Conjugates and reverse vaccinology to eliminate bacterial meningitis

Bacterial meningitis is caused mainly by Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitidis. Haemophilus influenzae type b vaccines have been extremely successful in eradicating the disease from those countries where the vaccine has been introduced. The recent licensure of the conjugated pneumococcal vaccine suggests that this pathogen also will be soon controlled. Consequently, if we succeed in developing effective vaccines against meningococcus, this will enable us to eliminate bacterial meningitis. The global elimination of bacterial meningitis is a goal which, if appropriate resources are applied, can be reached within the first fifteen years of the 21st century.     

Pédiatric haemophilus influenzae b meningitis in Dakar

OBJECTIVE: This study had for aim to determine the etiology of Haemophilus b pediatric meningitis. DESIGN: A retrospective study of 216 biologically confirmed cases was carried out during 6 years (January 1995- December 2000) on children 0 to 15 years of age, hospitalized at the Albert Royer Children Hospital Center. RESULTS: Haemophilus influenzae b is the first cause of pediatric meningitis (19.7%) followed by Nesseria meningitidis (14.5%), and Streptococcus pneumoniae (13.6%). The Haemophilus influenzae b meningitis cases are distributed all year round with a peak between January and March, that is to say, during the dry and cool season. They affect children at an average age of 11.7 months, with a sex ratio of 1.1 for boys. Almost all of the patients live in the low-socio-economic areas of the Dakar suburbs (92.8%). More than 90% of the H. influenzae b isolates are sensitive to ceftriaxone (96%) chloramphenicol (93%), and to ampicillin (91%). Clinical evolution is marked by death (17.8%) and recovery with psychological, sensory, and motor sequels (19.9%). CONCLUSION: This report should help to include the combined vaccine Antihaemophilus influenzae b in the Senegalese Broad Vaccination Program. The final aim is the reduction of morbidity and mortality of infections due to Haemophilus influenzae b.     

Bacterial meningitis and Haemophilus influenzae type b conjugate vaccine, Malawi

A retrospective database review showed that Haemophilus influenzae type b conjugate vaccine decreased the annual number of cases of H. influenzae type b meningitis in children in Blantyre, Malawi. Among young bacterial meningitis patients, HIV prevalence was high (36.7% during 1997-2009), and pneumococcus was the most common etiologic agent (57% in 2009).     

Invasive Haemophilus influenzae infections among children in Rochester, Minnesota: a population-based study

The incidence of invasive Haemophilus influenzae infections was studied among all residents of Rochester, Minnesota, under 20 years of age during the period 1975-1983. The incidence in children under 5 years of age was 115 and 64 cases per 100,000 children per year for all invasive cases and for meningitis, respectively. These rates are among the highest reported for an essentially all-Caucasian population in the United States, while the ratio of meningitis to non-meningitis cases (1.1:1) is among the lowest. This suggests possible under-ascertainment of non-meningitis cases in previous US studies of Haemophilus influenzae infections.     

Meningitis as cause of prelingual deafness

In an examination of 624 prelingual deaf children in the Christian Institute for deaf children 'Effatha' in Voorburg special attention was paid to deafness caused by meningitis. This diagnosis was made in 70 persons. In 41 of these the pathogen of meningitis could be traced. Streptococcus pneumoniae is the main causative organism of meningitis and subsequent deafness (60%). Haemophilus influenzae, Escherichia coli and Neisseria meningitidis follow with 12, 9 and 7% respectively. We emphasize the timely audiologic control of all children who suffered a meningitis.     

Invasive Haemophilus influenzae infections among children in Rochester, Minnesota: a population-based study

Summary. The incidence of invasive Haemophilus influenzae infections was studied among all residents of Rochester, Minnesota, under 20 years of age during the period 1975–1983. The incidence in children under 5 years of age was 115 and 64 cases per 100 000 children per year for all invasive cases and for meningitis, respectively. These rates are among the highest reported for an essentially all-Caucasian population in the United States, while the ratio of meningitis to non-meningitis cases (1.1:1) is among the lowest. This suggests possible under-ascertainment of non-meningitis cases in previous US studies of Haemophilus influenzae infections.     

Epidemiology of Haemophilus influenzae serotype a, North American Arctic, 2000-2005

Before the introduction of Haemophilus influenzae type b (Hib) conjugate vaccines, rates of invasive H. influenzae disease among indigenous people of the North American Arctic were among the highest in the world. Routine vaccination reduced rates to low levels; however, serotype replacement with non-type b strains may result in a reemergence of invasive disease in children. We reviewed population-based data on invasive H. influenzae in Alaska and northern Canada from 2000-2005; 138 cases were reported. Among 88 typeable isolates, 42 (48%) were H. influenzae type a (Hia); 35 (83%) occurred in indigenous peoples. Among Hia patients, median age was 1.1 years; 62% were male; 1 adult died. Common clinical manifestations included meningitis, pneumonia, and septic arthritis. Overall annual incidence was 0.9 cases per 100,000 population. Incidence among indigenous children <2 years of age in Alaska and northern Canada was 21 and 102, respectively. Serotype a is now the most common H. influenzae serotype in the North American Arctic; the highest rates are among indigenous children.     

Epidemiology of Haemophilus influenzae type b meningitis in Israel, 1981-90

BACKGROUND AND METHODS. In the Western world, Haemophilus influenzae type b is an important cause of morbidity and long-term disability in children. The availability of vaccines capable of preventing H. influenzae type b disease in very young infants stimulated this longitudinal observational review of the epidemiology of H. influenzae type b meningitis in Israel, based on cases reported to the Ministry of Health in the decade 1981-90. RESULTS. In the last decade, H. influenzae type b accounted for 884 cases of meningitis, making it the main cause of bacterial meningitis in children. Almost all cases were in children under the age of 5 years, the great majority under 18 months. Age-standardized incidence rates were the same in Jews and in non-Jews, and in both sectors incidence was slightly higher in males than in females. The case fatality rate was 3.3%. CONCLUSIONS. The new Haemophilus b conjugate vaccines are reported to be safe, effective at an early age, and compatible with current vaccination schedules. Their availability means that control of invasive disease caused by this organism is within reach. Use of the vaccines in infants should be encouraged and their effect on morbidity patterns should be closely monitored.     

Polymerase chain reaction assay and bacterial meningitis surveillance in remote areas, Niger

To compensate for the lack of laboratories in remote areas, the national reference laboratory for meningitis in Niger used polymerase chain reaction (PCR) to enhance the surveillance of meningitis caused by Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. PCR effectively documented the wide geographic spread of N. meningitidis serogroup W135.     

不可分型流感嗜血杆菌疫苗研究进展

不可分型流感嗜血杆菌(non-typeable haemophilus influenzae,NTHi)可导致多种感染性疾病,如鼻窦炎、中耳炎、结膜炎、脑膜炎、菌血症等。随着b型流感嗜血杆菌疫苗的应用,NTHi逐渐成为侵袭性及非侵袭型流感嗜血杆菌病的主要病原体,因此目前亟待研究一种安全有效的疫苗来预防NTHi的感染。本文主要针对近年来的一些热点候选抗原及已进行临床试验的疫苗做一综述,为后续的疫苗研制提供依据。     

Haemophilus influenzae meningitis 5 years after introduction of the Haemophilus influenzae type b conjugate vaccine in Brazil

The long-term impact of Haemophilus influenzae type b (Hib) conjugate vaccine, introduced throughout Latin America in the late 1990s, has not been evaluated. Active surveillance for H. influenzae meningitis was performed from August 9, 1996 to August 8, 2004 in Metropolitan Salvador, Brazil. Five years after the introduction of Hib conjugate vaccine, Hib meningitis incidence decreased from 2.39 to 0.06 cases per 100,000 population (98%) overall, and from 60.9 to 3.1 cases per 100,000 population (95%) in children <1 year of age. A transient serotype replacement phenomenon was observed associated with a small increase of meningitis due to two H. influenzae type a clonal groups. These findings indicate that Hib immunization campaign has led to the virtual elimination of Hib disease in this region.     

Prophylaxis in bacterial meningitis

A questionnaire about the use of prophylactic antibiotics in bacterial meningitis was sent to medical officers of environmental health and microbiologists in England. There was broad agreement that prophylaxis should be offered to close contacts of acute meningitis due to Neisseria meningitidis but not to contacts of meningitis caused by Streptococcus pneumoniae. Overall 28% of those who replied said they could consider giving prophylaxis to contacts of meningitis due to Haemophilus influenzae. Rifampicin was the most common choice of drug. The indications for prophylaxis in bacterial meningitis are discussed.     

Bacterial meningitis in Navojo Indians.

An analysis of 219 confirmed cases of bacterial meningitis among Navajo Indians during a 5-year period, July 1, 1968, through June 30, 1973, revealed that 56 percent were caused by Haemophilus influenzae, 26 percent by Neisseria meningitidis, 6 percent by Mycobacterium tuberculosis, and 6 percent by other organisms. The annual incidence of H. influenzae meningitis (17.7 per 100,000 persons) and that of pneumococcal meningitis (8.0 per 100,000) were much higher than the rates for these diseases reported from other population groups. The annual incidence of meningococcal meningitis (2.0 per 100,000) was similar to that found elsewhere. There was an ususual concentration of cases during the first year of life; 78 percent of H. influenzae, 64 percent of pneumococcal, and 50 percent of meningococcal meningitis occurred during this time. However, bacterial meningitis during the first month of life was not frequent (0.29 per 1,000 live births). Case fatality rates were similar to those reported for other population groups.     

Case-fatality ratio of bacterial meningitis in the African meningitis belt: we can do better

In the African meningitis belt, reported case-fatality ratio (CFR) for meningitis are usually calculated on the basis of presumed cases. We reviewed 3509 presumed cases of bacterial meningitis reported in Niger for which a cerebrospinal fluid (CSF) sample had been tested later at the reference laboratory. The main aetiologies were Neisseria meningitidis (1496 cases), Streptococcus pneumoniae (303 cases) and Haemophilus influenzae (105 cases). The CFR of meningococcal meningitis was lower for serogroup A (5.5%) than for serogroups X (12%) and W135 (12.7%). With a CFR of 49.8%, pneumococcal meningitis, albeit representing only 20.7% of confirmed cases, accounted for 50% of the deaths. The disease burden of pneumococcal meningitis must be better taken into consideration in the future. As most treatments are presumptive, there is a urgent need for an easy-to-administer, cheap first-line treatment effective on N. meningitidis as well as on S. pneumoniae and H. influenzae that would replace the single-dose oily chloramphenicol treatment which is the most frequent treatment administered today, independent of microbial aetiology and season. The development of diagnostic tools really suitable for remote health facilities also is an urgent challenge.     

Epidemiologic profile of Haemophilus influenzae infection in Tunisia

Haemophilus influenzae, a commensal bacteria, is frequently incriminated in broncho--pulmonary surinfections and severe diseases as meningitis, pneumonia and septic arthritis, particularly in young children. A multicenter study was conducted to establish the epidemiological profile of Haemophilus influenzae diseases, to determine the rate of antibiotics resistance for guide therapeutic and preventive strategies. The identification was based on the requirements for X and V factors, and the serotype b determined by agglutination. The betalactamase production was done by nitrocefin test. Antimicrobial susceptibility testing was determined on Muller Hinton chocolate agar with isovitalex. During the two year period, (January 1998 December 1999), 192 isolates of H. Influenzae were collected, 61% were recovered from invasive infections (44 meningitis, 8 bacteremia, 2 arthritis). The serotype b was identified in 55.7% of cases, 67.3% were invasive strains. 24.5% of isolates were producing betalactamase particularly invasive serotype b strains. All isolates of H. influenzae were susceptible to cefotaxim and to ofloxacin. Resistance rates to other antibiotics were: erythromycin 56.2%, tetracyclin 10.3%, rifampin 12%, chloramphénicol 1%, cotrimoxazole 16.5%, 11.5% amikacin and 20% gentamicin. The incidence of meningitis remained frequent in our country, involving the introduction of the vaccination in official calendar. Nevertheless, the surveillance of H. influenzae invasives infections and the serotyping of isolates were necessary to evaluate the impact of the immunization.     

The changing epidemiology of invasive bacterial infections in Massachusetts children, 1984 through 1991.

Coincident with the licensure of Haemophilus influenzae b conjugate vaccines from 1987 to 1990, the incidence of meningitis and other invasive infections caused by H influenzae type b declined in Massachusetts children by 87% and 91%, respectively. By 1991, Neisseria meningitidis had replaced H influenzae b as the leading cause of bacterial meningitis, accounting for 57% of cases. During the period 1984 through 1991, serogroup C displaced sero-group B as the most common cause of N meningitidis disease. Streptococcus pneumoniae caused 92% of nonmeningitis invasive disease, with sero-groups 14, 6, 19, 18, 4, 23, and 9 causing 94.5% of infections. These findings have implications for the development of additional polysaccharide-protein conjugate vaccines for the prevention of childhood infections.     

Guidelines in bacterial meningitis in children

A committee of the Scientific Council of the National Organization for Quality Assurance in Hospitals has published a report on the diagnosis and management of children with meningitis. Agreement was achieved on the diagnostic investigations that should precede antibiotic treatment, and on the prognosis and follow-up of children recovered from meningitis. No agreement was reached on the role of cephalosporins and aminoglycosides in the antibiotic treatment of bacterial meningitis. Furthermore there was no consensus on the prophylactic administration of rifampicin to family members of patients with meningitis caused by Neisseria meningitidis or Haemophilus influenzae. The arguments pro and contra are mentioned and considered.     

2010-2018年濮阳市细菌性脑炎脑膜炎症候群流行病学监测及病原谱分析

目的分析濮阳市细菌性脑炎脑膜炎症候群监测结果,了解疾病流行特征及病原谱构成。方法对3所哨点医院报告的细菌性脑炎脑膜炎症候群病例开展流行病学调查,采集脑脊液、血液和临床分离菌株,对脑脊液和血标本进行细菌培养,对病原菌进行鉴定。结果470例监测病例中,127例检出病原菌,病例病原确诊率为27.02%;人群分布以3岁以下散居儿童为主,男女性别比为1.81:1,春季和秋季为发病高峰,抗生素的应用对病原菌检出率有明显影响(χ2=7.6,P<0.01);分离鉴定病原27种,主要病原构成比分别为:肺炎链球菌32.28%、单核细胞增生李斯特氏菌11.81%、无乳链球菌7.09%、脑膜炎奈瑟氏菌4.72%、流感嗜血杆菌4.72%。结论2010-2018年濮阳市细菌性脑炎脑膜炎症候群病原构成以肺炎链球菌、单核细胞增生李斯特氏菌、无乳链球菌、脑膜炎奈瑟氏菌为主。自2015年首次分离出单核细胞增生李斯特氏菌以来,单核细胞增生李斯特氏菌、无乳链球菌和脑膜炎奈瑟氏菌伴随肺炎链球菌成为近年来引起该市细菌性脑炎脑膜炎的优势流行菌株。     

Bacteriology of community acquired meningitis in Sfax, Tunisia (1993-2001)

OBJECTIVE: The aim of this study was to analyze the distribution of bacteria responsible for community-acquired meningitis and the pattern of resistance of common species. DESIGN: All bacteriologically confirmed cases of community-acquired meningitis were recorded between 1993 and 2001. RESULTS: Two hundred twenty-four cases of bacterial meningitis were recorded. The most frequent species were Haemophilus influenzae and Streptococcus pneumoniae followed by Neisseria meningitidis with respectively 37.1%, 32.1%, and 10.7% of cases. The yearly distribution of these bacteria did not show any epidemic peak. Enterobacteria and group B Streptococcus were the most frequently identified pathogens in neonatal meningitis. H. influenzae was the predominant microorganism in children between one month and five years of age, (66.4%) followed by S. pneumoniae (23.5%). S. pneumoniae was the predominant bacteria responsible fore more than half of the cases over five years of age. 28.8% of H. influenzae strains produced beta-lactamase. 27.2% of S. pneumoniae strains were less susceptible to penicillin. Resistance rates for amoxicillin and cefotaxime were respectively 10.6% and 7.5%. Only one strain of N. meningitidis (4.2%) presented with a decreased susceptibility to penicillin. CONCLUSIONS: In our study, H. influenzae and S. pneumoniae were the main microorganisms responsible for community-acquired meningitis. High resistance rates were found for these bacteria: 28.8% of H. influenzae to ampicillin and 27.2% of S. pneumoniae to penicillin.     

Future challenges in the elimination of bacterial meningitis

Despite the widespread implementation of several effective vaccines over the past few decades, bacterial meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis and Group B Streptococcus (GBS) still results in unacceptably high levels of human mortality and morbidity. A residual disease burden due to bacterial meningitis is also apparent due to a number of persistent or emerging pathogens, including Mycobacterium tuberculosis, Escherichia coli, Staphylococcus aureus, Salmonella spp. and Streptococcus suis. Here, we review the current status of bacterial meningitis caused by these pathogens, highlighting how past and present vaccination programs have attempted to counter these pathogens. We discuss how improved pathogen surveillance, implementation of current vaccines, and development of novel vaccines may be expected to further reduce bacterial meningitis and related diseases in the future.