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Background: The introduction of pneumococcal conjugate vaccines (PCV) has reduced carriage of vaccine-type (VT) pneumococci in many settings. We determined the impact of The Gambia's national PCV programme on carriage of VT pneumococci in the population., Methods: Seven-valent PCV (PCV7) was introduced in August 2009 without catch-up and with doses scheduled at 2, 3, 4 months of age; it was replaced by PCV13 in May 2011. We did cross-sectional carriage surveys in 2009, 2015, and 2017 in age-stratified, population-based samples. Nasopharyngeal specimens were collected and processed according to WHO guidelines. We calculated observed and adjusted prevalence ratios (PR) of VT carriage before and after PCV introduction., Findings: We enrolled 2988, 3162, and 2709 participants in 2009, 2015, and 2017 respectively. The baseline (2009) prevalence of VT pneumococcal carriage among children aged 0-4 years was 42.6 %, which declined to 14.9 % and 17.5 % in 2015 and 2017 respectively (adjPR 0.32 [95 % CI 0.27, 0.38] and 0.38 [0.31, 0.46] respectively). VT prevalence among children aged 5-14 years was 16.6 %, 15.1 %, and 15.8 % in the three surveys (2017 vs 2009, adjPR 0.70 [0.58, 0.83]). VT prevalence among 15-44 year-olds was 6.4 %, 5.7 %, and 7.1 % in the three surveys (2017 vs 2009, adjPR 0.59 [0.46, 0.75]), while in those aged ≥ 45 years it was 4.5 %, 6.5 %, and 4.5 % respectively. Non-VT carriage increased in all age-groups. Prevalent residual serotypes were 34 and 15B (age 0-4 years), 3 and 34 (age 5-14 years), and 3 and 16F (age ≥ 15 years)., Conclusions: Introduction of PCV was associated with reduced VT pneumococcal carriage in young, and older children, although with substantial residual prevalence. Persisting VT, and non-VT, carriage indicate significant, persistent transmission of pneumococci in the population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The Gambia introduced seven-valent pneumococcal conjugate vaccine (PCV7) in August 2009, followed by PCV13 in May, 2011, using a schedule of three primary doses without a booster dose or catch-up immunisation. We aimed to assess the long-term impact of PCV on disease incidence., Methods: We did 10 years of population-based surveillance for invasive pneumococcal disease (IPD) and WHO defined radiological pneumonia with consolidation in rural Gambia. The surveillance population included all Basse Health and Demographic Surveillance System residents aged 2 months or older. Nurses screened all outpatients and inpatients at all health facilities using standardised criteria for referral. Clinicians then applied criteria for patient investigation. We defined IPD as a compatible illness with isolation of Streptococcus pneumoniae from a normally sterile site (cerebrospinal fluid, blood, or pleural fluid). We compared disease incidence between baseline (May 12, 2008-May 11, 2010) and post-vaccine years (2016-2017), in children aged 2 months to 14 years, adjusting for changes in case ascertainment over time., Findings: We identified 22 728 patients for investigation and detected 342 cases of IPD and 2623 cases of radiological pneumonia. Among children aged 2-59 months, IPD incidence declined from 184 cases per 100 000 person-years to 38 cases per 100 000 person-years, an 80% reduction (95% CI 69-87). Non-pneumococcal bacteraemia incidence did not change significantly over time (incidence rate ratio 0·88; 95% CI, 0·64-1·21). We detected zero cases of vaccine-type IPD in the 2-11 month age group in 2016-17. Incidence of radiological pneumonia decreased by 33% (95% CI 24-40), from 10·5 to 7·0 per 1000 person-years in the 2-59 month age group, while pneumonia hospitalisations declined by 27% (95% CI 22-31). In the 5-14 year age group, IPD incidence declined by 69% (95% CI -28 to 91) and radiological pneumonia by 27% (95% CI -5 to 49)., Interpretation: Routine introduction of PCV13 substantially reduced the incidence of childhood IPD and pneumonia in rural Gambia, including elimination of vaccine-type IPD in infants. Other low-income countries can expect substantial impact from the introduction of PCV13 using a schedule of three primary doses., Funding: Gavi, The Vaccine Alliance; Bill & Melinda Gates Foundation; UK Medical Research Council; Pfizer Ltd., Competing Interests: Declaration of interests RA was employed by GlaxoSmithKline Vaccines and received grant awards from WHO, Gavi, and the Bill & Melinda Gates Foundation whilst employed at MRC Gambia. MK, SH, and BG received grants from the Bill & Melinda Gates Foundation. MK received grants from Gavi, Merck, and Pfizer, and personal fees from Pfizer. All other authors declare no competing interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Rifampicin is one of the key drugs used to treat tuberculosis and is currently used orally. The use of higher oral doses of rifampicin is desired for better therapeutic efficacy, but this is accompanied by increased risk of systemic toxicity thus limiting its recommended oral dose to 10 mg/kg per day. Inhaled delivery of rifampicin is a potential alternative mode of delivery, to achieve high drug concentrations in both the lung and potentially the systemic circulation. In addition, rifampicin exists either as amorphous or crystalline particles, which may show different pharmacokinetic behaviour. However, disposition behaviour of amorphous and crystalline rifampicin formulations after inhaled high-dose delivery is unknown. In this study, rifampicin pharmacokinetics after intra-tracheal administration of carrier-free, amorphous and crystalline powder formulations to Sprague Dawley rats were evaluated. The formulations were administered once daily for seven days by oral, intra-tracheal and oral plus intra-tracheal delivery, and the pharmacokinetics were studied on day 0 and day 6. Intra-tracheal administration of the amorphous formulation resulted in a higher area under the plasma concentration curve (AUC) compared to the crystalline formulation. For both formulations, the intra-tracheal delivery led to significantly higher AUC compared to the oral delivery at the same dose suggesting higher rifampicin bioavailability from the inhaled route. Increasing the intra-tracheal dose resulted in a more than dose proportional AUC suggesting non-linear pharmacokinetics of rifampicin from the inhaled route. Upon repeated administration for seven days, no significant decrease in the AUCs were observed suggesting the absence of rifampicin induced enzyme auto-induction in this study. The present study suggests an advantage of inhaled delivery of rifampicin in achieving higher drug bioavailability compared to the oral route., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: WHO estimates that a third of the world's population has latent tuberculosis infection and that less than 5% of those infected are diagnosed and treated to prevent tuberculosis. We aimed to systematically review studies that report the steps from initial tuberculosis screening through to treatment for latent tuberculosis infection, which we call the latent tuberculosis cascade of care. We specifically aimed to assess the number of people lost at each stage of the cascade., Methods: We did a systematic review and meta-analysis of study-level observational data. We searched MEDLINE (via OVID), Embase, and Health Star for observational studies, published between 1946 and April 12, 2015, that reported primary data for diagnosis and treatment of latent tuberculosis infection. We did meta-analyses using random and fixed effects analyses to identify percentages of patients with latent tuberculosis infection completing each step in the cascade. We also estimated pooled proportions in subgroups stratified by different characteristics of interest to assess risk factors for losses., Results: We identified 58 studies, describing 70 distinct cohorts and 748 572 people. Steps in the cascade associated with greater losses included completion of testing (71·9% [95% CI 71·8-72·0] of people intended for screening), completion of medical evaluation (43·7% [42·5-44·9]), recommendation for treatment (35·0% [33·8-36·4]), and completion of treatment if started (18·8% [16·3-19·7]). Steps with fewer losses included receiving test results, referral for evaluation if test positive, and accepting to start therapy if recommended. Factors associated with fewer losses were immune-compromising medical indications, being part of contact investigations, and use of rifamycin-based regimens., Interpretation: We identify major losses at several steps in the cascade of care for latent tuberculosis infection. Improvements in management of latent tuberculosis will need programmatic approaches to address the losses at each step in the cascade., Funders: Canadian Institutes of Health Research., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2016 Mackenzie et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

The study of the contacts of patients with tuberculosis has a long history. Where tuberculosis is endemic, regular recruitment of tuberculosis cases and their household contacts can be done for research and strategic intervention. This recruitment provides a platform whereby host, pathogen, and environmental factors related to tuberculosis can be investigated and new interventions can be assessed. We describe the types of study possible within a tuberculosis case-contact study platform and its essential components, including recruitment and follow-up of the patients with tuberculosis, their household contacts and community controls, assessments and sampling, and data management and processing. Sample handling and storage, local engagement, ethical challenges, and the strengths and weaknesses of study design are all important issues in case-contact research. A case-contact study platform is a powerful research tool to answer fundamental questions in tuberculosis and has relevance to the study of other major infectious diseases., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Understanding the immunogenicity of BCG in a population where it has failed will facilitate the design of new TB vaccines. We assessed the immunogenicity of M. bovis BCG over 12 months by ELISPOT assay. Forty-one adolescents and young Gambian male adults received a tuberculin skin test (TST) which was followed one week later by BCG vaccination, but the 23 control subjects received neither of these. TST alone significantly induced PPD-specific IFN-gamma producing cells. Twenty-three percent of subjects did not respond to BCG, which was associated with higher pre-existing ex vivo response to PPD. Paradoxically, amongst BCG responders there was a correlation between pre-existing response and subsequent response to BCG. We conclude that BCG is immunogenic, but this effector response is short-lived and can be limited in higher pre-existing anti-mycobacterial immunity, suggesting a possible threshold beyond which BCG immunogenicity is inhibited.

Tuberculosis remains a substantial global health problem despite effective drug treatments. The efficacy of BCG, the only available vaccine, is variable, especially in tuberculosis-endemic regions. Recent advances in the development of new vaccines against tuberculosis mean that the first of these are now entering into early clinical trials. A recombinant modified vaccinia virus Ankara expressing a major secreted antigen from Mycobacterium tuberculosis, antigen 85A, was the first new tuberculosis vaccine to enter into clinical trials in September 2002. This vaccine is known as MVA85A. In a series of phase I clinical trials in the UK, MVA85A had an excellent safety profile and was highly immunogenic. MVA85A was subsequently evaluated in a series of phase I trials in The Gambia, a tuberculosis-endemic area in west Africa. This vaccine is the only new subunit tuberculosis vaccine to enter into clinical trials in Africa to date. Here, we discuss some of the issues that were considered in the protocol design of these studies including recruitment, inclusion and exclusion criteria, reimbursement of study participants, and HIV testing. These issues are highly relevant to early clinical trials with all new tuberculosis vaccines in the developing world.