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Background Little information is available about the effect of pneumococcal conjugate vaccines (PCVs) in low-income countries. We measured the effect of these vaccines on invasive pneumococcal disease in The Gambia where the 7-valent vaccine (PCV7) was introduced in August, 2009, followed by the 13-valent vaccine (PCV13) in May, 2011. Methods We conducted population-based surveillance for invasive pneumococcal disease in individuals aged 2 months and older who were residents of the Basse Health and Demographic Surveillance System (BHDSS) in the Upper River Region, The Gambia, using standardised criteria to identify and investigate patients. Surveillance was done between May, 2008, and December, 2014. We compared the incidence of invasive pneumococcal disease between baseline (May 12, 2008–May 11, 2010) and after the introduction of PCV13 (Jan 1, 2013–Dec 31, 2014), adjusting for changes in case ascertainment over time. Findings We investigated 14 650 patients, in whom we identified 320 cases of invasive pneumococcal disease. Compared with baseline, after the introduction of the PCV programme, the incidence of invasive pneumococcal disease decreased by 55% (95% CI 30–71) in the 2–23 months age group, from 253 to 113 per 100 000 population. This decrease was due to an 82% (95% CI 64–91) reduction in serotypes covered by the PCV13 vaccine. In the 2–4 years age group, the incidence of invasive pneumococcal disease decreased by 56% (95% CI 25–75), from 113 to 49 cases per 100 000, with a 68% (95% CI 39–83) reduction in PCV13 serotypes. The incidence of non-PCV13 serotypes in children aged 2–59 months increased by 47% (−21 to 275) from 28 to 41 per 100 000, with a broad range of serotypes. The incidence of non-pneumococcal bacteraemia varied little over time. Interpretation The Gambian PCV programme reduced the incidence of invasive pneumococcal disease in children aged 2–59 months by around 55%. Further surveillance is needed to ascertain the maximum effect of the vaccine in the 2–4 years and older age groups, and to monitor serotype replacement. Low-income and middle-income countries that introduce PCV13 can expect substantial reductions in invasive pneumococcal disease. Funding GAVI’s Pneumococcal vaccines Accelerated Development and Introduction Plan (PneumoADIP), Bill & Melinda Gates Foundation, and the UK Medical Research Council.
This population-based surveillance study was undertaken in Upper River Region, The Gambia, where the UK Medical Research Council has a field station in the town of Basse. Residents of the Basse Health and Demographic Surveillance System (BHDSS) are served by Basse Health Centre and five smaller health facilities (appendix p 16). We conducted surveillance for all cases of suspected pneumonia, sepsis, and meningitis between May 12, 2008, and Dec 31, 2014. The surveillance population included all residents of the BHDSS aged 2 months or older. The population is enumerated every 4 months, with births, deaths, migrations, and vaccinations recorded. The estimated population in 2014 was 178 510, of whom 32 530 (18%) were children younger than 5 years. Children younger than 6 months who presented at maternal and child health clinics were eligible to receive all three doses of the vaccine, whereas older children who presented at the clinics were eligible to receive one dose. PCV7 was introduced on Aug 19, 2009, and replaced by PCV13 in May, 2011, without catch-up vaccination. The study was approved by the Gambia Government–MRC Joint Institutional Ethics Committee (number 1087) and the ethics committee of the London School of Hygiene & Tropical Medicine (London, UK). Participants or their guardians gave written, informed consent. The surveillance methods used in our population-based study have been described previously.10 In brief, nurses assessed all individuals who presented as an outpatient or who were admitted to one of the six health facilities in the study area (Basse, Gambissara, Demba Kunda, Fatoto, Garawol, and Koina). Enrolment involved standardised screening of patients for referral to a clinician in Basse. Clinicians used standardised criteria to identify patients with suspected pneumonia, sepsis, or meningitis, and requested blood culture, lumbar puncture, or chest radiography according to protocol (appendix pp 7–9, 17). Aspiration of pleural fluid of lung aspiration was performed for patients with a pleural effusion or dense peripheral consolidation radiologically. We defined invasive pneumococcal disease as suspected pneumonia, sepsis, or meningitis with isolation. Vaccine failure was defined as invasive pneumococcal disease following two or more doses of PCV covering the homologous serotype, given more than 14 days before the event.11, 12 Weight was recorded on a digital scale (TANITA, Arlington Heights, IL, USA) and height with a ShorrBoard (Weigh and Measure, Olney, MD, USA). Rapid malaria tests (ICT Diagnostics, Cape Town, South Africa) were done on all patients with suspected pneumonia, sepsis, or meningitis from August to December (the malaria transmission season) each year and in a 10% random sample from January to July each year. This random sample was chosen by random selection of the final digit of the patients’ surveillance identity number (0–9) and during the dry season any patient whose identity number ended in zero had a malaria test. Samples were not collected between Oct 5 and Nov 3, 2010, when the field station flooded. Blood, lung aspirate, cerebrospinal fluid, pleural fluid, and other microbiological samples were processed in Basse using conventional microbiological culture and identification techniques.13 S pneumoniae was identified by morphology and optochin sensitivity. All pneumococcal isolates were confirmed at the WHO Regional Reference Laboratory (MRC Fajara, The Gambia), and serotyped with a latex agglutination assay using factor and group-specific antisera (Statens Serum Institut, Copenhagen, Denmark). Serotypes 6A and 6B were differentiated from 6C by PCR.14 Serotyping of 10% of isolates was repeated at the National Institute for Communicable Diseases in South Africa (Johannesburg, South Africa). The laboratories in Basse and Fajara submitted to external quality assurance throughout the study (UK National External Quality Assessment Service [Sheffield, UK], the WHO Reference Laboratory in Denmark, and the Royal Australasian College of Pathologists [Sydney, Australia]). The primary outcome of the study was the incidence of invasive pneumococcal disease, in four categories: overall invasive pneumococcal disease; invasive pneumococcal disease caused by PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, 23F, and cross-reactive 6A);15 invasive pneumococcal disease caused by serotypes in PCV13 but not PCV7 (1, 3, 5, 7F, and 19A, excluding serotype 6A); and invasive pneumococcal disease caused by non-vaccine serotypes. We calculated the incidence of invasive pneumococcal disease by dividing the number of cases by the mid-point population estimates from the BHDSS and multiplying by 100 000. Age groups were prespecified as 2–23 months, 2–4 years, 5–14 years, and 15 years and older (adults). To calculate the incidence in 2008, we extrapolated cases for the unobserved period Jan 1–May 11, 2008. We derived the number of unobserved cases in 2008 by multiplying the number of observed cases from May 12 to Dec 31, 2008, by the average ratio of cases before and after May 12 in each of the years 2009 and 2011–14. The unobserved cases were grouped using the pre-PCV age and serotype distribution from 2008–09. For the flood period in 2010 (Oct 5–Nov 3, 2010), we extrapolated cases using the number of observed cases in 2010 multiplied by the average ratio of cases during the same period in each of the years 2009 and 2011–14. We applied the age and serotype distribution of the observed cases in 2010 to the unobserved cases in 2010. We corrected for age-specific changes in the number of individuals eligible for investigation per unit population by adjusting the counts of annual invasive pneumococcal disease by age group, assuming the same serotype distribution as that of the observed cases each year. We adjusted annual age-specific counts of invasive pneumococcal disease to the mean rate of enrolment of patients eligible for investigation. We assessed the effect of the PCV vaccination programme by calculating the ratio of the incidence of invasive pneumococcal disease in the last 2 years of surveillance (2013–14) compared with the baseline first 2 years (May 12, 2008–May 11, 2010). We used the Poisson distribution to calculate incidence rate ratios (IRRs) and 95% CIs. The widths of the confidence intervals were inflated to allow for overdispersion found in the 2–23-month and 5–14-year age groups, estimated from a patient-level Poisson regression analysis of 2008–09 pre-PCV invasive pneumococcal disease data. Statistical significance was set at a p value less than 0·05. To investigate potential bias caused by temporal changes in health-care seeking, patient investigation, or confounding attributable to secular trends in epidemic serotypes, we did three a-priori stratified analyses, excluding: outpatients, cases identified by lung aspiration alone, and cases caused by serotypes 1 or 5 which exhibit temporal variation in prevalence. To assess the effect of temporal trends in invasive bacterial disease, we analysed the incidence of non-pneumococcal bacteraemia, as a control condition, extrapolating case counts for missing periods in the same manner as for invasive pneumococcal disease. We also analysed temporal changes in the prevalence of contaminated blood cultures, malnutrition, and malaria in patients eligible for investigation. We used Stata version 12.1 and MATLAB version R2015a for our analyses. The study was funded by GAVI’s Pneumococcal vaccines Accelerated Development and Introduction Plan (PneumoADIP), the Bill & Melinda Gates Foundation, and the UK Medical Research Council. None of the funding sources had any role in collection, analysis, or interpretation of the data. The corresponding author had full access to all the data and was responsible for the final decision to submit for publication.
