Conducting clinical research in a resource-constrained setting: lessons from a longitudinal cohort study in The Gambia.

Clinical research conducted to Good Clinical Practice (GCP) standards is increasingly being undertaken in resource-constrained low-income and middle-income countries (LMICs) settings. This presents unique challenges that differ from those faced in high-income country (HIC) contexts, due to a dearth of infrastructure and unique socio-cultural contexts. Field experiences by research teams working in these LMIC contexts are thus critical to advancing knowledge on successful research conduct in these settings. The Medical Research Council Unit The Gambia at London School of Hygiene and Tropical Medicine has operated in The Gambia, a resource-constrained LMIC for over 70 years and has developed numerous research support platforms and systems. The unit was the lead clinical collaborator in a recently completed Expanded Program on Immunization Consortium (EPIC) study, involving a multicountry collaboration across five countries including the USA, Canada, Belgium, Papua New Guinea and The Gambia. The EPIC study recruited and completed follow-up of 720 newborn infants over 2 years. In this paper, we provide in-depth field experience covering challenges faced by the Gambian EPIC team in the conduct of this study. We also detail some reflections on these challenges. Our findings are relevant to the international research community as they highlight practical day-to-day challenges in conducting GCP standard clinical research in resource-constrained LMIC contexts. They also provide insights on how study processes can be adapted early during research planning to mitigate challenges

Maternal colonization and early-onset neonatal bacterial sepsis in the Gambia, West Africa: a genomic analysis of vertical transmission

OBJECTIVES: To define bacterial aetiology of neonatal sepsis and estimate the prevalence of neonatal infection from maternal genital tract bacterial carriage among mother-newborn pairs. METHODS: We carried out a cross-sectional study of newborns with clinical sepsis admitted to three hospitals in the Gambia neonatal wards. Neonatal blood cultures and maternal genital swabs were obtained at recruitment. We used whole-genome sequencing to explore vertical transmission for neonates with microbiologically confirmed bloodstream infection by comparing phenotypically-matched paired neonatal blood cultures and maternal genital tract bacterial isolates. RESULTS: We enrolled 203 maternal-newborn pairs. Two-thirds (67%; 137/203) of neonates presented with early-onset sepsis (days 0-6 after birth) of which 26% (36/137) were because of a clinically-significant bacterial pathogen. Blood culture isolates from newborns with early-onset sepsis because of Staphylococcus aureus (n = 5), Klebsiella pneumonia (n = 2), and Enterococcus faecalis (n = 1), phenotypically matched their maternal genital tract isolates. Pairwise single-nucleotide variants comparisons showed differences of 12 to 52 single-nucleotide variants only between maternal and newborn S. aureus isolates, presumably representing vertical transmission with a transmission rate of 14% (5/36). CONCLUSIONS: We found a low prevalence of vertical transmission of maternal genital tract colonization in maternal-newborn pairs for early-onset neonatal sepsis in the West African context. Identifying infection acquisition pathways among newborns is essential to prioritize preventive interventions, which could be targeted at the mother or infection control in the hospital environment, depending on the major pathways of transmission

Immunogenicity and safety of a 10-valent pneumococcal conjugate vaccine administered as a 2 + 1 schedule to healthy infants in The Gambia: a single-centre, double-blind, active-controlled, randomised, phase 3 trial.

BACKGROUND: Three pneumococcal conjugate vaccines (PCVs) are currently licensed and WHO prequalified for supply by UN agencies. Here, we aimed to investigate the safety and immunogenicity of SIIPL-PCV compared with PHiD-CV and PCV13, when administered to infants according to a 2 + 1 schedule. METHODS: This single-centre, double-blind, active-controlled, randomised, phase 3 trial was done in Medical Research Council Unit The Gambia at the London School of Hygiene & Tropical Medicine clinical trial facilities within two government health centres in the western region of The Gambia. Healthy, PCV-naive infants aged 6-8 weeks were enrolled if they weighed at least 3·5 kg and had no clinically significant health complaints, as determined by history and clinical examination. Eligible infants were randomly assigned (1:1:1) to receive either SIIPL-PCV, PHiD-CV, or PCV13 using permuted blocks of variable size. Parents and the trial staff assessing all study outcomes were masked to vaccine group. The first PCV vaccine was given with other routine Expanded Programme on Immunization vaccines when infants were aged 6-8 weeks (visit 1). At visit 2, routine vaccines alone (without a PCV) were administered. At visit 3, the second dose of the PCV was administered alongside other routine vaccines. At visit 4, a blood sample was collected. Visits 1-4 took place at intervals of 4 weeks. The booster PCV was administered at age 9-18 months (visit 5), with final follow-up 4 weeks after the booster (visit 6). The primary immunogenicity outcome compared the serotype-specific IgG geometric mean concentrations (GMCs) generated by SIIPL-PCV with those generated by PHiD-CV and PCV13, 4 weeks after the booster. We used descriptive 95% CIs without adjustment for multiplicity. Immunogenicity analyses were done in the per protocol population (defined as all children who received all the assigned study vaccines, who had an immunogenicity measurement available, and who had no protocol deviations that might interfere with the immunogenicity assessment). This trial was registered with the Pan African Clinical Trials Registry, PACTR201907754270299, and ClinicalTrials.gov, NCT03896477. FINDINGS: Between July 18 and Nov 14, 2019, 745 infants were assessed for study eligibility. Of these, 85 infants (11%) were ineligible and 660 (89%) were enrolled and randomly assigned to receive SIIPL-PCV (n=220), PHiD-CV (n=220), or PCV13 (n=220). 602 infants (91%) were included in the per protocol immunogenicity population. The median age at vaccination was 46 days (range 42-56). 342 infants (52%) were female and 318 (48%) were male. Post-booster serotype-specific IgG GMCs generated by SIIPL-PCV ranged from 1·54 μg/mL (95% CI 1·38-1·73) for serotype 5 to 12·46 μg/mL (11·07-14·01) for serotype 6B. Post-booster GMCs against shared serotypes generated by PHiD-CV ranged from 0·80 μg/mL (0·72-0·88) for serotype 5 to 17·31 μg/mL (14·83-20·20) for serotype 19F. Post-booster GMCs generated by PCV13 ranged from 2·04 μg/mL (1·86-2·24) for serotype 5 to 15·54 μg/mL (13·71-17·60) for serotype 6B. Post-booster IgG GMCs generated by SIIPL-PCV were higher than those generated by PHiD-CV for seven of the eight shared serotypes (1, 5, 6B, 7F, 9V, 14, and 23F). The GMC generated by serotype 19F was higher after PHiD-CV. The SIIPL-PCV to PHiD-CV GMC ratios for shared serotypes ranged from 0·64 (95% CI 0·52-0·79) for serotype 19F to 2·91 (2·47-3·44) for serotype 1. The serotype 1 GMC generated by SIIPL-PCV was higher than that generated by PCV13, whereas serotype 5, 6A, 19A, and 19F GMCs were higher after PCV13. The SIIPL-PCV to PCV13 GMC ratios ranged from 0·72 (0·60-0·87) for serotype 19A to 1·44 (1·23-1·69) for serotype 1. INTERPRETATION: SIIPL-PCV was safe and immunogenic when given to infants in The Gambia according to a 2 + 1 schedule. This PCV is expected to provide similar protection against invasive and mucosal pneumococcal disease to the protection provided by PCV13 and PHiD-CV, for which effectiveness data are available. Generating post-implementation data on the impact of SIIPL-PCV on pneumococcal disease endpoints remains important. FUNDING: Bill & Melinda Gates Foundation

Neonatal admissions, quality of care and outcome: 4 years of inpatient audit data from The Gambia's teaching hospital.

BACKGROUND: National facility-based neonatal mortality audits are an important source of data to identify areas for improvement of service delivery and outcome of care. OBJECTIVES: To examine admissions to the neonatal unit, Edward Francis Small Teaching Hospital, Banjul, The Gambia and make recommendations for programme action to reduce mortality through improvements in the quality of care, particularly with respect to suspected neonatal infections. METHODS: Case notes were reviewed for all neonates admitted to the neonatal unit during a 5-year period (1 January 2009 to 31 December 2013) to assess outcome and quality of care. Data for 2009 were subsequently excluded because of the low proportion of records retrieved. RESULTS: Of the 4944 admissions between 1 January 2010 and 31 December 2013, 1734 infants (35%) died, with 57% of all deaths occurring within the first 48 hours of admission. There were 1267 early neonatal deaths (deaths occurring during the first 7 days of life), 67% of which occurred during the first 48 hours of life. Independent predictors of neonatal death in the multivariable analysis were; maternal lack of antenatal care, non-teaching hospital delivery, admission weight 6.9 mmol/L) and hypothermia (axillary temperature < 36.5 ˚C). Forty-eight per cent of newborns had point-of-admission hypothermia. Possible severe bacterial infection (pSBI) accounted for 44% (2166/4944) of admissions, prematurity/low birthweight for 27% (1340/4944) and intrapartum-related conditions for 20%. Only 5% (104/2166) of pSBI cases had at least one supportive investigation; 41 had a chest radiograph, 26 had a blood culture and 43 had a lumbar puncture. Although 94% of the newborns received intravenous antibiotics, 55% of those who did lacked clinical evidence of pSBI and had no diagnostic work-up. CONCLUSION: Priority areas for action include infection prevention and improved diagnosis and management. There is also scope to reduce hypothermia with feasible interventions particularly targeting preterm infants. Improved patient records and audit data with linked action and accountability are interventions which could prevent such deaths of newborns in The Gambia and other developing countries