Progress toward the global control of Neisseria meningitidis: 21st century vaccines, current guidelines, and challenges for future vaccine development

The control of meningitis, meningococcemia and other infections caused by Neisseria meningitidis is a significant global health challenge. Substantial progress has occurred in the last twenty years in meningococcal vaccine development and global implementation. Meningococcal protein-polysaccharide conjugate vaccines to serogroups A, C, W, and Y (modeled after the Haemophilus influenzae b conjugate vaccines) provide better duration of protection and immunologic memory, and overcome weak immune responses in infants and young children and hypo-responsive to repeated vaccine doses seen with polysaccharide vaccines. ACWY conjugate vaccines also interfere with transmission and reduce nasopharyngeal colonization, thus resulting in significant herd protection. Advances in serogroup B vaccine development have also occurred using conserved outer membrane proteins with or without OMV as vaccine targets. Challenges for meningococcal vaccine research remain including developing combination vaccines containing ACYW(X) and B, determining the ideal booster schedules for the conjugate and MenB vaccines, and addressing issues of waning effectiveness.

Related papers:

title: Epidemic meningitis, meningococcaemia, and Neisseria meningitidis

abstract: Meningococcus, an obligate human bacterial pathogen, remains a worldwide and devastating cause of epidemic meningitis and sepsis. However, advances have been made in our understanding of meningococcal biology and pathogenesis, global epidemiology, transmission and carriage, host susceptibility, pathophysiology, and clinical presentations. Approaches to diagnosis, treatment, and chemoprophylaxis are now in use on the basis of these advances. Importantly, the next generation of meningococcal conjugate vaccines for serogroups A, C, Y, W-135, and broadly effective serogroup B vaccines are on the horizon, which could eliminate the organism as a major threat to human health in industrialised countries in the next decade. The crucial challenge will be effective introduction of new meningococcal vaccines into developing countries, especially in sub-Saharan Africa, where they are urgently needed.

title: Neisseria meningitidis: biology, microbiology, and epidemiology.
abstract: Neisseria meningitidis (the meningococcus) causes significant morbidity and mortality in children and young adults worldwide through epidemic or sporadic meningitis and/or septicemia. In this review, we describe the biology, microbiology, and epidemiology of this exclusive human pathogen. N.meningitidis is a fastidious, encapsulated, aerobic gram-negative diplococcus. Colonies are positive by the oxidase test and most strains utilize maltose. The phenotypic classification of meningococci, based on structural differences in capsular polysaccharide, lipooligosaccharide (LOS) and outer membrane proteins, is now complemented by genome sequence typing (ST). The epidemiological profile of N. meningitidis is variable in different populations and over time and virulence of the meningococcus is based on a transformable/plastic genome and expression of certain capsular polysaccharides (serogroups A, B, C, W-135, Y and X) and non-capsular antigens. N. meningitidis colonizes mucosal surfaces using a multifactorial process involving pili, twitching motility, LOS, opacity associated, and other surface proteins. Certain clonal groups have an increased capacity to gain access to the blood, evade innate immune responses, multiply, and cause systemic disease. Although new vaccines hold great promise, meningococcal infection continues to be reported in both developed and developing countries, where universal vaccine coverage is absent and antibiotic resistance increasingly more common.

title: The current situation of meningococcal disease in Latin America and updated Global Meningococcal Initiative (GMI) recommendations.
abstract: The Global Meningococcal Initiative (GMI) was established in 2009 and comprises an international team of scientists, clinicians, and public health officials with expertise in meningococcal disease (MD). Its primary goal is to promote global prevention of MD through education, research, international cooperation, and developing recommendations that include decreasing the burden of severe disease. The group held its first roundtable meeting with experts from Latin American countries in 2011, and subsequently proposed several recommendations to reduce the regional burden of MD. A second roundtable meeting was convened with Latin American representatives in June 2013 to reassess MD epidemiology, vaccination strategies, and unmet needs in the region, as well as to update the earlier recommendations. Special emphasis was placed on the emergence and spread of serogroup W disease in Argentina and Chile, and the control measures put in place in Chile were a particular focus of discussions. The impact of routine meningococcal vaccination programs, notably in Brazil, was also evaluated. There have been considerable improvements in MD surveillance systems and diagnostic techniques in some countries (e.g., Brazil and Chile), but the lack of adequate infrastructure, trained personnel, and equipment/reagents remains a major barrier to progress in resource-poor countries. The Pan American Health Organization's Revolving Fund is likely to play an important role in improving access to meningococcal vaccines in Latin America. Additional innovative approaches are needed to redress the imbalance in expertise and resources between countries, and thereby improve the control of MD. In Latin America, the GMI recommends establishment of a detailed and comprehensive national/regional surveillance system, standardization of laboratory procedures, adoption of a uniform MD case definition, maintaining laboratory-based surveillance, replacement of polysaccharide vaccines with conjugate formulations (wherever possible), monitoring and evaluating implemented vaccination strategies, conducting cost-effectiveness studies, and developing specific recommendations for vaccination of high-risk groups.

title: Impact of MenAfriVac in nine countries of the African meningitis belt, 2010-15: an analysis of surveillance data.
abstract: In preparation for the introduction of MenAfriVac, a meningococcal group A conjugate vaccine developed for the African meningitis belt, an enhanced meningitis surveillance network was established. We analysed surveillance data on suspected and confirmed cases of meningitis to quantify vaccine impact.



We compiled and analysed surveillance data for nine countries in the meningitis belt (Benin, Burkina Faso, Chad, Côte d'Ivoire, Ghana, Mali, Niger, Nigeria, and Togo) collected and curated by the WHO Inter-country Support Team between 2005 and 2015. The incidence rate ratios (IRRs) of suspected and confirmed cases in vaccinated and unvaccinated populations were estimated with negative binomial regression models. The relative risk of districts reaching the epidemic threshold of ten per 100 000 per week was estimated according to district vaccination status.



The incidence of suspected meningitis cases declined by 57% (95% CI 55-59) in vaccinated compared with unvaccinated populations, with some heterogeneity observed by country. We observed a similar 59% decline in the risk of a district reaching the epidemic threshold. In fully vaccinated populations, the incidence of confirmed group A disease was reduced by more than 99%. The IRR for non-A serogroups was higher after completion of MenAfriVac campaigns (IRR 2·76, 95% CI 1·21-6·30).



MenAfriVac introduction has led to substantial reductions in the incidence of suspected meningitis and epidemic risk, and a substantial effect on confirmed group A meningococcal meningitis. It is important to continue strengthening surveillance to monitor vaccine performance and remain vigilant against threats from other meningococcal serogroups and other pathogens.



World Health Organization.

title: Meningococcal disease in the Asia-Pacific region: Findings and recommendations from the Global Meningococcal Initiative.
abstract: The Global Meningococcal Initiative (GMI) is a global expert group that includes scientists, clinicians, and public health officials with a wide range of specialties. The purpose of the Initiative is to promote the global prevention of meningococcal disease (MD) through education, research, and cooperation. The first Asia-Pacific regional meeting was held in November 2014. The GMI reviewed the epidemiology of MD, surveillance, and prevention strategies, and outbreak control practices from participating countries in the Asia-Pacific region.Although, in general, MD is underreported in this region, serogroup A disease is most prominent in low-income countries such as India and the Philippines, while Taiwan, Japan, and Korea reported disease from serogroups C, W, and Y. China has a mixed epidemiology of serogroups A, B, C, and W. Perspectives from countries outside of the region were also provided to provide insight into lessons learnt. Based on the available data and meeting discussions, a number of challenges and data gaps were identified and, as a consequence, several recommendations were formulated: strengthen surveillance; improve diagnosis, typing and case reporting; standardize case definitions; develop guidelines for outbreak management; and promote awareness of MD among healthcare professionals, public health officials, and the general public.

title: Meningococcal disease in the Middle East and Africa: Findings and updates from the Global Meningococcal Initiative.
abstract: The Global Meningococcal Initiative (GMI) has recently considered current issues in Middle Eastern and African countries, and produced two recommendations: (i) that vaccination of attendees should be considered for some types of mass-gathering events, as some countries mandate for the Hajj, and (ii) vaccination of people with human immunodeficiency virus should be used routinely, because of increased meningococcal disease (MD) risk. Differences exist between Middle Eastern and African countries regarding case and syndrome definitions, surveillance, and epidemiologic data gaps. Sentinel surveillance provides an overview of trends and prevalence of different capsular groups supporting vaccine selection and planning, whereas cost-effectiveness decisions require comprehensive disease burden data, ideally counting every case. Surveillance data showed importance of serogroup B MD in North Africa and serogroup W expansion in Turkey and South Africa. Success of MenAfriVac® in the African "meningitis belt" was reviewed; the GMI believes similar benefits may follow development of a low-cost meningococcal pentavalent vaccine, currently in phase 1 clinical trial, by 2022. The importance of carriage and herd protection for controlling invasive MD and the importance of advocacy and awareness campaigns were also highlighted.

title: An IgG monoclonal antibody to group B meningococci cross-reacts with developmentally regulated polysialic acid units of glycoproteins in neural and extraneural tissues.
abstract: The structurally similar polysialic acid capsules of group B meningococci and Escherichia coli K1 are poor immunogens, and attempts are currently being made to improve their immunogenicity by chemical modifications. An IgG monoclonal antibody to these polysialic acid capsules was used for the study of the presence of structurally similar components in tissue glycoproteins to investigate the reasons for the poor immunogenicity and to evaluate potential dangers in active or passive immunization. By immunoblotting polysialic acid was detected outside the brain in newborn rat kidney, heart, and muscle. It appeared in immunoblots as one component and with similar mobility to the neural cell adhesion molecule N-CAM. Specificity studies of the antibody and endosialidase treatment showed that the polysialic acid glycans detected were composed of chains as long as eight sialic acid residues or more. The polysialic acid was not detected in the corresponding tissues of the adult animal. These results indicate that polysialic acid units are developmentally regulated components of both neural and extraneural tissues, and are bound to components with properties similar to a known cell-adhesion molecule. This together with the presence of low amounts of polysialic acid even in the adult brain, suggests potential hazards in vaccination trials and suggested immunotherapy of meningitis caused by group B meningococci or E. coli K1, which should be carefully assessed.

title: Sialylation of Neisseria meningitidis lipooligosaccharide inhibits serum bactericidal activity by masking lacto-N-neotetraose
abstract: Exogenous sialylation of gonococcal lipooligosaccharide causes resistance to serum bactericidal activity. The aim of this study was to determine how lipooligosaccharide sialylation affects the serum sensitivities of group C Neisseria meningitidis strains. The relationship between the degree of sialylation or expression of the lipooligosaccharide sialic acid acceptor, lacto-N-neotetraose (LNnT), of nine meningococcal strains and their sensitivities to a pool of normal human sera was assessed. All strains expressed LNnT that was variously endogenously sialylated. Susceptibility to serum bactericidal activity ranged from extremely sensitive to resistant in 50% serum. For endogenously sialylated strains, the amount of killing correlated with the amount of free LNnT above a threshold of expression; strains that expressed less than the threshold survived in 25% serum. All strains added more sialic acid when they were grown in medium that contained cytidine monophospho-N-acetylneuraminic acid. Exogenous sialylation reduced the expression of free LNnT and significantly increased serum resistance. Exogenous sialylation affected killing through both classical and alternative complement pathways. The killing of exogenously sialylated strains also correlated with the amount of free LNnT. The amounts of endogenous, exogenous, and total sialic acid bound to LNnT did not correlate with the resistance of strains to serum bactericidal activity; rather, the loss of free LNnT expression by sialylation was associated with resistance. In conclusion, the expression of free LNnT by group C meningococcal strains is directly associated with the amount of killing of organisms in pooled human sera. Both endogenous and exogenous lipooligosaccharide sialylation are associated with increased serum resistance by masking LNnT.

title: Serogroup B meningococcal vaccines.
abstract: Neisseria meningitidis causes severe, often fatal septicemia and meningitis. Polysaccharide vaccines that offer protection against infection with meningococcal serogroups A, C, Y and W-135 are effective in older children and adults, and have been widely used. New polysaccharide-conjugate vaccines against one or more of these serogroups are now in use or under accelerated development; however, a broadly protective vaccine against infection by serogroup B N meningitidis is not yet available. Serogroup B contributes significantly to the burden of meningococcal disease in many industrialized countries where both epidemic and endemic serogroup B infections occur. Vaccines effective against specific strains responsible for serogroup B epidemic disease have been developed, but the development of a safe serogroup B vaccine that is cross protective against multiple strains and is effective in infants and young children is a challenge. In spite of these difficulties, promising approaches stemming from a better understanding of meningococcal pathogenesis and of the genetics of serogroup B N meningitidis continue to evolve. Progress toward an effective serogroup B vaccine, an important addition for meningococcal disease prevention, is the focus of this review. The epidemiology and pathogenesis of meningococcal disease are detailed, along with discussion of the challenges faced in the development of efficacious serogroup B vaccines.

title: Molecular typing of meningococci: recommendations for target choice and nomenclature.
abstract: The diversity and dynamics of Neisseria meningitidis populations generate a requirement for high resolution, comprehensive, and portable typing schemes for meningococcal disease surveillance. Molecular approaches, specifically DNA amplification and sequencing, are the methods of choice for various reasons, including: their generic nature and portability, comprehensive coverage, and ready implementation to culture negative clinical specimens. The following target genes are recommended: (1) the variable regions of the antigen-encoding genes porA and fetA and, if additional resolution is required, the porB gene for rapid investigation of disease outbreaks and investigating the distribution of antigenic variants; (2) the seven multilocus sequence typing loci-these data are essential for the most effective national, and international management of meningococcal disease, as well as being invaluable in studies of meningococcal population biology and evolution. These targets have been employed extensively in reference laboratories throughout the world and validated protocols have been published. It is further recommended that a modified nomenclature be adopted of the form: serogroup: PorA type: FetA type: sequence type (clonal complex), thus: B: P1.19,15: F5-1: ST-33 (cc32).

title: Biology and pathogenesis of the evolutionarily successful, obligate human bacterium Neisseria meningitidis.
abstract: For at least two hundred years, Neisseria meningitidis (the meningococcus), the cause of epidemic meningitis and sepsis, has inflicted rapid death, disability and fear on disparate human populations. The meningococcus is also recognized as a highly successful commensal organism exclusively found in humans. The evolution of N. meningitidis as an exclusive human commensal and sometimes a fulminant and fatal pathogen represents an important case study in microbial pathogenesis. We review the general status of our knowledge of pathogenesis of meningococcal carriage, transmission and virulence behavior with particular emphasis on the relevance of research on this topic to vaccine development.

title: Human immunity to the meningococcus. II. Development of natural immunity.
abstract: Results of the present study suggest that natural immunity to meningococcal disease is initiated, reinforced, and broadened by intermittent carriage of different strains of meningococci throughout life. In young adults, carriage of meningococci in the nasopharynx is an efficient process of immune sensitization. 92% of carriers of serogroup B, C, or Bo meningococci were found to develop increased titers of serum bactericidal activity to their own meningococcal isolate, and 87% developed bactericidal activity to heterologous strains of pathogenic meningococci. The rise in bactericidal titer occurred within 2 wk of onset of the carrier state, and was accompanied by an increase in titer of specific IgG, IgM, and IgA antibodies to meningococci. In early childhood, when few children have antibodies to pathogenic meningococci, active immunization seems to occur as a result of carriage of atypical, nonpathogenic strains. Immunity to systemic meningococcal infection among infants in the neonatal period is associated with the passive transfer of IgG antibodies from mother to fetus. The antigenic determinants which initiate the immune response to meningococci include the group-specific C polysaccharide, cross-reactive antigens, and type-specific antigens.

title: Immunoglobulin deficiencies and meningococcal disease.
abstract: Five male military recruits were studied for evidence of immunologic deficiencies. Four had recovered recently from a first-episode meningococcal meningitis and one presented with recurrent meningococcemia. A selective decrease in IgG and IgA was found in one of the first-episode patients and a selective IgG2 subclass deficiency in the recurrent case. No complement abnormalities were detected, however, in any of the five cases. These results present further proof of the crucial role of immunoglobulins in the defense against N. meningitidis and they stress the necessity of a through examination of humoral immunity before military career enlistment.

title: Sporadic Meningococcal Disease in Adults: Results of a 5-Year Population-Based Study
abstract: Infections due to Neisseria meningitidis continue to cause significant mortality and morbidity in the United States . About 3000 cases of meningococcal disease occur each year; recent increases in disease caused by serogroups C and B have been observed [2, 3], and meningococci that are relatively resistant to penicillin have been reported . Most meningococcal disease in the United States is sporadic. The highest attack rates are seen in young children, but many cases occur in adults . Despite a substantial number of cases and a 10% to 20% fatality rate , a comprehensive study of sporadic meningococcal disease in adults has not been done. Case reports suggest that presentations other than meningococcemia and meningococcal meningitis (for example, pneumonia) may occur in adults with sporadic meningococcal disease [5, 6]. Risk factors for adults, other than complement or immunoglobulin deficiencies [7], are not understood. Since 1988, we have investigated the epidemiology and clinical spectrum of invasive bacterial pathogens in metropolitan Atlanta through active population-based surveillance [8-10]. An important benefit of this approach is the identification of all disease in a defined population, which avoids the selection bias associated with the more commonly used hospital-base case series approach. In our study, we analyzed cases of meningococcal disease in adults ( 18 years of age) who were identified during 5 years of prospective, population-based surveillance.  Cases were defined by isolation of N. meningitidis from blood or cerebrospinal fluid and were identified by a prospective laboratory-based surveillance in metropolitan Atlanta [8-10], an eight-county area with 32 hospitals and a total population of 2 344 514 persons, including 1 743 276 adults 18 years of age or older (1990 census). All patients were living in the surveillance area at the time of infection. Surveillance was done from 1 December 1988 to 30 November 1993. Among the adults, 70% were white, 27% were black, and 3% were of other racial backgrounds; 47% were men, and 53% were women. The numbers of adults estimated in the surveillance area to be alive and infected with the human immunodeficiency virus (HIV) were as follows: in 1989, 3250; in 1990, 4146; in 1991, 4776; in 1992, 6660; and in 1993, ]. Isolates were identified as N. meningitidis at hospital laboratories and serogrouped using standard techniques. Strain identification, serogrouping, and penicillin susceptibility of all available isolates were confirmed at the Centers for Disease Control and Prevention. We obtained initial case reports from hospital laboratories and infection-control practitioners. We did laboratory audits at all hospitals every 6 months to evaluate reporting accuracy and to identify cases that were not reported originally (< 4% of cases). We reviewed the medical records of all adult patients to determine clinical features and underlying conditions. Incidence calculations were based on population data from the 1990 census. Relative risk was calculated as previously described . Patients were classified as having meningococcemia, chronic meningococcemia, meningococcal meningitis, or meningococcal bacteremia without sepsis on the basis of of meningococcal disease (Table 1) described by Wolf and Birbara [11], Apicella , and Benoit [13]. Table 1. Clinical Features of 44 Adults with Sporadic Meningococcal Disease in Metropolitan Atlanta (1988-1993)  From December 1988 to December 1993, 132 cases of sporadic meningococcal disease occurred in metropolitan Atlanta. Forty-four of the 132 cases (33%) occurred in adults 18 years of age or older. The annual incidence of meningococcal disease per 100 000 persons (95% Poisson CIs) in the total population was 1.13 (CI, 0.94 to 1.34; n = 132). The incidence in children 0 to 4 years old was 6.80 (CI, 5.2 to 8.73; n = 61) and in children 5 to 17 years old, 1.28 (CI, 0.84 to 1.86; n = 27). The incidence in all adults was 0.50 (CI, 0.37 to 0.68; n = 44); in adults 18 to 24 years old, 1.17 (CI, 0.65 to 1.93; n = 15); in adults 25 to 49 years old, 0.25 (CI, 0.13 to 0.43; n = 13); and in adults 50 years of age or older, 0.72 (CI, 0.41 to 1.17, n = 16). The incidence of meningococcal disease in black adults was 0.68 (CI, 0.39 to 1.10; n = 16); in white adults, 0.46 (CI, 0.30 to 0.66; n = 28); in women, 0.45 (CI, 0.28 to 0.69; n = 21); and in men, 0.56 (CI, 0.36 to 0.84; n = 23). In adults, most cases (33 of 44) occurred from November through April. No epidemic outbreaks or case clusters were reported in the surveillance area during the study, nor were any cases in adults secondary cases. However, two cases were associated with a defined exposure (one in a laboratory researcher working with large quantities of serogroup B N. meningitidis and one in a student exposed to an outbreak outside the surveillance area). Clinical features of the 44 adults with sporadic meningococcal disease are shown in Table 1. Fourteen adults (32%) presented with acute meningococcemia; 7 of these 14 were hypotensive, and 5 presented with a petechial, purpuric, or maculopapular rash. Seven of these 14 adults presented with rhinorrhea, cough, or sore throat, but there was no evidence of a defined respiratory infection, except in one adult infected with HIV, who presented with meningococcal pneumonia, respiratory failure, and sepsis. Four percent (2 of 44) of adults presented with chronic meningococcemia. Fourteen of the 44 adults (32%) presented with meningitis. One had maxillary sinusitis, and 5 had sore throat, cough, or rhinorrhea at presentation. A generalized rash was noted at presentation in 10 of 44 adults (71%) with meningitis. Fourteen of the 44 adults (32%) presented with bacteremia without sepsis. None of these patients had or developed a rash or meningitis. All but 1 presented with a defined respiratory infection (Table 1). Overall, 34% of adults (15 of 44) had pneumonia, sinusitis, or tracheobronchitis as the likely source for the meningococcal bacteremia (Table 1), with pneumonia present in 10 of 44 cases (23%). Seven of the 10 adults with pneumonia were 50 years of age or older (4 were older than 75 years old). Pneumonia was not present in adults 18 to 24 years old. A petechial or purpuric rash was noted at presentation in 13 of the 44 adults with sporadic meningococcal disease (32%) (Table 1); an additional 3 (7%) had a maculopapular rash, and 27 (61%) had no rash (13 of these 27 were black). Overall, 3 of 16 black persons (19%) compared with 14 of 28 white persons (50%) were noted to have a rash. No adults developed a rash after admission. Underlying conditions (Table 2) were identified in 21 of the 44 adults with meningococcal disease. Of the 15 cases among persons 18 to 24 years old, 14 of whom presented with meningococcemia or meningococcal meningitis, 2 (13%) had an underlying risk factor. However, complement screening assays were not done in 7 of the 15. (Overall, complement screening was done in 36% of adults [16 of 44].) Table 2. Underlying Conditions in 44 Adults with Sporadic Meningococcal Disease* Among persons 25 to 49 years old, 46% (6 of 13) had an underlying illness or risk factor (Table 2). Three were infected with HIV. Based on the estimates of HIV infection in the Atlanta population, the risk for meningococcal disease was increased in adults with HIV infection (relative risk, 23.8; CI, 7.4 to 76.7; P < 0.001), and the estimated annual incidence of meningococcal disease in adults with HIV infection was 11.2/100 000 adults. In adults 50 years of age or older, 81% (13 of 16) had at least one chronic underlying illness (Table 2). Overall, 19 of 29 adults older than 24 years of age had an immunocompromising condition compared with 2 of 15 adults younger than 24 years of age (relative risk, 4.91 [CI, 1.32 to 18.34]; P = 0.001, Fisher exact test). The association of capsular serogroup and meningococcal disease in adults is shown in Table 1 and Table 2. Serogroup data were available for 38 of 44 isolates: Eighteen (47%) were serogroup C; 14 (37%) were serogroup B; 4 (11%) were serogroup Y, and 2 (5%) were serogroup W-135. Isolates from cases of meningitis were either serogroup C (53%) or B (47%). Serogroup C was the identified serogroup in 10 of 12 cases with major sequelae (Table 1) and was the responsible serogroup in 9 of 13 isolates from adults 18 to 24 years old (Table 2). In contrast, bacteremia without sepsis was caused by serogroups B, Y, and W-135 in 8 of 11 cases with isolates. Similarly, pneumonia was caused by serogroups B, Y, and W-135 in eight of nine cases with isolates, and these serogroups were found in 80% (16 of 20) of isolates from cases with underlying conditions (Table 2). All 38 isolates available for testing were sensitive to penicillin.  During our 5-year study, one third of blood or cerebrospinal fluid culture-confirmed meningococcal cases in Atlanta occurred in adults, a result consistent with previous estimates . Rash and meningitis, the two most obvious signs of meningococcal infection, were absent in more than half of the adults. This emphasizes the need for heightened awareness of the different clinical presentations of meningococcal disease in adults in order to implement infection control measures designed to decrease secondary transmission . For example, nosocomial outbreaks have occurred because of transmission of N. meningitidis from patients with meningococcal pneumonia to hospital staff and to other patients . Upper respiratory symptoms, which may be caused by co-infections  or mucosal damage produced directly by meningococci , were noted in most of the adults in our series. In addition, more than one third of adults with meningococcal bacteremia presented with clinical pneumonia, purulent tracheobronchitis, or sinusitis. Meningococcal lobar and bronchopneumonia was first reported during the 1918-1919 influenza pandemic.

title: Tobacco smoke as a risk factor for meningococcal disease.
abstract: Since 1992 the US Pacific Northwest has experienced a substantial increase in the incidence of serogroup B meningococcal disease. The current meningococcal polysaccharide vaccine is poorly immunogenic in young children and does not protect against N. meningitidis serogroup B. Defining alternative approaches to the prevention and control of meningococcal disease is of considerable public health importance.



We performed a case-control study comparing 129 patients in Oregon and southwest Washington with 274 age- and area-matched controls. We used conditional logistic regression analysis to determine which exposures remained associated with disease after adjusting for other risk factors and confounders and calculated the proportion of disease attributable to modifiable exposures.



After adjustment for all other significant exposures identified, having a mother who smokes was the strongest independent risk factor for invasive meningococcal disease in children < 18 years of age [odds ratio (OR), 3.8; 95% confidence interval (CI) 1.6 to 8.9)], with 37% (CI 15 to 65) of all cases in this age group potentially attributable to maternal smoking. Adult patients were more likely than controls to have a chronic underlying illness (OR 10.8, CI 2.7 to 43.3), passive tobacco smoke exposure (OR 2.5, CI 0.9 to 6.9) and to smoke tobacco (OR 2.4, CI 0.9 to 6.6). Dose-response effects were seen for passive smoke exposure and risk of disease in all age groups.



Tobacco smoke exposure independently increases the risk of developing meningococcal disease.

title: Respiratory viruses and mycoplasma as cofactors for epidemic group A meningococcal meningitis.
abstract: To investigate the role of coincident respiratory viral and mycoplasmal agents in the pathogenesis of meningococcal meningitis, we performed a matched case-control study of 62 patients with group A meningococcal meningitis during an epidemic in Chad. Case patients were more likely than controls to have nasal colonization or infection with respiratory viruses and Mycoplasma species (matched odds ratio, 23; 95% confidence interval, 3.1 to 170). Respiratory pathogens were found more commonly in older patients with meningitis (odds ratios were 2.9 for children under age 5 years and 46.5 in those over age 15 years), consistent with the increasing risk of meningitis with age during epidemics. In controls, the presence of respiratory pathogens increased the risk of upper-respiratory-tract symptoms but did not significantly increase meningococcal carriage.

title: Meningococcal carriage among a university student population - United States, 2015.
abstract: Several outbreaks of serogroup B meningococcal disease have occurred among university students in recent years. In the setting of high coverage of the quadrivalent meningococcal conjugate vaccine and prior to widespread use of serogroup B meningococcal vaccines among adolescents, we conducted surveys to characterize the prevalence and molecular characteristics of meningococcal carriage among university students.



Two cross-sectional oropharyngeal carriage surveys were conducted among undergraduates at a Rhode Island university. Isolates were characterized using slide agglutination, real-time polymerase chain reaction (rt-PCR), and whole genome sequencing. Adjusted prevalence ratios and 95% confidence intervals were calculated using Poisson regression to determine risk factors for carriage.



A total of 1837 oropharyngeal specimens were obtained from 1478 unique participants. Overall carriage prevalence was 12.7-14.6% during the two survey rounds, with 1.8-2.6% for capsular genotype B, 0.9-1.0% for capsular genotypes C, W, or Y, and 9.9-10.8% for nongroupable strains by rt-PCR. Meningococcal carriage was associated with being male, smoking, party or club attendance, recent antibiotic use (inverse correlation), and recent respiratory infections.



In this university setting, the majority of meningococcal carriage was due to nongroupable strains, followed by serogroup B. Further evaluation is needed to understand the dynamics of serogroup B carriage and disease among university students.

title: Environmental Risk and Meningitis Epidemics in Africa
abstract: Epidemics of meningococcal meningitis occur in areas with particular environmental characteristics. We present evidence that the relationship between the environment and the location of these epidemics is quantifiable and propose a model based on environmental variables to identify regions at risk for meningitis epidemics. These findings, which have substantial implications for directing surveillance activities and health policy, provide a basis for monitoring the impact of climate variability and environmental change on epidemic occurrence in Africa.

title: Increased Risk for Meningococcal Disease Among Men Who Have Sex With Men in the United States, 2012–2015
abstract: Several clusters of serogroup C meningococcal disease among men who have sex with men (MSM) have been reported in the United States in recent years. The epidemiology and risk of meningococcal disease among MSM is not well described.



All meningococcal disease cases among men aged 18-64 years reported to the National Notifiable Disease Surveillance System between January 2012 and June 2015 were reviewed. Characteristics of meningococcal disease cases among MSM and men not known to be MSM (non-MSM) were described. Annualized incidence rates among MSM and non-MSM were compared through calculation of the relative risk and 95% confidence intervals. Isolates from meningococcal disease cases among MSM were characterized using standard microbiological methods and whole-genome sequencing.



Seventy-four cases of meningococcal disease were reported among MSM and 453 among non-MSM. Annualized incidence of meningococcal disease among MSM was 0.56 cases per 100000 population, compared to 0.14 among non-MSM, for a relative risk of 4.0 (95% confidence interval [CI], 3.1-5.1). Among the 64 MSM with known status, 38 (59%) were infected with human immunodeficiency virus (HIV). HIV-infected MSM had 10.1 times (95% CI, 6.1-16.6) the risk of HIV-uninfected MSM. All isolates from cluster-associated cases were serogroup C sequence type 11.



MSM are at increased risk for meningococcal disease, although the incidence of disease remains low. HIV infection may be an important factor for this increased risk. Routine vaccination of HIV-infected persons with a quadrivalent meningococcal conjugate vaccine in accordance with Advisory Committee on Immunization Practices recommendations should be encouraged.

title: High Risk for Invasive Meningococcal Disease Among Patients Receiving Eculizumab (Soliris) Despite Receipt of Meningococcal Vaccine
abstract: Use of eculizumab (Soliris, Alexion Pharmaceuticals), a terminal complement inhibitor, is associated with a 1,000-fold to 2,000-fold increased incidence of meningococcal disease (1). Administration of meningococcal vaccines is recommended for patients receiving eculizumab before beginning treatment (2,3). Sixteen cases of meningococcal disease were identified in eculizumab recipients in the United States during 2008-2016; among these, 11 were caused by nongroupable Neisseria meningitidis. Fourteen patients had documentation of receipt of at least 1 dose of meningococcal vaccine before disease onset. Because eculizumab recipients remain at risk for meningococcal disease even after receipt of meningococcal vaccines, some health care providers in the United States as well as public health agencies in other countries recommend antimicrobial prophylaxis for the duration of eculizumab treatment; a lifelong course of treatment is expected for many patients. Heightened awareness, early care seeking, and rapid treatment of any symptoms consistent with meningococcal disease are essential for all patients receiving eculizumab treatment, regardless of meningococcal vaccination or antimicrobial prophylaxis status.

title: Vaccines for Biodefense and Emerging and Neglected Diseases
abstract: The last 20 years has seen a rapid increase in infectious diseases, particularly those that are termed 'emerging diseases' such as SARS, 'neglected diseases' such as malaria and those that are deemed biothreats such as anthrax. It is well-recognized that the most effective modality for preventing infectious diseases is vaccination. This book provides researchers with a better understanding of what is currently known about these diseases, including whether there is a vaccine available or under development. It also informs readers of the key issues in development of a vaccine for each disease. This book provides a comprehensive treatise of the agents that are responsible for emerging and neglected diseases and those that can be used as biothreats. It includes the processes such as the vaccine development pathway, vaccine manufacturing and regulatory issues that are critical to the generation of these vaccines to the marketplace. Each chapter will include a map of the world showing where that particular disease is naturally found.

title: Complications of meningococcal disease in college students.
abstract: A retrospective study was conducted to provide a description of the risk, complications, fatality, and sequelae associated with invasive meningococcal disease in college students admitted in the Allegheny county (Pennsylvania) hospital system from January 1990 to May 1999.

title: Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP).
abstract: Meningococcal disease describes the spectrum of infections caused by Neisseria meningiditis, including meningitdis, bacteremia, and bacteremic pneumonia. Two quadrivalent meningococcal polysaccharide-protein conjugate vaccines that provide protection against meningococcal serogroups A, C, W, and Y (MenACWY-D [Menactra, manufactured by Sanofi Pasteur, Inc., Swiftwater, Pennsylvania] and MenACWY-CRM [Menveo, manufactured by Novartis Vaccines, Cambridge, Massachusetts]) are licensed in the United States for use among persons aged 2 through 55 years. MenACWY-D also is licensed for use among infants and toddlers aged 9 through 23 months. Quadrivalent meningococcal polysaccharide vaccine (MPSV4 [Menommune, manufactured by sanofi pasteur, Inc., Swiftwater, Pennsylvania]) is the only vaccine licensed for use among persons aged ≥56 years. A bivalent meningococcal polysaccharide protein conjugate vaccine that provides protection against meningococcal serogroups C and Y along with Haemophilus influenzae type b (Hib) (Hib-MenCY-TT [MenHibrix, manufactured by GlaxoSmithKline Biologicals, Rixensart, Belgium]) is licensed for use in children aged 6 weeks through 18 months. This report compiles and summarizes all recommendations from CDC's Advisory Committee on Immunization Practices (ACIP) regarding prevention and control of meningococcal disease in the United States, specifically the changes in the recommendations published since 2005 (CDC. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2005;54 [). As a comprehensive summary of previously published recommendations, this report does not contain any new recommendations; it is intended for use by clinicians as a resource. ACIP recommends routine vaccination with a quadrivalent meningococcal conjugate vaccine (MenACWY) for adolescents aged 11 or 12 years, with a booster dose at age 16 years. ACIP also recommends routine vaccination for persons at increased risk for meningococcal disease (i.e., persons who have persistent complement component deficiencies, persons who have anatomic or functional asplenia, microbiologists who routinely are exposed to isolates of N. meningitidis, military recruits, and persons who travel to or reside in areas in which meningococcal disease is hyperendemic or epidemic). Guidelines for antimicrobial chemoprophylaxis and for evaluation and management of suspected outbreaks of meningococcal disease also are provided.

title: Vaccination against meningococcal disease in Europe: review and recommendations for the use of conjugate vaccines.
abstract: At the end of 2005, six European countries had implemented public immunization campaigns with serogroup C conjugate vaccines, and all had experienced substantial declines in the incidence of serogroup C disease. A quadrivalent ACWY meningococcal vaccine is in use in the USA, but serogroup A is extremely rare in Europe and serogroups Y and W135 are infrequent causes of disease. This paper outlines recommendations on the use of conjugate vaccines in Europe based on the experience with meningococcal C conjugate (MCC) vaccines so far.

title: Genomic epidemiology of age-associated meningococcal lineages in national surveillance: an observational cohort study
abstract: Invasive meningococcal disease (IMD) is a worldwide health issue that is potentially preventable with vaccination. In view of its sporadic nature and the high diversity of Neisseria meningitidis, epidemiological surveillance incorporating detailed isolate characterisation is crucial for effective control and understanding the evolving epidemiology of IMD. The Meningitis Research Foundation Meningococcus Genome Library (MRF-MGL) exploits whole-genome sequencing (WGS) for this purpose and presents data on a comprehensive and coherent IMD isolate collection from England and Wales via the internet. We assessed the contribution of these data to investigating IMD epidemiology.  WGS data were obtained for all 899 IMD isolates available for England and Wales in epidemiological years 2010–11 and 2011–12. The data had been annotated at 1720 loci, analysed, and disseminated online. Information was also available on meningococcal population structure and vaccine (Bexsero, GlaxoSmithKline, Brentford, Middlesex, UK) antigen variants, which enabled the investigation of IMD-associated genotypes over time and by patients' age groups. Population genomic analyses were done with a hierarchical gene-by-gene approach.  The methods used by MRF-MGL efficiently characterised IMD isolates and information was provided in plain language. At least 20 meningococcal lineages were identified, three of which (hyperinvasive clonal complexes 41/44 [lineage 3], 269 [lineage 2], and 23 ) were responsible for 528 (59%) of IMD isolates. Lineages were highly diverse and showed evidence of extensive recombination. Specific lineages were associated with IMD in particular age groups, with notable diversity in the youngest and oldest individuals. The increased incidence of IMD from 1984 to 2010 in England and Wales was due to successive and concurrent epidemics of different lineages. Genetically, 74% of isolates were characterised as encoding group B capsules: 16% group Y, 6% group W, and 3% group C. Exact peptide matches for individual Bexsero vaccine antigens were present in up to 26% of isolates.  The MRF-MGL represents an effective, broadly applicable model for the storage, analysis, and dissemination of WGS data that can facilitate real-time genomic pathogen surveillance. The data revealed information crucial to effective deployment and assessment of vaccines against N meningitidis. Funding Meningitis Research Foundation, Wellcome Trust, Public Health England, European Union.

title: HUMAN IMMUNITY TO THE MENINGOCOCCUS IV. IMMUNOGENICITY OF GROUP A AND GROUP C MENINGOCOCCAL POLYSACCHARIDES IN HUMAN VOLUNTEERS
abstract: High molecular weight group A and group C meningococcal polysaccharides had no significant toxicity for mice or guinea pigs. Furthermore, these polysaccharide preparations contained negligible amounts of biologically active endotoxin. The high molecular weight group A and group C meningococcal polysaccharides were excellent immunogens in six human volunteers. Antibodies belonging to the immunoglobulin classes IgG, IgM, and IgA were produced. These antibodies were highly meningococcocidal in the presence of complement.

title: Meningococcal infections. 2. Field trial of group C meningococcal polysaccharide vaccine in 1969-70.
abstract: A second large-scale field trial of group C meningococcal polysaccharide vaccine in US Army recruits confirmed the efficacy and safety of the vaccine. When the results of all studies over a 2-year period were combined, the reduction in group-specific disease rates was 89.5%.

title: HUMAN IMMUNITY TO THE MENINGOCOCCUS I. THE ROLE OF HUMORAL ANTIBODIES
abstract: Susceptibility to systemic meningococcal disease is related to a selective deficiency of humoral antibodies to pathogenic strains of meningococci. In a study of the age-specific incidence of meningococcal meningitis in the United States, it was found that the proportion of individuals with serum bactericidal activity to meningococci of serogroups A, B, and C was reciprocally related to the incidence of disease. The prevalence of bactericidal activity was highest at birth and among adults, and lowest in infants between 6 and 24 months of age. Sera from 51 of 54 prospective cases of meningococcal disease among military recruits were deficient in antibodies to homologous and heterologous strains of pathogenic meningococci as determined by serum bactericidal activity and indirect immunofluorescence. Such sera, however, could support the bactericidal activity of purified human gamma globulin (Cohn fraction II), and such individuals could respond immunologically to infection with meningococci. The implication is that susceptible persons are deficient in antimeningococcal antibodies because they have not received significant exposure to meningococcal antigens in the past. The fate of individuals who lack bactericidal antibodies to pathogenic meningococci was determined during an outbreak of group C meningitis among military recruits. The incidence of disease was found to be primarily associated with the incidence of exposure of susceptibles to the pathogenic strains. Whereas 81.5% of the presumed susceptibles acquired a meningococcal strain, only 24.1% acquired an organism similar to the prevalent disease-producing strains. Of the exposed susceptibles, 38.5% developed systemic meningococcal disease.

title: Thymus-independent and thymus-dependent responses to polysaccharide antigens.
abstract: Immune responses to polysaccharide antigens are thymus-independent (TI). Conversion of a polysaccharide antigen to a thymus-dependent (TD) antigen by covalent coupling to an immunogenic protein carrier alters the response to the polysaccharide in several important ways. Of primary importance for the prevention of invasive diseases in infants caused by encapsulated bacteria is the shift of the peak antibody response to a much younger age. Another important change is the development of memory B cells primed and ready to respond to either the polysaccharide, as would be encountered during an infection, or to a second dose of the same antigen. Additional immunoglobulin isotypes not seen or seen as a minor component in response to the polysaccharide are also a feature of the TD response. Finally, the diversity of the antibody population is increased after immunization with a TD vaccine compared with that seen after immunization with a TI vaccine.

title: The Global Meningococcal Initiative: global epidemiology, the impact of vaccines on meningococcal disease and the importance of herd protection
abstract: The 2015 Global Meningococcal Initiative (GMI) meeting discussed the global importance of meningococcal disease (MD) and its continually changing epidemiology.  Although recent vaccination programs have been successful in reducing incidence in many countries (e.g. Neisseria meningitidis serogroup [Men]C in Brazil, MenA in the African meningitis belt), new clones have emerged, causing outbreaks (e.g. MenW in South America, MenC in Nigeria and Niger). The importance of herd protection was highlighted, emphasizing the need for high vaccination uptake among those with the highest carriage rates, as was the need for boosters to maintain individual and herd protection following decline of immune response after primary immunization.  The GMI Global Recommendations for Meningococcal Disease were updated to include a recommendation to enable access to whole-genome sequencing as for surveillance, guidance on strain typing to guide use of subcapsular vaccines, and recognition of the importance of advocacy and awareness campaigns.

title: Effectiveness of meningococcal serogroup C vaccine programmes.
abstract: Since the introduction of monovalent meningococcal serogroup C (MenC) glycoconjugate (MCC) vaccines and the implementation of national vaccination programmes, the incidence of MenC disease has declined markedly as a result of effective short-term vaccination and reduction in acquisition of MenC carriage leading to herd protection. Monovalent and quadrivalent conjugate vaccines are commonly used vaccines to provide protection against MenC disease worldwide. Studies have demonstrated that MCC vaccination confers protection in infancy (0-12 months) from the first dose but this is only short-term. NeisVac-C(®) has the greatest longevity of the currently licensed MCC vaccines in terms of antibody persistence, however antibody levels have been found to fall rapidly after early infant vaccination with two doses of all MCC vaccines - necessitating a booster at ∼12 months. In toddlers, only one dose of the MCC vaccine is required for routine immunization. If herd protection wanes following catch-up campaigns, many children may become vulnerable to infection. This has led many to question whether an adolescent booster is also required.

title: Impact of meningococcal serogroup C conjugate vaccines on carriage and herd immunity.
abstract: 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.



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.



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.



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.

title: Impact of meningococcal C conjugate vaccination four years after introduction of routine childhood immunization in Brazil.
abstract: Routine infant immunization with meningococcal C conjugate (MCC) vaccination started in Brazil in November 2010, scheduled at three and five months plus a booster at 12-15months of age. No catch-up was implemented. We assessed the impact of vaccination on meningococcal C disease (MenC) four years after vaccination start in the National Immunization Program.



We performed an ecological quasi-experimental design from 2008 to 2014 using a deterministic linkage between the National Notification and the National Reference Laboratory databases for meningitis. We conducted an interrupted time-series analysis considering Brazil except for Salvador municipality, because an epidemic of serogroup C disease occurred in this city, which prompted a mass vaccination campaign with catch-up for adolescents in 2010. Observed MenC rates in the post-vaccination period were compared to expected rates calculated from the pre-vaccination years. Results for Salvador were presented as descriptive data. An additional time-series analysis was performed for the state of São Paulo.



A total of 18,136 MenC cases were analyzed. The highest incidence rates were observed for infants aged <12months and no second incident peak was observed for adolescents. For Brazil, MenC rates were reduced by 67.2% (95%CI 43.0-91.4%) for infants <12months of age, 92.0% (77.3-106.8%) for the age-group 12-23months, and 64.6% (24.6-104.5%) for children aged 2-4years. For children 5-9years old, MenC rates reduced 19.2% (9.5-28.9%). Overall, 955 MenC cases were averted in Brazil in individuals aged <40years after MCC vaccination. 
After four years of infants and toddlers vaccination start, MenC invasive disease reduced in the target population. This investigation provide a robust baseline to ascertain how much the upcoming catch-up dose in 12-13years of age will accelerate the decrease in MenC incidence rates among youths in Brazil.

title: Meningococcal disease before and after the introduction of meningococcal serogroup C conjugate vaccine. Federal District, Brazil.
abstract: To analyze the behavior of meningococcal disease in the Federal District, Brazil, from 2005 to 2011, and to assess the direct impact of the meningococcal serogroup C conjugate vaccine.



A descriptive study of cases of meningococcal disease among residents of the Federal District. We included in the study confirmed cases of meningococcal disease reported to the local surveillance. To reduce underreporting we compared data to the Brazilian Mortality Database and the Public Health Laboratory Database. We studied sociodemographic, clinical, and pathogen-related variables. For the assessment of the impact of meningococcal serogroup C conjugate vaccine, which was introduced in 2010 for children under two years of age, we compared the incidence of meningococcal disease before and after vaccine introduction in the recommended age groups for vaccination.



We identified 309 cases of meningococcal disease, of which 52.1% were males. The average case fatality rate was 20.7%, the median age was three years and there was a predominance of serogroup C (70.2%) and C:23:P1.14-6 phenotype throughout the study period. In 2005-2009, 2010 and 2011, the incidence rates of meningococcal disease were 2.0, 1.8 and 0.8/100,000 inhabitants/year, while mortality rates were 0.4, 0.4 and 0.2/100,000 inhabitants/year, respectively. In the first and last periods, the incidence in poorer and more affluent areas were, respectively, 2.0 and 0.8, and 0.9 and 0.0/100,000 inhabitants/year. Comparing 2009 (the year prior to the introduction of meningococcal serogroup C conjugate vaccine) and 2011, there was 85% reduction in the incidence of serogroup C meningococcal disease in children under four years of age, from 9.0 to 1.3/100,000 (p<0.01).



The meningococcal serogroup C conjugate vaccine strategy implemented in Brazil proved highly effective and had a strong direct impact on the target population. However, case fatality rates of meningococcal disease remain high with a wide gap in the risk of disease between poor and affluent areas, pointing to the need to reexamine the current strategy on a regular base.

title: Clinical evaluation of a group B meningococcal N-propionylated polysaccharide conjugate vaccine in adult, male volunteers.
abstract: The safety and immunogenicity of a group B meningococcal vaccine, consisting of N-propionylated (NPr) B capsular polysaccharide conjugated to tetanus toxoid, was tested for the first time, in 17 healthy male volunteers aged between 18 and 40 years. Four escalating dosages of vaccine were tested and each was given as three intramuscular injections at 4-week intervals. The vaccine was well tolerated and induced only mild and transient, dose-dependent, injection-site reactions. One month after the last injection, there was no evidence of the production of autoantibodies or antibodies binding to PSA-NCAM. The vaccine induced an increase in the pre-existing titres of IgM specific to B polysaccharide and NPr B polysaccharide. Moreover, it induced IgG antibodies specific to NPr B polysaccharide, which were undetectable before vaccination. However, no functional activity of vaccine-induced antibodies was demonstrated in bactericidal assays, opsonophagocytic tests or passive protection tests.

title: Recent Progress in the Prevention of Serogroup B Meningococcal Disease
abstract: The widespread use of meningococcal polysaccharide conjugate vaccines has highlighted the challenge of providing protection against serogroup B disease. Over a period of 4 decades, vaccine development has focused on subcapsular protein antigens, first with outer membrane vesicle (OMV) vaccines against epidemic outbreaks, and more recently on new multicomponent vaccines designed to offer better cross-protection against the antigenically diverse strains responsible for endemic disease. Because of the low incidence of meningococcal disease, the protective efficacy of these vaccines has not been determined in clinical studies, and their licensure has been based on serological data; however, the serological assays used to predict protective coverage have limitations. As a result, evidence of the effectiveness of these vaccines against different strains and the contribution of specific antigens to protection can only be provided by epidemiological analyses following their implementation in sufficiently large populations. The recent inclusion of the four-component meningococcal serogroup B (4CMenB) vaccine, Bexsero, in the infant immunization program in the UK has provided preliminary evidence that the vaccine is effective. Ongoing surveillance will provide valuable data on its longer-term impact and antigenic coverage. Further development of protein-based vaccines against meningococcal disease is anticipated to improve antigenic coverage and adjust to changes in circulating strains. At the same time, alternative immunization strategies may be explored to improve overall vaccine effectiveness by, for example, protecting the youngest infants or providing herd protection.

title: Advances in the development of vaccines against Neisseria meningitidis.
abstract: Developments during the past decade have renewed hopes for solving this seemingly intractable problem. Knowledge of the meningococcal genome has led to the identification of novel antigens that have been incorporated into the NMB vaccines now being studied in clinical trials. However, it remains unclear whether these vaccines will provide sufficient immunogenicity in infants as well as wide-ranging coverage. This review highlights the evolution of meningococcal vaccines in general and discusses strategies being used to overcome the barriers to developing vaccines against NMB. Epidemiology of N. meningitidis Infection Meningococcal disease is a global health problem. The World Health Organization estimates that there are 1.2 million cases of invasive meningococcal disease and 135,000 related deaths annually. 3 Although the disease occurs sporadically in industrialized countries, with an incidence of 0.35 cases per 100,000 population in the United States and of 1.01 per 100,000 in Europe (ranging from 0.25 to 4.4 per 100,000 in Italy and Malta, respectively), 4 the major disease burden is in the nonindustrialized countries. A recent epidemic in Nigeria resulted in 4164 cases and 171 deaths in 1 week alone. 5 The meningococcus is pathogenic only in humans. It colonizes the nasopharynx asymptomatically in up to 40% of the adult population but occasionally causes invasive disease. When the infection is classified according to the polysaccharide capsule surrounding the bacterium, only six capsular groups (A, B, C, W-135, X, and Y) are associated with invasive disease. 6 The epidemiology of disease caused by these groups varies: group A is responsible for large epidemics in Africa, in which the incidence approaches 1000 cases per 100,000 population (and may involve environmental factors), whereas groups B and C cause disease predominantly in industrialized and newly industrialized countries. 2,6 Recently, groups W-135 and X (predominantly in Africa) and group Y (in the United States and other countries) have emerged as important disease-causing isolates.

title: Use of Serogroup B Meningococcal Vaccines in Adolescents and Young Adults: Recommendations of the Advisory Committee on Immunization Practices, 2015.
abstract: At its June 2015 meeting, the Advisory Committee on Immunization Practices (ACIP) recommended that adolescents and young adults aged 16–23 years may be vaccinated with a serogroup B meningococcal (MenB) vaccine to provide short-term protection against most strains of serogroup B meningococcal disease. This report summarizes the deliberations of ACIP, the rationale for its decision, and recommendations for use of MenB vaccines in adolescents and young adults. Two MenB vaccines have recently been licensed by the Food and Drug Administration (FDA) for use in the United States and approved for use in persons aged 10–25 years: MenB-FHbp (Trumenba, Wyeth Pharmaceuticals, Inc.) and MenB-4C (Bexsero, Novartis Vaccines). Both MenB vaccines were licensed based on statutory regulations for accelerated approval, which enabled FDA to approve the MenB vaccines for serious or life-threatening diseases based on safety and demonstration that vaccine effectiveness, as measured by bactericidal antibody responses with assays using several MenB test strains that were representative of prevalent strains in the United States, is reasonably likely to predict clinical benefit. As a requirement for accelerated approval, confirmatory studies in the postmarketing period will be conducted to verify and further describe the effectiveness of the vaccines against an extended number of MenB strains that represent a broader diversity of endemic disease. Additional postlicensure safety data are also needed and will be reviewed by ACIP as they become available.

title: Serum bactericidal antibody assays - The role of complement in infection and immunity.
abstract: Complement is an essential component of the immune system and human pathogenic organisms have developed various mechanisms for evading complement mediated serum killing. The "gold standard" for measuring the ability of vaccine-induced antibody to kill Neisseria meningitidis is the serum bactericidal antibody (SBA) assay which measures complement mediated killing via antibody. This assay requires active complement, either intrinsic from the serum being tested or the addition of exogenous complement, either from a human or from another species such as rabbit. For serogroup C, an SBA titre of ≥4 was established as the correlate of protection when using human complement and ≥8 as the threshold when using rabbit complement, based on comparative assay results. Licensure of meningococcal vaccines, including polysaccharide protein conjugate vaccines and serogroup B vaccines has been based on the immune responses measured with the SBA assay, thus on a surrogate of vaccine efficacy. This review examines the use of complement and the SBA assay to assess immunity to meningococcal infection, and provides examples of vaccine trials in different age groups where various assays have been used.

title: Serum bactericidal activity correlates with the vaccine efficacy of outer membrane vesicle vaccines against Neisseria meningitidis serogroup B disease.
abstract: For evaluation of serum bactericidal activity (SBA) as surrogate for the efficacy of outer membrane vesicle (OMV) vaccines against Neisseria meningitidis serogroup B disease, we have reanalyzed data from a randomized double blind placebo-controlled efficacy trial involving 172000 secondary school students (aged 13-14 years) in Norway (1988-1991). A cohort of the efficacy trial consisting of 880 individuals was selected for immunogenicity studies. An efficacy of 87% was calculated for a 10-month observation period. However, after an observation period of 29 months, the estimated efficacy against group B disease induced by vaccination was 57%. The immunogenicity study showed that the SBA geometric mean titer (GMT) for the vaccinees was 2.4 before vaccination and 19.0 six weeks after the second vaccine dose. One year after vaccination the GMT was reduced to 2.8. A separate three-dose study with 304 adolescents showed that with a third dose at 10 months after the second dose (i.e. when cases of disease started to appear) a strong booster response was induced. Ten months after the second dose the SBA was reduced to near pre-immunization level. Following the third dose the SBA geometric mean titer of 2.7 increased to 62.3. One year after the third dose, the GMT was markedly higher than 6 weeks after the second dose (12.6 versus 8.8). Thus, protection after vaccination corresponds with the level of SBA. In order to reach lasting protective levels of SBA in a population, three vaccine doses are probably required. Measurements of SBA are likely to be useful for evaluating various upcoming formulations and improvements of immunization regimens for OMV vaccines.

title: Clinical efficacy of meningococcus group A capsular polysaccharide vaccine in children three months to five years of age.
abstract: We performed field trials in the course of an epidemic in Finland to learn whether Group A memingococcal capsular polysaccharide vaccine protects infants and young children from meningitis. The first trial involved 130,178 children between the ages of three months and five years; 49,295 children received the vaccine, 48,977 received a control Haemophilus influenzae Type b polysaccharide vaccine, and 31.906 remained unvaccinated. No cases of meningitis or sepsis caused by Group A meningococci were seen in the first year of observation among the children vaccinated with meningococcal vaccine whereas six occurred among those vaccinated with the H. influenzae vaccine and 13 among those not vaccinated. In the second trial 21,007 children of the same ages received the meningococcal vaccine. No cases caused by Group A occurred among those vaccinated, although five to seven would have been expected within the year. Meningococcal Group A vaccine appears efficacious in young infants and children.

title: Serum antibodies to capsular polysaccharide vaccine of group A Neissera meningitidis followed for three years in infants and children.
abstract: The persistence of antibodies to the capsular polysaccharide of group A Neissera meningitidis was studied in 2,030 persons vaccinated at the age of 10 weeks to 19 years and followed for three years. Both the initial antibody response and the persistence of elevated serum titers of antibody were markedly age-dependent. In infants younger than 12 months, a statistically significant antibody response was obtained after a booster dose of vaccine and was maintained for one year. In infants aged 12-17 months, the response after booster vaccination was higher and was maintained for two years. Children older than 17 months did not receive a booster injection. The initial response in the age group 18-23 months was good, but the decline of antibody level was more rapid, so that an elevated antibody titer was not maintained for more than one year. With increasing age, the decrease of the vaccination-induced antibody levels was progressively slower throughout the age bracket studied.

title: Human immune response to various doses of group Y and W135 meningococcal polysaccharide vaccines
abstract: A divalent vaccine containing equal weights of Neisseria meningitidis group Y and group W135 capsular polysaccharides was inoculated subcutaneously into groups of 32 military recruit volunteers at doses of 10, 25, 50, and 100 micrograms in 10-microliter/microgram volumes. At 4 weeks, the two higher doses induced significantly greater binding antibody responses than did the two lower doses. Differences in response were not found between the two higher doses or between the two lower doses. An additional 32 volunteers received a dose of 25 micrograms in a 20-microliter/microgram volume. Binding antibody response to this vaccine did not differ from the response to doses of 10 and 25 microgram in 10-microliter/microgram volumes. In contrast, bactericidal antibody responses did not differ among doses. Bactericidal antibody was induced in 100% of individuals with low (greater than 4 log2) preexisting serum bactericidal activity, regardless of dose. Bactericidal antibody nonresponse was restricted to individuals with high preexisting serum bactericidal titers. The discrepant dose response between binding and bactericidal antibody resulted from the induction of nonlytic antibody by the higher doses. We conclude that there are no advantages to doses in excess of 5 micrograms of these two chemically similar polysaccharides for the target population of young adult military recruits.

title: Hyporesponsiveness and its clinical implications after vaccination with polysaccharide or glycoconjugate vaccines
abstract: Hyporesponsiveness (immune tolerance) follows vaccination with meningococcal polysaccharide and many pneumococcal polysaccharide serotypes. Hyporesponsiveness after Haemophilus influenzae type b polysaccharide vaccination has not been directly observed, but may follow exposure during disease in some individuals. Use of currently licensed conjugate vaccines has not been associated with hyporesponsiveness to date, with the possible exception of pneumococcal serotype 3. Introduction of polysaccharide vaccines anywhere into a conjugate vaccination schedule may result in reduced immune responses on subsequent exposure. This review of vaccine-induced hyporesponsiveness and its potential clinical implications considers recent evidence suggesting that hyporesponsiveness may occur for specific components of combined conjugate vaccines, such as pneumococcal serotype 3. These data have implications for the development of new multivalent vaccines.

title: History of meningococcal vaccines and their serological correlates of protection.
abstract: For over a hundred years Neisseria meningitidis has been known to be one of the major causes of bacterial meningitis. However, effective vaccines were not developed until the latter part of the 20th century. The first of these were based on purified high molecular weight capsular polysaccharides and more recently the development of glycoconjugate vaccines has made paediatric immunisation programmes possible. The prevention of group B meningococcal disease has remained a challenge throughout this period. This review charts the history of the development of meningococcal vaccines and the importance of serological correlates of protection in their evaluation.

title: Seroconversion and duration of immunity after vaccination against group C meningococcal infection in young children.
abstract: An increase in the incidence of group C meningococcal disease was observed in the Murcia Region (Spain) during 1996-1997. In September 1997, a massive vaccination campaign was implemented among the population aged 18 months to 19 years. The aim of this study was to assess the seroconversion rate of children aged 18-59 months and the persistence of immune response 1 year after vaccination. A total of 296 children were included. Blood samples were obtained before vaccination and 1 month and 1 year after vaccination. Three point seven percent of the children had bactericidal antibody titres of >/=1:8 before vaccination. One month after vaccination seroconversion was 63.7%, with a growing trend related to age at vaccination (p<0.0001). The increase in antibody titres was shown to be quantitatively greater above the age of 36 months (p<0.0001). One year after vaccination only 4.3% of the children who initially seroconverted still had bactericidal activity. Seroconversion in children under 5 increases with age but antibodies decline rapidly in the year following vaccination.

title: Induction of immunologic refractoriness in adults by meningococcal C polysaccharide vaccination.
abstract: Thirty-four adults were vaccinated with 1/50 of the usual dose of meningococcal polysaccharide vaccine (1 microg of A, C, Y, and W135 polysaccharides, given intramuscularly). This dose was selected as a probe to assess B cell memory. The probe elicited meningococcal C bactericidal antibody responses in all 18 adults who had been vaccinated 4 years earlier with an investigational meningococcal A and C oligosaccharide-protein conjugate vaccine and in the majority of the 11 subjects vaccinated for the first time. In contrast, the responses of the 5 adults given a full dose of licensed polysaccharide vaccine 4 years earlier were <1/10 of those of the other 2 groups. Thus, adults previously given a full dose of meningococcal polysaccharide vaccine show evidence of immunologic refractoriness to group C polysaccharide, whereas refractoriness is not observed after conjugate vaccination. These findings have implications for the use of meningococcal polysaccharide vaccine when the risk of disease is low.

title: Reduced antibody response to revaccination with meningococcal serogroup A polysaccharide vaccine in adults.
abstract: Widespread use of meningococcal A and C polysaccharide (MACP) vaccines has raised concerns about induction of hyporesponsiveness to these polysaccharides. Immunological hyporesponsiveness to C polysaccharide has been clearly documented in infants, children and adults but only limited data from Gambian children are available for A polysaccharide. We investigated whether a second dose of MACP, given 6 months after an initial dose affected the immunological response as measured by the serum bactericidal assay (SBA) and enzyme-linked immunosorbent assay (ELISA), to serogroup A meningococci in young adults (university students, n=36). Serogroup A SBA responses 1 month following the second dose of MACP (geometric mean titre (GMT) 103.6, 95% CI 45.6-235.1) were approximately one third of the levels observed 1 month post first dose (GMT 281.9, 95% CI 134.9-581.4). The serogroup A-specific IgG levels post second dose (GMC 21.2, 95% CI 15.3-29.4) were also significantly lower at an average of three-quarters the level post first dose (GMC 28.7, 95% CI 20.8-39.7). This confirms that revaccination with MACP vaccine, 6 months following the initial dose, results in a reduced immunological response to A polysaccharide in adults. Repeated vaccination with MACP vaccine may be ineffective and development and use of meningococcal serogroup A conjugate vaccines should be encouraged.

title: Immune response to revaccination with meningococcal A and C polysaccharides in Gambian children following repeated immunisation during early childhood.
abstract: Forty-two Gambian children randomised to receive two doses of meningococcal A/C polysaccharide vaccine (MPS) in infancy and either MPS (n = 15), meningococcal A/C conjugate (n = 13) or inactivated polio vaccine (IPV n = 14) at 2 years, were revaccinated with MPS at 5 years of age along with 39 matched control children. Meningococcal A and C polysaccharide antibodies were analysed by ELISA and bactericidal assay (SBA) in sera taken before and 10 days after revaccination. The geometric mean group SBA titre in the MPS group following revaccination was about half that of the unvaccinated controls (0.51 95%CI: 0.28, 0.90) for group A and less than half that of the controls for group C (0.41, 95%CI: 0.16, 1.03 P = 0.06). The group C SBA response in the conjugate group was 14-fold higher than in the MPS group (P < 0.001). Multiple doses of meningococcal polysaccharide in childhood may therefore attenuate the SBA response to both group A and group C polysaccharides. In contrast, vaccination with meningococcal A/C conjugate after MPS in infancy gives immunological memory to N. meningitidis group C.

title: Quadrivalent meningococcal vaccines: hyporesponsiveness as an important consideration when choosing between the use of conjugate vaccine or polysaccharide vaccine.
abstract: Regional variations in the incidence and the distribution of serogroups which are responsible of meningococcal disease necessitate multivalent vaccines to ensure broad coverage for travelers. For almost 30 years, this has been provided by quadrivalent polysaccharide vaccine to protect against serogroups A, C, W-135 and Y, but with the advent of quadrivalent conjugate vaccines is there still a case to use the polysaccharide? The well documented hyporesponsiveness induced by polysaccharide vaccines after repeated administration, most clearly observed against serogroup C, suggest that, where available, conjugate vaccines should always be considered ahead of polysaccharide vaccine.

title: Meningococcal carriage, meningococcal disease and vaccination.
abstract: Group A meningococcal carriage rates were determined 6 months before and 6 and 18 months after a mass vaccination campaign with a combined group A and group C meningococcal polysaccharide vaccine in a rural area of The Gambia. During the first pre-vaccination survey, performed during an outbreak of meningococcal disease, the carriage rate was high (16%). The carriage rate remained high during a second survey made 6 months after a vaccination campaign that covered approximately 90% of the study population. A year later very few group A meningococcal carriers were found. Membrane protein patterns of isolates obtained before and after vaccination were similar. We conclude that vaccination had little influence on the carriage rate of group A meningococci but that this was influenced by changes in herd immunity or by other unidentified factors.

title: Safety, immunogenicity, and immune memory of a novel meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine (MCV-4) in healthy adolescents.
abstract: A meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine (MCV-4; Menactra; Sanofi Pasteur Inc, Swiftwater, Pa) was developed to improve the profile of currently licensed products. The objective of this study was to compare the tolerability, immunogenicity, and immune memory of MCV-4 with those of a quadrivalent polysaccharide vaccine (PSV-4; Menomune A/C/Y/W-135; Sanofi Pasteur Inc).



A randomized, double-blind trial was performed at 11 clinical centers in the United States. The vaccine MCV-4 or PSV-4 was administered to 881 healthy 11- to 18-year-olds. Sera were collected prevaccination and 28 days postvaccination. Three-year follow-up and booster vaccination with MCV-4 were performed in a participant subset from each group and a control group.



Proportion of participants with a 4-fold or greater increase in serum bactericidal antibody against each serogroup 28 days after initial vaccination, geometric mean serum bactericidal antibody titers, and safety assessments.



Both vaccines were well tolerated; most reactions were mild. More MCV-4 recipients reported solicited local reactions (68.9%) than PSV-4 recipients (30.2%). Both MCV-4 and PSV-4 were highly immunogenic; similar proportions of participants had 4-fold or greater increases in serum bactericidal antibody (range, 80.1%-96.7%) to the 4 serogroups. Three-year follow-up showed persistence of serum bactericidal antibody and booster responses to MCV-4 consistent with immune memory in participants previously vaccinated with MCV-4, but not in those who had previously received PSV-4.



The vaccine MCV-4 was well tolerated and highly immunogenic. Persistence of bactericidal activity with MCV-4, but not PSV-4, was evident 3 years after the initial immunization. Booster response was demonstrated after a second vaccination with MCV-4.

title: Persistence of the immune response after MenACWY-CRM vaccination and response to a booster dose, in adolescents, children and infants
abstract: Persistence of bactericidal antibodies following vaccination is extremely important for protection against invasive meningococcal disease, given the epidemiology and rapid progression of meningococcal infection. We present an analysis of antibody persistence and booster response to MenACWY-CRM, in adolescents, children and infants, from 7 clinical studies. Immunogenicity was assessed using the serum bactericidal assay with both human and rabbit complement. Post-vaccination hSBA titers were high, with an age- and serogroup-specific decline in titers up to 1 y and stable levels up to 5 y The waning of hSBA titers over time was more pronounced among infants and toddlers and the greatest for serogroup A. However, rSBA titers against serogroup A were consistently higher and showed little decline over time, suggesting that protection against this serogroup may be sustained. A single booster dose of MenACWY-CRM administered at 3 to 5 y induced a robust immune response in all age groups.

title: A decade of herd protection after introduction of meningococcal serogroup C conjugate vaccination.
abstract: Vaccination with meningococcal serogroup C (MenC) conjugate (MCC) polysaccharide vaccines led to a substantial decline in MenC disease in the vaccinated and the unvaccinated population. The decline in the unvaccinated population can be explained by herd protection by reduced colonization of meningococci expressing the MenC capsule. The duration of such herd protection is unknown.



In a nationwide study from the Netherlands, we compared MenC invasive disease between 1998 and the introduction of MCC vaccination (2002) with that from 2002 to 2012, in age groups eligible and not eligible for vaccination. The proportions of isolates from clonal complexes with high serogroup C capsule expression rate during carriage (sequence type [ST] 11 and ST-8 complex) was compared between the pre- and postvaccination periods.



A total of 814 patients with invasive MenC disease were included for analysis. There was a 99% decline in MenC disease in patients eligible for vaccination and a 93% decline in those not eligible. Thirty-six percent of the overall MenC reduction between the first and last 4 years of the observation period occurred in the unvaccinated population. Clonal complex was determined in 350 (43%) isolates. The proportion of cases caused by clonal complex ST-11 and ST-8 serogroup C meningococci decreased from 251 of 268 (94%) before, to 46 of 57 (81%) after MCC vaccine introduction (P = .004).



Our findings provide further evidence that herd protection results from reduced carriage of virulent meningococci. Herd protection was responsible for >36% of MCC vaccine impact and lasted for ≥10 years.

title: Herd immunity from meningococcal serogroup C conjugate vaccination in England: database analysis
abstract: In November 1999, the United Kingdom introduced routine meningococcal serogroup C conjugate vaccination for infants. The vaccine was also offered to everyone aged under 18 years in a phased catch-up  The first to be vaccinated were adolescents, and the entire programme was completed by the end of 2000. On the basis of direct protection provided by the vaccine, 1 2 this catch-up programme was likely to be cost effective.3

Maiden et al described a 67% reduction (from 0.45% to 0.15%) in the prevalence of nasopharyngeal carriage of serogroup C meningococci in adolescents before and after the vaccination  A fall in meningococcal carriage would be expected to reduce exposure among unvaccinated children and therefore to enhance the effectiveness of meningococcal conjugate vaccine. We present rates of disease in vaccinated and unvaccinated children to provide the first evidence of an indirect effect from meningococcal conjugate vaccine.

Since December 1999 we have investigated the vaccination history of all cases of …

title: Review of meningococcal vaccines with updates on immunization in adults
abstract: Meningococcal disease is a serious and global life-threatening disease. Six serogroups (A, B, C, W-135, X, and Y) account for the majority of meningococcal disease worldwide. Meningococcal polysaccharide vaccines were introduced several decades ago and have led to the decline in the burden of disease. However, polysaccharide vaccines have several limitations, including poor immunogenicity in infants and toddlers, short-lived protection, lack of immunologic memory, negligible impact on nasopharyngeal carriage, and presence of hyporesponsiveness after repeated doses. The chemical conjugation of plain polysaccharide vaccines has the potential to overcome these drawbacks. Meningococcal conjugate vaccines include the quadrivalent vaccines (MenACWY-DT, MenACWY-CRM, and MenACWY-TT) as well as the monovalent A and C vaccines. These conjugate vaccines were shown to elicit strong immune response in adults. This review addresses the various aspects of meningococcal disease, the limitations posed by polysaccharide vaccines, the different conjugate vaccines with their immunogenicity and reactogenicity in adults, and the current recommendations in adults.

title: Meningococcal Conjugate Vaccines Policy Update: Booster Dose Recommendations
abstract: The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention and the American Academy of Pediatrics approved updated recommendations for the use of quadravalent (serogroups A, C, W-135, and Y) meningococcal conjugate vaccines (Menactra [Sanofi Pasteur, Swiftwater, PA] and Menveo [Novartis, Basel, Switzerland]) in adolescents and in people at persistent high risk of meningococcal disease. The recommendations supplement previous Advisory Committee on Immunization Practices and American Academy of Pediatrics recommendations for meningococcal vaccinations. Data were reviewed pertaining to immunogenicity in high-risk groups, bactericidal antibody persistence after immunization, current epidemiology of meningococcal disease, meningococcal conjugate vaccine effectiveness, and cost-effectiveness of different strategies for vaccination of adolescents. This review prompted the following recommendations: (1) adolescents should be routinely immunized at 11 through 12 years of age and given a booster dose at 16 years of age; (2) adolescents who received their first dose at age 13 through 15 years should receive a booster at age 16 through 18 years or up to 5 years after their first dose; (3) adolescents who receive their first dose of meningococcal conjugate vaccine at or after 16 years of age do not need a booster dose; (4) a 2-dose primary series should be administered 2 months apart for those who are at increased risk of invasive meningococcal disease because of persistent complement component (eg, C5–C9, properdin, factor H, or factor D) deficiency (9 months through 54 years of age) or functional or anatomic asplenia (2–54 years of age) and for adolescents with HIV infection; and (5) a booster dose should be given 3 years after the primary series if the primary 2-dose series was given from 2 through 6 years of age and every 5 years for persons whose 2-dose primary series or booster dose was given at 7 years of age or older who are at risk of invasive meningococcal disease because of persistent component (eg, C5–C9, properdin, factor H, or factor D) deficiency or functional or anatomic asplenia.

title: Safety and immunogenicity of a tetravalent polysaccharide vaccine against meningococcal disease.
abstract: Meningococcal disease, including meningitis and sepsis, usually follows an invasive infection by Neisseria meningitidis, and is a major cause of death and morbidity worldwide. Currently available meningococcal vaccines that consist of pure capsular polysaccharides (serogroups A, C, W-135 and Y) are generally safe and efficacious in adults and children aged > 2 years. The purpose of this study was to evaluate the immunogenicity, safety and reactogenicity of a single dose of GlaxoSmithKline Biologicals' Mencevax ACWY vaccine in healthy Taiwanese subjects aged 2-30 years.



This open, single center, Phase III study was conducted in Taiwan. A single dose of the Mencevax ACWY vaccine was administered to subjects aged 2-30 years. Immunogenicity and safety of the vaccine were evaluated after vaccination.



The immunogenicity results obtained 1 month after vaccination with Mencevax ACWY vaccine indicated that the vaccine elicited a good immune response in vaccinees aged 2-30 years. This was both in terms of functional activity directed against meningococcal polysaccharide (A, C, W-135 and Y) as measured by serum bactericidal assay (> 93% activity against all serogroups), and specific IgG concentrations measured by ELISA (> 96% seropositivity to all serogroups).



The tetravalent polysaccharide Mencevax ACWY meningococcal vaccine was well tolerated and immunogenic in subjects aged 2-30 years in Taiwan.

title: Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP).
abstract: This report summarizes and updates an earlier published statement issued by the Advisory Committee on Immunization Practices concerning the control and prevention of meningococcal disease (MMWR 1997:46[No. RR-5]:1-21) and provides updated recommendations regarding the use of meningococcal vaccine.

title: Risk of Guillain–Barré syndrome after meningococcal conjugate vaccination
abstract: A new meningococcal conjugate vaccine (MCV4) was introduced in 2005. Shortly after, case reports of Guillain–Barré syndrome (GBS), a serious demyelinating disease, began to be reported to the Vaccine Adverse Event Reporting System. In 2006, the Centers for Disease Control and Prevention and the Food and Drug Administration requested the evaluation of GBS risk after MCV4 vaccination. We conducted a study to assess the risk of GBS after MCV4 vaccination using health plan administrative and claims data together with the review of primary medical records of potential cases.

title: Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine.
abstract: Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55years of age. The aim of this study was to assess the safety of MenACWY-D administered as part of routine clinical care to patients at Kaiser Permanente Northern California (KPNC).



This was an observational, retrospective study that included all KPNC members who received MenACWY-D during the study period. We monitored all vaccine recipients for non-elective hospitalizations, emergency department visits, and selected outcomes captured in the clinic setting (Bell's palsy, seizures, neuritis, Guillain-Barré syndrome, encephalopathy, encephalitis, epilepsy, transverse myelitis, multiple sclerosis, hypersensitivity reactions, idiopathic thrombocytopenic purpura, diabetes, arthritis, hemolytic anemia, collagen-vascular disease) through 6months after vaccination. Using vaccine recipients as their own controls, we calculated incidence rate ratios (IRRs) of outcomes during the post-vaccination risk interval and compared these with rates during a comparison interval more remote from vaccination. We also compared rates of outcomes in MenACWY-D recipients with those in matched controls who received selected vaccines in the prior year. We reviewed medical records for selected outcomes.



From April 2005 through April 2006, 31,561 KPNC patients (>99% of whom were 11-55years of age) received MenACWY-D. Overall, there were 21 outcomes with significantly elevated IRRs and 44 outcomes with significantly reduced IRRs. Medical record review of outcomes with significantly elevated IRRs did not suggest any relationship with MenACWY-D. Two serious adverse events were considered possibly related to vaccination by the study investigator.



This study did not detect any safety concerns following MenACWY-D and provides reassurance that MenACWY-D administered as part of routine care was not associated with unexpected safety risks.

title: Using the tetravalent meningococcal polysaccharide-protein conjugate vaccine in the prevention of meningococcal disease
abstract: Invasive meningococcal disease occurs worldwide causing an estimated 50,000–135,000 deaths each year in addition to significant sequelae. In developed countries the disease is usually sporadic but outbreaks and epidemics, usually due to serogroups B and C, have occurred. In the US, an increasing number of cases are due to serogroup Y. In developing nations, epidemics due to serogroups A and more recently W-135, are common. The tetravalent meningococcal conjugate vaccine to serogroups A, C, Y, and W-135 (MCV4) has been demonstrated to be highly immunogenic and promote immune memory. This article will describe the rationale for the vaccine and its potential role to significantly decrease mortality and morbidity of meningococcal disease in those areas and populations at greatest risk from these serogroups.

title: Meningococcal quadrivalent tetanus toxoid conjugate vaccine (MenACWY-TT, Nimenrix™): A review of its immunogenicity, safety, co-administration, and antibody persistence
abstract: Meningococcal disease is a major cause of morbidity and mortality worldwide with reported epidemics and outbreaks in different parts of the world. Despite the availability of antimicrobial therapy, challenges remain in early recognition and prevention of disease. Several vaccines have been developed to date aiming at preventing disease spread.  MenACWY-TT (Nimenrix™) has been extensively studied for use in different age groups. Phase II and III randomized trials have demonstrated its immunogenicity when administered in children aged 1 year and older, adolescents and adults. It has an acceptable safety profile with minor adverse events comparable to other vaccines. Follow up studies have shown persistence of protective antibodies up to three years. MenACWY-TT was safely and effectively co-administered with different recommended vaccines.  MenACWY-TT is a safe and immunogenic vaccine that can be used to protect against these four serogroups in individuals older than 1 year of age.

title: Immunogenicity and Safety of an Investigational Combined Haemophilus influenzae Type B-Neisseria meningitidis Serogroups C and Y-Tetanus Toxoid Conjugate Vaccine
abstract: Neisseria meningitidis serogroups B, C, and Y cause most meningococcal disease in industrialized countries. A Haemophilus influenzae type b-meningococcal serogroups C and Y-tetanus toxoid conjugate vaccine (HibMenCY-TT) was evaluated.  A total of 1104 infants (randomized 3:1:1) were vaccinated at 2, 4, and 6 months with HibMenCY-TT, MenC-CRM197 + Hib-TT, or Hib-TT. At 12 to 15 months, HibMenCY-TT and MenC-CRM-primed children received HibMenCY-TT; Hib-TT-primed received N. meningitidis serogroup B Hib-outer membrane protein complex. Antibody concentrations and rabbit/human complement serum bactericidal antibody titers (rSBA/hSBA) were determined. Safety was monitored after each dose (diary cards for first 31 days) until 6 months postdose 4.  Postdose 3, rates of antipolyribosylribitol phosphate ≥1 &mgr;g/mL and rSBA-MenC ≥1:128 in HibMenCY-TT recipients were noninferior to licensed controls. Percentages reaching 0.15 &mgr;g/mL (1.0 &mgr;g/mL postdose 3) and antipolyribosylribitol phosphate GMC were significantly higher after HibMenCY-TT than Hib-TT postdose 2 and postdose 3. The GMC remained significantly higher before and after dose 4. Proportions of HibMenCY-TT recipients with rSBA ≥1:8 were 95.6% (MenC), 98.6% (MenY) postdose-2, ≥99% for MenC/Y postdose 3 and 4; hSBA ≥1:4 were 95.5% (MenC), 89.8% (MenY) postdose 2, >97% for MenC/Y postdose 3 and 4. HibMenCY-TT had a similar safety profile to control vaccines.  HibMenCY-TT induced noninferior Hib and MenC responses compared with monovalent Hib and MenC conjugates with a comparable safety profile. Bactericidal antibodies against MenC/Y were induced after 2 doses of HibMenCY-TT.

title: Introduction and Rollout of a New Group A Meningococcal Conjugate Vaccine (PsA-TT) in African Meningitis Belt Countries, 2010–2014
abstract: A group A meningococcal conjugate vaccine (PsA-TT) was developed specifically for the African “meningitis belt” and was prequalified by the World Health Organization (WHO) in June 2010. The vaccine was first used widely in Burkina Faso, Mali, and Niger in December 2010 with great success. The remaining 23 meningitis belt countries wished to use this new vaccine. With the help of African countries, WHO developed a prioritization scheme and used or adapted existing immunization guidelines to mount PsA-TT vaccination campaigns. Vaccine requirements were harmonized with the Serum Institute of India, Ltd. Burkina Faso was the first country to fully immunize its 1- to 29-year-old population in December 2010. Over the next 4 years, vaccine coverage was extended to 217 million Africans living in 15 meningitis belt countries. The new group A meningococcal conjugate vaccine was well received, with country coverage rates ranging from 85% to 95%. The rollout proceeded smoothly because countries at highest risk were immunized first while attention was paid to geographic contiguity to maximize herd protection. Community participation was exemplary.

title: Effect of a serogroup A meningococcal conjugate vaccine (PsA–TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study
abstract: A serogroup A meningococcal polysaccharide–tetanus toxoid conjugate vaccine (PsA–TT, MenAfriVac) was licensed in India in 2009, and pre-qualified by WHO in 2010, on the basis of its safety and immunogenicity. This vaccine is now being deployed across the African meningitis belt. We studied the effect of PsA–TT on meningococcal meningitis and carriage in Chad during a serogroup A meningococcal meningitis epidemic.  We obtained data for the incidence of meningitis before and after vaccination from national records between January, 2009, and June, 2012. In 2012, surveillance was enhanced in regions where vaccination with PsA–TT had been undertaken in 2011, and in one district where a reactive vaccination campaign in response to an outbreak of meningitis was undertaken. Meningococcal carriage was studied in an age-stratified sample of residents aged 1–29 years of a rural area roughly 13–15 and 2–4 months before and 4–6 months after vaccination. Meningococci obtained from cerebrospinal fluid or oropharyngeal swabs were characterised by conventional microbiological and molecular methods.  Roughly 1·8 million individuals aged 1–29 years received one dose of PsA–TT during a vaccination campaign in three regions of Chad in and around the capital N'Djamena during 10 days in December, 2011. The incidence of meningitis during the 2012 meningitis season in these three regions was 2·48 per 100 000 (57 cases in the 2·3 million population), whereas in regions without mass vaccination, incidence was 43·8 per 100 000 (3809 cases per 8·7 million population), a 94% difference in crude incidence (p<0·0001), and an incidence rate ratio of 0·096 (95% CI 0·046–0·198). Despite enhanced surveillance, no case of serogroup A meningococcal meningitis was reported in the three vaccinated regions. 32 serogroup A carriers were identified in 4278 age-stratified individuals (0·75%) living in a rural area near the capital 2–4 months before vaccination, whereas only one serogroup A meningococcus was isolated in 5001 people living in the same community 4–6 months after vaccination (adjusted odds ratio 0·019, 95% CI 0·002–0·138; p<0·0001).  PSA–TT was highly effective at prevention of serogroup A invasive meningococcal disease and carriage in Chad. How long this protection will persist needs to be established.

title: Effect of outer membrane vesicle vaccine against group B meningococcal disease in Norway
abstract: For more than 15 years, Norway has had the highest incidence of meningococcal disease in northern Europe, with 80% of cases being due to serogroup B meningococci. The case-fatality has remained high, at about 10%. In this study, an outer membrane vaccine, which had previously been shown to induce an increase in bactericidal antibodies to the parent strain, was assessed in a large-scale, randomised, double-blind trial. From October, 1988, 171,800 students in secondary schools volunteered to take part in a double-blind, placebo-controlled, efficacy trial with school as the randomisation unit. Hospitals and clinics that routinely receive patients with infectious disease were asked to report urgently all cases of suspected meningitis and/or septicaemia in 13-21-year-old students in Norway. These cases were registered and further investigated according to a detailed protocol. 89 out of the 221 cases investigated by June 3, 1991, were shown to be severe systemic disease due to group B meningococci. 36 cases in 35 schools took part in the trial (11 schools with vaccinated students and 24 with students given placebo). The calculated rate of protection was thus 57.2% (p = 0.012, one-sided test). The findings suggest that, although the vaccine conferred protection against group B meningococcal disease, the effect was insufficient to justify a public vaccination programme.

title: Properties and clinical performance of vaccines containing outer membrane vesicles from Neisseria meningitidis.
abstract: Meningococcal outer membrane proteins have been used for over 20 years in more than 80 million doses; either as carrier protein in a Haemophilus influenzae type b (Hib) polysaccharide conjugate vaccine or as vesicle vaccine formulations against meningococcal disease. Conventional wild-type outer membrane vesicle (wtOMV) vaccines are the only formulations that have shown efficacy against serogroup B meningococcal disease. This has been demonstrated in Cuba, Norway and New Zealand; where epidemics, dominated by one particular strain or clone, were causing high rates of disease and wtOMV vaccines have been used for epidemic control. The most significant limitation for widespread use of wtOMV is that the immune response is strain-specific in infants, mostly directed against the immuno-dominant porin protein, PorA. The natural orientation of surface-exposed membrane antigens and the preservation of good physico-chemical stability are key features of OMV vaccines. The efficacy, tolerability and safety of wtOMV vaccines have been well proven. The most recent experience from New Zealand demonstrated a vaccine effectiveness of 80% for children less than 5 years of age, over a period of 24 months. Such results are encouraging for the further use of "tailor-made" OMV vaccines for epidemic control. Moreover, it provides opportunities for development of OMV vaccines with various additional cross-protective potential. There is good reason to believe that in the coming few years the "OMV-concept" will be exploited further and that a number of cross-protective "universal" antigens will be included in vaccines against serogroup B meningococcal disease. The desire to have a global vaccine strategy that enables susceptible individuals to be protected against all the relevant serogroups of meningococcal disease may become a reality.

title: Immunogenicity and safety of a hexavalent meningococcal outer-membrane-vesicle vaccine in children of 2-3 and 7-8 years of age.
abstract: To study the reactogenicity and immunogenicity of a hexavalent meningococcal outer-membrane-vesicle vaccine (OMV), two different dosages of this vaccine (7.5 and 15 microg of individual PorA proteins) consisting of vesicles expressing class 1 outer-membrane proteins (OMPs) of subtypes P1.7,16; P1.5,2; P1.19,15 and P1.5(c), 10; P1.12,13; P1.7(h),4 were administered to a group of 7-8 year (n=165) and a group of 2-3 year old children (n=172). Control groups of children with similar ages were vaccinated against hepatitis B. All participants received three injections. Pre- and postimmunisation sera were tested for bactericidal antibodies against six isogenic meningococcal vaccine strains expressing different PorA proteins. Antibody titres against OMP of the two different vesicles (PL16215 and PL10124) were measured by ELISA. The meningococcal hexavalent OMV vaccine was well tolerated. No statistically significant differences were seen between the high and low dose of hexavalent meningococcal OMV vaccine. The percentage of children showing a fourfold increase of bactericidal antibody titres against the specific serosubtype varied in toddlers from 28 to 98% and in older children from 16 to 100%. Both ELISA antibody titres and bactericidal activity showed the highest level in the youngest age-group.

title: Identification of vaccine candidates against serogroup B meningococcus by whole-genome sequencing.
abstract: Neisseria meningitidis is a major cause of bacterial septicemia and meningitis. Sequence variation of surface-exposed proteins and cross-reactivity of the serogroup B capsular polysaccharide with human tissues have hampered efforts to develop a successful vaccine. To overcome these obstacles, the entire genome sequence of a virulent serogroup B strain (MC58) was used to identify vaccine candidates. A total of 350 candidate antigens were expressed in Escherichia coli, purified, and used to immunize mice. The sera allowed the identification of proteins that are surface exposed, that are conserved in sequence across a range of strains, and that induce a bactericidal antibody response, a property known to correlate with vaccine efficacy in humans.

title: Use of Serogroup B Meningococcal Vaccines in Persons Aged ≥10 Years at Increased Risk for Serogroup B Meningococcal Disease: Recommendations of the Advisory Committee on Immunization Practices, 2015
abstract: In October 2014, the Food and Drug Administration (FDA) licensed the first serogroup B meningococcal (MenB) vaccine (MenB-FHbp [Trumenba, Wyeth Pharmaceuticals, Inc.]) as a 3-dose series. In January 2015, FDA licensed a second MenB vaccine (MenB-4C [Bexsero, Novartis Vaccines]) as a 2-dose series. Both vaccines were approved for use in persons aged 10-25 years. Following outbreaks of serogroup B meningococcal disease on two college campuses in 2013, both MenB vaccines were granted Breakthrough Therapy designations, which expedites drug development and review by FDA, and were licensed based on accelerated approval regulations. On February 26, 2015, the Advisory Committee on Immunization Practices (ACIP) recommended use of MenB vaccines among certain groups of persons aged ≥10 years who are at increased risk for serogroup B meningococcal disease. This report summarizes information on MenB administration and provides recommendations and guidance for use of these vaccines among persons aged ≥10 years in certain groups who are at increased risk for serogroup B meningococcal disease, and reviews the evidence considered by ACIP to make these recommendations. Recommendations for broader use of MenB vaccines in adolescents and college students will be considered separately by ACIP.

title: Safety and immunogenicity of a four-component meningococcal group B vaccine (4CMenB) and a quadrivalent meningococcal group ACWY conjugate vaccine administered concomitantly in healthy laboratory workers.
abstract: Safety precautions for laboratory staff working with meningococci should primarily rely on laboratory procedures preventing exposure to aerosols containing viable meningococci. Despite this, vaccination is a key component of protection in the occupational setting. In the UK in 2009, there were no licensed vaccines for meningococcal capsular group B or conjugate vaccines for capsular groups A, C, W and Y. We therefore undertook a Phase II trial in laboratory workers to investigate the safety and immunogenicity of a four component group B vaccine (4CMenB) and a quadrivalent group A, C, W and Y conjugate vaccine (ACWY-CRM). Enrolment was open to staff aged 18-65 years at the Public Health Laboratory, Manchester who may have had a potential occupational exposure risk to meningococci. 4CMenB was administered at 0, 2 and 6 months in the non-dominant arm and ACWY-CRM concomitantly at 0 months in the dominant arm. Pre- and post-vaccination blood samples were taken and analysed by the serum bactericidal antibody (SBA) assay against A, C, W and Y strains and a panel of seven diverse group B strains. Diary cards were used to record any local and systemic reactions following each vaccination. In total, 38 staff were enrolled and received initial vaccinations with 31 completing the trial per protocol. Both vaccines were proven safe, with local reactogenicity being more commonly reported following 4CMenB than ACWY-CRM. High proportions of subjects had putative protective SBA titres pre-vaccination, with 61-84 and 61-87% protected against A, C, W and Y strains and diverse MenB strains, respectively. Post-vaccination, SBA titres increased with 95-100 and 90-100% of subjects with protective SBA titres against A, C, W and Y strains and diverse MenB strains, respectively. These data suggest that 4CMenB and ACWY-CRM are safe when administered concomitantly and have the potential to enhance protection for laboratory workers.

title: Safety, immunogenicity, and tolerability of meningococcal serogroup B bivalent recombinant lipoprotein 2086 vaccine in healthy adolescents: a randomised, single-blind, placebo-controlled, phase 2 trial.
abstract: Neisseria meningitidis serogroup B is a major cause of invasive meningococcal disease, but a broadly protective vaccine is not currently licensed. A bivalent recombinant factor H-binding protein vaccine (recombinant lipoprotein 2086) has been developed to provide broad coverage against diverse invasive meningococcus serogroup B strains. Our aim was to test the immune response of this vaccine.



This randomised, placebo-controlled trial enrolled healthy adolescents from 25 sites in Australia, Poland, and Spain. Exclusion criteria were previous invasive meningococcal disease or serogroup B vaccination, previous adverse reaction or known hypersensitivity to the vaccine, any significant comorbidities, and immunosuppressive therapy or receipt of blood products in the past 6 months. Participants were randomly assigned with a computerised block randomisation scheme to receive ascending doses of vaccine (60, 120, or 200 μg) or placebo at 0, 2, and 6 months. Principal investigators, participants and their guardians, and laboratory personnel were masked to the allocation; dispensing staff were not. Immunogenicity was measured by serum bactericidal assays using human complement (hSBA) against eight diverse meningococcus serogroup B strains. The co-primary endpoints were seroconversion for the two indicator strains (PMB1745 and PMB17) analysed by the Clopper-Pearson method. Local and systemic reactions and adverse events were recorded. The study is registered at ClinicalTrials.gov, number NCT00808028.



539 participants were enrolled and 511 received all three study vaccinations--116 in the placebo group, 21 in the 60 μg group, 191 in the 120 μg group, and 183 in the 200 μg group. The proportion of participants responding with an hSBA titre equal to or greater than the lower limit of quantitation of the hSBA assays (reciprcocal titres of 7 to 18, depending on test strain) was similar for the two largest doses and ranged from 75·6 to 100·0% for the 120 μg dose and 67·9 to 99·0% for the 200 μg dose. Seroconversion for the PMB1745 reference strain was 17 of 19 (89·5%) participants for the 60 μg dose, 103 of 111 (92·8%) participants for the 120 μg dose, 94 of 100 (94·0%) participants for the 200 μg dose, and four of 73 (5·5%) participants for placebo. For the PMB17 reference strain seroconversion was 17 of 21 (81·0%) participants for the 60 μg dose, 97 of 112 (86·6%) participants for the 120 μg dose, 89 of 105 (84·8%) participants for the 200 μg dose, and one of 79 (1·3%) participants for placebo. The hSBA response was robust as shown by the high proportion of responders at hSBA titres up to 16. Mild-to-moderate injection site pain was the most common local reaction (50 occurrences with the 60 μg dose, 437 with the 120 μg dose, 464 with the 200 μg dose, and 54 with placebo). Systemic events, including fatigue and headache, were generally mild to moderate. Overall, adverse events were reported by 18 participants (81·8%) in the 60 μg group, 77 (38·9%) in the 120 μg group, 92 (47·2%) in the 200 μg group, and 54 (44·6%) in the placebo group. Fevers were rare and generally mild (one in the 60 μg group, 24 in the 120 μg group, 35 in the 200 μg group, and five in the placebo group; range, 0-6·3% after each dose). Incidence and severity of fever did not increase with subsequent vaccine dose within groups. One related serious adverse event that resolved without sequelae occurred after the third dose (200 μg).



The bivalent recombinant lipoprotein 2086 vaccine is immunogenic and induces robust hSBA activity against diverse invasive meningococcus serogroup B disease strains and the vaccine is well tolerated. Recombinant lipoprotein 2086 vaccine is a promising candidate for broad protection against invasive meningococcus serogroup B disease.

title: Effectiveness and impact of a reduced infant schedule of 4CMenB vaccine against group B meningococcal disease in England: a national observational cohort study
abstract: In September, 2015, the UK became the first country to introduce the multicomponent group B meningococcal (MenB) vaccine (4CMenB, Bexsero) into a publicly funded national immunisation programme. A reduced two-dose priming schedule was offered to infants at 2 months and 4 months, alongside an opportunistic catch-up for 3 month and 4 month olds. 4CMenB was predicted to protect against 73-88% of MenB strains. We aimed to assess the effectiveness and impact of 4CMenB in vaccine-eligible infants in England.



Public Health England (PHE) undertakes enhanced surveillance of meningococcal disease through a combination of clinical, public health, and laboratory reporting. Laboratory-confirmed cases of meningococcal disease are followed up with PHE local health protection teams, general practitioners, and hospital clinicians to collect demographic data, vaccination history, clinical presentation, and outcome. For cases diagnosed between Sept 1, 2015, and June 30, 2016, vaccine effectiveness was assessed using the screening method. Impact was assessed by comparing numbers of cases of MenB in vaccine-eligible children to equivalent cohorts in the previous 4 years and to cases in vaccine-ineligible children.



Coverage of 4CMenB in infants eligible for routine vaccination was high, achieving 95·5% for one dose and 88·6% for two doses by 6 months of age. Two-dose vaccine effectiveness was 82·9% (95% CI 24·1-95·2) against all MenB cases, equivalent to a vaccine effectiveness of 94·2% against the highest predicted MenB strain coverage of 88%. Compared with the prevaccine period, there was a 50% incidence rate ratio (IRR) reduction in MenB cases in the vaccine-eligible cohort (37 cases vs average 74 cases; IRR 0·50 [95% CI 0·36-0·71]; p=0·0001), irrespective of the infants' vaccination status or predicted MenB strain coverage. Similar reductions were observed even after adjustment for disease trends in vaccine-eligible and vaccine-ineligible children.



The two-dose 4CMenB priming schedule was highly effective in preventing MenB disease in infants. Cases in vaccine-eligible infants halved in the first 10 months of the programme. While ongoing national surveillance will continue to monitor the longer-term impact of the programme, these findings represent a step forward in the battle against meningococcal disease and will help reassure that the vaccine protects against this deadly infection.



Public Health England.

title: Immunogenicity, Safety, and Tolerability of Bivalent rLP2086 Meningococcal Group B Vaccine Administered Concomitantly With Diphtheria, Tetanus, and Acellular Pertussis and Inactivated Poliomyelitis Vaccines to Healthy Adolescents
abstract: Concomitant administration of bivalent rLP2086 (Trumenba [Pfizer, Inc] and diphtheria, tetanus, and acellular pertussis and inactivated poliovirus vaccine (DTaP/IPV) was immunologically noninferior to DTaP/IPV and saline and was safe and well tolerated. Bivalent rLP2086 elicited robust and broad bactericidal antibody responses to diverse Neisseria meningitidis serogroup B strains expressing antigens heterologous to vaccine antigens after 2 and 3 vaccinations.  Bivalent rLP2086, a Neisseria meningitidis serogroup B (MnB) vaccine (Trumenba [Pfizer, Inc]) recently approved in the United States to prevent invasive MnB disease in individuals aged 10–25 years, contains recombinant subfamily A and B factor H binding proteins (fHBPs). This study evaluated the coadministration of Repevax (diphtheria, tetanus, and acellular pertussis and inactivated poliovirus vaccine [DTaP/IPV]) (Sanofi Pasteur MSD, Ltd) and bivalent rLP2086.  Healthy adolescents aged ≥11 to <19 years received bivalent rLP2086 + DTaP/IPV or saline + DTaP/IPV at month 0 and bivalent rLP2086 or saline at months 2 and 6. The primary end point was the proportion of participants in whom prespecified levels of antibodies to DTaP/IPV were achieved 1 month after DTaP/IPV administration. Immune responses to bivalent rLP2086 were measured with serum bactericidal assays using human complement (hSBAs) against 4 MnB test strains expressing fHBP subfamily A or B proteins different from the vaccine antigens.  Participants were randomly assigned to receive bivalent rLP2086 + DTaP/IPV (n = 373) or saline + DTaP/IPV (n = 376). Immune responses to DTaP/IPV in participants who received bivalent rLP2086 + DTaP/IPV were noninferior to those in participants who received saline + DTaP/IPV. The proportions of bivalent rLP2086 + DTaP/IPV recipients with prespecified seroprotective hSBA titers to the 4 MnB test strains were 55.5%–97.3% after vaccination 2 and 81.5%–100% after vaccination 3. The administration of bivalent rLP2086 was well tolerated and resulted in few serious adverse events.  Immune responses to DTaP/IPV administered with bivalent rLP2086 to adolescents were noninferior to DTaP/IPV administered alone. Bivalent rLP2086 was well tolerated and elicited substantial and broad bactericidal responses to diverse MnB strains in a high proportion of recipients after 2 vaccinations, and these responses were further enhanced after 3 vaccinations.

title: Updated Recommendations for Use of MenB-FHbp Serogroup B Meningococcal Vaccine — Advisory Committee on Immunization Practices, 2016
abstract: Two serogroup B meningococcal (MenB) vaccines are currently licensed for use in persons aged 10-25 years in the United States. The two vaccines are MenB-FHbp (Trumenba, Pfizer, Inc.) (1) and MenB-4C (Bexsero, GlaxoSmithKline Biologicals, Inc.) (2). In February 2015, the Advisory Committee on Immunization Practices (ACIP) recommended use of MenB vaccines among certain groups of persons aged ≥10 years who are at increased risk for serogroup B meningococcal disease* (Category A) (3), and in June 2015, ACIP recommended that adolescents and young adults aged 16-23 years may be vaccinated with MenB vaccines to provide short-term protection against most strains of serogroup B meningococcal disease (Category B†) (4). Consistent with the original Food and Drug Administration (FDA) licensure for the two available MenB vaccines, ACIP recommended either a 3-dose series of MenB-FHbp or a 2-dose series of MenB-4C. Either MenB vaccine can be used when indicated; ACIP does not state a product preference. The two MenB vaccines are not interchangeable; the same vaccine product must be used for all doses in a series. In April 2016, changes to the dosage and administration of MenB-FHbp were approved by FDA to allow for both a 2-dose series (administered at 0 and 6 months) and a 3-dose series (administered at 0, 1-2, and 6 months) (5,6). In addition, the package insert now states that the choice of dosing schedule depends on the patient's risk for exposure and susceptibility to serogroup B meningococcal disease. These recommendations are regarding use of the 2- and 3-dose schedules of MenB-FHbp vaccine (Trumenba) and replace previous ACIP recommendations for use of MenB-FHbp vaccine published in 2015 (3,4). Recommendations regarding use of MenB-4C (Bexsero) are unchanged (3,4).

title: Meningococcal serogroup B-specific responses after vaccination with bivalent rLP2086: 4 year follow-up of a randomised, single-blind, placebo-controlled, phase 2 trial.
abstract: Bivalent rLP2086 is a recombinant factor H binding protein-based vaccine approved in the USA for prevention of meningococcal serogroup B disease in 10-25-year-olds. We aimed to assess the persistence of bactericidal antibodies up to 4 years after a three-dose schedule of bivalent rLP2086.



We did this randomised, single-blind, placebo-controlled, phase 2 trial at 25 sites in Australia, Poland, and Spain. In stage 1 of the study (February, 2009-May, 2010), healthy adolescents (aged 11-18 years) were randomly assigned, via an interactive voice and web-response system with computer-generated sequential random numbers, to receive either ascending doses of vaccine (60 μg, 120 μg, and 200 μg) or placebo at months 0, 2, and 6. Dispensing staff were not masked to group allocation, but allocation was concealed from principal investigators, participants and their guardians, and laboratory personnel. In stage 2 of the study (reported here), we enrolled healthy adolescents who had received three doses of 120 μg bivalent rLP2086 (the optimum dose level identified in stage 1) or saline. Immunogenicity was determined in serum bactericidal antibody assay using human complement (hSBA) by use of four meningococcal serogroup B test strains expressing vaccine-heterologous factor H binding protein variants: PMB80 (A22), PMB2001 (A56), PMB2948 (B24), and PMB2707 (B44). Immunogenicity in stage 2 was assessed at months 6, 12, 24, and 48 post-vaccination. We did analysis by intention to treat. 
Between March 17, 2010, and Feb 8, 2011, 170 participants who received 120 μg of bivalent rLP2086 and 80 participants who received placebo in stage 1 of the study were entered into stage 2; 210 participants completed stage 2 up to 48 months. 1 month after the third vaccination, 93% (n=139/149) to 100% (n=48/48) of vaccine recipients achieved protective hSBA titres equal to or greater than the lower limit of quantification to each test strain, compared with 0% (n=0/25) to 35% (n=8/23) of control recipients. Despite initial declines in seroprotective hSBA titres for all four test strains, for three test strains (A22, A56, and B24), more than 50% of bivalent rLP2086 recipients continued to achieve titres equal to or greater than the lower limit of quantification at months 6 (57% [n=93/163] to 89% [n=42/47]), 12 (54% [n=84/155] to 69% [n=33/48]), 24 (53%  to 54% [n=82/152]), and 48 (51% [n=24/47] to 59% [n=79/134]); corresponding values in the control group were 14% (n=11/80) to 22% (n=5/23) at month 6, 13% (n=10/78) to 29% (n=22/76) at month 12, 16% (n=12/74) to 36% (n=8/22) at month 24, and 24% (n=16/68) to 35% (n=8/23) at month 48. For test strain B44, hSBA titres equal to or greater than the lower limit of quantification were shown in 37% (n=18/49) of vaccine recipients at 6 months, in 29% (n=14/48) at 12 months, in 22% (n=11/49) at 24 months, and in 20% (n=10/49) at 48 months, compared with 0% (n=0/25) of control recipients at month 6, 4% (n=1/25) at months 12 and 24, and 12% (n=3/25) at month 48. Adverse events were reported in seven (4%) of 170 participants in the bivalent rLP2086 group and two (3%) of 80 participants in the control group; no event was deemed related to vaccine.



After three doses of bivalent rLP2086, protective hSBA titres above the correlate of protection (≥1/4) were elicited up to 4 years in more than 50% of participants for three of four meningococcal serogroup B test strains representative of disease-causing meningococci expressing vaccine-heterologous antigens. Further studies will be needed to assess possible herd immunity effects with meningococcal serogroup B vaccines and the need for a booster dose to sustain individual protection against invasive meningococcal disease.

title: Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial
abstract: Meningococcal conjugate vaccines protect individuals directly, but can also confer herd protection by interrupting carriage transmission. We assessed the effects of meningococcal quadrivalent glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in 18-24-year-olds.



In this phase 3, observer-blind, randomised controlled trial, university students aged 18-24 years from ten sites in England were randomly assigned (1:1:1, block size of three) to receive two doses 1 month apart of Japanese Encephalitis vaccine (controls), 4CMenB, or one dose of MenACWY-CRM then placebo. Participants were randomised with a validated computer-generated random allocation list. Participants and outcome-assessors were masked to the treatment group. Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over 1 year. Primary outcomes were cross-sectional carriage 1 month after each vaccine course. Secondary outcomes included comparisons of carriage at any timepoint after primary analysis until study termination. Reactogenicity and adverse events were monitored throughout the study. Analysis was done on the modified intention-to-treat population, which included all enrolled participants who received a study vaccination and provided at least one assessable swab after baseline. 
Between Sept 21 and Dec 21, 2010, 2954 participants were randomly assigned (987 assigned to control [984 analysed], 979 assigned to 4CMenB [974 analysed], 988 assigned to MenACWY-CRM [983 analysed]); 33% of the 4CMenB group, 34% of the MenACWY-CRM group, and 31% of the control group were positive for meningococcal carriage at study entry. By 1 month, there was no significant difference in carriage between controls and 4CMenB (odds ratio 1·2, 95% CI 0·8-1·7) or MenACWY-CRM (0·9, [0·6-1·3]) groups. From 3 months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (18·2% [95% CI 3·4-30·8] carriage reduction), capsular groups BCWY (26·6% [10·5-39·9] carriage reduction), capsular groups CWY (29·6% [8·1-46·0] carriage reduction), and serogroups CWY (28·5% [2·8-47·5] carriage reduction) compared with control vaccination. Significantly lower carriage rates were also noted in the MenACWY-CRM group compared with controls: 39·0% (95% CI 17·3-55·0) carriage reduction for serogroup Y and 36·2% (15·6-51·7) carriage reduction for serogroup CWY. Study vaccines were generally well tolerated, with increased rates of transient local injection pain and myalgia in the 4CMenB group. No safety concerns were identified.



Although we detected no significant difference between groups at 1 month after vaccine course, MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates during 12 months after vaccination and therefore might affect transmission when widely implemented.

title: Meningococcal carriage: the dilemma of 4CMenB vaccine
abstract: www.thelancet.com Published online August 19, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60935-1 1 The prevalence of acute bacterial meningitis and septicaemia due to Haemophilus infl uenzae b (Hib), Streptococcus pneumoniae, and Neisseria meningitidis has greatly decreased in Europe and North America since the successful introduction of capsular polysaccharide conjugate vaccines targeting Hib, serogroup C (and ACWY in the USA) meningococci, and S pneumoniae. Incidence of meningitis due to N meningitidis serogroup A has also decreased in sub-Saharan Africa since the introduction of the meningococcal serogroup A conjugate vaccine (MenAfriVac). A key point in the success of conjugate vaccines is that not only can they prevent disease directly, but they can also reduce carriage of these bacteria, and thereby provide indirect protection in unvaccinated people. Further reduction of the burden of these diseases can be achieved by development and implementation of vaccines against serogroup B meningococci, additional S pneumoniae serotypes (or a universal pneumococcal vaccine), and a serogroup B streptococcal vaccine (for newborn babies). N meningitidis serogroup B is now the most common cause of meningitis in children in Europe. Capsular polysaccharide from N meningitidis serogroup B is poorly immunogenic because its homology to neural cell adhesion molecules prevents development of capsular-based vaccines. The licensing of a multicomponent protein-based vaccine (4CMenB, Bexsero) against meningococci of serogroup B in December, 2013, crowned a period of pioneering research in reverse vaccinology. This vaccine is expected to be eff ective against 78% of cases of N meningitidis serogroup B in Europe, creating the opportunity for tailoring of national European recommendations. The UK Joint Committee on Vaccination and Immunisation recommended vaccination in infants with a schedule of two plus one (two doses, one at 2 months and one at 4 months, and a booster at 12 months). In France, the technical committee for vaccination recommended the vaccine for at-risk individuals and for outbreak control. Both committees emphasised the need to understand the eff ect of the vaccine on carriage of meningococci to assess potential herd immunity. In The Lancet, Robert Read and colleagues report a phase 3, observer-blind, randomised controlled trial that assessed the eff ects on carriage of meningococci in nearly 3000 students (aged 18–24 years) at 10 university sites in England who received two doses of 4CMenB, one dose of MenACWY-CRM plus one dose of placebo, or two doses of Japanese encephalitis virus vaccine (control vaccine) in a 1:1:1 ratio, followed-up for 12 months. By 1 month, no signifi cant diff erence was recorded in carriage between controls and people in the 4CMenB or MenACWY-CRM groups. However, from 3 months, a signifi cant reduction in carriage of isolates of serogroups CWY was recorded in the MenACWY-CRM group (36·2%, Odds Ratio 0·6, 95% CI 0·5–0·8) compared with the control group. This reduction was higher for CWY capsule-producing isolates than it was when all CWY isolates were considered on the sole basis of harbouring the CWY genes, irrespective of detectable production of the capsule. This observation is explained by the fact that MenACWY-CRM vaccine effi ciently targets the CWY isolates when the capsule is expressed on the bacterial surface. One could argue that vaccinated people mount an immune response that then aff ects acquisition of these bacteria, rather than carriage clearance. Similar observations were also seen in the 4CMenB group 3 months after completion of vaccination. However, there was a reduction in carriage of all meningococcal isolates (BCWY) irrespective of their serogroups. No signifi cant diff erence in carriage prevalence was noted between the 4CMenB and control groups for all B isolates or disease-associated sequence types of B isolates. The eff ect of the vaccine on all meningococci is not surprising, because the 4CMenB vaccine does not target the capsular polysaccharides and is directed against proteins that are present in meningococcal isolates independently from their serogroups. It is noteworthy that the eff ect of 4CMenB and MenACWY-CRM vaccines on carriage isolates was most pronounced against serogroup Y isolates. Whether this indicated the relatively high incidence of serogroup Y carriage, especially in fi rst-year students during the study period, remains to be explored. The 4CMenB vaccine was predicted to be eff ective against serogroup B meningococci, if the isolates produced at least one of the vaccine components at a similar or higher concentration than a threshold that Meningococcal carriage: the dilemma of 4CMenB vaccine

title: Meningococcal Carriage Following a Vaccination Campaign With MenB-4C and MenB-FHbp in Response to a University Serogroup B Meningococcal Disease Outbreak—Oregon, 2015–2016
abstract: Limited data exist on the impact of the serogroup B meningococcal (MenB) vaccines MenB-FHbp and MenB-4C on meningococcal carriage and herd protection. We therefore assessed meningococcal carriage following a MenB vaccination campaign in response to a university serogroup B meningococcal disease outbreak in 2015.



A convenience sample of students recommended for vaccination provided oropharyngeal swab specimens and completed questionnaires during 4 carriage surveys over 11 months. Isolates were tested by real-time polymerase chain reaction analysis, slide agglutination, and whole-genome sequencing. Vaccination history was verified via university records and the state immunization registry.



A total of 4225 oropharyngeal swab specimens from 3802 unique participants were analyzed. Total meningococcal and genotypically serogroup B carriage prevalence among sampled students were stable, at 11%-17% and 1.2%-2.4% during each round, respectively; no participants carried the outbreak strain. Neither 1-3 doses of MenB-FHbp nor 1-2 doses of MenB-4C was associated with decreased total or serogroup B carriage prevalence.



While few participants completed the full MenB vaccination series, limiting analytic power, these data suggest that MenB-FHbp and MenB-4C do not have a large, rapid impact on meningococcal carriage and are unlikely to provide herd protection in the context of an outbreak response.

title: Emerging clinical experience with vaccines against group B meningococcal disease.
abstract: The prevention of paediatric bacterial meningitis and septicaemia has recently entered a new era with the availability of two vaccines against capsular group B meningococcus (MenB). Both of these vaccines are based on sub-capsular proteins of the meningococcus, an approach that overcomes the challenges set by the poorly immunogenic MenB polysaccharide capsule but adds complexity to predicting and measuring the impact of their use. This review describes the development and use of MenB vaccines to date, from the use of outer membrane vesicle (OMV) vaccines in MenB outbreaks around the world, to emerging evidence on the effectiveness of the newly available vaccines. While recent data from the United Kingdom supports the potential for protein-based vaccines to provide direct protection against MenB disease in immunised children, further research is required to understand the breadth and duration of this protection. A more detailed understanding of the impact of immunisation with these vaccines on nasopharyngeal carriage of the meningococcus is also required, to inform both their potential to induce herd immunity and to preferentially select for carriage of strains not susceptible to vaccine-induced antibodies. Although a full understanding of the potential impact of these vaccines will only be possible with this additional information, the availability of new tools to prevent the devastating effect of invasive MenB disease is a significant breakthrough in the fight against childhood sepsis and meningitis.

title: The changing epidemiology of meningococcal disease in North America 1945–2010
abstract: The epidemiology of Invasive Meningococcal Disease (IMD) is distinct in the United States and Canada compared with other countries. This review describes the incidence, mortality and vaccination strategies relevant to IMD in these countries over the past 65 y. The incidence of IMD has remained consistently low in both countries during this period. Serogroup B and serogroup C have been the most prominent disease-causing serogroups. Notably, serogroup Y has recently become an important cause of IMD in the USA, but has not been as prominent in Canada. Periodic rises in incidence have been characterized by local outbreaks that have raised public concern, especially those caused by serogroup C in Canada, and serogroup B in the USA. Case fatality rates have remained consistent at around 10–20%, but vary by age and serogroup. Recent outbreaks have led to the introduction of vaccination programs for both outbreak control and routine immunization.

title: Elevated Risk for Invasive Meningococcal Disease Among Persons With HIV
abstract: Invasive meningococcal disease (IMD) is life-threatening. Current recommendations for receipt of meningococcal vaccine to prevent IMD do not include HIV-infected adults.  HIV infection and IMD are reportable diseases in New York City. Investigators linked databases and found that, compared with the general population, people living with HIV/AIDS (PLWHA) had a relative risk for IMD of 10. Risk was greatest in persons with CD4+ counts less than 0.200109 cells/L. Serotypes in nearly 90% of IMD cases in adult PLWHA are included in current meningococcal vaccines.  Studies of vaccine effectiveness are needed in adult PLWHA, who may be appropriate candidates for routine immunization with meningococcal vaccine. The Editors Infection with HIV is associated with an increased risk for several bacterial infections, most notably Mycobacterium tuberculosis, Streptococcus pneumonia, nontyphoid Salmonella, Haemophilus influenzae, and Staphylococcus aureus(1, 2). Data on the relationship between HIV and Neisseria meningitidis are limited. An analysis of surveillance data from 1988 to 1993 from the 8-county metropolitan area of Atlanta, Georgia, found that HIV-infected adults aged 25 to 49 years had a nearly 24-fold increased risk for invasive meningococcal disease (IMD) (3). More recently, Cohen and colleagues reported that the incidence of IMD in HIV-infected individuals of all ages in South Africa was 11 times greater than that among HIV-uninfected individuals (4). Moreover, the Centers for Disease Control and Prevention (CDC) recently published data from its Active Bacterial Core surveillance sites indicating that the cumulative annual incidence of IMD in individuals who meet the case definition for AIDS is approximately 13 times greater than in those who do not (5). In 2005, a new tetravalent meningococcal polysaccharideprotein conjugate vaccine (MCV4) was approved and recommended for routine use in young adolescents (aged 11 to 12 years) on the basis of an increased risk for IMD in college students living in dormitories and a cost-effectiveness analysis (6). Current MCV4 recommendations, however, do not include people living with HIV/AIDS (PLWHA), other than HIV-infected adolescents (5). The absence of meningococcal vaccine recommendations in HIV-infected adults is due, in part, to insufficient data on vaccine efficacy in HIV-infected adults, the duration of immunity, and the concern over the cost-effectiveness of such recommendations. To explore the relationship between HIV and IMD in New York City (NYC), we matched population-based IMD surveillance data with HIV and vital statistics registries to calculate rates of IMD and IMD-related death from 2000 to 2011 among PLWHA and persons not known to be HIV-infected. We also analyzed the serogroup distribution among IMD cases and evaluated the effect of immune status and viral load (VL) on risk for IMD among PLWHA.An outbreak of serogroup C IMD was recognized in NYC among men who have sex with men (MSM) in the fall of 2012 after the data analysis for this article was completed (7). A total of 17 cases and 6 deaths were identified in 2012 and 2013, with 10 of the cases having occurred in PLWHA. These 17 cases were not included in the analysis.  Study Population Both IMD and HIV are reportable diseases in NYC. We included IMD cases in NYC that were diagnosed during 2000 to 2011, met the Council of State and Territorial Epidemiologists case definitions for confirmed or probable meningococcal disease (8), and were reported to the NYC Department of Health and Mental Hygiene (DOHMH). The IMD diagnosis date was defined as the date of the clinical specimen or findings that met the case definition. Cases of IMD from 2000 to 2011 were matched to the DOHMH's Office of Vital Statistics death registry to determine vital status and underlying cause of death. Death due to IMD was defined as death occurring within 30 days of diagnosis with a final cause consistent with meningococcal disease. When IMD was not specifically listed as the cause of death, the record was reviewed by 2 independent medical reviewers who both needed to concur that the death was due to IMD. The state of New York mandated confidential, name-based reporting of HIV-related events in 1998, with implementation in June 2000. The law requires reporting of all diagnoses of HIV and AIDS, all HIV-related illness, all positive Western blot test results for HIV antibody, all VL and CD4+ cell count values, and all HIV genotypes (914). The NYC HIV Surveillance Registry (HSR) is a population-based registry of all AIDS cases diagnosed in NYC since 1981 and all HIV cases diagnosed since 2000. The HSR is regularly matched to local and national vital statistics death registries to update vital status for PLWHA and is continuously updated with HIV-related laboratory reports. Since 2005, all CD4+ cell count and HIV VL results have been electronically reported to the HSR. Incoming laboratory reports from providers and laboratories that cannot be matched to an existing person in the registry initiate a field investigation to confirm through medical record review that the case meets surveillance definitions for HIV, AIDS, or both (15) and to record data elements to be used to establish a date of diagnosis and collect other data required for surveillance. We matched case patients with IMD to the HSR by using a deterministic automated algorithm comprising 36 keys based on combinations of first name; last name; date of birth; Social Security number; and the soundex function in SAS, version 9.2 (SAS Institute, Cary, North Carolina), which adjusts for names spelled phonetically. The algorithm was ordered hierarchically such that lower keys were considered to represent matches more likely to be true. Exact matches on keys 1 to 7 were accepted as true matches without further review. Matches on keys 8 to 36 prompted a manual review by 2 independent reviewers with access to additional information about potentially matching pairs of case patients, such as residential address (16). To account for the W-shaped age distribution of IMD (17) and control for the confounding effect of age on the relative risk (RR) for IMD in PLWHA, we excluded case patients younger than 15 years and older than 64 years from the study population. The primary IMD syndrome was determined by clinical and laboratory findings per the following hierarchy if multiple syndromes existed: meningococcemia > meningitis > bacteremia > other (for example, joint or pneumonia). The IMD serogroup was determined by slide agglutination at the NYC Public Health Laboratory or by polymerase chain reaction at the Wadsworth Center State Public Health Laboratory. Statistical Analysis The number of PLWHA was estimated as the product of age-specific HIV prevalence rates (calculated from HSR data as persons diagnosed with HIV in NYC and reported to DOHMH by 30 September 2012) and intercensal population estimates for persons aged 15 to 64 years and was then averaged for 2000 to 2011. Populations for 3-year intervals were similarly estimated. The population of HIV-uninfected persons aged 15 to 64 years was calculated as the difference between the average total NYC populations and the interval-specific PLWHA population estimates. Descriptive statistics and the chi-square test were used to compare case patients with IMD on categorical variables by HIV status and also to test for trend in the proportion of patients with IMD who were HIV-infected over time. Means and SDs were used to compare continuous variables by HIV status. The average annual incidence rate of IMD per 100000 persons was computed for the 12-year period (20002011) and by 3-year intervals (20002002, 20032005, 20062008, and 20092011) among both PLWHA and HIV-uninfected persons. The RRs for IMD among PLWHA and 95% CIs were calculated for the 12- and 3-year intervals. The RR for IMD was also stratified by 3 age categories (15 to 24, 25 to 44, and 45 to 64 years) and by sex over the entire interval. Cigarette smoking frequently appears in the literature as a risk factor for IMD (1821). Questions on smoking were added to IMD case investigations in 2006, and data were available for three quarters of IMD cases during this period (cases with missing data were excluded). We used population-based estimates of smoking prevalence from the NYC Community Health Survey for 2006 and 2007 (39.6% among respondents self-reporting HIV infection and 18.8% among those self-reporting no HIV/AIDS) (22) to estimate the smoking prevalence among individuals without IMD in order to stratify the RR for IMD in PLWHA by smoking status. A sensitivity analysis of HIV ascertainment was also conducted using data from a serosurvey of undiagnosed HIV infection. The RR was recalculated by adding 14% to the PLWHA population with no additional cases of IMD (23). To compare the IMD case-fatality ratio (CFR) among patients with IMD and HIV and those with IMD only, we divided the CFR among the former for 2000 to 2011 by the CFR among the latter. A multivariate logistic regression model was used to obtain an age-adjusted odds ratio (OR) of death in case patients with IMD and HIV. The proportion of IMD cases potentially preventable by MCV4 vaccination (serogroups A, C, Y, and W) was compared by HIV status. To explore whether immune suppression and lack of HIV viral suppression were associated with higher IMD risk in PLWHA, we performed separate casecontrol analyses of the odds of IMD by CD4+ cell count and HIV VL among a subset of case patients with IMD and HIV. People living with HIV/AIDS with CD4+ cell counts and VL from the HSR in 2005 or later and test dates within 91 days of the IMD diagnosis date were eligible for selection (before 2005, only low CD4+ cell counts and detectable VL were reportable). All persons without IMD in the HSR who had CD4+ cell counts and VL were eligible to serve as control patients. For the 2 analyses, case patients w

title: Recommendations for Use of Meningococcal Conjugate Vaccines in HIV-Infected Persons - Advisory Committee on Immunization Practices, 2016.
abstract: At its June 2016 meeting, the Advisory Committee on Immunization Practices (ACIP) recommended routine use of meningococcal conjugate vaccine (serogroups A, C, W, and Y; including MenACWY-D [Menactra, Sanofi Pasteur] or MenACWY-CRM [Menveo, GlaxoSmithKline]) for persons aged ≥2 months with human immunodeficiency virus (HIV) infection. ACIP has previously recommended routine vaccination of persons aged ≥2 months who have certain medical conditions that increase risk for meningococcal disease (1), including persons who have persistent (e.g., genetic) deficiencies in the complement pathway (e.g., C3, properdin, Factor D, Factor H, or C5-C9); persons receiving eculizumab (Soliris, Alexion Pharmaceuticals) for treatment of atypical hemolytic uremic syndrome or paroxysmal nocturnal hemoglobinuria (because the drug binds C5 and inhibits the terminal complement pathway); and persons with functional or anatomic asplenia (including persons with sickle cell disease). Routine vaccination with meningococcal conjugate vaccine is also recommended for all healthy adolescents in the United States (1). This report summarizes the evidence considered by ACIP in recommending vaccination for HIV-infected persons, and provides recommendations and guidance for use of meningococcal conjugate vaccines (serogroups A, C, W, and Y) among HIV-infected persons aged ≥2 months; the majority of meningococcal disease among HIV-infected persons is caused by these four serogroups.

title: Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria.
abstract: The terminal complement inhibitor eculizumab was recently shown to be effective and well tolerated in patients with paroxysmal nocturnal hemoglobinuria (PNH). Here, we extended these observations with results from an open-label, non-placebo-controlled, 52-week, phase 3 clinical safety and efficacy study evaluating eculizumab in a broader PNH patient population. Eculizumab was administered by intravenous infusion at 600 mg every 7 +/- 2 days for 4 weeks; 900 mg 7 +/- 2 days later; followed by 900 mg every 14 +/- 2 days for a total treatment period of 52 weeks. Ninety-seven patients at 33 international sites were enrolled. Patients treated with eculizumab responded with an 87% reduction in hemolysis, as measured by lactate dehydrogenase levels (P < .001). Baseline fatigue scores in the FACIT-Fatigue instrument improved by 12.2 +/- 1.1 points (P < .001). Eculizumab treatment led to an improvement in anemia. The increase in hemoglobin level occurred despite a reduction in transfusion requirements from a median of 8.0 units of packed red cells per patient before treatment to 0.0 units per patient during the study (P < .001). Overall, transfusions were reduced 52% from a mean of 12.3 to 5.9 units of packed red cells per patient. Forty-nine patients (51%) achieved transfusion independence for the entire 52-week period. Improvements in hemolysis, fatigue, and transfusion requirements with eculizumab were independent of baseline levels of hemolysis and degree of thrombocytopenia. Quality of life measures were also broadly improved with eculizumab treatment. This study demonstrates that the beneficial effects of eculizumab treatment in patients with PNH are applicable to a broader population of PNH patients than previously studied.

title: Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies
abstract: In the past decade, a large body of evidence has accumulated in support of the critical role of dysregulation of the alternative complement pathway in atypical haemolytic uraemic syndrome (aHUS) and C3 glomerulopathies. These findings have paved the way for innovative therapeutic strategies based on complement blockade, and eculizumab, a monoclonal antibody targeting the human complement component 5, is now widely used to treat aHUS. In this article, we review 28 case reports and preliminary data from 37 patients enrolled in prospective trials of eculizumab treatment for episodes of aHUS involving either native or transplanted kidneys. Eculizumab may be considered as an optimal first-line therapy when the diagnosis of aHUS is unequivocal and this treatment has the potential to rescue renal function when administered early after onset of the disease. However, a number of important issues require further study, including the appropriate duration of treatment according to an individual's genetic background and medical history, the optimal strategy to prevent post-transplantation recurrence of aHUS and a cost–efficacy analysis. Data regarding the efficacy of eculizumab in the control of C3 glomerulopathies are more limited and less clear, but several observations suggest that eculizumab may act on the most inflammatory forms of this disorder.

title: Eculizumab in Paroxysmal Nocturnal Haemoglobinuria
abstract: Eculizumab is a monoclonal antibody that binds with high affinity to the complement protein C5, preventing terminal complement-mediated intravascular haemolysis in patients with paroxysmal nocturnal haemoglobinuria (PNH). In three well designed clinical trials in patients with PNH, eculizumab blocked serum haemolytic activity and decreased transfusion rates. Pooled data from the three clinical trials demonstrated that eculizumab treatment decreased the overall thromboembolism rate in patients with PNH. Eculizumab carries a black box warning for the potential increased risk of meningococcal infections and requires patients to receive the meningococcal vaccine at least 2 weeks before starting treatment. Eculizumab is the first drug to be approved by the US FDA for the treatment of PNH and is a novel treatment that offers a new option for patients with PNH.

title: The introduction of the meningococcal B (MenB) vaccine (Bexsero®) into the national infant immunisation programme--New challenges for public health.
abstract: The United Kingdom is the first country to introduce Bexsero(®) (GSK Biologicals), a multicomponent, protein-based vaccine against meningococcal group B (MenB), into the national infant immunisation programme. This vaccine is like no other licensed vaccine and poses a number of implementation and surveillance challenges in England. From 01 September 2015, UK infants were offered a reduced two dose primary immunisation schedule at 2 and 4 months followed by a booster at 12 months. Because of high rates of fever post-vaccination, parents were advised to give their infants three doses of prophylactic paracetamol, with the first dose given as soon as possible after the primary MenB vaccination dose. Since the vaccine only protects against 73-88% of MenB strains causing invasive disease in England, clinical isolates and PCR-positive samples will require extensive characterisation by the Meningococcal Reference Unit (MRU) at Public Health England (PHE) in order to monitor vaccine effectiveness and identify potential vaccine failures. PHE is also conducting detailed clinical and epidemiological surveillance to assess the impact of the MenB immunisation programme on the morbidity and mortality associated with invasive meningococcal disease in infants and young children.

title: Immunogenicity of a Meningococcal B Vaccine during a University Outbreak.
abstract: BACKROUND
In December 2013, a multicomponent meningococcal serogroup B (4CMenB) vaccine was used before licensure on the basis of special consideration by the Food and Drug Administration to respond to an outbreak of Neisseria meningitidis B at a U.S. university. Data suggested that vaccination would control the outbreak because isolates expressed antigens that were closely related to the vaccine antigens (factor H-binding protein [fHbp] and neisserial heparin-binding antigen). We quantified the immune responses induced by 4CMenB during the outbreak.



We conducted a seroprevalence survey among students to assess vaccination status and collect serum specimens to quantify titers of serum bactericidal antibodies (SBA) with an assay that included human complement (hSBA). We compared the proportion of vaccinated and unvaccinated participants who were seropositive for the outbreak strain and for one closely related reference strain (44/76-SL, which included fHbp) and one mismatched reference strain (5/99, which included neisserial adhesin A), both of which were used in vaccine development. Seropositivity was defined as an hSBA titer of 4 or higher.



Among the 499 participants who received two doses of the 4CMenB vaccine 10 weeks apart, 66.1% (95% confidence interval [CI], 61.8 to 70.3) were seropositive for the outbreak strain, although the geometric mean titer was low at 7.6 (95% CI, 6.7 to 8.5). Among a random subgroup of 61 vaccinees who also received two doses but did not have a detectable protective response to the outbreak strain, 86.9% (95% CI, 75.8 to 94.2) were seropositive for the 44/76-SL strain, for which there was a geometric mean titer of 17.4 (95% CI, 13.0 to 23.2), whereas 100% of these vaccinees (95% CI, 94.1 to 100) were seropositive for the 5/99 strain and had a higher geometric mean titer (256.3; 95% CI, 187.3 to 350.7). The response to the outbreak strain was moderately correlated with the response to the 44/76-SL strain (Pearson's correlation,0.64; P<0.001) but not with the response to the 5/99 strain (Pearson's correlation,-0.06; P=0.43).



Eight weeks after the second dose of the 4CMenB vaccine was administered, there was no evidence of an hSBA response against the outbreak strain in 33.9% of vaccinees, although no cases of meningococcal disease caused by N. meningitidis B were reported among vaccinated students. (Funded by Princeton University and others.).

title: Serogroup W135 meningococcal disease in Hajj pilgrims
abstract: An outbreak of W135 meningococcal disease occurred in the spring of 2000 among pilgrims returning from Saudi Arabia and their contacts. Clinical isolates from England and France were examined and compared with reference strains from other countries. Characterisation of isolates by a range of typing methods showed them to be of clonal origin (ET-37) and closely related to other meningococci with an established propensity to cause disease clusters. A reappraisal of vaccination strategies for travellers is required.

title: Epidemiological investigation of an outbreak of meningococcal meningitis in Makkah (Mecca), Saudi Arabia, 1992.
abstract: During March and April of 1992, the health surveillance system began detecting increasing numbers of cases of meningococcal disease (MCD) in the Islamic holy city of Makkah (Mecca). We identified 102 bacteriologically confirmed cases (CC) and 80 suspected cases (SC) of MCD. Neisseria meningitidis was identified as Group A, III-1 clone. The ratio of male:female cases was 2.9:1. All age groups of males were affected. There was only one case among women aged 10-30; 50% of the adult female cases were 55 or older. The case-fatality ratio (CFR) was 14.7% among CC. Pakistanis, who comprised about one-third of the CC, had a CFR of 26.7%. Fifty-nine percent of CC were religious visitors. CC in residents were most common in persons living near the Holy Mosque (Haram), where the carriage rate reached 86%. A mass vaccination program against MCD was instituted, using AC bivalent meningococcal vaccine (MCV). An abrupt drop, from a mean of 15 CC per week to 2 CC per week (only in visitors), coincided with vaccinating 600,000 persons over 2 weeks. Makkah residents who had been vaccinated against MCD were less likely to have contracted MCD (OR = 0.17, 95% CI: 0.06-0.50). MCV was of no significant protective value if it had been administered 5 years before the outbreak. The main reason for not being vaccinated as stated by both cases (71%) and controls (45%) was not knowing about the disease. The age and sex differences probably relate to differences in exposures to crowded conditions. Health education should illuminate the seriousness of the disease and the importance of vaccination.

title: Neisseria meningitidis nasopharyngeal carriage during the Hajj: A cohort study evaluating the need for ciprofloxacin prophylaxis.
abstract: The annual Muslim pilgrimage has the potential of increase risk for acquisition of Neisseria meningitidis. Here, we evaluate the Hajj impact on the prevalence of N. meningitidis carriage in a paired and non-paired cohort of pilgrims. Secondary objectives were to calculate the compliance with recommended vaccination.



This is a prospective paired (arriving and departing), non-paired arriving and non-paired departing cohort study with the collection of nasopharyngeal samples at the start and the end of the Hajj.



The study included unpaired arriving pilgrims at King Abdul Aziz International Airport (N=1055), unpaired departing cohort (N=373), and a paired cohort (N=628) who were tested on arrival and departure. Meningococcal vaccination was received by all pilgrims, 98.2% received quadrivalent polysaccharide vaccine (ACWY), and 1.8% received meningococcal quadrivalent conjugate vaccine (MCV4). Only 1.61% and 23.03% received pneumococcal and influenza vaccines, respectively. Of the 1055 arriving unpaired pilgrim, 36 (3.4%) tested positive for nasopharyngeal carriage of N. meningitidis, and 24 (66.7%) of these were serogroup B, the remainder were non-groupable. Haemophilus influenza was detected among 45 (4.3%), and 11 (1%) carriers were positive for both N. meningitidis and H. influenzae. Out of 373 in the unpaired departing cohort, 6 (1.61%) tested positive for N. meningitidis, and 34 (9.1%) were positive for H. influenzae. Of the 628 paired cohort pilgrims, 36 (5.7%) pilgrims were positive for N. meningitidis at arrival and 16 (2.5%) pilgrims were positive after the hajj.



This the largest study of the epidemiology of N. meningitidis among pilgrims. The study showed a significant difference in the carriage between pilgrims from high endemicity and other pilgrims with a predominance of serogroup B. The continued use of ciprofloxacin as prophylactic antibiotics should be reconsidered as well as the consideration to add serogroup B as a required vaccination.

title: Emergence of a new Neisseria meningitidis clonal complex 11 lineage 11.2 clade as an effective urogenital pathogen
abstract: Neisseria meningitidis (Nm) remains a leading cause of meningitis and rapidly fatal sepsis in otherwise healthy individuals. Historically, Nm is not recognized as a significant cause of urogenital infections. Since 2015, a significant increase of meningococcal urethritis primarily among heterosexual men has been reported in multiple US cities. We defined that a unique nonencapsulated Nm clade, which belonged to the cc11/ET-15 hyperinvasive lineage, was linked to these Nm urethritis clusters. The clade isolates causing urethritis clusters in the United States may have adapted to the urogenital environment with two unique molecular fingerprints: the insertion of IS1301 with associated deletion of capsule, enhancing mucosal adherence, and the acquisition of the gonococcal denitrification pathway by gene conversion, promoting anaerobic growth. Neisseria meningitidis (Nm) clonal complex 11 (cc11) lineage is a hypervirulent pathogen responsible for outbreaks of invasive meningococcal disease, including among men who have sex with men, and is increasingly associated with urogenital infections. Recently, clusters of Nm urethritis have emerged primarily among heterosexual males in the United States. We determined that nonencapsulated meningococcal isolates from an ongoing Nm urethritis outbreak among epidemiologically unrelated men in Columbus, Ohio, are linked to increased Nm urethritis cases in multiple US cities, including Atlanta and Indianapolis, and that they form a unique clade (the US Nm urethritis clade, US_NmUC). The isolates belonged to the cc11 lineage 11.2/ET-15 with fine type of PorA P1.5–1, 10–8; FetA F3-6; PorB 2–2 and express a unique FHbp allele. A common molecular fingerprint of US_NmUC isolates was an IS1301 element in the intergenic region separating the capsule ctr-css operons and adjacent deletion of cssA/B/C and a part of csc, encoding the serogroup C capsule polymerase. This resulted in the loss of encapsulation and intrinsic lipooligosaccharide sialylation that may promote adherence to mucosal surfaces. Furthermore, we detected an IS1301-mediated inversion of an ∼20-kb sequence near the cps locus. Surprisingly, these isolates had acquired by gene conversion the complete gonococcal denitrification norB-aniA gene cassette, and strains grow well anaerobically. The cc11 US_NmUC isolates causing urethritis clusters in the United States may have adapted to a urogenital environment by loss of capsule and gene conversion of the Neisseria gonorrheae norB-aniA cassette promoting anaerobic growth.

title: Effectiveness of a group B outer membrane vesicle meningococcal vaccine against gonorrhoea in New Zealand: a retrospective case-control study
abstract: Gonorrhoea is a major global public health problem that is exacerbated by drug resistance. Effective vaccine development has been unsuccessful, but surveillance data suggest that outer membrane vesicle meningococcal group B vaccines affect the incidence of gonorrhoea. We assessed vaccine effectiveness of the outer membrane vesicle meningococcal B vaccine (MeNZB) against gonorrhoea in young adults aged 15-30 years in New Zealand.



We did a retrospective case-control study of patients at sexual health clinics aged 15-30 years who were born between Jan 1, 1984, and Dec 31, 1998, eligible to receive MeNZB, and diagnosed with gonorrhoea or chlamydia, or both. Demographic data, sexual health clinic data, and National Immunisation Register data were linked via patients' unique personal identifier. For primary analysis, cases were confirmed by laboratory isolation or detection of Neisseria gonorrhoeae only from a clinical specimen, and controls were individuals with a positive chlamydia test only. We estimated odds ratios (ORs) comparing disease outcomes in vaccinated versus unvaccinated participants via multivariable logistic regression. Vaccine effectiveness was calculated as 100×(1-OR).



11 of 24 clinics nationally provided records. There were 14 730 cases and controls for analyses: 1241 incidences of gonorrhoea, 12 487 incidences of chlamydia, and 1002 incidences of co-infection. Vaccinated individuals were significantly less likely to be cases than controls (511 [41%] vs 6424 [51%]; adjusted OR 0·69 [95% CI 0·61-0·79]; p<0·0001). Estimate vaccine effectiveness of MeNZB against gonorrhoea after adjustment for ethnicity, deprivation, geographical area, and sex was 31% (95% CI 21-39).



Exposure to MeNZB was associated with reduced rates of gonorrhoea diagnosis, the first time a vaccine has shown any protection against gonorrhoea. These results provide a proof of principle that can inform prospective vaccine development not only for gonorrhoea but also for meningococcal vaccines.



GSK Vaccines.

title: The VR2 Epitope on the PorA P1.7-2,4 Protein Is the Major Target for the Immune Response Elicited by the Strain-Specific Group B Meningococcal Vaccine MeNZB
abstract: A protracted epidemic of group B meningococcal disease in New Zealand led to the testing of a strain-specific tailor-made vaccine, MeNZB. Immunogenicity levels achieved during age group trials enabled New Zealand's regulatory authority to grant licensure to deliver MeNZB to all individuals under age 20. During the trials target strains for serum bactericidal antibody measurements included the vaccine target strain NZ98/254 and two comparator epidemic-type strains (NZ94/167 and NZ02/09). In this study, 12 other strains differing variously from the vaccine strain by their capsular group, PorB type, and PorA variable region specificities, or PorA expression, were used as target strains. The PorA specificity of the serum bactericidal antibody responses to the vaccine was determined for 40 vaccinees. Sets of 10 pre- and postvaccination sera were chosen randomly from the young infant, older infant, toddler, and school-age group trials. Antibody recognition of linearized PorA proteins was also determined using immunoblotting. Across all age groups vaccine-induced serum bactericidal antibodies specifically targeted the VR2 P1.4 epitope of the PorA P1.7-2,4 protein irrespective of the PorB type and/or capsular type of the target strain. Deletion of amino acids within the VR2 epitope or replacement of the epitope through genetic exchange allowed strains variously to resist antibody-directed complement-mediated lysis and negated PorA-specific antibody recognition in immunoblots. The demonstration that the immunodominant antibody response was specifically for the VR2 P1.4 epitope of the PorA protein supports the public health decision to use a strain-specific vaccine for the control of New Zealand's epidemic of meningococcal disease.

title: Genomic Analysis of the Evolution and Global Spread of Hyper-invasive Meningococcal Lineage 5
abstract: The predominant model for bacterial pandemics is the emergence of a virulent variant that diversifies as it spreads in human populations. We investigated a 40-year meningococcal disease pandemic caused by the hyper-invasive ET-5/ST-32 complex.  A global collection of Neisseria meningitidis isolates dating from 1969 to 2008 was whole genome sequenced (WGS) and analysed using a gene-by-gene approach at http://pubmlst.org/neisseria.  Analysis of WGS data identified a ‘Lineage 5 pan genome’ of 1940 genes, 1752 (92%) of which were present in all isolates (Lineage 5 ‘core genome’). Genetic diversity, which was mostly generated by horizontal gene transfer, was unevenly distributed in the genome; however, genealogical analysis of diverse and conserved core genes, accessory genes, and antigen encoding genes, robustly identified a star phylogeny with a number of sub-lineages. Most European and American isolates belonged to one of two closely related sub-lineages, which had diversified before the identification of the pandemic in the 1970s. A third, genetically more diverse sub-lineage, was associated with Asian isolates. Several isolates had acquired DNA from the related gonococcus.  These data were inconsistent with a single point of origin followed by pandemic spread, rather suggesting that the sub-lineages had diversified and spread by asymptomatic transmission, with multiple distinct strains causing localised hyperendemic outbreaks.

title: Assessing the Risk of Laboratory-Acquired Meningococcal Disease
abstract: Neisseria meningitidis is infrequently reported as a laboratory-acquired infection. Prompted by two cases in the United States in 2000, we assessed this risk among laboratorians. We identified cases of meningococcal disease that were possibly acquired or suspected of being acquired in a laboratory by placing an information request on e-mail discussion groups of infectious disease, microbiology, and infection control professional organizations. A probable case of laboratory-acquired meningococcal disease was defined as illness meeting the case definition for meningococcal disease in a laboratorian who had occupational exposure to an N. meningitidis isolate of the same serogroup within 14 days of illness onset. Sixteen cases of probable laboratory-acquired meningococcal disease occurring worldwide between 1985 and 2001 were identified, including six U.S. cases between 1996 and 2000. Nine cases (56%) were serogroup B; seven (44%) were serogroup C. Eight cases (50%) were fatal. All cases occurred among clinical microbiologists. In 15 cases (94%), isolate manipulation was performed without respiratory protection. We estimated that an average of three microbiologists are exposed to the 3,000 meningococcal isolates seen in U.S. laboratories yearly and calculated an attack rate of 13/100,000 microbiologists between 1996 and 2001, compared to 0.2/100,000 among U.S. adults in general. The rate and case/fatality ratio of meningococcal disease among microbiologists are higher than those in the general U.S. population. Specific risk factors for laboratory-acquired infection are likely associated with exposure to droplets or aerosols containing N. meningitidis. Prevention should focus on the implementation of class II biological safety cabinets or additional respiratory protection during manipulation of suspected meningococcal isolates.

title: Do we need a new approach to making vaccine recommendations?
abstract: Controversy about the evidence, economics, ethics, lobbying, and decision making surrounding a new vaccine for serogroup B meningococcal disease should trigger change in the way we develop recommendations for new vaccines say Natasha Crowcroft and colleagues