Claire Oluwalana

Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: Randomised, double-blind, placebo-controlled trial

BACKGROUND Pneumonia is estimated to cause 2 million deaths every year in children. Streptococcus pneumoniae is the most important cause of severe pneumonia. We aimed to assess the efficacy of a nine-valent pneumococcal conjugate vaccine in children. METHODS We undertook a randomised, placebo-controlled, double-blind trial in eastern Gambia. Children age 6-51 weeks were randomly allocated three doses of either pneumococcal conjugate vaccine (n=8718) or placebo (8719), with intervals of at least 25 days between doses. Our primary outcome was first episode of radiological pneumonia. Secondary endpoints were clinical or severe clinical pneumonia, invasive pneumococcal disease, and all-cause admissions. Analyses were per protocol and intention to treat. FINDINGS 529 children assigned vaccine and 568 allocated placebo were not included in the per-protocol analysis. Results of per-protocol and intention-to-treat analyses were similar. By per-protocol analysis, 333 of 8189 children given vaccine had an episode of radiological pneumonia compared with 513 of 8151 who received placebo. Pneumococcal vaccine efficacy was 37% (95% CI 27-45) against first episode of radiological pneumonia. First episodes of clinical pneumonia were reduced overall by 7% (95% CI 1-12). Efficacy of the conjugate vaccine was 77% (51-90) against invasive pneumococcal disease caused by vaccine serotypes, 50% (21-69) against disease caused by all serotypes, and 15% (7-21) against all-cause admissions. We also found an efficacy of 16% (3-28) against mortality. 110 serious adverse events arose in children given the pneumococcal vaccine compared with 131 in those who received placebo. INTERPRETATION In this rural African setting, pneumococcal conjugate vaccine has high efficacy against radiological pneumonia and invasive pneumococcal disease, and can substantially reduce admissions and improve child survival. Pneumococcal conjugate vaccines should be made available to African infants.

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.

Epidemiologic and clinical characteristics of community-acquired invasive bacterial infections in children aged 2-29 months in The Gambia.

Background: The incidence of community-acquired bacteremia (CAB) in Africa is several-fold higher than in industrialized countries. We report here the incidence of invasive bacterial infections in rural Gambia and compare the clinical characteristics of children with pneumococcal infection with those of children with extraintestinal nontyphoidal salmonella infection (NTS) or other bacterial infections. Methods: As part of a pneumococcal conjugate vaccine trial, we investigated children aged 2–29 months who presented with signs suggestive of invasive bacterial infections. Results: The incidence of invasive bacterial infections in all subjects was 1009 (95% CI, 903–1124) cases per 100,000 person-years. It was 1108 (95% CI, 953–1282) among children who had not received pneumococcal conjugate vaccine. Incidence decreased with increasing age but remained relatively high in 24- to 29-month-olds for pneumococcal infections. Pneumococcal infection was more frequent than NTS infections in the hot dry season. Respiratory symptoms and signs, consolidation on chest radiograph, and a primary diagnosis of pneumonia were more frequent in children with pneumococcal infection than in those with NTS or other infections. Diarrhea, laboratory evidence of malaria infection, and a primary diagnosis of malaria were more common in children with NTS infections. Conclusions: Bacterial infections continue to cause significant morbidity in rural Africa. Although vaccines could greatly reduce the pneumococcal burden, a high index of suspicion and appropriate use of antimicrobials are needed to manage other causes of invasive bacterial infections.

Effects of Community-Wide Vaccination with PCV-7 on Pneumococcal Nasopharyngeal Carriage in The Gambia: A Cluster-Randomized Trial

In a cluster-randomized trial conducted in Gambian villages, Anna Roca and colleagues find that vaccination of children with pneumococcal conjugate vaccines reduced vaccine-type pneumococcal carriage even among nonvaccinated older children and adults.

Molecular epidemiology of pneumococci obtained from Gambian children aged 2–29 months with invasive pneumococcal disease during a trial of a 9-valent pneumococcal conjugate vaccine

BackgroundThe study describes the molecular epidemiology of Streptococcus pneumoniae causing invasive disease in Gambian childrenMethodsOne hundred and thirty-two S. pneumoniae isolates were recovered from children aged 2–29 months during the course of a pneumococcal conjugate vaccine trial conducted in The Gambia of which 131 were characterized by serotyping, antibiotic susceptibility, BOX-PCR and MLST.ResultsTwenty-nine different serotypes were identified; serotypes 14, 19A, 12F, 5, 23F, and 1 were common and accounted for 58.3% of all serotypes overall. MLST analysis showed 72 sequence types (STs) of which 46 are novel. eBURST analysis using the stringent 6/7 identical loci definition, grouped the isolates into 17 clonal complexes and 32 singletons. The population structure of the 8 serotype 1 isolates obtained from 4 vaccinated and 2 unvaccinated children were the same (ST 618) except that one (ST3336) of the isolates from an unvaccinated child had a novel ST which is a single locus variant of ST 618.ConclusionWe provide the first background data on the genetic structure of S. pneumoniae causing IPD prior to PC7V use in The Gambia. This data will be important for assessing the impact of PC7V in post-vaccine surveillance from The Gambia.

Immunogenicity and serotype-specific efficacy of a 9-valent pneumococcal conjugate vaccine (PCV-9) determined during an efficacy trial in The Gambia

This study aimed to determine the immunogenicity of a 9-valent pneumococcal conjugate vaccine (PCV-9) in a subgroup of Gambian children enrolled in a large vaccine efficacy trial. To place the antibody results in context, in this paper we also report previously unpublished data on serotype-specific clinical vaccine efficacy from the main trial. In the sub-study, a single 2-4 ml venous blood specimen was collected from 212 Gambian children 4-6 weeks after the administration of a third dose of PCV-9 or placebo. IgG antibodies to pneumococcal serotype 1, 4, 5, 6B, 9V, 14, 18C, 19F and 23F polysaccharides were measured by ELISA. The proportions of infants with antibody concentrations above 0.2, 0.35 and 1.0 microg/ml, and the geometric mean concentrations (GMCs) of anti-pneumococcal polysaccharide antibodies were substantially higher for each serotype in children who received three doses of PCV-9 than those in the placebo group. Among PCV-9 recipients, GMCs ranged between 2.61 and 11.09 microg/ml with the highest being against serotype 14 and the lowest against 9V polysaccharide. The estimated overall protective antibody level for all nine serotypes, based on the vaccine efficacy against vaccine-type invasive pneumococcal disease (IPD) of 77% (95% CI: 51, 90) observed in the trial, was 2.3 microg/ml (95% CI: 1.0, 5.0). The PCV-9 studied was immunogenic in a Gambian population where it was also found to be efficacious.

Epidemiology and clinical features of pneumonia according to radiographic findings in Gambian children

Objective  To assess the effect of vaccines against pneumonia in Gambian children.

Etiology of Severe Childhood Pneumonia in The Gambia, West Africa, Determined by Conventional and Molecular Microbiological Analyses of Lung and Pleural Aspirate Samples

Molecular analyses of lung aspirates from Gambian children with severe pneumonia detected pathogens more frequently than did culture and showed a predominance of bacteria, principally Streptococcuspneumoniae, >75% being of serotypes covered by current pneumococcal conjugate vaccines. Multiple pathogens were detected frequently, notably Haemophilus influenzae (mostly nontypeable) together with S. pneumoniae.

Discovery and Validation of Biomarkers to Guide Clinical Management of Pneumonia in African Children

Lipocalin 2 distinguishes severe and bacterial pneumonia from nonsevere and nonbacterial pneumonia with a high level of precision. The clinical impact of this biomarker requires large-scale clinical evaluation.

Effect on nasopharyngeal pneumococcal carriage of replacing PCV7 with PCV13 in the Expanded Programme of Immunization in The Gambia

Introduction In 2011, two years after the introduction of 7-valent Pneumococcal conjugate vaccine (PCV7), the Gambian immunization programme replaced PVC7 with PCV13 (13-valent). Our objective was to assess the additional impact of PCV13 on prevalence of pneumococcal nasopharyngeal carriage. Methods We recruited healthy Gambian infants who had received three PCV doses. Nasopharyngeal swabs were collected from infants and their mothers during two cross-sectional surveys (CSS) conducted in infants vaccinated with PCV7 (CSS1) and vaccinated with PCV13 (CSS2). Pneumococci were isolated and serotyped following standardized methods. Whole genome sequencing was performed on non-typable pneumococcus isolated in CSS1 and CSS2. Results 339 and 350 infants and their mothers were recruited in CSS1 and CSS2, respectively. Overall prevalence of pneumococcal carriage was 85.4% in infants. Among infants, prevalence of vaccine type (VT) carriage was lower in CSS2 [9.4% versus 4.9% (p = 0.025) for PCV7-VT; 33.3% versus 18.3% (p < 0.001) for PCV13-VT and 23.9% versus 13.7% (p = 0.001) for the 6 additional serotypes included in PCV13]. At CSS2, there was a decrease of serotypes 6A (from 15.3% to 5.7%, p < 0.001) and 19F (from 5.6% to 1.7%, p = 0.007), and an increase of non-typable pneumococci (0.3–6.0%, p < 0.001), most of which (82.4%) were from typable serotype backgrounds that had lost the ability to express a capsule. Prevalence of overall and VT carriage in mothers was similar in CSS1 and CSS2. Conclusions Replacing PCV7 for PCV13 rapidly decreased prevalence of VT carriage among vaccinated Gambian infants. An indirect effect in mothers was not observed yet. Vaccine-driven selection pressure may have been responsible for the increase of non-typable isolates.