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 her

Serogroup W135 Meningococcal Meningitis, Northern Cameroon, 2007–2008

We analyzed results of recent microbiologic surveillance of meningitis in northern Cameroon. During the 2007 and 2008 meningitis seasons, all 57 identified meningococcal isolates were serogroup W135. This situation might indicate that the area is experiencing a period between epidemic waves due to 2 different clones of serogroup A meningococci

An Outbreak of Serotype 1 Streptococcus pneumoniae Meningitis in Northern Ghana with Features That Are Characteristic of Neisseria meningitidis Meningitis Epidemics

BackgroundThe Kassena-Nankana District (KND) of northern Ghana lies in the African meningitis belt, where epidemics of bacterial meningitis have been reoccurring every 8-12 years. These epidemics are generally caused by Neisseria meningitidis an organism that is considered to be uniquely capable of causing meningitis epidemics MethodsWe recruited all patients with suspected meningitis in the KND between 1998 and 2003. Cerebrospinal fluid samples were collected and analyzed by standard microbiological techniques. Bacterial isolates were subjected to serotyping, multilocus sequence typing (MLST), and antibiotic-resistance testing ResultsA continual increase in the incidence of pneumococcal meningitis was observed from 2000 to 2003. This outbreak exhibited strong seasonality, a broad host age range, and clonal dominance, all of which are characteristic of meningococcal meningitis epidemics in the African meningitis belt. The case-fatality rate for pneumococcal meningitis was 44.4%; the majority of pneumococcal isolates were antibiotic sensitive and expressed the serotype 1 capsule. MLST revealed that these isolates belonged to a clonal complex dominated by sequence type (ST) 217 and its 2 single-locus variants, ST303 and ST612 ConclusionsThe S. pneumoniae ST217 clonal complex represents a hypervirulent lineage with a high propensity to cause meningitis, and our results suggest that this lineage might have the potential to cause an epidemic. Serotype 1 is not included in the currently licensed pediatric heptavalent pneumococcal vaccine. Mass vaccination with a less complex conjugate vaccine that targets hypervirulent serotypes should, therefore, be considere

Serogroup W135 Meningococcal Meningitis, Northern Cameroon, 2007–2008

We analyzed results of recent microbiologic surveillance of meningitis in northern Cameroon. During the 2007 and 2008 meningitis seasons, all 57 identified meningococcal isolates were serogroup W135. This situation might indicate that the area is experiencing a period between epidemic waves due to 2 different clones of serogroup A meningococci

Clonal Waves of Neisseria Colonisation and Disease in the African Meningitis Belt: Eight- Year Longitudinal Study in Northern Ghana

BACKGROUND: The Kassena-Nankana District of northern Ghana lies in the African “meningitis belt” where epidemics of meningococcal meningitis have been reoccurring every eight to 12 years for the last 100 years. The dynamics of meningococcal colonisation and disease are incompletely understood, and hence we embarked on a long-term study to determine how levels of colonisation with different bacterial serogroups change over time, and how the patterns of disease relate to such changes. METHODS AND FINDINGS: Between February 1998 and November 2005, pharyngeal carriage of Neisseria meningitidis in the Kassena-Nankana District was studied by twice-yearly colonisation surveys. Meningococcal disease was monitored throughout the eight-year study period, and patient isolates were compared to the colonisation isolates. The overall meningococcal colonisation rate of the study population was 6.0%. All culture-confirmed patient isolates and the majority of carriage isolates were associated with three sequential waves of colonisation with encapsulated (A ST5, X ST751, and A ST7) meningococci. Compared to industrialised countries, the colonising meningococcal population was less constant in genotype composition over time and was genetically less diverse during the peaks of the colonisation waves, and a smaller proportion of the isolates was nonserogroupable. We observed a broad age range in the healthy carriers, resembling that of meningitis patients during large disease epidemics. CONCLUSIONS: The observed lack of a temporally stable and genetically diverse resident pharyngeal flora of meningococci might contribute to the susceptibility to meningococcal disease epidemics of residents in the African meningitis belt. Because capsular conjugate vaccines are known to impact meningococcal carriage, effects on herd immunity and potential serogroup replacement should be monitored following the introduction of such vaccines

The economic burden of meningitis to households in Kassena-Nankana District of Northern Ghana

Objective To estimate the direct and indirect costs of meningitis to households in the Kassena-Nankana District of Ghana. Methods A Cost of illness (COI) survey was conducted between 2010 and 2011. The COI was computed from a retrospective review of 80 meningitis cases answers to questions about direct medical costs, direct non-medical costs incurred and productivity losses due to recent meningitis incident. Results The average direct and indirect costs of treating meningitis in the district was GH¢152.55 (US$101.7) per household. This is equivalent to about two months minimum wage earned by Ghanaians in unskilled paid jobs in 2009. Households lost 29 days of work per meningitis case and thus those in minimum wage paid jobs lost a monthly minimum wage of GH¢76.85 (US$51.23) due to the illness. Patients who were insured spent an average of GH¢38.5 (US$25.67) in direct medical costs whiles the uninsured patients spent as much as GH¢177.9 (US$118.6) per case. Patients with sequelae incurred additional costs of GH¢22.63 (US$15.08) per case. The least poor were more exposed to meningitis than the poorest. Conclusion Meningitis is a debilitating but preventable disease that affects people living in the Sahel and in poorer conditions. The cost of meningitis treatment may further lead to impoverishment for these households. Widespread mass vaccination will save households' an equivalent of GH¢175.18 (US$117) and impairment due to meningitis

A Phase II, Randomized Study on an Investigational DTPw-HBV/Hib-MenAC Conjugate Vaccine Administered to Infants in Northern Ghana

BACKGROUND: Combining meningococcal vaccination with routine immunization in infancy may reduce the burden of meningococcal meningitis, especially in the meningitis belt of Africa. We have evaluated the immunogenicity, persistence of immune response, immune memory and safety of an investigational DTPw-HBV/Hib-MenAC conjugate vaccine given to infants in Northern Ghana. METHODS AND FINDINGS: In this phase II, double blind, randomized, controlled study, 280 infants were primed with DTPw-HBV/Hib-MenAC or DTPw-HBV/Hib vaccines at 6, 10 and 14 weeks of age. At 12 months of age, children in each group received a challenge dose of serogroup A+C polysaccharides. Antibody responses were assessed pre, and one month-post dose 3 of the priming schedule and pre and 1 month after administration of the challenge dose. One month post-dose 3, 87.8% and 88.2% of subjects in the study group had bactericidal meningococcal serogroup A (SBA-MenA) and meningococcal serogroup C (SBA-MenC) antibody titres > or = 1:8 respectively. Seroprotection/seropositivity rates to the 5 antigens administered in the routine EPI schedule were non-inferior in children in the study group compared to those in the control group. The percentages of subjects in the study group with persisting SBA-MenA titres > or = 1:8 or SBA-MenC titres > or = 1:8 at the age of 12 months prior to challenge were significantly higher than in control group (47.7% vs 25.7% and 56.4% vs 5.1% respectively). The administration of 10 microg of serogroup A polysaccharide increased the SBA-MenA GMT by 14.0-fold in the DTPW-HBV/HibMenAC-group compared to a 3.8 fold increase in the control-group. Corresponding fold-increases in SBA-MenC titres following challenge with 10 microg of group C polysaccharide were 18.8 and 1.9 respectively. Reactogenicity following primary vaccination or the administration of the challenge dose was similar in both groups, except for swelling (Grade 3) after primary vaccination which was more frequent in children in the vaccine than in the control group (23.7%; 95%CI [19.6-28.1] of doses vs 14.1%; 95% CI [10.9-17.8] of doses). Fifty-nine SAEs (including 8 deaths), none of them related to vaccination, were reported during the entire study. CONCLUSIONS: Three dose primary vaccination with DTPw-HBV/Hib-MenAC was non-inferior to DTPw-HBV/Hib for the 5 common antigens used in the routine EPI schedule and induced bactericidal antibodies against Neisseria meningitidis of serogroups A and C in the majority of infants. Serogroup A and C bactericidal antibody levels had fallen below titres associated with protection in nearly half of the infants by the age of 12 months confirming that a booster dose is required at about that age. An enhanced memory response was shown after polysaccharide challenge. This vaccine could provide protection against 7 important childhood diseases (including meningococcal A and C) and be of particular value in countries of the African meningitis belt. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN35754083

Molecular Characteristics and Epidemiology of Meningococcal Carriage, Burkina Faso, 2003

Meningococcal serogroups are genetically diverse and short-lived in the African meningitis belt

Epidemiology, Molecular Characterization and Antibiotic Resistance of Neisseria meningitidis from Patients ≤15 Years in Manhiça, Rural Mozambique

BACKGROUND: The epidemiology of meningococcal disease in Mozambique and other African countries located outside the "meningitis belt" remains widely unknown. With the event of upcoming vaccines microbiological and epidemiological information is urgently needed. METHODS: Prospective surveillance for invasive bacterial infections was conducted at the Manhiça District hospital (rural Mozambique) among hospitalized children below 15 years of age. Available Neisseria meningitidis isolates were serogrouped and characterized by Multilocus Sequence Typing (MLST). Antibiotic resistance was also determined. RESULTS: Between 1998 and 2008, sixty-three cases of confirmed meningococcal disease (36 meningitis, 26 sepsis and 1 conjunctivitis) were identified among hospitalized children. The average incidence rate of meningococcal disease was 11.6/100,000 (8/100,000 for meningitis and 3.7/100,000 for meningococcemia, respectively). There was a significant rise on the number of meningococcal disease cases in 2005-2006 that was sustained till the end of the surveillance period. Serogroup was determined for 43 of the 63 meningococcal disease cases: 38 serogroup W-135, 3 serogroup A and 2 serogroup Y. ST-11 was the most predominant sequence type and strongly associated with serogroup W-135. Two of the three serogroup A isolates were ST-1, and both serogroup Y isolates were ST-175. N. meningitidis remained highly susceptible to all antibiotics used for treatment in the country, although the presence of isolates presenting intermediate resistance to penicillin advocates for continued surveillance. CONCLUSIONS: Our data show a high rate of meningococcal disease in Manhiça, Mozambique, mainly caused by serogroup W-135 ST-11 strains, and advocates for the implementation of a vaccination strategy covering serogroup W-135 meningococci in the country

Meningococcal Factor H Binding Proteins in Epidemic Strains from Africa: Implications for Vaccine Development

Epidemics of meningococcal meningitis are common in sub-Saharan Africa. Most are caused by encapsulated serogroup A strains, which rarely cause disease in industrialized countries. A serogroup A polysaccharide protein conjugate vaccine recently was introduced in some countries in sub-Saharan Africa. The antibodies induced, however, may allow replacement of serogroup A strains with serogroup W-135 or X strains, which also cause epidemics in this region. Protein antigens, such as factor H binding protein (fHbp), are promising for prevention of meningococcal serogroup B disease. These proteins also are present in strains with other capsular serogroups. Here we report investigation of the potential of fHbp vaccines for prevention of disease caused by serogroup A, W-135 and X strains from Africa. Four fHbp amino acid sequence variants accounted for 81% of the 106 African isolates studied. While there was little cross-protective activity by antibodies elicited in mice by recombinant fHbp vaccines from each of the four sequence variants, a prototype native outer membrane vesicle (NOMV) vaccine from a mutant with over-expressed fHbp elicited antibodies with broad protective activity. A NOMV vaccine has the potential to supplement coverage by the group A conjugate vaccine and help prevent emergence of disease caused by non-serogroup A strains