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1.  A Licensed Combined Haemophilus influenzae Type b-Serogroups C and Y Meningococcal Conjugate Vaccine 
The highest incidence of meningococcal disease occurs in infants younger than 1 year of age. However, in the US, prior to June 2012, there was no meningococcal vaccine licensed for use in this age group. In the US, where both serogroups C and Y contribute substantially to the overall epidemiology of invasive meningococcal disease, a vaccine combining these capsular polysaccharides was developed. We review the newly licensed HibMenCY-TT (MenHibrix™, GlaxoSmithKline Biologicals, Rixensart, Belgium), a novel vaccine containing Haemophilus influenzae type b (Hib) and serogroups C and Y Neisseria meningitidis conjugated to tetanus toxoid. We describe the vaccine, summarize the clinical trial data, and describe the patient populations recommended to receive HibMenCY-TT as their primary vaccination against Hib. Phase II and III clinical trials found HibMenCY-TT to be well tolerated, safe, and immunogenic when administered at 2, 4, 6, and 12–15 months of age for primary vaccination against both Hib and serogroups C and Y meningococcal disease. In October 2012, the Advisory Committee on Immunisation Practice in the US recommended HibMenCY-TT vaccination for infants at increased risk of meningococcal disease. HibMenCY-TT may be given concomitantly with other routine infant vaccines. It induces antibodies against Hib as well as bactericidal activity against meningococcal serogroup C and Y without increasing the number of injections required. As meningococcal disease epidemiology is dynamic, global surveillance remains essential. In the future, other countries may also benefit from the addition of HibMenCY-TT into their vaccine armamentarium against meningococcal disease.
doi:10.1007/s40121-013-0007-5
PMCID: PMC4108092  PMID: 25135819
Conjugate vaccine; Haemophilus influenzae type b; Infant vaccination; Meningococcal disease; Neisseria meningitidis; Serogroup C; Serogroup Y
2.  Immunogenicity and safety of the quadrivalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine (MenACWY-TT) in 2–10-year-old children: results of an open, randomised, controlled study 
European Journal of Pediatrics  2013;172(5):601-612.
In Europe, the introduction of monovalent meningococcal serogroup C (MenC) conjugate vaccines has resulted in a significant decline in MenC invasive disease. However, given the potential for strain evolution and increasing travel to areas of high endemicity, protection against additional serogroups is needed. In this study, the immunogenicity, measured by a serum bactericidal activity assay using rabbit complement (rSBA), and the safety of a quadrivalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine (MenACWY-TT) were compared to that of a licensed monovalent MenC conjugate vaccine (MenC-CRM197) in children 2–10 years of age. Children were randomised (3:1) to receive a single dose of either MenACWY-TT or MenC-CRM197. Non-inferiority of the immunogenicity of MenACWY-TT versus MenC-CRM197 in terms of rSBA-MenC vaccine response was demonstrated. Exploratory analyses suggested that rSBA-MenC geometric mean titres adjusted for pre-vaccination titres were lower in children vaccinated with MenACWY-TT compared to MenC-CRM197. Nevertheless, at 1 month post-vaccination, ≥99.3 % of the children who received MenACWY-TT had rSBA titres ≥1:128 for each of the four vaccine serogroups, which is the more conservative correlate of protection. The reactogenicity and safety profile of MenACWY-TT was clinically acceptable and no serious adverse events considered related to vaccination were reported throughout the study. Conclusion: When administered to European school-age children, MenACWY-TT has a clinically acceptable safety profile and, when compared with MenC-CRM197, the potential to broaden protection against meningococcal disease caused by serogroups A, W-135 and Y while maintaining protection against MenC. This study has been registered at www.clinicaltrials.gov NCT00674583.
doi:10.1007/s00431-012-1924-0
PMCID: PMC3631514  PMID: 23307281
Quadrivalent meningococcal vaccine; Conjugate vaccine; Tetanus toxoid; Child; Bactericidal activity; Randomised trial
3.  A Phase II, Randomized Study on an Investigational DTPw-HBV/Hib-MenAC Conjugate Vaccine Administered to Infants in Northern Ghana 
PLoS ONE  2008;3(5):e2159.
Background
Combining meningococcal vaccination with routine immunization in infancy may reduce the burden of meningococcal meningitis, especially in the meningitis belt of Africa. We have evaluated the immunogenicity, persistence of immune response, immune memory and safety of an investigational DTPw-HBV/Hib-MenAC conjugate vaccine given to infants in Northern Ghana.
Methods and Findings
In this phase II, double blind, randomized, controlled study, 280 infants were primed with DTPw-HBV/Hib-MenAC or DTPw-HBV/Hib vaccines at 6, 10 and 14 weeks of age. At 12 months of age, children in each group received a challenge dose of serogroup A+C polysaccharides. Antibody responses were assessed pre, and one month-post dose 3 of the priming schedule and pre and 1 month after administration of the challenge dose. One month post-dose 3, 87.8% and 88.2% of subjects in the study group had bactericidal meningococcal serogroup A (SBA-MenA) and meningococcal serogroup C (SBA-MenC) antibody titres ≥1∶8 respectively. Seroprotection/seropositivity rates to the 5 antigens administered in the routine EPI schedule were non-inferior in children in the study group compared to those in the control group. The percentages of subjects in the study group with persisting SBA-MenA titres ≥ 1∶8 or SBA-MenC titres ≥1∶8 at the age of 12 months prior to challenge were significantly higher than in control group (47.7% vs 25.7% and 56.4% vs 5.1% respectively). The administration of 10 μg of serogroup A polysaccharide increased the SBA-MenA GMT by 14.0-fold in the DTPW-HBV/HibMenAC-group compared to a 3.8 fold increase in the control-group. Corresponding fold-increases in SBA-MenC titres following challenge with 10 μg of group C polysaccharide were 18.8 and 1.9 respectively. Reactogenicity following primary vaccination or the administration of the challenge dose was similar in both groups, except for swelling (Grade 3) after primary vaccination which was more frequent in children in the vaccine than in the control group (23.7%; 95%CI [19.6–28.1] of doses vs 14.1%; 95% CI [10.9–17.8] of doses). Fifty-nine SAEs (including 8 deaths), none of them related to vaccination, were reported during the entire study.
Conclusions
Three dose primary vaccination with DTPw-HBV/Hib-MenAC was non-inferior to DTPw-HBV/Hib for the 5 common antigens used in the routine EPI schedule and induced bactericidal antibodies against Neisseria meningitidis of serogroups A and C in the majority of infants. Serogroup A and C bactericidal antibody levels had fallen below titres associated with protection in nearly half of the infants by the age of 12 months confirming that a booster dose is required at about that age. An enhanced memory response was shown after polysaccharide challenge. This vaccine could provide protection against 7 important childhood diseases (including meningococcal A and C) and be of particular value in countries of the African meningitis belt.
Trial Registration
Controlled-Trials.com ISRCTN35754083
doi:10.1371/journal.pone.0002159
PMCID: PMC2374896  PMID: 18478093
4.  Immunogenicity and Safety of a Quadrivalent Meningococcal Serogroups A, C, W-135 and Y Tetanus Toxoid Conjugate Vaccine (MenACWY-TT) Administered to Adults Aged 56 Years and Older: Results of an Open-Label, Randomized, Controlled Trial 
Drugs & Aging  2013;30(5):309-319.
Background
The burden of invasive meningococcal disease is substantial in older adults in whom the case fatality rate is high. Travelers to regions with high rates of meningococcal disease, such as Hajj pilgrims, are at increased risk of meningococcal infection, and disease transmission from travelers to their close contacts has been documented. In younger individuals, meningococcal conjugate vaccines offer advantages over polysaccharide vaccines in terms of duration of protection and boostability, and induction of herd immune effects through reductions in nasopharyngeal carriage of meningococci. To date, few data are available evaluating meningococcal conjugate vaccine use in adults >55 years of age.
Objective
To evaluate the immunogenicity and safety of quadrivalent meningococcal serogroups A, C, W-135 and Y vaccine with all serogroups conjugated to tetanus toxoid (MenACWY-TT, Nimenrix™, GlaxoSmithKline, Belgium) and a licensed quadrivalent polysaccharide vaccine (MenPS, Mencevax™ GlaxoSmithKline, Belgium) in adults >55 years of age.
Methods
This was a phase IIIb, open-label, randomized (3:1), controlled study conducted at one study center in Lebanon. A total of 400 healthy adults between 56 and 103 years of age without previous MenPS or tetanus toxoid vaccination within the previous 5 years or meningococcal conjugate vaccination at any time previously were included. They received a single-dose vaccination with MenACWY-TT or MenPS with blood sampling before and 1 month after vaccination. The main outcome measures were serum bactericidal activity (rabbit complement source: rSBA) vaccine response (VR) rate [rSBA titer of ≥1:32 in initially seronegative subjects (rSBA titer <1:8); ≥4-fold increase in subjects with pre-vaccination rSBA titers between 1:8 and 1:128, and ≥2-fold increase in subjects with pre-vaccination rSBA titers ≥1:128]. The percentages of subjects with rSBA titers ≥1:8 and ≥1:128 and rSBA geometric mean titers (GMTs) were assessed. Solicited adverse events were recorded for 4 days following vaccination, and all other adverse events, including the incidence of new onset chronic diseases, were recorded for 31 days after vaccination.
Results
One month after a single dose of MenACWY-TT, the rSBA VR rate in the MenACWY-TT group was 76.6 % for serogroup A, 80.3 % for serogroup C, 77.5 % for serogroup W-135 and 81.9 % for serogroup Y. VR rates in the MenPS group were 91.7, 84.8, 87.1 and 89.1 %, respectively. One month after vaccination, ≥93.2 % of subjects in the MenACWY-TT group and ≥93.9 % in the MenPS group had rSBA titers ≥1:128. In each group, GMTs increased by ≥13-fold for each serogroup. rSBA VR and GMTs tended to be lower in subjects who were over 65 years compared to 56–65 years of age. Only 6.3 % of MenACWY-TT recipients had anti-TT ≥0.1 IU/ml prior to vaccination, increasing to 28.1 % post-vaccination. The rSBA GMTs were 1.9- to 4-fold higher in anti-TT responders. Each local and general solicited symptom was reported by no more than 3.0 % of subjects in either group. No serious adverse events were considered vaccine related.
Conclusion
In adults 56 years of age and older, MenACWY-TT was immunogenic, with a vaccine response rate ≥76 % and with ≥93 % of subjects achieving rSBA titers ≥1:128 against all four serogroups after a single dose. MenACWY-TT induced low anti-TT concentrations in this population, which deserves further study.
Electronic supplementary material
The online version of this article (doi:10.1007/s40266-013-0065-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s40266-013-0065-0
PMCID: PMC3634976  PMID: 23494214
5.  Randomized trial to assess the immunogenicity, safety and antibody persistence up to three years after a single dose of a tetravalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine in toddlers 
Human Vaccines & Immunotherapeutics  2012;8(12):1892-1903.
Effective vaccines offering broad protection to toddlers, who are at high risk for invasive meningococcal disease, are needed. Here, the immunogenicity, safety and antibody persistence of the tetravalent meningococcal ACWY tetanus toxoid conjugate vaccine (MenACWY-TT) were evaluated in toddlers. Healthy participants aged 12 to 23 mo (n = 304) were randomized (3:1) to receive one dose of MenACWY-TT or a monovalent meningococcal serogroup C conjugate vaccine (MenC-CRM197). Serum bactericidal activity was evaluated with assays using rabbit (rSBA) and human (hSBA) complement up to three years post-vaccination. MenACWY-TT was demonstrated to be non-inferior to MenC-CRM197 in terms of immunogenicity to serogroup C, and the pre-specified immunogenicity criteria for serogroups A, W-135 and Y were met. Exploratory analyses suggested that rSBA geometric mean titers (GMTs), hSBA GMTs and proportions of toddlers with rSBA titers ≥ 1:128 and hSBA titers ≥ 1:4 and ≥ 1:8 were higher for all serogroups at one month post-vaccination with MenACWY-TT compared with MenC-CRM197. At three years post-vaccination, at least 90.8% and 73.6% of MenACWY-TT recipients retained rSBA titers ≥ 1:8 for all serogroups and hSBA titers ≥ 1:4 for serogroups C, W-135 and Y, respectively, but the percentages of toddlers with hSBA titers ≥ 1:4 for serogroup A decreased to 21.8%. In both groups, grade 3 adverse events were infrequently reported and no serious adverse events were considered causally related to vaccination. These results suggest that one single dose of MenACWY-TT induces a robust and persistent immune response and has an acceptable safety profile in toddlers. This study has been registered at www.clinicaltrials.gov NCT00427908.
doi:10.4161/hv.22166
PMCID: PMC3656082  PMID: 23032159
tetravalent meningococcal vaccine; conjugate vaccine; toddler; bactericidal activity; persistence; safety
6.  A randomized study to assess the immunogenicity, antibody persistence and safety of a tetravalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine in children aged 2–10 years 
Human Vaccines & Immunotherapeutics  2012;8(12):1882-1891.
Incidence of meningococcal diseases is high in children, and effective vaccines are needed for this age group. In this phase II, open, controlled study, 309 children aged 2–10 y from Finland were randomized (3:1) into two parallel groups to receive one dose of meningococcal ACWY-tetanus toxoid conjugate vaccine (ACWY-TT group; n = 231) or a licensed meningococcal ACWY polysaccharide vaccine (Men-PS group; n = 78). Serum bactericidal activity using rabbit complement (rSBA) was evaluated up to three years post-vaccination. Exploratory comparisons suggested that rSBA vaccine response rates and geometric mean titers (GMTs) for each serogroup at one month post-vaccination and rSBA GMTs for serogroups A, W-135 and Y up to three years post-vaccination were higher in the ACWY-TT compared with Men-PS group, but did not detect any difference between groups in terms of rSBA-MenC GMTs at three years post-vaccination; this is explained by the higher proportion of children from the Men-PS group who were excluded because they were re-vaccinated with a monovalent meningococcal serogroup C vaccine due to loss of protective antibody levels against this serogroup. Although there was a higher incidence of local reactogenicity in the ACWY-TT group, general and unsolicited symptoms reporting rates were comparable in both groups. This study showed that MenACWY-TT was immunogenic with a clinically acceptable safety profile in children aged 2–10 y. MenACWY-TT induced higher functional antibody titers for all serogroups, which persisted longer for serogroups A, W-135 and Y, than the MenACWY polysaccharide vaccine. This study has been registered at www.clinicaltrials.gov NCT00427908.
doi:10.4161/hv.22165
PMCID: PMC3656081  PMID: 23032168
tetravalent meningococcal vaccine; conjugate vaccine; polysaccharide vaccine; bactericidal activity; child; safety; immunogenicity; persistence
7.  Critical appraisal of a quadrivalent CRM197 conjugate vaccine against meningococcal serogroups A, C W-135 and Y (Menveo®) in the context of treatment and prevention of invasive disease 
Worldwide, invasive meningococcal disease affects about 500,000 people annually. Case fatality in developed countries averages 10%, and higher rates are reported in less prosperous regions. According to the World Health Organization, the most important pathogenic serogroups are A, B, C, W-135, X, and Y. Clinical features of invasive meningococcal disease make diagnosis and management difficult. Antibiotic measures are recommended for prophylaxis after exposure and for treatment of invasive meningococcal disease cases; however, resistant strains may be emerging. Vaccines are generally regarded as the best preventative measure for invasive meningococcal disease. Polysaccharide vaccines against serogroups A, C, W-135, and Y using protein conjugation technology have clear advantages over older plain polysaccharide formulations without a protein component. The first quadrivalent meningococcal conjugate vaccine (MenACWY-D) was licensed in the US in 2005. More recently, MenACWY-CRM (Menveo®) was licensed in Europe, the US, the Middle East, and Latin America. MenACWY-CRM uses cross-reactive material 197, a nontoxic mutant of diphtheria toxin, as the carrier protein. MenACWY-CRM offers robust immunogenicity in all age groups, with a tolerability profile similar to that of a plain polysaccharide vaccine. Given its potential for protecting persons from infancy to old age, MenACWY-CRM offers the opportunity to protect broad populations against invasive meningococcal disease. The most optimal strategy for use of the vaccine has to be assessed country by country on the basis of local epidemiology, individual health care systems, and need.
doi:10.2147/IDR.S12716
PMCID: PMC3163984  PMID: 21904459
invasive meningococcal disease; quadrivalent meningococcal conjugate vaccine; Neisseria meningitidis
8.  Meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine: a new conjugate vaccine against invasive meningococcal disease 
Invasive meningococcal disease is a serious infection that occurs worldwide. It is caused by Neisseria meningitidis, of which six serogroups (A, B, C, W-135, X, and Y) are responsible for most infections. The case fatality rate of meningococcal disease remains high and can lead to significant sequelae. Vaccination remains the best strategy to prevent meningococcal disease. Polysaccharide vaccines were initially introduced in the late 1960s but their limitations (poor immunogenicity in infants and toddlers and hyporesponsiveness after repeated doses) have led to the development and use of meningococcal conjugate vaccines, which overcome these limitations. Two quadrivalent conjugated meningococcal vaccines – MenACWY-DT (Menactra®) and MenACWY-CRM197 (Menveo®) – using diphtheria toxoid or a mutant protein, respectively, as carrier proteins have already been licensed in the US. Recently, a quadrivalent meningococcal vaccine conjugated to tetanus toxoid (MenACWY-TT; Nimenrix®) was approved for use in Europe in 2012. The immunogenicity of MenACWY-TT, its reactogenicity and safety profile, as well as its coadministration with other vaccines are discussed in this review. Clinical trials showed that MenACWY-TT was immunogenic in children above the age of 12 months, adolescents, and adults, and has an acceptable reactogenicity and safety profile. Its coadministration with several other vaccines that are commonly used in children, adolescents, and adults did not affect the immunogenicity of MenACWY-TT or the coadministered vaccine, nor did it affect its reactogenicity and safety. Other studies are now ongoing in order to determine the immunogenicity, reactogenicity, and safety of MenACWY-TT in infants from the age of 6 weeks.
doi:10.2147/IDR.S36243
PMCID: PMC3979687  PMID: 24729718
coadministration; immunogenicity; meningococcal conjugate vaccine; reactogenicity and safety
9.  Meningococcal Serogroup A, C, W135 and Y Conjugated Vaccine: A Cost-Effectiveness Analysis in the Netherlands 
PLoS ONE  2013;8(5):e65036.
Background
In 2002, vaccination with a serogroup C meningococcal conjugate vaccine (MenC) was introduced in the Netherlands for all children aged 14 months. Despite its success, herd immunity may wane over time. Recently, a serogroup A,C,W135,Y meningococcal conjugate vaccine (MenACWY) was licensed for use in subjects of 12 months of age and above.
Objectives
To evaluate the cost-effectiveness of meningococcal vaccination at 14 months and an additional vaccination at the age of 12 years, both with the MenACWY vaccine.
Methods
A decision analysis cohort model, with 185,000 Dutch newborns, was used to evaluate the cost-effectiveness of different immunization strategies. For strategies including a vaccination at 12 years of age, an additional cohort with adolescents aged 12 years was followed. The incremental cost-effectiveness ratio (ICER) was estimated for the current disease incidence and for a scenario when herd immunity is lost.
Results
Vaccination with MenACWY at 14 months is cost-saving. Vaccinating with MenACWY at 14 months and at 12 years would prevent 7 additional cases of meningococcal serogroup A,C,W135,Y disease in the birth cohort and adolescent cohort followed for 99 years compared to the current vaccine schedule of a single vaccination with MenC at 14 months. With the current incidence, this strategy resulted in an ICER of €635,334 per quality adjusted life year. When serogroup C disease incidence returns to pre-vaccination levels due to a loss of vaccine-induced herd-immunity, vaccination with MenACWY at 14 months and at 12 years would be cost-saving.
Conclusions
Routine vaccination with MenACWY is cost-saving. With the current epidemiology, a booster-dose with MenACWY is not likely cost-effective. When herd immunity is lost, a booster-dose has the potential of being cost-effective. A dynamic model should be developed for more precise estimation of the cost-effectiveness of the prevention of disappearance of herd immunity.
doi:10.1371/journal.pone.0065036
PMCID: PMC3669019  PMID: 23741448
10.  Immune response, antibody persistence, and safety of a single dose of the quadrivalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine in adolescents and adults: results of an open, randomised, controlled study 
BMC Infectious Diseases  2013;13:116.
Background
The best strategy to protect individuals against meningococcal disease is to immunize against multiple serogroups. Immunogenicity, antibody persistence, and safety of the EU-licensed meningococcal ACWY-tetanus toxoid conjugate vaccine (MenACWY-TT) were evaluated in healthy participants aged 11–55 years from the Philippines and Saudi Arabia.
Methods
In this phase IIb, open, controlled study, 500 participants were randomised (3:1) to receive one dose of MenACWY-TT or a licensed meningococcal polysaccharide vaccine (Men-PS). Functional antibody responses against meningococcal serogroups A, C, W-135, and Y were assessed by a serum bactericidal antibody assay using rabbit complement (rSBA) at Month 0, Month 1, Year 1, Year 2, and Year 3. Vaccine response was defined as an rSBA titre ≥32 at Month 1 in participants who were seronegative (rSBA titre <8) pre-vaccination and as at least a four-fold increase in titre in participants who were seropositive pre-vaccination. Solicited symptoms were recorded up to Day 4, safety outcomes up to Month 6, and serious adverse events related to vaccination up to Year 3.
Results
Pre-specified criteria for non-inferiority of MenACWY-TT versus Men-PS were met in terms of rSBA vaccine response and incidence of grade 3 general symptoms. At Month 1, 82.7%–96.3% of MenACWY-TT and 69.7%–91.7% in Men-PS recipients had a vaccine response for each serogroup. At Year 3, ≥99.1% and ≥92.9% of MenACWY-TT recipients retained rSBA titres ≥8 and ≥128, respectively, as compared to ≥86.7% and ≥80.0% in the Men-PS group. Both vaccines had a clinically acceptable safety profile, although injection site redness and swelling were more frequent in MenACWY-TT recipients.
Conclusions
These results suggest that MenACWY-TT could protect adolescents and adults against meningococcal disease up to three years post-vaccination.
Trial registration
This study is registered at http://www.clinicaltrials.gov/NCT00356369.
doi:10.1186/1471-2334-13-116
PMCID: PMC3599520  PMID: 23510357
Quadrivalent meningococcal vaccine; Conjugate vaccine; Bactericidal activity; Persistence; Safety; The Philippines; Saudi Arabia
11.  Meningococcal disease: changes in epidemiology and prevention 
Clinical Epidemiology  2012;4:237-245.
The human bacterial pathogen Neisseria meningitidis remains a serious worldwide health threat, but progress is being made toward the control of meningococcal infections. This review summarizes current knowledge of the global epidemiology and the pathophysiology of meningococcal disease, as well as recent advances in prevention by new vaccines. Meningococcal disease patterns and incidence can vary dramatically, both geographically and over time in populations, influenced by differences in invasive meningococcal capsular serogroups and specific genotypes designated as ST clonal complexes. Serogroup A (ST-5, ST-7), B (ST-41/44, ST-32, ST-18, ST-269, ST-8, ST-35), C (ST-11), Y (ST-23, ST-167), W-135 (ST-11) and X (ST-181) meningococci currently cause almost all invasive disease. Serogroups B, C, and Y are responsible for the majority of cases in Europe, the Americas, and Oceania; serogroup A has been associated with the highest incidence (up to 1000 per 100,000 cases) and large outbreaks of meningococcal disease in sub-Saharan Africa and previously Asia; and serogroups W-135 and X have emerged to cause major disease outbreaks in sub-Saharan Africa. Significant declines in meningococcal disease have occurred in the last decade in many developed countries. In part, the decline is related to the introduction of new meningococcal vaccines. Serogroup C polysaccharide-protein conjugate vaccines were introduced over a decade ago, first in the UK in a mass vaccination campaign, and are now widely used; multivalent meningococcal conjugate vaccines containing serogroups A, C, W-135, and/or Y were first used for adolescents in the US in 2005 and have now expanded indications for infants and young children, and a new serogroup A conjugate vaccine has recently been introduced in sub-Saharan Africa. The effectiveness of these conjugate vaccines has been enhanced by the prevention of person-to-person transmission and herd immunity. In addition, progress has been made in serogroup B-specific vaccines based on conserved proteins and outer membrane vesicles. However, continued global surveillance is essential in understanding and predicting the dynamic changes in the epidemiology and biological basis of meningococcal disease and to influence the recommendations for current and future vaccines or other prevention strategies.
doi:10.2147/CLEP.S28410
PMCID: PMC3470458  PMID: 23071402
Neisseria meningitidis; meningococcal disease; conjugate vaccines; meningococcal vaccines
12.  Quadrivalent Meningococcal Vaccination of Adults: Phase III Comparison of an Investigational Conjugate Vaccine, MenACWY-CRM, with the Licensed Vaccine, Menactra▿  
Clinical and Vaccine Immunology : CVI  2009;16(12):1810-1815.
Neisseria meningitidis is a leading cause of bacterial meningitis in the United States, with the highest case fatality rates reported for individuals ≥15 years of age. This study compares the safety and immunogenicity of the Novartis Vaccines investigational quadrivalent meningococcal CRM197 conjugate vaccine, MenACWY-CRM, to those of the licensed meningococcal conjugate vaccine, Menactra, when administered to healthy adults. In this phase III multicenter study, 1,359 adults 19 to 55 years of age were randomly assigned to one of four groups (1:1:1:1 ratio) to receive a single dose of one of three lots of MenACWY-CRM or a single dose of Menactra. Serum samples obtained at baseline and 1 month postvaccination were tested for serogroup-specific serum bactericidal activity using human complement (hSBA). The hSBA titers following vaccination with MenACWY-CRM and Menactra were compared in noninferiority and prespecified superiority analyses. Reactogenicity was similar in the MenACWY-CRM and Menactra groups, and neither vaccine was associated with a serious adverse event. When compared with Menactra, MenACWY-CRM met the superiority criteria for the proportions of recipients achieving a seroresponse against serogroups C, W-135, and Y and the proportion of subjects achieving postvaccination titers of ≥1:8 for serogroups C and Y. MenACWY-CRM's immunogenicity was statistically noninferior (the lower limit of the two-sided 95% confidence interval was more than −10%) to that of Menactra for all four serogroups, with the postvaccination hSBA geometric mean titers being consistently higher for MenACWY-CRM than for Menactra. MenACWY-CRM is well tolerated in adults 19 to 55 years of age, with immune responses to each of the serogroups noninferior and, in some cases, statistically superior to those to Menactra.
doi:10.1128/CVI.00207-09
PMCID: PMC2786376  PMID: 19812260
13.  Association of Secondhand Smoke Exposure with Pediatric Invasive Bacterial Disease and Bacterial Carriage: A Systematic Review and Meta-analysis 
PLoS Medicine  2010;7(12):e1000374.
Majid Ezzati and colleagues report the findings of a systematic review and meta-analysis that probes the association between environmental exposure to secondhand smoke and the epidemiology of pediatric invasive bacterial disease.
Background
A number of epidemiologic studies have observed an association between secondhand smoke (SHS) exposure and pediatric invasive bacterial disease (IBD) but the evidence has not been systematically reviewed. We carried out a systematic review and meta-analysis of SHS exposure and two outcomes, IBD and pharyngeal carriage of bacteria, for Neisseria meningitidis (N. meningitidis), Haemophilus influenzae type B (Hib), and Streptococcus pneumoniae (S. pneumoniae).
Methods and Findings
Two independent reviewers searched Medline, EMBASE, and selected other databases, and screened articles for inclusion and exclusion criteria. We identified 30 case-control studies on SHS and IBD, and 12 cross-sectional studies on SHS and bacterial carriage. Weighted summary odd ratios (ORs) were calculated for each outcome and for studies with specific design and quality characteristics. Tests for heterogeneity and publication bias were performed. Compared with those unexposed to SHS, summary OR for SHS exposure was 2.02 (95% confidence interval [CI] 1.52–2.69) for invasive meningococcal disease, 1.21 (95% CI 0.69–2.14) for invasive pneumococcal disease, and 1.22 (95% CI 0.93–1.62) for invasive Hib disease. For pharyngeal carriage, summary OR was 1.68 (95% CI, 1.19–2.36) for N. meningitidis, 1.66 (95% CI 1.33–2.07) for S. pneumoniae, and 0.96 (95% CI 0.48–1.95) for Hib. The association between SHS exposure and invasive meningococcal and Hib diseases was consistent regardless of outcome definitions, age groups, study designs, and publication year. The effect estimates were larger in studies among children younger than 6 years of age for all three IBDs, and in studies with the more rigorous laboratory-confirmed diagnosis for invasive meningococcal disease (summary OR 3.24; 95% CI 1.72–6.13).
Conclusions
When considered together with evidence from direct smoking and biological mechanisms, our systematic review and meta-analysis indicates that SHS exposure may be associated with invasive meningococcal disease. The epidemiologic evidence is currently insufficient to show an association between SHS and invasive Hib disease or pneumococcal disease. Because the burden of IBD is highest in developing countries where SHS is increasing, there is a need for high-quality studies to confirm these results, and for interventions to reduce exposure of children to SHS.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The deleterious health effects of smoking on smokers are well established, but smoking also seriously damages the health of nonsmokers. Secondhand smoke (SHS), which is released by burning cigarettes and exhaled by smokers, contains hundreds of toxic chemicals that increase the risk of adults developing lung cancer and heart disease. Children, however, are particularly vulnerable to the effects of SHS exposure (also known as passive smoking) because they are still developing physically. In addition, children have little control over their indoor environment and thus can be heavily exposed to SHS. Exposure to SHS increases the risk of ear infections, asthma, respiratory symptoms (coughing, sneezing, and breathlessness), and lung infections such as pneumonia and bronchitis in young children and the risk of sudden infant death syndrome during the first year of life.
Why Was This Study Done?
Several studies have also shown an association between SHS exposure (which damages the lining of the mouth, throat, and lungs and decreases immune defenses) and potentially fatal invasive bacterial disease (IBD) in children. In IBD, bacteria invade the body and grow in normally sterile sites such as the blood (bacteremia) and the covering of the brain (meningitis). Three organisms are mainly responsible for IBD in children—Streptococcus pneumoniae, Haemophilus influenzae type B (Hib), and Neisseria meningitidis. In 2000, S. pneumonia (pneumococcal disease) alone killed nearly one million children. Here, the researchers undertake a systematic review and meta-analysis of the association between SHS exposure in children and two outcomes—IBD and the presence of IBD-causing organisms in the nose and throat (bacterial carriage). A systematic review uses predefined criteria to identify all the research on a given topic; meta-analysis is a statistical method that combines the results of several studies. By combining data, it is possible to get a clearer view of the causes of a disease than is possible from individual studies.
What Did the Researchers Do and Find?
The researchers identified 30 case-control studies that compared the occurrence of IBD over time in children exposed to SHS with its occurrence in children not exposed to SHS. They also identified 12 cross-sectional studies that measured bacterial carriage at a single time point in children exposed and not exposed to SHS. The researchers used the data from these studies to calculate a “summary odds ratio” (OR) for each outcome—a measure of how SHS exposure affected the likelihood of each outcome. Compared with children unexposed to SHS, exposure to SHS doubled the likelihood of invasive meningococcal disease (a summary OR for SHS exposure of 2.02). Summary ORs for invasive pneumococcal disease and Hib diseases were 1.21 and 1.22, respectively. However, these small increases in the risk of developing these IBDs were not statistically significant unlike the increase in the risk of developing meningococcal disease. That is, they might have occurred by chance. For bacterial carriage, summary ORs for SHS exposure were 1.68 for N. meningitidis, 1.66 for S. pneumonia (both these ORs were statistically significant), and 0.96 for Hib (a nonsignificant decrease in risk).
What Do These Findings Mean?
These findings indicate that SHS exposure is significantly associated with invasive meningococcal disease among children. However, the evidence that SHS exposure is associated with invasive pneumococcal and Hib disease is only suggestive. These findings also indicate that exposure to SHS is associated with an increased carriage of N. meningitidis and S. pneumoniae. The accuracy and generalizability of these findings is limited by the small number of studies identified, by the lack of studies from developing countries where SHS exposure is increasing and the burden of IBD is high, and by large variations between the studies in how SHS exposure was measured and IBD diagnosed. Nevertheless, they suggest that, by reducing children's exposure to SHS (by, for example, persuading parents not to smoke at home), the illness and death caused by IBDs among children could be greatly reduced. Such a reduction would be particularly welcome in developing countries where vaccination against IBDs is low.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000374.
The US Centers for Disease Control and Prevention provides information on secondhand smoke, on children and secondhand smoke exposure, on meningitis, and on Hib infection
The US Environmental Protection Agency also provides information on the health effects of exposure to secondhand smoke (in English and Spanish) and a leaflet (also in English and Spanish) entitled Secondhand Tobacco Smoke and the Health of Your Family
The US Office of the Surgeon General provides information on the health consequences of involuntary exposure to tobacco smoke
The World Health Organization provides a range of information on the global tobacco epidemic
The World Health Organization has information on meningococcal disease (in English only) and on Hib (in several languages)
The US National Foundation for Infectious Diseases provides a fact sheet on pneumococcal disease
doi:10.1371/journal.pmed.1000374
PMCID: PMC2998445  PMID: 21151890
14.  Clonal Waves of Neisseria Colonisation and Disease in the African Meningitis Belt: Eight- Year Longitudinal Study in Northern Ghana 
PLoS Medicine  2007;4(3):e101.
Background
The Kassena-Nankana District of northern Ghana lies in the African “meningitis belt” where epidemics of meningococcal meningitis have been reoccurring every eight to 12 years for the last 100 years. The dynamics of meningococcal colonisation and disease are incompletely understood, and hence we embarked on a long-term study to determine how levels of colonisation with different bacterial serogroups change over time, and how the patterns of disease relate to such changes.
Methods and Findings
Between February 1998 and November 2005, pharyngeal carriage of Neisseria meningitidis in the Kassena-Nankana District was studied by twice-yearly colonisation surveys. Meningococcal disease was monitored throughout the eight-year study period, and patient isolates were compared to the colonisation isolates. The overall meningococcal colonisation rate of the study population was 6.0%. All culture-confirmed patient isolates and the majority of carriage isolates were associated with three sequential waves of colonisation with encapsulated (A ST5, X ST751, and A ST7) meningococci. Compared to industrialised countries, the colonising meningococcal population was less constant in genotype composition over time and was genetically less diverse during the peaks of the colonisation waves, and a smaller proportion of the isolates was nonserogroupable. We observed a broad age range in the healthy carriers, resembling that of meningitis patients during large disease epidemics.
Conclusions
The observed lack of a temporally stable and genetically diverse resident pharyngeal flora of meningococci might contribute to the susceptibility to meningococcal disease epidemics of residents in the African meningitis belt. Because capsular conjugate vaccines are known to impact meningococcal carriage, effects on herd immunity and potential serogroup replacement should be monitored following the introduction of such vaccines.
An analysis of pharyngeal carriage of meningococci in one district of Ghana examined the features of the isolates that might contribute to the susceptibility to meningococcal epidemics in the African meningitis belt.
Editors' Summary
Background.
Bacterial meningitis is a rare but often fatal infection of the meninges—the thin membrane around the brain and the spinal cord. It can be caused by several types of bacteria, but meningococcal meningitis, which is caused by Neisseria meningitidis, is the most common form of bacterial meningitis in children and the second most common form in adults. About 10% of healthy people have N. meningitidis growing in their nose and throat; the bacteria are spread by exposure to infected respiratory secretions. In these “carriers,” the immune system keeps the bug in check but sometimes this surveillance fails, N. meningitidis enters the bloodstream and travels to the brain, where it infects the meninges and causes inflammation. The symptoms of meningococcal meningitis are sudden fever, headache, and a stiff neck and, even if strong antibiotics are given quickly, 10%–15% of patients die.
Why Was This Study Done?
Outbreaks of meningococcal meningitis occur all over the world, but the highest burden of disease is in the African meningitis belt, which stretches across sub-Saharan Africa from Senegal to Ethiopia. Here, localized epidemics of meningococcal meningitis occur every eight to 12 years during the dry season. Control of these epidemics relies on their early detection followed by mass immunization. This approach can be hard to implement in countries with limited resources, but the introduction of other control measures (for example, routine childhood immunization) requires an understanding of how the spread of different strains of N. meningitides through the community causes periodic epidemics. In this study, the researchers have studied the long-term dynamics of colonization by N. meningitidis and the occurrence of meningococcal meningitis in one region of the African meningitis belt.
What Did the Researchers Do and Find?
The researchers took throat swabs twice a year from people living in rural northern Ghana for eight years. They tested each swab for N. meningitidis and determined the serogroup of the bacteria they found. Bacterial serogroups differ only in terms of the antigens (molecules recognized by the immune system) that they express; N. meningitidis is classified into 13 serogroups based on the sugars that coat its surface. The researchers also used DNA sequencing to group the bacterial isolates into genoclouds—genetically closely related groups of meningococci represented by a sequence type (ST) number. Finally, they monitored meningococcal disease throughout the study and determined the serogroup and genocloud of patient isolates. Their results show colonization of 6% of the study population by N. meningitidis and reveal three consecutive waves of colonization and disease characterized by the presence of a serogroup A ST5 genocloud, a serogroup X ST751 genocloud, and finally a serogroup A ST7 genocloud. Colonizing bacteria isolated in this study in Ghana, the researchers report, changed their genotype more frequently but were less genetically diverse than those isolated in industrialized countries. In addition, the commonest serogroups of N. meningitidis in carriers in Ghana were disease-causing serogroups, whereas in industrialized countries these serogroups are rarely seen in carriers. However, non-groupable bacteria (bacteria that lack surface sugars), although common in industrialized countries, were rare in Ghana.
What Do These Findings Mean?
These findings begin to explain why epidemics of meningococcal meningitis are common in the African meningitis belt. Because there isn't a stable, genetically diverse population of N. meningitidis in carriers, the immune systems of people living here may not be optimally prepared to deal with new bacterial clones that arrive in the region, and this lack of immunity could result in frequent epidemics. However, because the researchers took relatively few samples every six months from one small area of the meningitis belt, the genetic diversity of N. meningitidis over the whole region might be considerably greater than that colonizing the study population. Nevertheless, the description of successive waves of meningococci colonization in Ghana has important implications for the proposed introduction of childhood vaccination against meninogococcal disease in the African meningitis belt. If this vaccination program goes ahead, warn the researchers, it will be essential to monitor which strains of N. meningitidis are colonizing the population and to have emergency plans ready to deal with any emerging disease-causing serogroups that are not covered by the vaccine.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040101.
The Web sites of the institutions at which this research was performed, the Swiss Tropical Institute and the Navrongo Health Research Centre, provide more information about the programs
The World Health Organization provides information on meningococcal disease, including the African meningitis belt (in English, Spanish, Chinese, Russian, and Arabic)
Information on meningitis and vaccines and their potential use in Africa is available from the Meningitis Vaccine Project (in English and French)
Medline Plus has encyclopedia pages on meningococcal meningitis
The US Centers for Disease Control and Prevention provides information on meningococcal disease (in English and Spanish)
doi:10.1371/journal.pmed.0040101
PMCID: PMC1831736  PMID: 17388665
15.  Immunogenicity and Safety of a Multicomponent Meningococcal Serogroup B Vaccine and a Quadrivalent Meningococcal CRM197 Conjugate Vaccine against Serogroups A, C, W-135, and Y in Adults Who Are at Increased Risk for Occupational Exposure to Meningococcal Isolates▿  
Laboratory staff who work with meningococcal isolates are at increased risk for developing invasive disease relative to the general population. This was the first study of laboratory workers who received both a conjugate vaccine against meningococcal serogroups A, C, W-135, and Y (Men ACWY-CRM, Menveo) and an investigational multicomponent vaccine against serogroup B containing factor H binding protein, neisserial adhesin A, Neisseria heparin binding antigen, and New Zealand strain outer membrane vesicles (4CMenB). Healthy adults (18 to 50 years of age) received three doses of 4CMenB at baseline, 2 months, and 6 months followed by a single dose of MenACWY-CRM 1 month later. Immunogenicity was assessed via serum bactericidal assay using human complement (hSBA) at 1 month postvaccination; solicited reactogenicity and adverse events were monitored. Fifty-four participants enrolled. Bactericidal immune responses were evident after each dose of 4CMenB, as assessed by hSBA geometric mean titers and percentages of subjects with hSBA titers of ≥4 against the test strains or a 4-fold rise in titer over baseline. At 1 month postvaccination, most MenACWY-CRM recipients had hSBA titers of ≥8 against serogroups A, C, W-135, and Y. Few participants discontinued due to an adverse event or vaccine reaction. Rates of solicited reactions were lower after MenACWY-CRM than after 4CMenB administration. Sequential administration of 4CMenB and MenACWY-CRM provided robust evidence of an immune response against serogroups A, B, C, W-135, and Y in laboratory workers routinely exposed to meningococcal isolates.
doi:10.1128/CVI.00304-10
PMCID: PMC3067382  PMID: 21177912
16.  Meningococcal glycoconjugate vaccines 
Human Vaccines  2011;7(2):170-182.
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 meningitidis 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 US 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.
doi:10.4161/hv.7.2.13717
PMCID: PMC3166476  PMID: 21178398
meningococcus; Neisseria meningitidis; glycoconjugate vaccines; meningococcal disease; immunity; vaccination
17.  New Rapid Diagnostic Tests for Neisseria meningitidis Serogroups A, W135, C, and Y 
PLoS Medicine  2006;3(9):e337.
Background
Outbreaks of meningococcal meningitis (meningitis caused by Neisseria meningitidis) are a major public health concern in the African “meningitis belt,” which includes 21 countries from Senegal to Ethiopia. Of the several species that can cause meningitis, N. meningitidis is the most important cause of epidemics in this region. In choosing the appropriate vaccine, accurate N. meningitidis serogroup determination is key. To this end, we developed and evaluated two duplex rapid diagnostic tests (RDTs) for detecting N. meningitidis polysaccharide (PS) antigens of several important serogroups.
Methods and Findings
Mouse monoclonal IgG antibodies against N. meningitidis PS A, W135/Y, Y, and C were used to develop two immunochromatography duplex RDTs, RDT1 (to detect serogroups A and W135/Y) and RDT2 (to detect serogroups C and Y). Standards for Reporting of Diagnostic Accuracy criteria were used to determine diagnostic accuracy of RDTs on reference strains and cerebrospinal fluid (CSF) samples using culture and PCR, respectively, as reference tests. The cutoffs were 105 cfu/ml for reference strains and 1 ng/ml for PS. Sensitivities and specificities were 100% for reference strains, and 93.8%–100% for CSF serogroups A, W135, and Y in CSF. For CSF serogroup A, the positive and negative likelihood ratios (± 95% confidence intervals [CIs]) were 31.867 (16.1–63.1) and 0.065 (0.04–0.104), respectively, and the diagnostic odds ratio (± 95% CI) was 492.9 (207.2–1,172.5). For CSF serogroups W135 and Y, the positive likelihood ratio was 159.6 (51.7–493.3) Both RDTs were equally reliable at 25 °C and 45 °C.
Conclusions
These RDTs are important new bedside diagnostic tools for surveillance of meningococcus serogroups A and W135, the two serogroups that are responsible for major epidemics in Africa.
There are several strains ofNeisseria meningitidis that can cause seasonal outbreaks of meningitis in Africa. Treatment of patients and containment of the epidemic through vaccination depends on which strain is responsible. The new dipstick tests described here are accurate and suitable for storage and use in resource-poor settings.
Editors' Summary
Background
Bacterial meningitis, a potentially deadly infection of tissues that line the brain and spinal cord, affects over 1 million people each year. Patients with bacterial meningitis usually have fever, headache, and stiff neck, and may become unconscious and die if the disease is not treated within hours. Most cases of bacterial meningitis occur in Africa, particularly in the arid savannah region south of the Sahara known as the Sahel, where epidemic outbreaks of meningitis occur periodically. This region, also called the “meningitis belt,” extends from Senegal and adjacent coastal countries in West Africa across the continent to Ethiopia. Although most outbreaks tend to occur in the dry season, they differ in frequency in different areas of the meningitis belt, and may involve any of several kinds of bacteria. One of the major causes of epidemic meningitis is Neisseria meningitidis, a meningococcus bacterium that exists in several different groups. Group A has been a common cause of epidemic meningitis in Africa, and some outbreaks were due to group C. More recently, group W135 has emerged as an epidemic strain. In addition to prompt diagnosis and treatment of individual cases, effective public health strategies for controlling meningococcal meningitis include rapid identification of outbreaks and determination of the type of bacteria involved, followed by mass vaccination of people in the surrounding area without delay. Vaccines are chosen on the basis of the responsible meningococcal serogroup: either the inexpensive bivalent vaccine A/C or the expensive, less readily available trivalent vaccine A/C/W135. Before the advent of W135 as an epidemic clone, bivalent vaccine was applied in the meningitis belt without identification of the serogroup. With the appearance of the W135 strain in 2003, however, the determination of serogroup before vaccination is important to select an effective vaccine and avoid misspending of limited funds.
Why Was This Study Done?
Because there are few laboratories in the affected countries and epidemiological surveillance systems are inadequate, it is difficult for health authorities to mount a rapid and effective vaccination campaign in response to an outbreak. In addition, because the two main bacteria (meningococcus and pneumococcus) that cause meningitis require different antibiotic treatments, it is important for doctors to find out quickly which bacteria is causing an individual case. The authors of this study wanted to develop a rapid and easy test that can tell whether meningococcus is the cause of a particular case of meningitis, and if so, which group of meningococcus is involved. As most outbreaks in the meningitis belt occur in rural areas that are distant from well-equipped medical laboratories, it was necessary to develop a test that can be carried out at the patient's bedside by nurses, does not require refrigeration or laboratory equipment, and is highly accurate in distinguishing among the different groups of meningococcus.
What Did the Researchers Do and Find?
The researchers have developed a rapid test to determine whether a patient's meningitis is caused by one of the four most common groups of meningococcus circulating in Africa. The test is done on the patient's spinal fluid, which is obtained by a lumbar puncture (spinal tap) as part of the usual evaluation of a patient thought to have meningitis. The test uses two paper strips, also called dipsticks (one for groups A and W135/Y, and the other for groups C and Y), that can be placed in two separate tubes of the patient's spinal fluid. After several minutes, the appearance of red lines on the dipsticks shows whether one of the four groups of meningococcus is present. The dipsticks can be produced in large quantities and relatively cheaply. The researchers showed that the test dipsticks are stable for weeks in hot weather, and are therefore practical for bedside use in resource-poor settings. They examined the test on stored spinal fluid from patients in Niger and found that the dipstick test was able to identify the correct group of meningococcus more than 95% of the time for the three groups represented in these specimens (the results were compared to a standard DNA test or culture that are highly accurate for identifying the type of bacteria present but much more complicated and expensive).
What Do These Findings Mean?
The new dipstick test for meningococcal meningitis represents a major advance for health-care workers in remote locations affected by meningitis epidemics. This test can be stored without refrigeration and used at bedside in the hot temperatures typical of the African savannah during the meningitis season. The dipsticks are easier to use than currently available test kits, give more rapid results, and are more accurate in telling the difference between group Y and the increasingly important group W135. Further research is needed to determine whether the test can be used with other clinical specimens (such as blood or urine), and whether the test is dependable for detecting group C meningococcus, which is common in Europe but rare in Africa. Nonetheless, the dipstick test promises to be an important tool for guiding individual treatment decisions as well as public health actions, including vaccine selection, against the perennial threat of epidemic meningitis.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030337.
World Health Organization fact sheet on meningococcal meningitis
PATH Meningitis Vaccine Project
US Centers for Disease Control and Prevention page on meningococcal disease
doi:10.1371/journal.pmed.0030337
PMCID: PMC1563501  PMID: 16953658
18.  An evaluation of emerging vaccines for childhood meningococcal disease 
BMC Public Health  2011;11(Suppl 3):S29.
Background
Meningococcal meningitis is a major cause of disease worldwide, with frequent epidemics particularly affecting an area of sub-Saharan Africa known as the “meningitis belt”. Neisseria meningitidis group A (MenA) is responsible for major epidemics in Africa. Recently W-135 has emerged as an important pathogen. Currently, the strategy for control of such outbreaks is emergency use of meningococcal (MC) polysaccharide vaccines, but these have a limited ability to induce herd immunity and elicit an adequate immune response in infant and young children. In recent times initiatives have been taken to introduce meningococcal conjugate vaccine in these African countries. Currently there are two different types of MC conjugate vaccines at late stages of development covering serogroup A and W-135: a multivalent MC conjugate vaccine against serogroup A,C,Y and W-135; and a monovalent conjugate vaccine against serogroup A. We aimed to perform a structured assessment of these emerging meningococcal vaccines as a means of reducing global meningococal disease burden among children under 5 years of age.
Methods
We used a modified CHNRI methodology for setting priorities in health research investments. This was done in two stages. In the first stage we systematically reviewed the literature related to emerging MC vaccines relevant to 12 criteria of interest. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies). They answered questions from CHNRI framework and their “collective optimism” towards each criterion was documented on a scale from 0 to 100%.
Results
For MenA conjugate vaccine the experts showed very high level of optimism (~ 90% or more) for 7 out of the 12 criteria. The experts felt that the likelihood of efficacy on meningitis was very high (~ 90%). Deliverability, acceptability to health workers, end users and the effect on equity were all seen as highly likely (~ 90%). In terms of the maximum potential impact on meningitis disease burden, the median potential effectiveness of the vaccines in reduction of overall meningitis mortality was estimated to be 20%; (interquartile range 20-40% and min. 8%, max 50 %). For the multivalent meningococcal vaccines the experts had similar optimism for most of the 12 CHNRI criteria with slightly lower optimism in answerability and low development cost criteria. The main concern was expressed over the cost of product, its affordability and cost of implementation.
Conclusions
With increasing recognition of the burden of meningococcal meningitis, especially during epidemics in Africa, it is vitally important that strategies are taken to reduce the morbidity and mortality attributable to this disease. Improved MC vaccines are a promising investment that could substantially contribute to reduction of child meningitis mortality world-wide.
doi:10.1186/1471-2458-11-S3-S29
PMCID: PMC3231902  PMID: 21501447
19.  Antibody persistence and immune memory 15 months after priming with an investigational tetravalent meningococcal tetanus toxoid conjugate vaccine (MenACWY-TT) in toddlers and young children 
The present extension study, conducted in children originally vaccinated at 12–14 mo or 3–5 y of age, assessed antibody persistence and immune memory induced by an investigational tetravalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine (MenACWY-TT). In the original study, participants were randomized to receive one dose of MenACWY-TT or licensed age-appropriate meningococcal control vaccines. Fifteen months post-vaccination, all participants underwent serum sampling to evaluate antibody persistence and participants previously vaccinated as toddlers received a polysaccharide challenge to assess immune memory development.
 
Exploratory comparisons showed that (1) All children and ≥ 92.3% of the toddlers maintained serum bactericidal (rSBA) titers ≥ 1:8 at 15 mo post MenACWY-TT vaccination; statistically significantly higher rSBA geometric mean titers (GMTs) were observed compared with control vaccines. (2) At one month after polysaccharide challenge, all toddlers primed with MenACWY-TT or with the monovalent serogroup C conjugate vaccine had rSBA titers ≥ 1:8 and ≥ 1:128 for serogroup C and similar rSBA-GMTs; rSBA-GMTs for serogroups A, W-135 and Y were statistically significantly higher in toddlers primed with MenACWY-TT compared with the control vaccine. Thus, a single dose of MenACWY-TT induced persisting antibodies in toddlers and children and immune memory in toddlers.
This study has been registered at www.clinicaltrials.gov NCT00126984.
doi:10.4161/hv.20229
PMCID: PMC3495722  PMID: 22485049
children; immune memory; meningococcal vaccine; persistence; tetanus toxoid; toddlers
20.  Accelerating Policy Decisions to Adopt Haemophilus influenzae Type b Vaccine: A Global, Multivariable Analysis 
PLoS Medicine  2010;7(3):e1000249.
Jessica Shearer and colleagues analyze data from 147 countries to identify factors that influence the time taken to introduce routine vaccination against Haemophilus influenzae type b (Hib).
Background
Adoption of new and underutilized vaccines by national immunization programs is an essential step towards reducing child mortality. Policy decisions to adopt new vaccines in high mortality countries often lag behind decisions in high-income countries. Using the case of Haemophilus influenzae type b (Hib) vaccine, this paper endeavors to explain these delays through the analysis of country-level economic, epidemiological, programmatic and policy-related factors, as well as the role of the Global Alliance for Vaccines and Immunisation (GAVI Alliance).
Methods and Findings
Data for 147 countries from 1990 to 2007 were analyzed in accelerated failure time models to identify factors that are associated with the time to decision to adopt Hib vaccine. In multivariable models that control for Gross National Income, region, and burden of Hib disease, the receipt of GAVI support speeded the time to decision by a factor of 0.37 (95% CI 0.18–0.76), or 63%. The presence of two or more neighboring country adopters accelerated decisions to adopt by a factor of 0.50 (95% CI 0.33–0.75). For each 1% increase in vaccine price, decisions to adopt are delayed by a factor of 1.02 (95% CI 1.00–1.04). Global recommendations and local studies were not associated with time to decision.
Conclusions
This study substantiates previous findings related to vaccine price and presents new evidence to suggest that GAVI eligibility is associated with accelerated decisions to adopt Hib vaccine. The influence of neighboring country decisions was also highly significant, suggesting that approaches to support the adoption of new vaccines should consider supply- and demand-side factors.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, immunization averts more than 2 million deaths by preparing people's immune systems to recognize and attack disease-causing organisms (pathogens) rapidly and effectively. Although the immune system is designed to protect the human body against infections, the first time a person is exposed to a pathogen (usually during early childhood) their immune system can take some time to respond. As a result, they can become seriously ill or even die. However, the immune system “learns” from the experience and when the pathogen is encountered again, the immune system swings into action much more quickly. Immunization or vaccination is a safe way to make individuals resistant to infectious diseases. It works by exposing them to weakened or dead pathogens or to pathogen molecules (antigens) that the immune system recognizes as foreign. Widespread, routine immunization of children is, therefore, an essential component of national and global strategies to reduce childhood illnesses and deaths.
Why Was This Study Done?
Although many factors affect the uptake of immunization (in particular, vaccine prices), national policy decisions to adopt new vaccines are an essential step toward improving coverage. Unfortunately, these decisions are often delayed in developing countries. Thus, although many industrialized countries have routinely immunized their children with the highly effective Haemophilus influenza type b (Hib) conjugate vaccine since it became available in the early 1990s, only 13 low-income countries were using the vaccine in 2004. Hib bacteria, which cause pneumonia (lung infection) and meningitis (brain inflammation), kill about 370,000 unvaccinated young children every year. In this study, the researchers try to explain delays in the adoption of routine Hib vaccination in developing countries by analyzing the associations between Hib vaccination and factors such as national economic status, local Hib burden, and eligibility for support from the Global Alliance for Vaccines and Immunisation (GAVI Alliance; a public–private partnership that offers financial, technical, and health systems support for the introduction of national immunization programs to developing countries that meet certain eligibility criteria).
What Did the Researchers Do and Find?
The researchers used a statistical approach called accelerated failure time analysis to analyze data collected in 147 countries between 1990 and 2007 on vaccine costs, Hib disease incidence, GAVI eligibility, and other factors that could influence decision-makers' perceptions of the costs and benefits of Hib vaccination. After allowing for gross national income, region, and burden of Hib disease, the researchers identified several factors that influenced the time between the availability of a Hib conjugate vaccine in a country and a decision being made to introduce routine Hib vaccination. The receipt of GAVI support speeded the decision to adopt vaccination by 63%, for example, and sharing borders with two or more countries that had adopted the vaccine speeded the decision by 50%. By contrast, for each 1% increase in vaccine costs, the time to decision to adopt vaccination was delayed by 2%. The 1998 and 2006 World Health Organization recommendations on routine Hib vaccination and the existence of local studies on Hib disease had no influence on the time to decision.
What Do These Findings Mean?
These findings confirm previous studies that showed that increases in the price of Hib vaccine increase the time to adoption. In addition, they suggest that GAVI eligibility accelerates decisions to adopt this vaccine and show that the decisions made by neighboring countries are important, which suggests that policy diffusion may occur. Thus, in the case of adoption of the Hib vaccine, both supply-side and demand-side factors seem to be important. Its is relevant to note that during writing of the article, JCS, MLS, MRR, APB, and RAH were employed by the Hib Initiative, which was funded by the GAVI Alliance. The findings do not necessarily represent the views, policies or decisions of the Hib Initiative or the GAVI Alliance. Importantly, these findings are explanatory, not predictive, so they cannot be applied directly to new vaccines to improve their rate of adoption. Nevertheless, these findings highlight the potential importance of setting up formal and informal networks to facilitate policy diffusion and suggest that long-term price and supply certainty might be factors that could help to accelerate national decisions to adopt new and/or underutilized vaccines and other public-health technologies.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000249.
The World Health Organization provides information on immunization and on Haemophilus influenza type b (in several languages)
The GAVI Alliance Web site describes the work of this public–private partnership and provides details of developing countries eligible for Hib vaccination support
The Hib Initiative aims to reduce the risk of childhood death and disability through sustained use of Hib vaccine
MedlinePlus provides links to further resources on immunization and information on the Haemophilus influenzae type b vaccine (in English and Spanish)
doi:10.1371/journal.pmed.1000249
PMCID: PMC2838745  PMID: 20305714
21.  The investigational meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine (ACWY-TT) and the seasonal influenza virus vaccine are immunogenic and well-tolerated when co-administered in adults 
Co-administration of meningococcal serogroups A, C, W-135 and Y conjugate vaccine (ACWY-TT) with seasonal influenza vaccine was investigated in a subset of adults enrolled in a larger study evaluating lot-to-lot consistency of ACWY-TT and non-inferiority to licensed tetravalent meningococcal polysaccharide vaccine (MenPS). Subjects in this sub-study were randomized (3:1:1) to receive ACWY-TT alone (ACWY-TT group) or with seasonal influenza vaccine (Coad), or licensed MenPS alone. Serum bactericidal antibodies (rSBA) and serum haemagglutination-inhibition (HI) antibody titers were measured pre- and 1 mo post-vaccination. Non-inferiority of the Coad group compared with ACWY-TT group was demonstrated in terms of rSBA geometric mean antibody titers (GMTs) to serogroups A, W-135 and Y. For serogroup C the pre-defined non-inferiority limit was marginally exceeded. Post-vaccination rSBA GMTs were significantly higher (exploratory analysis) in the Coad group compared with the MenPS group for serogroups A, W-135, and Y and were similar to the MenPS group for serogroup C. Overall, > 97% of subjects achieved rSBA titers ≥ 1:128 for all serogroups. The Coad group met all criteria defined by the Committee on Human Medicinal Products (CHMP) for seroprotection, seroconversion and seroconversion factor for HI antibodies for all three influenza strains. Grade 3 solicited local/general symptoms were reported by ≤ 1.9% of subjects in any group. These data support the co-administration of ACWY-TT with seasonal influenza vaccine when protection is needed against both diseases.
 
This study is registered at clinicaltrials.gov NCT00453986
doi:10.4161/hv.20212
PMCID: PMC3495724  PMID: 22485048
ACWY vaccine; Neisseria meningitidis; adult; co-administration; immunogenicity; influenza vaccine; polysaccharide vaccine; vaccine
22.  Immunogenicity, Reactogenicity, and Immune Memory after Primary Vaccination with a Novel Haemophilus influenzae-Neisseria meningitidis Serogroup C Conjugate Vaccine▿  
Clinical and Vaccine Immunology  2007;14(4):426-434.
We evaluated two formulations of a new combined Haemophilus influenzae type b (Hib)-meningococcal serogroup C (MenC)-tetanus toxoid (TT) conjugated vaccine and two formulations of a new MenC-TT vaccine (trials 711202/001 and 711202/008; clinical trial register numbers NCT00135486 and NCT00135564 [www.ClinicalTrials.gov]). A total of 520 healthy infants were randomized to receive primary vaccination (at 2, 3, and 4 months) with either MenC-TT plus diphtheria-tetanus-acellular pertussis (DTPa)-hepatitis B virus (HBV)-inactivated poliovirus (IPV)/Hib, Hib-MenC-TT plus DTPa-HBV-IPV, or MenC-CRM197 plus DTPa-HBV-IPV/Hib (control). At 12 to 15 months, subjects received a polysaccharide challenge with meningococcal polysaccharide C plus a DTPa-HBV-IPV/Hib booster. Immune responses were assessed 1 month after dose 2, 1 month after dose 3, and prior to and 1 month after the booster. After primary vaccination, there was no difference between groups in seroprotection rates as measured by titers of serum bactericidal antibody (SBA) to MenC (≥1:8) or concentrations of anti-polyribosyl ribitol phosphate (PRP) antibody (≥0.15 μg/ml). Prior to the booster, there was no difference between groups in SBA seroprotection rates, whereas anti-PRP seroprotection rates were significantly higher after priming with Hib-MenC-TT. Booster doses induced large increases in SBA and anti-PRP antibodies in primed groups, indicating successful priming with induction of immune memory. Reactogenicity and safety were similar in all groups during the primary and booster phases. A novel combined Hib-MenC-TT conjugate vaccine induced MenC and Hib responses comparable to those induced by licensed monovalent vaccines. A Hib-MenC-TT conjugate vaccine provides vaccination against two major pathogens in a single injection and is a suitable candidate for use in primary or booster vaccination schedules.
doi:10.1128/CVI.00377-06
PMCID: PMC1865605  PMID: 17287313
23.  Meningococcal Factor H Binding Proteins in Epidemic Strains from Africa: Implications for Vaccine Development 
Background
Factor H binding protein (fHbp) is an important antigen for vaccines against meningococcal serogroup B disease. The protein binds human factor H (fH), which enables the bacteria to resist serum bactericidal activity. Little is known about the vaccine-potential of fHbp for control of meningococcal epidemics in Africa, which typically are caused by non-group B strains.
Methodology/Principal Findings
We investigated genes encoding fHbp in 106 serogroup A, W-135 and X case isolates from 17 African countries. We determined complement-mediated bactericidal activity of antisera from mice immunized with recombinant fHbp vaccines, or a prototype native outer membrane vesicle (NOMV) vaccine from a serogroup B mutant strain with over-expressed fHbp. Eighty-six of the isolates (81%) had one of four prevalent fHbp sequence variants, ID 4/5 (serogroup A isolates), 9 (W-135), or 74 (X) in variant group 1, or ID 22/23 (W-135) in variant group 2. More than one-third of serogroup A isolates and two-thirds of W-135 isolates tested had low fHbp expression while all X isolates tested had intermediate or high expression. Antisera to the recombinant fHbp vaccines were generally bactericidal only against isolates with fHbp sequence variants that closely matched the respective vaccine ID. Low fHbp expression also contributed to resistance to anti-fHbp bactericidal activity. In contrast to the recombinant vaccines, the NOMV fHbp ID 1 vaccine elicited broad anti-fHbp bactericidal activity, and the antibodies had greater ability to inhibit binding of fH to fHbp than antibodies elicited by the control recombinant fHbp ID 1 vaccine.
Conclusion/Significance
NOMV vaccines from mutants with increased fHbp expression elicit an antibody repertoire with greater bactericidal activity than recombinant fHbp vaccines. NOMV vaccines are promising for prevention of meningococcal disease in Africa and could be used to supplement coverage conferred by a serogroup A polysaccharide-protein conjugate vaccine recently introduced in some sub-Saharan countries.
Author Summary
Epidemics of meningococcal meningitis are common in sub-Saharan Africa. Most are caused by encapsulated serogroup A strains, which rarely cause disease in industrialized countries. A serogroup A polysaccharide protein conjugate vaccine recently was introduced in some countries in sub-Saharan Africa. The antibodies induced, however, may allow replacement of serogroup A strains with serogroup W-135 or X strains, which also cause epidemics in this region. Protein antigens, such as factor H binding protein (fHbp), are promising for prevention of meningococcal serogroup B disease. These proteins also are present in strains with other capsular serogroups. Here we report investigation of the potential of fHbp vaccines for prevention of disease caused by serogroup A, W-135 and X strains from Africa. Four fHbp amino acid sequence variants accounted for 81% of the 106 African isolates studied. While there was little cross-protective activity by antibodies elicited in mice by recombinant fHbp vaccines from each of the four sequence variants, a prototype native outer membrane vesicle (NOMV) vaccine from a mutant with over-expressed fHbp elicited antibodies with broad protective activity. A NOMV vaccine has the potential to supplement coverage by the group A conjugate vaccine and help prevent emergence of disease caused by non-serogroup A strains.
doi:10.1371/journal.pntd.0001302
PMCID: PMC3167780  PMID: 21909444
24.  Is a single dose of meningococcal serogroup C conjugate vaccine sufficient for protection? experience from the Netherlands 
Background
The first meningococcal serogroup C (MenC) conjugate vaccine was licensed in 1999 and introduced in the United Kingdom. Countries that have implemented the MenC vaccine since then in their national immunisation programmes use different schedules. Nevertheless, all involved countries seem to experience substantial declines in the incidence of MenC disease.
Discussion
Since 2001, the MenC conjugate vaccine has been implemented in the Netherlands by offering a single dose to all children aged 14 months. Prior to the introduction of the vaccine into the national immunisation programme, a catch-up vaccination campaign was initiated in which a single dose of the MenC conjugate vaccine was offered to all children aged from 14 months up to and including 18 years. Since then, there has been no report of any case of MenC disease among immunocompetent vaccinees. Administration of a single dose of MenC conjugate vaccine after infancy could be beneficial considering the already complex immunisation schedules with large numbers of vaccinations in the first year of life. The present paper deals with the advantages and critical aspects of a single dose of the MenC conjugate vaccine.
Summary
A single dose of MenC conjugate vaccine at the age of 14 months in combination with a catch up vaccine campaign appeared to be a successful strategy to prevent MenC disease in the Netherlands, thereby confirming that a single dose of the vaccine could sufficiently protect against disease. Nevertheless, this approach can only be justified in countries with a relatively low incidence of serogroup C meningococcal disease in the first year of life. Furthermore, a good surveillance programme is recommended for timely detection of vaccine breakthroughs and outbreaks among non-vaccinees, since long-term protection after a single dose in the second year of life cannot currently be guaranteed.
doi:10.1186/1471-2334-12-35
PMCID: PMC3293716  PMID: 22316426
25.  The Long Road to an Effective Vaccine for Meningococcus Group B (MenB) 
Neisseria meningitidis infection can cause life-threatening meningitis and meningococcal septicaemia. Over the past 40 years, vaccines against most of the main meningococcal serogroups have offered increasingly good protection from disease, with one major exception in the developed world: serogroup B meningococcus (MenB). In the United States, MenB accounts for about a quarter of cases of meningococcal meningitis, with the bulk of the rest caused by meningococcus serogroups C (MenC) and Y (MenY). In the UK, where a vaccine against MenC is widely used, MenB is now responsible for nearly 90% of cases of invasive meningococcal disease. Recent attempts to create a universal MenB vaccine have been thwarted by the variability of the surface proteins of MenB and by the similarity of the MenB capsule to human glycoproteins. This review discusses current meningococcal vaccine strategies and their limitations with regard to MenB, and examines a promising new strategy for the rational design of a MenB vaccine. Thanks to a fusion of a rational reverse genetics approach and a membrane vesicle approach, a MenB vaccine, 4CMenB (Bexsero®), has finally gained regulatory approval in Europe and could be in clinical use by the end of 2013.
doi:10.1016/S2049-0801(13)70037-2
PMCID: PMC4306095  PMID: 25628885
Evidence Based Medicine; Mass Media; Misrepresentation; Randomised Controlled Trials

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