Impact of the introduction of pneumococcal conjugate vaccination on pneumonia in The Gambia: population-based surveillance and case-control studies

Background Pneumococcal conjugate vaccines (PCVs) are used in many low-income countries but their impact on the incidence of pneumonia is unclear. The Gambia introduced PCV7 in August, 2009, and PCV13 in May, 2011. We aimed to measure the impact of the introduction of these vaccines on pneumonia incidence. Methods We did population-based surveillance and case-control studies. The primary endpoint was WHO-defined radiological pneumonia with pulmonary consolidation. Population-based surveillance was for suspected pneumonia in children aged 2–59 months (minimum age 3 months in the case-control study) between May 12, 2008, and Dec 31, 2015. Surveillance for the impact study was limited to the Basse Health and Demographic Surveillance System (BHDSS), whereas surveillance for the case-control study included both the BHDSS and Fuladu West Health and Demographic Surveillance System. Nurses screened all outpatients and inpatients at all health facilities in the surveillance area using standardised criteria for referral to clinicians in Basse and Bansang. These clinicians recorded clinical findings and applied standardised criteria to identify patients with suspected pneumonia. We compared the incidence of pneumonia during the baseline period (May 12, 2008, to May 11, 2010) and the PCV13 period (Jan 1, 2014, to Dec 31, 2015). We also investigated the effectiveness of PCV13 using case-control methods between Sept 12, 2011, and Sept 31, 2014. Controls were aged 90 days or older, and were eligible to have received at least one dose of PCV13; cases had the same eligibility criteria with the addition of having WHO-defined radiological pneumonia. Findings We investigated 18 833 children with clinical pneumonia and identified 2156 cases of radiological pneumonia. Among children aged 2–11 months, the incidence of radiological pneumonia fell from 21·0 cases per 1000 person-years in the baseline period to 16·2 cases per 1000 person-years (23% decline, 95% CI 7–36) in 2014–15. In the 12–23 month age group, radiological pneumonia decreased from 15·3 to 10·9 cases per 1000 person-years (29% decline, 12–42). In children aged 2–4 years, incidence fell from 5·2 to 4·1 cases per 1000 person-years (22% decline, 1–39). Incidence of all clinical pneumonia increased by 4% (–1 to 8), but hospitalised cases declined by 8% (3–13). Pneumococcal pneumonia declined from 2·9 to 1·2 cases per 1000 person-years (58% decline, 22–77) in children aged 2–11 months and from 2·6 to 0·7 cases per 1000 person-years (75% decline, 47–88) in children aged 12–23 months. Hypoxic pneumonia fell from 13·1 to 5·7 cases per 1000 person-years (57% decline, 42–67) in children aged 2–11 months and from 6·8 to 1·9 cases per 1000 person-years (72% decline, 58–82) in children aged 12–23 months. In the case-control study, the best estimate of the effectiveness of three doses of PCV13 against radiological pneumonia was an adjusted odds ratio of 0·57 (0·30–1·08) in children aged 3–11 months and vaccine effectiveness increased with greater numbers of doses (p=0·026). The analysis in children aged 12 months and older was underpowered because there were few unvaccinated cases and controls. Interpretation The introduction of PCV in The Gambia was associated with a moderate impact on the incidence of radiological pneumonia, a small reduction in cases of hospitalised pneumonia, and substantial reductions of pneumococcal and hypoxic pneumonia in young children. Low-income countries that introduce PCV13 with reasonable coverage can expect modest reductions in hospitalised cases of pneumonia and a marked impact on the incidence of severe childhood pneumonia. Funding GAVI’s Pneumococcal vaccines Accelerated Development and Introduction Plan, Bill & Melinda Gates Foundation, and UK Medical Research Council. We did population-based surveillance for suspected pneumonia, septicaemia, and meningitis in the Basse Health and Demographic Surveillance System (BHDSS; appendix p 8; population of 171 269 in 2012) between May 12, 2008, and Dec 31, 2015. The surveillance population included all residents aged 2 months or older and was enumerated every 4 months. This surveillance analysis was restricted to children aged 2–59 months. We did a case-control study to estimate the effectiveness of PCV13 against radiological pneumonia with consolidation between Sept 12, 2011, and Sept 31, 2014. During this period, surveillance was extended to all residents younger than 5 years in the Fuladu West Health and Demographic Surveillance System (FWHDSS; appendix p 8), as well as in the BHDSS. The FWHDSS population was enumerated annually. Cases had WHO-defined radiological pneumonia and were aged 90 days or older (ie, aged ≥3 months) and eligible to have received at least one dose of PCV13; matched community controls had to meet the same eligibility criteria, with the exception of the radiological pneumonia. All cases in both the surveillance and case-control studies were confirmed residents in the study area. Children who had received three doses of PCV7 were ineligible for the case-control study and those who had received one or more dose of PCV7 were excluded from the case-control analysis. Cases and controls were excluded if they had a major congenital abnormality or suspected or confirmed immune deficiency. Individuals were eligible to be selected as controls more than once but were ineligible if they had previously been enrolled as a case (appendix p 5). For each case, three community controls were randomly selected from the population register matched on the date of birth plus or minus 15 days. Controls were enrolled at home visits within 3 months of case enrolment. The surveillance methods have been described previously.11, 12 In brief, nurses screened all outpatients and inpatients at all health facilities in the BHDSS and FWHDSS using standardised criteria for referral to clinicians in Basse and Bansang (appendix p 18). Screening included measurement of O2 saturation with a pulse oximeter (Nellcor N-65, Covidien, Boulder, CO, USA). Clinicians recorded clinical findings and applied standardised criteria to identify patients with suspected pneumonia, septicaemia, or meningitis, and requested blood culture, lumbar puncture, or chest radiography in accordance with a standardised protocol (appendix, pp 19, 20). Aspiration of pleural fluid or lung aspiration was done for selected patients with pleural effusions or large, dense, peripheral consolidation. All enrolled patients underwent rapid malaria tests (ICT Diagnostics, Cape Town, South Africa) from August to December (the malaria transmission season) every year. Surveillance was interrupted between Oct 5 and Nov 3, 2010, when the field station flooded. Radiographs were obtained with consistent methods to produce digital images in accordance with WHO recommendations.10 Radiographs were read by two independent readers and readings discordant for end-point consolidation were resolved by a paediatric radiologist. All readers were calibrated to the WHO standard, achieving κ scores of 0·8 or higher before reading radiographs. For the case-control study, radiographs were read in real time by two independent readers with discordant readings resolved by a third reader. All readers were recalibrated to the WHO standard every 6 months achieving κ scores of 0·7 or higher before continuing to read radiographs. Vaccination dates were recorded from hand-held cards and in real time at maternal-child-health clinics in the BHDSS. Standardised questionnaires were used to collect data on risk factors and potential confounders (appendix p 24). Laboratory samples for the surveillance study were processed in Basse with consistent standardised methods.13 S pneumoniae was identified by morphology and optochin sensitivity. Pneumococcal isolates were serotyped at the Medical Research Council (MRC) Fajara laboratory, by use of latex agglutination.12 The Gambia Government/MRC Joint Institutional Ethics Committee (number 1087) and the London School of Hygiene & Tropical Medicine ethics committee approved the study. Parents or guardians of study participants gave written informed consent. The primary endpoint was radiological pneumonia with consolidation, as defined by WHO.10 Secondary endpoints were radiological pneumonia with consolidation plus isolation of S pneumoniae from a sterile site (blood, cerebrospinal fluid, lung aspirate, or pleural fluid); clinical pneumonia, defined as cough or difficulty breathing for less than 14 days accompanied by one or more of raised respiratory rate for age, lower chest wall indrawing, nasal flaring, grunting, O2 saturation less than 92%, altered consciousness, inability to sit or feed, convulsions, dull chest percussion note, coarse crackles, or bronchial breathing; clinical pneumococcal pneumonia (defined as for clinical pneumonia with the addition of isolation of S pneumoniae from a sterile site; and hypoxic pneumonia, defined as clinical pneumonia with peripheral O2 saturation less than 90%. We further categorised pneumococcal pneumonia outcomes according to PCV13 serotype (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) or non-PCV13 serotype groups. We defined the exploratory endpoint of bronchiolitis as clinical pneumonia with wheeze detectable on auscultation without dullness to percussion, bronchial breathing, or radiological pneumonia. We calculated annual incidence of each type of pneumonia by dividing number of cases by the mid-year population estimates from the BHDSS. To calculate annual incidence in 2008 and 2010, we used the number of observed cases to extrapolate the unobserved cases from Jan 1 to May 11, 2008, and during the flood in 2010 (appendix p 3). Repeated episodes in an individual were included if they were separated by more than 30 days. We adjusted for observed increases in the number of children referred to clinicians per unit population over time by multiplying annual event counts by a correction factor that assumed the rate of referral in the absence of bias was constant (appendix p 4).12 We calculated the ratio of the incidence in the last 2 years of surveillance (2014–15) to the incidence in the baseline first 2 years (May 12, 2008, to May 11, 2010; ie, extrapolated cases were not included). We assumed a Poisson distribution to calculate incidence rate ratios (IRRs) and 95% CIs. CIs for the 2–4 year age group were inflated to allow for over dispersion, which was estimated from a subject-level Poisson regression analysis of radiological pneumonia data from 2008 to 2009. Categorical analyses used Fisher’s exact test. Statistical significance was set at a p value of less than 0·05. We used STATA version 12.1 and MATLAB version R2015a for the analyses. To investigate potential bias due to temporal changes in health-care seeking, patient investigation, or confounding by secular trends in epidemic serotypes, we did three a-priori stratified analyses, which excluded outpatients, cases identified by lung aspiration alone, and cases caused by serotype 1 or 5. To assess the effect of temporal trends related to bacterial pneumonia, we evaluated the incidence of clinical pneumonia due to bacteria other than pneumococcus as a control condition. We also evaluated the prevalence of malnutrition and malaria over time in patients with suspected pneumonia.12 The sample size for the case-control study assumed three-dose coverage of 90% in controls. Enrolment of 881 cases with three controls each would have 80% power to detect vaccine effectiveness of 35% at a significance level of 5%. We used conditional logistic regression to estimate odds ratios of radiological pneumonia for three compared with zero doses of PCV13 and to test for trend by number of doses. Vaccine effectiveness was defined as 1 minus the odds ratio. Effectiveness estimates were adjusted for age and all potential confounding variables: gender, maternal age, mother’s education, number of children younger than 5 years in the household, number of children sleeping in the same room, illness in previous 3 months, previous hospital admission, distance to clinic or hospital, malnutrition, and socioeconomic status based on asset score.14 We based vaccination status on doses received at least 14 days before presentation of the case. Since a high proportion of Gambian children are fully vaccinated by the age of 12 months, we stratified vaccine effectiveness by age 3–11 months and 12 months or older. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.