Ousman Secka

Randomised trial of Haemophilus influenzae type-b tetanus protein conjugate for prevention of pneumonia and meningitis in Gambian infants

Summary Background In developing countries, pneumonia and meningitis due to Haemophilus influenzae type b (Hib) are common in children under age 12 months and the mortality from meningitis is high. Protein-polysaccharide conjugate vaccines have brought Hib disease under control in industrialised countries. We did a double-blind randomised trial in The Gambia to assess the efficacy of a Hib conjugate vaccine for the prevention of meningitis, pneumonia, and other invasive diseases due to Hib. Methods Between March, 1993, and October, 1995, 42 848 infants were randomly allocated the conjugate vaccine Hib polysaccharide tetanus protein (PRP-T) mixed with diphtheria-tetanus-pertussis vaccine (DTP), or DTP alone at age 2 months, 3 months, and 4 months. Children who presented with signs of invasive Hib were investigated by blood culture and, where appropriate, by lumbar puncture, chest radiograph, or percutaneous lung aspirate. Children were followed up for between 5 and 36 months. Findings The median ages at which children received the study vaccine were 11 weeks, 18 weeks, and 24 weeks. 83% of children enrolled received all three doses of vaccine. 17 cases of culture-positive Hib pneumonia, 28 of Hib meningitis, and five of other forms of invasive Hib disease were detected amongst the study children. The efficacy of the vaccine for the prevention of all invasive disease after three doses was 95% (PRP-T vaccinees 1, controls 19 [95% Cl 67–100]), for the prevention of Hib pneumonia after two or three doses, 100% (vaccinees 0, controls 10 [55–100]), and for the prevention of radiologically defined pneumonia at any time after enrolment, 21·1% (PRP-T vaccinees 198, controls 251 [4·6–34·9]). Interpretation PRP-T conjugate Hib vaccine prevented most cases of meningitis and pneumonia due to Hib in Gambian infants. The reduction in the overall incidence of radiologically defined pneumonia in PRP-T vaccinees suggests that about 20% of episodes of pneumonia in young Gambian children are due to Hib. The introduction of Hib vaccines into developing countries should substantially reduce childhood mortality due to pneumonia and meningitis.

Elimination of Haemophilus influenzae type b (Hib) disease from The Gambia after the introduction of routine immunisation with a Hib conjugate vaccine: a prospective study

BACKGROUND Routine immunisation of infants in The Gambia with a Haemophilus influenzae type b (Hib) polysaccharide-tetanus toxoid conjugate vaccine began in May, 1997. We investigated the effectiveness of the vaccine when delivered through the expanded programme on immunisation and the effect of national immunisation on incidence of Hib disease. METHODS Surveillance for Hib disease was maintained in the western half of The Gambia using standard methods with an emphasis on meningitis. We estimated vaccine efficacy using the case control method, and vaccine coverage and population denominators for incidence rates using a cluster sample survey. Prevalence of Hib carriage in a sample of 1-2-year old children attending health centres for vaccination was ascertained with oropharyngeal swabs plated onto antiserum agar. FINDINGS Between May, 1997, and April, 2002, a total of 5984 children were examined for possible Hib infections. 49 children had Hib disease, 36 of whom had meningitis. The annual incidence rates of Hib meningitis before any use of the vaccine (1990-93) dropped from over 200 per 100,000 children aged younger than 1 year to none per 100,000 in 2002, and from 60 to no cases per 100,000 in children younger than 5 years. The prevalence of Hib carriage decreased from 12% to 0.25% (p<0.0001). Two doses of vaccine were needed for direct protection from Hib disease (vaccine efficacy 94%, 95% CI 62-99). Since most children received a protective dose after the age of greatest disease risk, indirect effects were important in reducing disease incidence. INTERPRETATION The Gambian Hib immunisation programme reduced the occurrence of Hib disease despite irregular vaccine supply. The effect of the programme in The Gambia has important implications for the introduction of the vaccine into routine immunisation programmes of other developing countries.

Nasopharyngeal carriage of pneumococci in Gambian children and in their families.

BACKGROUND Nasopharyngeal carriage of pneumococci is prevalent among children in developing countries but little is known about the relationship of nasopharyngeal carriage to invasive disease or about the way in which pneumococci spread within households. OBJECTIVES To determine the prevalence of nasopharyngeal carriage in healthy and sick Gambian children and to investigate transmission within households. METHODS Nasopharyngeal swabs were obtained by the per nasal route and cultured for pneumococci on selective media. Pneumococci were serotyped with the use of latex particles coated with type-specific antisera. RESULTS Pneumococci were isolated from the nasopharynx of 73 (90.1%) of 81 children with invasive pneumococcal disease, 86 (76.1%) of 113 healthy, age-matched control children and 911 (85.1%) of 1071 sick children. Pneumococci belonging to serotypes 1, 14 and 12 were isolated significantly more frequently from cases than from matched controls. In 43 (76.8%) of 56 children with invasive disease, pneumococci isolated from the nasopharynx and from the blood or other sterile site belonged to the same serotype. Pneumococci of the same serotype as the bacterium responsible for invasive disease in a child were obtained from 72 (8.5%) of 843 family members, most frequently from young siblings of the case patients. CONCLUSION Nasopharyngeal carriage of pneumococci is more prevalent among young Gambian children than among adults and invasive infections are probably acquired more frequently from siblings than from parents. However, further studies are needed to confirm this hypothesis with more discriminating markers than polysaccharide serotyping.

Pneumococcal disease among children in a rural area of west Africa.

BACKGROUND The pneumococcus is a frequent cause of pneumonia and other serious infections among young children in developing countries. Defining the pattern of pneumococcal infection in these countries is important so that, with the advent of pneumococcal conjugate vaccines, rational vaccination policies can be developed. METHODS Children younger than 5 years of age who attended clinics in a rural area of The Gambia, West Africa, were screened by assistants during a 2-year period. Children with predefined features suggestive of a diagnosis of pneumonia, meningitis or septicemia were referred to the Medical Research Council Field Station at Basse for investigation. RESULTS Of 2898 children investigated 103 cases of invasive pneumococcal disease (70 definite and 33 probable) were identified, suggesting that the incidence of this infection in the study community is at least 554/100,000/year in children younger than 1 year of age and 240/100,000/year in those younger than 5 years, rates many times higher than those found in industrialized societies. The mean age of presentation was 15 months; more boys than girls were affected. Cases of pneumonia were encountered 8 times more frequently than those of meningitis. Antibiotic resistance was rarely found and cases of pneumonia, but not meningitis, responded well to treatment. Case-fatality rates in children with pneumonia and meningitis were 1 and 55%, respectively. The most prevalent pneumococcal serotypes were types 6, 14, 19, 1 and 5. CONCLUSION About 60% of invasive pneumococcal infection in children in this community could potentially be prevented by a nine-valent pneumococcal conjugate vaccine (types 1, 4, 5, 6B, 9, 14, 18, 19F and 23) given at the ages of 2, 3 and 4 months.

Vaccination with a Haemophilus influenzae Type b Conjugate Vaccine Reduces Oropharyngeal Carriage of H. influenzae Type b among Gambian Children

The effect of a Haemophilus influenzae type b (Hib) polyribosylribitol phosphate-tetanus toxoid conjugate vaccine (Hib/PRP-T) on oropharyngeal carriage of Hib was studied during an efficacy trial in Gambian infants. Children were vaccinated with Hib/PRP-T and diphtheria-tetanus toxoids-pertussis (DTP) or DTP alone at ages 2, 3, and 4 months. Groups of 1000 children aged 1-2 years were studied each year for 4 years. Hib was detected by production of a halo on antiserum agar plates. Carriage was significantly lower among children fully vaccinated with Hib/PRP-T given with DTP (4.4%; 95% confidence interval [CI], 3.8%-5.7%) than among children fully vaccinated with DTP alone (11.0%; 95% CI, 8.9%-13.0%) (protective effect adjusted by year = 60%; 95% CI, 44%-72%; P < .001). Hib carriage varied by year among nonvaccinated children. Hib conjugate vaccines are likely to produce a herd protective effect in underdeveloped communities, as recorded in Europe and the United States.

Importance of enteric bacteria as a cause of pneumonia, meningitis and septicemia among children in a rural community in the Gambia, West Africa

Two thousand eight hundred ninety-eight children younger than 5 years old were investigated during a 2-year period in a rural area of The Gambia for possible pneumonia, meningitis or septicemia. After clinical examination and appropriate investigations, 1014 children were diagnosed as having pneumonia, 31 as having meningitis and 100 as having septicemia. Nine hundred seven children had a final diagnosis of malaria including 702 who satisfied the World Health Organization criteria for a diagnosis of pneumonia. A bacterial etiology was established in 115 (11%) patients with a final diagnosis of pneumonia, in 25 (81%) with meningitis and in 29 (29%) with suspected septicemia. Overall the

Bacteraemia in patients admitted to an urban hospital in West Africa

BackgroundFew studies on bacteraemia in Africa have been published. We aimed to prospectively identify the causative organisms of bacteraemia in The Gambia and their relation to clinical diagnoses, outcome and antimicrobial susceptibility.MethodsBetween November 2003 and February 2005 we studied those admitted to the Medical Research Council hospital who were suspected of having bacteraemia. We documented clinical features, outcome, pathogens identified and their susceptibility patterns, and searched for factors associated with bacteraemia.Results871 patients were admitted and had a blood culture taken. The median age was 2 years (range 2 months to 80 years) and 36 of 119 tested were HIV positive; 54.5% were male. 297 (34%) had a positive result and 93 (10.7% overall) were considered a genuine pathogen. Those with bacteraemia were more likely to die in hospital (OR 2.79; 1.17–6.65, p = 0.017) and to have a high white cell count (WCC; OR 1.81;95% CI 1.09–3.02; p = 0.022). Three organisms accounted for 73% of bacteraemias: Streptococcus pneumoniae (45.2%), Staphylococcus aureus (18.3%) and Escherichia coli (9.7%) while non-typhoidal salmonellae (NTS) accounted for 8.6%. Antimicrobial susceptibility of S. pneumoniae was very high to penicillin (97.5%); high resistance was found to co-trimoxazole. S. aureus was generally highly susceptible to cloxacillin, gentamicin and chloramphenicol. E. coli and NTS were all susceptible to ciprofloxacin and mostly susceptible to gentamicin. Thirteen (33%) S. pneumoniae isolates were of serotypes contained in a 7-valent pneumococcal conjugate vaccine and 20 (51.3%) were of the same serogroup.ConclusionIn The Gambia, those with bacteraemia are more likely than those without to die in hospital and to have a raised peripheral blood WCC. S. pneumoniae is the most common organism isolated. Introduction of a pneumococcal conjugate vaccine can be expected to lead to a reduction in disease incidence.

Immunization with a pneumococcal capsular polysaccharide vaccine during pregnancy

The feasibility of preventing invasive pneumococcal infections during the first few months of life by immunization during pregnancy has been investigated. One hundred and fifty Gambian women were immunized with either a 23-valent pneumococcal polysaccharide vaccine or a meningococcal polysaccharide vaccine during the last trimester of pregnancy. Pregnant women showed a good antibody response to five of the six pneumococcal polysaccharides tested (types 1, 3, 5, 6, 14 and 19) but not to type 6 polysaccharide. Mean cord blood/maternal blood IgG antibody ratios varied from 24% (type 1) to 49% (type 3) and differed substantially between individual mother/infant pairs. Pneumococcal antibody levels were higher at birth in infants of women immunized with pneumococcal polysaccharide vaccine than in control infants. However, these antibodies disappeared rapidly during the first few months of life and it is uncertain how much clinical protection against pneumococcal infection maternal immunization would have provided.

Serotype and antimicrobial susceptibility patterns of isolates of Streptococcus pneumoniae causing invasive disease in The Gambia 1996–2003

Objectives  To describe the characteristics of pneumococcal isolates obtained from patients with invasive pneumococcal disease in The Gambia.

Effectiveness of an early supplementation scheme of high-dose vitamin A versus standard WHO protocol in Gambian mothers and infants: a randomised controlled trial

BACKGROUND Most developing countries have adopted a standard WHO dosing schedule for vitamin A supplementation. However, in 2002 the International Vitamin A Consultative Group (IVACG) Annecy Accord recommended a new high-dose regimen for mothers and infants. Our aim was to test whether the new high-dose regimen of vitamin A supplementation would increase maternal and infant plasma vitamin A, reduce infant Helicobacter pylori infection and nasopharyngeal pneumococcal carriage, and improve infant gut epithelial integrity. METHODS In an area of moderate vitamin A deficiency in rural Gambia, 220 mother-infant pairs were enrolled in a randomised double-blind trial between September, 2001, and October, 2004, that compared the IVACG high dose with the WHO dose. The primary endpoints were levels of maternal and infant plasma vitamin A, H pylori infection, pneumococcal carriage, and gut epithelial integrity. The trial is registered as ISRCTN 98554309. FINDINGS 197 infants completed follow-up to 12 months (99 high dose and 98 WHO dose). There were no adverse events at dosing. No differences were found in the primary outcomes for high-dose versus WHO schedule: maternal vitamin A concentration at 2 months +0.02 micromol/L (95% CI -0.10 to 0.15); infant vitamin A at 5 months +0.01 micromol/L (-0.06 to 0.08); H pylori infection at 12 months -0.3% (-14.7 to 14.2); maternal pneumococcal carriage at 12 months -2.0% (-13.7 to 9.7); infant pneumococcal carriage at 12 months -4.1% (-15.8 to 7.6); infant gut mucosal damage at 12 months 5.2% (-8.7 to 19.2). There were more clinic attendances by the high-dose group in the first 6 months of life (p=0.018). INTERPRETATION Our results do not lend support to the proposal to increase the existing WHO standard dosing schedule for vitamin A in areas of moderate vitamin A deficiency. Caution is urged for future studies because trials have shown possible adverse effects of higher doses of vitamin A, and potential negative interactions with the expanded programme on immunisation (EPI) vaccines.