conjugate vaccines in Africa.     

Capsule switching of Neisseria meningitidis

The different sialic acid (serogroups B, C, Y, and W-135) and nonsialic acid (serogroup A) capsular polysaccharides expressed by Neisseria meningitidis are major virulence factors and are used as epidemiologic markers and vaccine targets. However, the identification of meningococcal isolates with similar genetic markers but expressing different capsular polysaccharides suggests that meningococcal clones can switch the type of capsule they express. We identified, except for capsule, isogenic serogroups B [(α2→8)-linked polysialic acid] and C [(α2→9)-linked polysialic acid] meningococcal isolates from an outbreak of meningococcal disease in the U. S. Pacific Northwest. We used these isolates and prototype serogroup A, B, C, Y, and W-135 strains to define the capsular biosynthetic and transport operons of the major meningococcal serogroups and to show that switching from the B to C capsule in the outbreak strain was the result of allelic exchange of the polysialyltransferase. Capsule switching was probably the result of transformation and horizontal DNA exchange in vivo of a serogroup C capsule biosynthetic operon. These findings indicate that closely related virulent meningococcal clones may not be recognized by traditional serogroup-based surveillance and can escape vaccine-induced or natural protective immunity by capsule switching. Capsule switching may be an important virulence mechanism of meningococci and other encapsulated bacterial pathogens. As vaccine development progresses and broader immunization with capsular polysaccharide conjugate vaccines becomes a reality, the ability to switch capsular types may have important implications for the impact of these vaccines.     

Meningococcal disease

Due to a high complication and case fatality rate, meningococcal diseases are important health problems both in tropical countries experiencing severe epidemics as well as in countries of moderate climate zones. Worldwide N. meningitidis of sero-groups A, B, and C are predominant and to a lesser extent serogroups W (135) and Y play a role, whereas in Europe more than 90 % of meningococcal diseases are caused by serogroups B and C of N. meningitidis. In Germany and other developed countries the majority of cases occur in very young children and adolescents. Since many years, meningococcal polysaccharide vaccines against diseases due to N.meningitidis serogroup A, C, Y and W (135) are commercially available. Unfortunately, a vaccine against diseases caused by N. meningitidis serogroup B is still under development. The recently developed and licensed conjugated meningococcal vaccines against N. meningitidis serogroup C are also protective against disease in very young children. Eight countries in Western Europe as well as Australia have already established country-wide immunization programs for children and adolescents. Within only 2 to 3 years, well managed programs have achieved far-reaching control of meningococcal C disease in UK and the Netherlands. In Germany, the Advisory Committee on Immunization (STIKO recommends immunization for selected risk groups. The current increase of the percentage of meningococcal C diseases to 28 - 30 % gives reason for further discussion regarding immunization strategies. How-ever, the STIKO expressively declares, that in addition to the recommendation for risk groups, the physician can use all vaccines licensed in Germany without any restriction. It is his/her responsibility to advice the patients regarding immunization possibilities against the life-threatening meningococcal disease, particularly if cases are occurring.     

Meningococcal vaccine in travelers

PURPOSE OF REVIEW: New vaccines to prevent meningococcal disease have been licensed in recent years. It is therefore timely to discuss current vaccine strategies pertinent to international travelers in relation to the changing epidemiology. RECENT FINDINGS: Serogroup W135 achieved epidemic status in Africa in 2002, and then largely disappeared over a short time period. The year 2006 saw a marked epidemic rise in meningitis attack rates across the meningitis belt in Africa. This rise was mainly due to a new serogroup A strain, indicating that a new meningitis epidemic wave is beginning in Africa. Epidemics are also spreading south of the meningitis belt, including the Greater Lakes Area (Burundi, Rwanda, Republic of Tanzania). The new quadrivalent conjugate meningococcal vaccine is now licensed in North America but not elsewhere. In most other industrialized countries, the serogroup C conjugate vaccine is licensed. Plain polysaccharide quadrivalent vaccines are available almost worldwide. SUMMARY: Quadrivalent meningococcal vaccination is a visa requirement for Hajj and Umrah pilgrims to Saudi Arabia. Travelers to the meningitis belt during the dry season should be advised to receive meningococcal vaccine that covers all four serogroups. This recommendation should be extended to the Greater Lake Area, because of recent epidemics. Vaccine choices depend on availability.     

Low immunogenicity of quadrivalent meningococcal vaccines in solid organ transplant recipients

Immunization against meningococcal disease is recommended for solid organ transplant (SOT) recipients at high risk for meningococcal disease or travelling to an endemic country. However, the immunogenicity of meningococcal vaccines has not been studied in this population. We analyzed the immune response of quadrivalent (against Neisseria meningitidis serogroups A, C, Y, and W) polysaccharidic non‐conjugate and conjugate meningococcal vaccines in kidney‐ and liver‐transplant patients using bactericidal assays against the targeted serogroups. Upon vaccination with a non‐conjugate (n = 5) or a conjugate vaccine (n = 10), respectively, 40% and 50% of patients were able to mount an immune response, achieving at least the threshold correlated with protection defined as human serum bactericidal antibody titers of ≥4. Responders showed only partial and low responses (titers ≤64), thus predicting a rapid decline in bactericidal response. Only 1 patient developed a booster response to preexisting immunity. Our data argue for the need of additional measures for SOT recipients, when they are at risk of meningococcal disease.     

Meningococcal vaccines

Global control and prevention of meningococcal disease depends on the further development of vaccines that overcome the limitations of the current polysaccharide vaccines. Protein-polysaccharide conjugate vaccines likely will address the marginal protective antibody responses and short duration of immunity in young children derived from the A, C, Y, and W-135 capsular polysaccharides, but they will be expensive to produce and purchase, and may not offer a practical solution to the countries with greatest need. In addition, OMP vaccines have been tested extensively in humans and hold some promise in the development of a serogroup B vaccine, but are limited by the antigenic variability of these subcapsular antigens and the resulting strain-specific protection. Elimination of meningococcal disease likely will require a novel approach to vaccine development, ideally incorporating a safe and effective antigen or antigens common to all meningoccocal serogroups. As a solely human pathogen, however, N. meningitidis has developed many tools with which to evade the human immune system, and likely will pose a formidable challenge for years to come.     

Meningococcal Disease: Shifting Epidemiology and Genetic Mechanisms That May Contribute to Serogroup C Virulence

During the past decade, monovalent serogroup C and quadrivalent (serogroups A, C, W135, Y) meningococcal vaccination programs have been introduced in multiple industrialized countries. Many of these programs have been successful in reducing the burden of disease due to vaccine-preventable serogroups of Neisseria meningitidis in target age groups. As a result, disease burden in these countries has decreased and is primarily serogroup B, which is not vaccine preventable. Despite the success of these programs, meningococcal disease continues to occur and there is always concern that serogroup C organisms will adapt their virulence mechanisms to escape pressure from vaccination. This review highlights the current epidemiology of meningococcal disease in Europe and United States, as well as genetic mechanisms that may affect virulence of serogroup C strains and effectiveness of new vaccines.     

Epidemiological pattern of meningococcal disease in Valencia, Spain. Impact of a mass immunization campaign with meningococcal C polysaccharide vaccine

The objective of this study was to define the epidemiological pattern of meningococcal disease in the autonomous region of Valencia, Spain, and the impact of a mass immunization campaign against serogroup C meningococcus. Data were obtained from a prospective surveillance program for invasive bacterial diseases in children < 15 y of age that began in the Valencia region on 1 December, 1995. During the period 1996-98, 213 cases of meningococcal disease were detected, representing an annual incidence of 11.3/100,000 children < 15 y. Serogroup C accounted for 31% and 38.5% of cases in 1996 and 1997, respectively (annual incidences of 2.9 and 5.4 cases/100,000 children < 15 y). An immunization campaign with the meningococcal C polysaccharide vaccine, which included all persons between 18 months and 19 y of age, began in late 1997 (vaccination coverage of 86%). In 1998, the annual incidence of meningococcal C disease fell to 1.4 cases per 100,000 children < 15 y of age. These results mirror the increase in the reported incidence of serogroup C meningococcal disease in Spain in the 1990s, a trend that was reversed after the introduction of the mass vaccination campaign. Meningococcal polysaccharide vaccine seems to be an effective public health tool for the management of this serious communicable disease.     

Meningococcal polysaccharide-protein conjugate vaccines

It is now 5 years since the UK became the first country to introduce the serogroup C meningococcal polysaccharide-protein conjugate vaccines (MenC) into its routine immunisation schedule. This article reviews the global use of MenC with particular reference to the range of immunisation strategies used internationally. To date, concerns that MenC may result in an increase in meningococcal disease due to non-C serogroups have not been realised. The vaccine has proved to be highly safe and effective; however, concerns have arisen regarding the duration of vaccine effectiveness. Although booster doses of MenC may potentially extend the duration of protection offered by the vaccine, there are, as yet, no studies assessing this option. Clinical trials are underway to assess new combination conjugate vaccines (containing A, C, Y, and W polysaccharides), and it is probable that these more broadly protective vaccines will become available in the near future.     

Serological correlates of protection against meningococci in a cohort of university students,before and during an outbreak of serogroup C infection

The association between individual meningococcal antigens and the development of protective immunity to both serogroup C and B meningococci was studied before and during an outbreak of serogroup C infection among university students. Persons who became infected showed, in serum taken either before infection or on admission to the hospital, low levels of bactericidal activity against the outbreak strain; patients who survived infection developed bactericidal activity that correlated with production of antibodies to serogroup C capsular polysaccharide but not to either lipopolysaccharide or major outer-membrane proteins. Uninfected classmates also showed a strong correlation between bactericidal activity and the presence of anti-capsular antibodies. In contrast, bactericidal activity against serogroup B did not correlate with the presence of antibodies to capsular polysaccharide but did correlate with antibodies reacting with the porin proteins PorA and PorB. These studies support the introduction of conjugate MenC vaccines, validate strategies for prevention of serogroup B infection that are based on vaccines containing PorA, and suggest that PorB may also be an important component of such vaccines.