Serogroup A meningococcal conjugate vaccines: building sustainable and equitable vaccine strategies.

INTRODUCTION: For well over 100 years, meningococcal disease due to serogroup A Neisseria meningitidis (MenA) has caused severe epidemics globally, especially in the meningitis belt of sub-Saharan Africa. AREAS COVERED: The article reviews the background and identification of MenA, the global and molecular epidemiology of MenA, and the outbreaks of MenA in the African meningitis belt. The implementation (2010) of an equitable MenA polysaccharide-protein conjugate vaccine (PsA-TT, MenAfriVac) and the strategy to control MenA in sub-Saharan Africa is described. The development of a novel multi-serogroup meningococcal conjugate vaccine (NmCV-5) that includes serogroup A is highlighted. The PubMed database (1996-2019) was searched for studies relating to MenA outbreaks, vaccine, and immunization strategies; and the Neisseria PubMLST database of 1755 MenA isolates (1915-2019) was reviewed. EXPERT OPINION: Using strategies from the successful MenAfriVac campaign, expanded collaborative partnerships were built to develop a novel, low-cost multivalent component meningococcal vaccine that includes MenA. This vaccine promises greater sustainability and is directed toward global control of meningococcal disease in the African meningitidis belt and beyond. The new WHO global roadmap addresses the continuing problem of bacterial meningitis, including meningococcal vaccine prevention, and provides a framework for further reducing the devastation of MenA.

Meningococcal carriage within households in the African meningitis belt: A longitudinal pilot study.

OBJECTIVES: Carriers of Neisseria meningitidis are a key source of transmission. In the African meningitis belt, where risk of meningococcal disease is highest, a greater understanding of meningococcal carriage dynamics is needed. METHODS: We randomly selected an age-stratified sample of 400 residents from 116 households in Bamako, Mali, and collected pharyngeal swabs in May 2010. A month later, we enrolled all 202 residents of 20 of these households (6 with known carriers) and collected swabs monthly for 6 months prior to MenAfriVac vaccine introduction and returned 10 months later to collect swabs monthly for 3 months. We used standard bacteriological methods to identify N. meningitidis carriers and fit hidden Markov models to assess acquisition and clearance overall and by sex and age. RESULTS: During the cross-sectional study 5.0% of individuals (20/400) were carriers. During the longitudinal study, 73 carriage events were identified from 1422 swabs analyzed, and 16.3% of individuals (33/202) were identified as carriers at least once. The majority of isolates were non-groupable; no serogroup A carriers were identified. CONCLUSIONS: Our results suggest that the duration of carriage with any N. meningitidis averages 2.9 months and that males and children acquire and lose carriage more frequently in an urban setting in Mali. Our study informed the design of a larger study implemented in seven countries of the African meningitis belt.

Bacterial meningitis epidemiology and return of Neisseria meningitidis serogroup A cases in Burkina Faso in the five years following MenAfriVac mass vaccination campaign.

BACKGROUND: Historically, Neisseria meningitidis serogroup A (NmA) caused large meningitis epidemics in sub-Saharan Africa. In 2010, Burkina Faso became the first country to implement a national meningococcal serogroup A conjugate vaccine (MACV) campaign. We analyzed nationwide meningitis surveillance data from Burkina Faso for the 5 years following MACV introduction. METHODS: We examined Burkina Faso's aggregate reporting and national laboratory-confirmed case-based meningitis surveillance data from 2011-2015. We calculated incidence (cases per 100,000 persons), and described reported NmA cases. RESULTS: In 2011-2015, Burkina Faso reported 20,389 cases of suspected meningitis. A quarter (4,503) of suspected meningitis cases with cerebrospinal fluid specimens were laboratory-confirmed as either S. pneumoniae (57%), N. meningitidis (40%), or H. influenzae (2%). Average adjusted annual national incidence of meningococcal meningitis was 3.8 (range: 2.0-10.2 annually) and was highest among infants aged <1 year (8.4). N. meningitidis serogroup W caused the majority (64%) of meningococcal meningitis among all age groups. Only six confirmed NmA cases were reported in 2011-2015. Five cases were in children who were too young (n = 2) or otherwise not vaccinated (n = 3) during the 2010 MACV mass vaccination campaign; one case had documented MACV receipt, representing the first documented MACV failure. CONCLUSIONS: Meningococcal meningitis incidence in Burkina Faso remains relatively low following MACV introduction. However, a substantial burden remains and NmA transmission has persisted. MACV integration into routine childhood immunization programs is essential to ensure continued protection.

Four years of case-based surveillance of meningitis following the introduction of MenAfriVac in Moissala, Chad: lessons learned.

OBJECTIVE: Case-based surveillance of bacterial meningitis in sentinel districts has been recommended after the introduction of the conjugated vaccine against Neisseria meningitidis serogroup A (NmA), MenAfriVac, in the African meningitis belt. Here we report data and lessons learnt from four years of surveillance in the district of Moissala, Chad. METHODS: All suspected cases of meningitis were referred free of charge to the district hospital for lumbar puncture and treatment. Cerebrospinal fluid samples were tested with Pastorex latex agglutination in Moissala, and inoculated trans-isolate media were used for culture and PCR at the national reference laboratory and/or at the Norwegian Institute of Public Health. RESULTS: From July 2012 to December 2016, 237 suspected cases of meningitis were notified, and a specimen was collected from 224. Eighty-three samples were positive for a bacterial pathogen by culture, PCR or Pastorex, including 58 cases due to Streptococcus pneumoniae with only 28 of 49 pneumococcal meningitis confirmed by culture or PCR correctly identified by Pastorex. Four cases of NmA were detected by Pastorex, but none were confirmed by PCR. CONCLUSION: Implementation of case-based surveillance for meningitis is feasible in Chad, but has required political and technical engagement. Given the high proportion of S. pneumoniae and its poor detection by Pastorex, continued use of PCR is warranted for surveillance outside of outbreaks, and efforts to accelerate the introduction of pneumococcal conjugate vaccines are needed. Introduction of MenAfriVac in routine immunisation and future availability of a pentavalent meningococcal conjugate vaccine will be key elements for the sustained reduction in meningitis outbreaks in the area.

Notes from the Field: Meningococcal Disease in an International Traveler on Eculizumab Therapy - United States, 2015.

On June 2, 2015, CDC was notified that a male airline passenger, aged 41 years, with a fever of 105.4°F, headache, nausea, photophobia, diarrhea, and vomiting, which began approximately 3 hours after departure, was arriving to San Francisco, California, on a flight from Frankfurt, Germany. His symptoms reportedly started with neck stiffness 1 day earlier. Upon arrival, the patient was immediately transported to a local hospital, where he was in septic shock, which was followed by multisystem organ failure. Cerebrospinal fluid, obtained approximately 12 hours after initiation of treatment, was Gram stain- and culture-negative. Blood cultures, which were drawn before antibiotic treatment, were positive for Neisseria meningitides of indeterminate serogroup. A review of the patient's medical records revealed a history of paroxysmal nocturnal hemoglobinuria and current biweekly eculizumab (Soliris) therapy.

From Epidemic Meningitis Vaccines for Africa to the Meningitis Vaccine Project.

BACKGROUND: Polysaccharide vaccines had been used to control African meningitis epidemics for >30 years but with little or modest success, largely because of logistical problems in the implementation of reactive vaccination campaigns that are begun after epidemics are under way. After the major group A meningococcal meningitis epidemics in 1996-1997 (250,000 cases and 25,000 deaths), African ministers of health declared the prevention of meningitis a high priority and asked the World Health Organization (WHO) for help in developing better immunization strategies to eliminate meningitis epidemics in Africa. METHODS: WHO accepted the challenge and created a project called Epidemic Meningitis Vaccines for Africa (EVA) that served as an organizational framework for external consultants, PATH, the US Centers for Disease Control and Prevention (CDC), and the Bill & Melinda Gates Foundation (BMGF). Consultations were initiated with major vaccine manufacturers. EVA commissioned a costing study/business plan for the development of new group A or A/C conjugate vaccines and explored the feasibility of developing these products as a public-private partnership. Representatives from African countries were consulted. They confirmed that the development of conjugate vaccines was a priority and provided information on preferred product characteristics. In parallel, a strategy for successful introduction was also anticipated and discussed. RESULTS: The expert consultations recommended that a group A meningococcal conjugate vaccine be developed and introduced into the African meningitis belt. The results of the costing study indicated that the "cost of goods" to develop a group A - containing conjugate vaccine in the United States would be in the range of US$0.35-$1.35 per dose, depending on composition (A vs A/C), number of doses/vials, and presentation. Following an invitation from BMGF, a proposal was submitted in the spring of 2001. CONCLUSIONS: In June 2001, BMGF awarded a grant of US$70 million to create the Meningitis Vaccine Project (MVP) as a partnership between PATH and WHO, with the specific goal of developing an affordable MenA conjugate vaccine to eliminate MenA meningitis epidemics in Africa. EVA is an example of the use of WHO as an important convening instrument to facilitate new approaches to address major public health problems.

Costs of Neisseria meningitidis Group A Disease and Economic Impact of Vaccination in Burkina Faso.

BACKGROUND: Five years since the successful introduction of MenAfriVac in a mass vaccination campaign targeting 1- to 29-year-olds in Burkina Faso, consideration must be given to the optimal strategies for sustaining population protection. This study aims to estimate the economic impact of a range of vaccination strategies in Burkina Faso. METHODS: We performed a cost-of-illness study, comparing different vaccination scenarios in terms of costs to both households and health systems over a 26-year time horizon. These scenarios are (1) reactive vaccination campaign (baseline comparator); (2) preventive vaccination campaign; (3) routine immunization at 9 months; and (4) a combination of routine and an initial catchup campaign of children under 5. Costs were estimated from a literature review, which included unpublished programmatic documents and peer-reviewed publications. The future disease burden for each vaccination strategy was predicted using a dynamic transmission model of group A Neisseria meningitidis. RESULTS: From 2010 to 2014, the total costs associated with the preventive campaign targeting 1- to 29-year-olds with MenAfriVac were similar to the estimated costs of the reactive vaccination strategy (approximately 10 million US dollars [USD]). Between 2015 and 2035, routine immunization with or without a catch-up campaign of 1- to 4-year-olds is cost saving compared with the reactive strategy, both with and without discounting costs and cases. Most of the savings are accrued from lower costs of case management and household costs resulting from a lower burden of disease. After the initial investment in the preventive strategy, 1 USD invested in the routine strategy saves an additional 1.3 USD compared to the reactive strategy. CONCLUSIONS: Prevention strategies using MenAfriVac will be significantly cost saving in Burkina Faso, both for the health system and for households, compared with the reactive strategy. This will protect households from catastrophic expenditures and increase the development capacity of the population.

Serogroup A meningococcal conjugate vaccines in Africa.

Serogroup A meningococcal epidemics have been a recurrent public health problem, especially in resource-poor countries of Africa. Recently, the administration in mass vaccination campaigns of a single dose of the monovalent meningococcal conjugate vaccine, MenAfriVac, to the 1-29 year-old population of sub-Saharan Africa has prevented epidemics of meningitis caused by serogroup A Neisseria meningitidis. This strategy has also been shown to provide herd protection of the non-vaccinated population. Development of meningococcal conjugate vaccines covering other serogroups and enhanced use of the pneumococcal and Haemophilus influenzae type b conjugate vaccines must be pursued to fully control bacterial meningitis in sub-Saharan Africa.

Persistent low carriage of serogroup A Neisseria meningitidis two years after mass vaccination with the meningococcal conjugate vaccine, MenAfriVac.

BACKGROUND: The conjugate vaccine against serogroup A Neisseria meningitidis (NmA), MenAfriVac, is currently being introduced throughout the African meningitis belt. In repeated multicentre cross-sectional studies in Burkina Faso we demonstrated a significant effect of vaccination on NmA carriage for one year following mass vaccination in 2010. A new multicentre carriage study was performed in October-November 2012, two years after MenAfriVac mass vaccination. METHODS: Oropharyngeal samples were collected and analysed for presence of N. meningitidis (Nm) from a representative selection of 1-29-year-olds in three districts in Burkina Faso using the same procedures as in previous years. Characterization of Nm isolates included serogrouping, multilocus sequence typing, and porA and fetA sequencing. A small sample of invasive isolates collected during the epidemic season of 2012 through the national surveillance system were also analysed. RESULTS: From a total of 4964 oropharyngeal samples, overall meningococcal carriage prevalence was 7.86%. NmA prevalence was 0.02% (1 carrier), significantly lower (OR, 0.05, P = 0.005, 95% CI, 0.006-0.403) than pre-vaccination prevalence (0.39%). The single NmA isolate was sequence type (ST)-7, P1.20,9;F3-1, a clone last identified in Burkina Faso in 2003. Nm serogroup W (NmW) dominated with a carriage prevalence of 6.85%, representing 87.2% of the isolates. Of 161 NmW isolates characterized by molecular techniques, 94% belonged to the ST-11 clonal complex and 6% to the ST-175 complex. Nm serogroup X (NmX) was carried by 0.60% of the participants and ST-181 accounted for 97% of the NmX isolates. Carriage prevalence of serogroup Y and non-groupable Nm was 0.20% and 0.18%, respectively. Among the 20 isolates recovered from meningitis cases, NmW dominated (70%), followed by NmX (25%). ST-2859, the only ST with a serogroup A capsule found in Burkina Faso since 2004, was not found with another capsule, neither among carriage nor invasive isolates. CONCLUSIONS: The significant reduction of NmA carriage still persisted two years following MenAfriVac vaccination, and no cases of NmA meningitis were recorded. High carriage prevalence of NmW ST-11 was consistent with the many cases of NmW meningitis in the epidemic season of 2012 and the high proportion of NmW ST-11 among the characterized invasive isolates.

Emergence of a new epidemic Neisseria meningitidis serogroup A Clone in the African meningitis belt: high-resolution picture of genomic changes that mediate immune evasion.

In the African "meningitis belt," outbreaks of meningococcal meningitis occur in cycles, representing a model for the role of host-pathogen interactions in epidemic processes. The periodicity of the epidemics is not well understood, nor is it currently possible to predict them. In our longitudinal colonization and disease surveys, we have observed waves of clonal replacement with the same serogroup, suggesting that immunity to noncapsular antigens plays a significant role in natural herd immunity. Here, through comparative genomic analysis of 100 meningococcal isolates, we provide a high-resolution view of the evolutionary changes that occurred during clonal replacement of a hypervirulent meningococcal clone (ST-7) by a descendant clone (ST-2859). We show that the majority of genetic changes are due to homologous recombination of laterally acquired DNA, with more than 20% of these events involving acquisition of DNA from other species. Signals of adaptation to evade herd immunity were indicated by genomic hot spots of recombination. Most striking is the high frequency of changes involving the pgl locus, which determines the glycosylation patterns of major protein antigens. High-frequency changes were also observed for genes involved in the regulation of pilus expression and the synthesis of Maf3 adhesins, highlighting the importance of these surface features in host-pathogen interaction and immune evasion. Importance: While established meningococcal capsule polysaccharide vaccines are protective through the induction of anticapsular antibodies, findings of our longitudinal studies in the African meningitis belt have indicated that immunity to noncapsular antigens plays a significant role in natural herd immunity. Our results show that meningococci evade herd immunity through the rapid homologous replacement of just a few key genomic loci that affect noncapsular cell surface components. Identification of recombination hot spots thus represents an eminent approach to gain insight into targets of protective natural immune responses. Moreover, our results highlight the role of the dynamics of the protein glycosylation repertoire in immune evasion by Neisseria meningitidis. These results have major implications for the design of next-generation protein-based subunit vaccines.

Effect of a serogroup A meningococcal conjugate vaccine (PsA-TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study [corrected].

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: The Bill & Melinda Gates Foundation, the Wellcome Trust, and Médecins Sans Frontères.

Meningococcal carriage in the African meningitis belt.

A meningococcal serogroup A polysaccharide/tetanus toxoid conjugate vaccine (PsA-TT) (MenAfriVac(™) ) is being deployed in countries of the African meningitis belt. Experience with other polysaccharide/protein conjugate vaccines has shown that an important part of their success has been their ability to prevent the acquisition of pharyngeal carriage and hence to stop transmission and induce herd immunity. If PsA-TT is to achieve the goal of preventing epidemics, it must be able to prevent the acquisition of pharyngeal carriage as well as invasive meningococcal disease and whether PsA-TT can prevent pharyngeal carriage needs to be determined. To address this issue, a consortium (the African Meningococcal Carriage (MenAfriCar) consortium) was established in 2009 to investigate the pattern of meningococcal carriage in countries of the African meningitis belt prior to and after the introduction of PsA-TT. This article describes how the consortium was established, its objectives and the standardised field and laboratory methods that were used to achieve these objectives. The experience of the MenAfriCar consortium will help in planning future studies on the epidemiology of meningococcal carriage in countries of the African meningitis belt and elsewhere.

Lack of antigenic diversification of major outer membrane proteins during clonal waves of Neisseria meningitidis serogroup A colonization and disease.

In particular in the 'meningitis belt' of sub-Saharan Africa, epidemic meningococcal meningitis is a severe public health problem. In the past decades, serogroup A lineages have been the dominant etiologic agents, but also other serogroups have caused outbreaks. A comprehensive vaccine based on subcapsular outer membrane proteins (OMPs) is not available. Here, we have investigated whether meningococcal populations overcome herd immunity by changing antigenic properties of their OMPs. Meningococcal isolates were collected in the context of longitudinal studies in Ghana between 2002 and 2008 and in Burkina Faso between 2006 and 2007. Serogroup A strains isolated during two clonal waves of colonization and disease showed no diversification in the genes encoding their PorA, PorB, and FetA proteins. However, we detected occasional allelic exchange of opa genes, as well as wide variation in the number of intragenic tandem repeats, showing that phase variation of Opa protein expression is a frequent event. Altogether we observed a remarkable antigenic stability of the PorA, PorB and FetA proteins over years. Our results indicate that while herd immunity may be responsible for the disappearance of meningococcal clones over time, it is not a strong driving force for antigenic diversification of the major OMPs analyzed here.

Seroprevalence of bactericidal, specific IgG antibodies and incidence of meningitis due to group A Neisseria meningitidis by age in Burkina Faso 2008.

BACKGROUND: We investigated serological correlates of protection against Neisseria meningitidis serogroup A (NmA) in Burkina Faso before the introduction of NmA conjugate vaccine. METHODOLOGY/PRINCIPAL FINDINGS: We collected blood from a representative sample (N = 1022) of Bobo-Dioulasso residents. Sera were evaluated for serum bactericidal antibody (SBA) activity against NmA strains of immunotype L11 (F8238) and L10 (3125) and NmA-specific IgG. Seroprevalence was compared to the age-specific NmA meningitis incidence in Bobo-Dioulasso during March 2007-February 2008. Meningococcal carriage was evaluated in a subset (N = 538). Geometric mean titres (GMT)/concentrations (GMC) of SBA and NmA-specific IgG increased with age, peaking around age 20 years. Overall, 70% of our sample had NmA-specific IgG ≥2 ug/mL. Meningitis incidence was highest in those aged <6 months and 5-19 years. No NmA carriers were found. Compared to the reference strain SBA, GMTs were higher against a locally isolated strain and around 40-fold lower against Dutch strain 3125. CONCLUSIONS/SIGNIFICANCE: This study provides estimates of natural immunity to NmA, according to a variety of antibody measures, which will be helpful in ascertaining antibody persistence after MenAfriVac™ introduction. Age-specific seroprevalence of reference strain SBA titres most likely reflects exposure to meningococci and consecutive reactive immunity. We could not define any serological correlate of protection.

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

For over 100 years, large epidemics of meningococcal meningitis have occurred every few years in areas of the African Sahel and sub-Sahel known as the African meningitis belt. Until recently, the main approach to the control of these epidemics has been reactive vaccination with a polysaccharide vaccine after an outbreak has reached a defined threshold and provision of easy access to effective treatment but this approach has not prevented the occurrence of new epidemics. Meningococcal conjugate vaccines, which can prevent meningococcal carriage and thus interrupt transmission, may be more effective than polysaccharide vaccines at preventing epidemics. Because the majority of African epidemics have been caused by serogroup A meningococci, a serogroup A polysaccharide/tetanus toxoid protein conjugate vaccine (PsA-TT) has recently been developed. Results from an initial evaluation of the impact of this vaccine on meningococcal disease and meningococcal carriage in Burkina Faso have been encouraging. To review how the research agenda for meningococcal disease in Africa has been changed by the advent of PsA-TT and to define a new set of research priorities for study of meningococcal infection in Africa, a meeting of 41 scientists was held in Dakar, Senegal on April 24th and 25th 2012. The research recommendations developed during the course of this meeting are presented in this paper. The need for enhanced surveillance for meningitis in defined populations with good diagnostic facilities in African countries at risk of epidemics was identified as the highest priority. This is needed to determine the duration of protection against serogroup A meningococcal disease provided by PsA-TT and to determine the risk of disease and carriage caused by meningococci of other serogroups. Other research areas given high priority included identification and validation of serological correlates of protection against meningococcal disease and carriage, development of improved methods for detecting carriage and epidemiological studies aimed at determining the reasons underlying the peculiar epidemiology of meningococcal disease in the African meningitis belt. Minutes and working papers from the meeting are provided in supplementary tables and some of the presentations made at the meeting are available on the MenAfriCar consortium website (www.menafricar.org) and on the web site of the Centers for Disease Control (www.cdc.gov).

[Neisseria meningitidis: characterisation and epidemiology]. / Bactériologie de Neisseria meningitidis.

Neisseria meningitidis are Gram-negative cocci, whose reservoir is exclusively human. This bacterium has several virulence factors including capsule with antiphagocytic properties, lipopolysaccharide, iron uptake system, pili and an IgA1 protease. The strains can be typed by immunological or genotypic methods. Phenotypic determination defines the serogroup, serotype, subtype and immunotype. Molecular typing, a very discriminating method, allows the determination of clonal complexes. These two epidemiological approaches allow the characterization of N. meningitidis strains. Conversely to the other strains, invasive strains belong to a very limited number of clonal complexes (CC). The evolution of the genome of N. meningitidis is the consequence of horizontal transfer of DNA occurring by transformation or recombination and leading to capsular exchanges. The distribution of the different serogroups varies according to the different countries. In France, in 2010, the serogroups B, C, W135 and Y accounted respectively for 72%, 17%, 5% and 2% of cases of invasive infections. The recent emergence of serogroup X in Niger highlights the need for continuing epidemiological surveillance.