Application of Transthoracic Echocardiography for Cardiac Safety Evaluation in the Clinical Development Process of Vaccines Against Streptococcus pyogenes.

Superficial infections with Streptococcus pyogenes (Strep A), pharyngitis and impetigo can induce acute rheumatic fever, an autoimmune sequela manifesting mostly with arthritis and rheumatic carditis. Valvular heart damage can persist or advance following repeated episodes of acute rheumatic fever, causing rheumatic heart disease. Acute rheumatic fever and rheumatic heart disease disproportionately affect children and young adults in developing countries and disadvantaged communities in developed countries. People living with rheumatic heart disease are at risk of experiencing potentially fatal complications such as heart failure, bacterial endocarditis or stroke. Transthoracic echocardiography plays a central role in diagnosing both rheumatic carditis and rheumatic heart disease. Despite the obvious medical need, no licensed Strep A vaccines are currently available, as their clinical development process faces several challenges, including concerns for cardiac safety. However, the development of Strep A vaccines has been recently relaunched by many vaccine developers. In this context, a reliable and consistent safety evaluation of Strep A vaccine candidates, including the use of transthoracic echocardiography for detecting cardiac adverse events, could greatly contribute to developing a safe and efficacious product in the near future. Here, we propose a framework for the consistent use of transthoracic echocardiography to proactively detect cardiac safety events in clinical trials of Strep A vaccine candidates.

Throat and skin infections caused by certain types of bacteria, named Streptococcus pyogenes, are frequent worldwide; however, in many children from less developed countries and disadvantaged communities, infections with S. pyogenes lead to a condition called acute rheumatic fever, which usually affects the joints and the heart. Damage to the heart valves may evolve to rheumatic heart disease, a permanent condition with often life-threatening complications. Rheumatic heart disease is an important health problem in places and communities where S. pyogenes infections occur frequently. A vaccine against these bacteria would help lower the number of people with valvular heart disease; however, no such vaccine exists yet. Research on vaccines against S. pyogenes was on hold for almost 30 years because of initial concerns that vaccinated children might develop acute rheumatic fever more frequently. Recently, researchers started working again on vaccines against S. pyogenes, but concerns about the safety of such vaccines persist. Doctors can reliably use echocardiography to diagnose cases of rheumatic carditis (as a sign of acute rheumatic fever) and rheumatic heart disease. Here, we propose a simple approach for the consistent use of echocardiography in clinical research of vaccines against S. pyogenes that will allow the detection of any potential heart-related side effects of the vaccine.

Safety of the novel oral poliovirus vaccine type 2 (nOPV2) in infants and young children aged 1 to <5 years and lot-to-lot consistency of the immune response to nOPV2 in infants in The Gambia: a phase 3, double-blind, randomised controlled trial.

BACKGROUND: Novel oral poliovirus vaccine type 2 (nOPV2) has been engineered to improve the genetic stability of Sabin oral poliovirus vaccine (OPV) and reduce the emergence of circulating vaccine-derived polioviruses. This trial aimed to provide key safety and immunogenicity data required for nOPV2 licensure and WHO prequalification. METHODS: This phase 3 trial recruited infants aged 18 to <52 weeks and young children aged 1 to <5 years in The Gambia. Infants randomly assigned to receive one or two doses of one of three lots of nOPV2 or one lot of bivalent OPV (bOPV). Young children were randomised to receive two doses of nOPV2 lot 1 or bOPV. The primary immunogenicity objective was to assess lot-to-lot equivalence of the three nOPV2 lots based on one-dose type 2 poliovirus neutralising antibody seroconversion rates in infants. Equivalence was declared if the 95% CI for the three pairwise rate differences was within the -10% to 10% equivalence margin. Tolerability and safety were assessed based on the rates of solicited adverse events to 7 days, unsolicited adverse events to 28 days, and serious adverse events to 3 months post-dose. Stool poliovirus excretion was examined. The trial was registered as PACTR202010705577776 and is completed. FINDINGS: Between February and October, 2021, 2345 infants and 600 young children were vaccinated. 2272 (96·9%) were eligible for inclusion in the post-dose one per-protocol population. Seroconversion rates ranged from 48·9% to 49·2% across the three lots. The minimum lower bound of the 95% CIs for the pairwise differences in seroconversion rates between lots was -5·8%. The maximum upper bound was 5·4%. Equivalence was therefore shown. Of those seronegative at baseline, 143 (85·6%) of 167 (95% CI 79·4-90·6) infants and 54 (83·1%) of 65 (71·7-91·2) young children seroconverted over the two-dose nOPV2 schedule. The post-two-dose seroprotection rates, including participants who were both seronegative and seropositive at baseline, were 604 (92·9%) of 650 (95% CI 90·7-94·8) in infants and 276 (95·5%) of 289 (92·4-97·6) in young children. No safety concerns were identified. 7 days post-dose one, 78 (41·7%) of 187 (95% CI 34·6-49·1) infants were excreting the type 2 poliovirus. INTERPRETATION: nOPV2 was immunogenic and safe in infants and young children in The Gambia. The data support the licensure and WHO prequalification of nOPV2. FUNDING: Bill & Melinda Gates Foundation.

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.

Systematic review and meta-analysis on the etiology of bacterial pneumonia in children in sub-Saharan Africa.

Introduction: Before the introduction of vaccination to protect children from pneumonia, Streptococcus pneumoniae and Haemophilus influenzae type B (HiB) were the most frequent aetiological agents causing bacterial pneumonia in children under five years old. However, the etiology of childhood pneumonia appears to be changing and nonvaccine- type S. pneumoniae, non-typeable H. influenzae, and Staphylococcus aureus are becoming more relevant. Objective: We conducted a systematic review aimed at identifying the common causes of bacterial pneumonia in children in sub-Saharan Africa. Methods: We searched PubMed, Web of Science and African Index Medicus and included primary studies conducted since January 2010 that reported on the bacterial causes of pneumonia in children under five from sub-Saharan Africa. We extracted data items (about the study setting, pneumonia diagnosis, sampling, microbiological methods, and etiological agents) as well as study quality indicators. Results: Streptococcus pneumoniae was the most common bacteria in blood cultures from children with pneumonia (8%, 95% CI: 4-14%), and H. influenzae was second (3%, 95% CI: 1-17%). Children's nasopharynx commonly contained S. pneumoniae (66%), Moraxella catarrhalis (62%), and H. influenzae (44%). Conclusion: S. pneumoniae and H. influenzae cause bacterial pneumonia in sub-Saharan African children. Our review also highlights the prevalence of potentially pathogenic bacteria in the nasopharynx of children under five and calls for more research into how nasopharyngeal colonization causes pneumonia.

GeneXpert rollout in three high-burden tuberculosis countries in Africa: A review of pulmonary tuberculosis diagnosis and outcomes from 2001 to 2019.

Background: The rollout of GeneXpert aimed at increasing early diagnosis of tuberculosis to improve treatment outcomes and global tuberculosis targets. Objective: This study evaluated trends in tuberculosis diagnosis and outcomes pre- and post-introduction of GeneXpert in three African countries - the Democratic Republic of the Congo (DRC), Nigeria and South Africa. Methods: Data from 2001 to 2019 were extracted from the World Health Organization's data repository. Descriptive analysis, paired t-tests and interrupted time series models were used. Results: Estimated tuberculosis incidence decreased from 327/100 000 to 324/100 000 in the DRC, and from 1220/100 000 to 988/100 000 in South Africa. Incidence remained at 219/100 000 in Nigeria. The tuberculosis case notification rate did not change significantly. Increases in the new case treatment success rates were statistically significant (DRC: p = 0.0201; Nigeria: p = 0.0001; South Africa: p = 0.0017); decreases in mortality were also statistically significant (DRC: p = 0.0264; Nigeria: p = 0.0001; South Africa: p < 0.0001). Time series models showed insignificant increases in new tuberculosis cases in DRC (n = 1856, p = 0.085) and Nigeria (n = 785, p = 0.555) from 2011 to 2019; and a statistically significant decrease in South Africa (n = 15 269, p = 0.006). Conclusion: Improvements in tuberculosis treatment outcomes were achieved, but little progress has been made in new case notification due to varied implementation and scale-up of GeneXpert across the three countries. Implementation barriers need to be addressed to achieve the required tuberculosis targets.

COVID-19-related research in Africa: a cross-sectional review of the International Clinical Trial Registration Platform (ICTRP).

OBJECTIVE: The declaration of the coronavirus disease (COVID-19), a pandemic in early 2020, has seen an upsurge in research globally to fill gaps in the epidemiology of the SARS-CoV-2 virus impact on health care and clinical management, as well as possible prevention and treatment modalities. Published literature on the different types of COVID-19 research conducted globally is varied and is particularly limited in Africa. This study sets out to describe the COVID-19-related research registered and conducted on the African continent. METHODS: This is a cross-sectional study of all COVID-19-related studies available in the WHO's International Clinical Trials Registry Platform (ICTRP) repository. We extracted studies registered from March 1, 2020, to July 15, 2021. A descriptive analysis of the extracted data was performed, and the findings were presented. RESULTS: At extraction, a total of 12,533 COVID-19-related studies were listed on the ICTRP portal. We included 9803 studies, after excluding 2060 duplicate records and 686 records without a site/country. While 9347 studies (96%) were conducted outside of Africa, only 456 studies (4%) were conducted in the African continent, of which 270 (59.2%) were interventional studies, and 184 (40.4%) were observational studies. About 80% of the studies were conducted in Egypt and South Africa, and most of these involved testing of drugs and biologicals. CONCLUSION: The African continent hosts considerably fewer COVID-19-related research compared to other parts of the world. This may have implications on scientific evidence available for implementing COVID-19 control efforts. There is, therefore, a need for local funding and ownership of research projects and north-south collaboration in research.

Trends in clinical trial registration in sub-Saharan Africa between 2010 and 2020: a cross-sectional review of three clinical trial registries.

OBJECTIVE: Prospective registration of clinical trials is an ethical, scientific, and legal requirement that serves several functions, including minimising research wastage and publication bias. Sub-Saharan Africa (SSA) is increasingly hosting clinical trials over the past few years, and there is limited literature on trends in clinical trial registration and reporting in SSA. Therefore, we set out to determine the trends in clinical trials registered in SSA countries between 2010 and July 2020. METHODS: A cross-sectional study design was used to describe the type of clinical trials that are conducted in SSA from 1 January 2010 to 31 July 2020. The registries searched were ClinicalTrials.gov (CTG), the Pan African Clinical Trials Register (PACTR), and the International Standard Randomized Controlled Trial Number (ISRCTN). Data were extracted into Excel and imported into STATA for descriptive analysis. RESULTS: CTG had the highest number of registered trials at 2622, followed by PACTR with 1501 and ISRCTN with 507 trials. Trials were observed to increase gradually from 2010 and peaked at 2018-2019. Randomised trials were the commonest type, accounting for at least 80% across the three registries. Phase three trials investigating drugs targeted at infections/infestations were the majority. Few completed trials had their results posted: 58% in ISRCTN and 16.5% in CTG, thus suggesting reporting bias. CONCLUSION: Despite the gradual increase in clinical trials registered during the period, recent trends suggest a drop in the number of trials registered across the region. Strengthening national and regional regulatory capacity will improve clinical trial registration and minimise reporting bias in completed clinical trials.

Considerations for Establishing Successful Coronavirus Disease Vaccination Programs in Africa.

The accelerated development of coronavirus disease (COVID-19) candidate vaccines is intended to achieve worldwide immunity. Ensuring COVID-19 vaccination is crucial to stemming the pandemic, reclaiming everyday life, and helping restore economies. However, challenges exist to deploying these vaccines, especially in resource-limited sub-Saharan Africa. In this article, we highlight lessons learned from previous efforts to scale up vaccine distribution and offer considerations for policymakers and key stakeholders to use for successful COVID-19 vaccination rollout in Africa. These considerations range from improving weak infrastructure for managing data and identifying adverse events after immunization to considering financing options for overcoming the logistical challenges of vaccination campaigns and generating demand for vaccine uptake. In addition, providing COVID-19 vaccination can be used to promote the adoption of universal healthcare, especially in sub-Saharan Africa countries.

Acute respiratory distress syndrome (ARDS) as an adverse event following immunization: Case definition & guidelines for data collection, analysis, and presentation of immunization safety data.

This is a Brighton Collaboration Case Definition of the term "Acute Respiratory Distress Syndrome - ARDS" to be utilized in the evaluation of adverse events following immunization. The Case Definition was developed by a group of experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of vaccines for SARS-CoV-2 vaccines and other emerging pathogens. The case definition format of the Brighton Collaboration was followed to develop a consensus definition and defined levels of certainty, after an exhaustive review of the literature and expert consultation. The document underwent peer review by the Brighton Collaboration Network and by selected Expert Reviewers prior to submission. The comments of the reviewers were taken into consideration and edits incorporated in this final manuscript.

A scorecard of progress towards measles elimination in 15 west African countries, 2001-19: a retrospective, multicountry analysis of national immunisation coverage and surveillance data.

BACKGROUND: The WHO Regional Office for the Africa Regional Immunization Technical Advisory Group, in 2011, adopted the measles control and elimination goals for all countries of the African region to achieve in 2015 and 2020 respectively. Our aim was to track the current status of progress towards measles control and elimination milestones across 15 west African countries between 2001 and 2019. METHODS: We did a retrospective multicountry series analysis of national immunisation coverage and case surveillance data from Jan 1, 2001, to Dec 31, 2019. Our analysis focused on the 15 west African countries that constitute the Economic Community of West African States. We tracked progress in the coverage of measles-containing vaccines (MCVs), measles supplementary immunisation activities, and measles incidence rates. We developed a country-level measles summary scorecard using eight indicators to track progress towards measles elimination as of the end of 2019. The summary indicators were tracked against measles control and elimination milestones. FINDINGS: The weighted average regional first-dose MCV coverage in 2019 was 66% compared with 45% in 2001. 73% (11 of 15) of the west African countries had introduced second-dose MCV as of December, 2019. An estimated 4 588 040 children (aged 12-23 months) did not receive first-dose MCV in 2019, the majority (71%) of whom lived in Nigeria. Based on the scorecard, 12 (80%) countries are off-track to achieving measles elimination milestones; however, Cape Verde, The Gambia, and Ghana have made substantial progress. INTERPRETATION: Measles will continue to be endemic in west Africa after 2020. The regional measles incidence rate in 2019 was 33 times the 2020 elimination target of less than 1 case per million population. However, some hope exists as countries can look at the efforts made by Cape Verde, The Gambia, and Ghana and learn from them. FUNDING: None.

Immunogenicity and safety of a novel ten-valent pneumococcal conjugate vaccine in healthy infants in The Gambia: a phase 3, randomised, double-blind, non-inferiority trial.

BACKGROUND: An affordable pneumococcal conjugate vaccine (PCV) is needed to ensure sustainable access in low-income and middle-income countries. This trial examined the immunogenicity and safety of a novel ten-valent PCV (SIIPL-PCV) containing serotypes 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, and 23F compared with the pneumococcal polysaccharide protein D-conjugate vaccine (PHiD-CV; Synflorix; GlaxoSmithKline; Brentford, UK). METHODS: In this single-centre, randomised, double-blind, phase 3, non-inferiority trial in The Gambia, healthy, PCV-naive infants aged 6-8 weeks were enrolled and assigned using permuted block randomisation to receive one of three lots of SIIPL-PCV or to PHiD-CV in a ratio of 2:2:2:3. Parents and all staff assessing study outcomes were masked to group assignment. Vaccines (0·5 mL SIIPL-PCV or 0·5 mL PHiD-CV) were administered at ages 6, 10, and 14 weeks by intramuscular injection. Primary immunogenicity outcomes, measured at age 18 weeks, were serotype-specific IgG geometric mean concentrations (GMCs) and seroresponse rates (IgG ≥ 0·35 µg/mL). Lot-to-lot equivalence (objective 1) was shown if the upper and lower bounds of the two-sided 95% CI around the GMC ratio for each pairwise lot-to-lot comparison was between the 0·5 and 2·0 equivalence margins for all ten serotypes. The immunogenicity of SIIPL-PCV was defined as being non-inferior to that of PHiD-CV (objective 2) if, for at least seven of the ten serotypes in SIIPL-PCV, the lower bound of the 97·5% CI for the GMC ratio was greater than 0·5, or the lower bound of the 97·5% CI for differences in seroresponse rate was greater than -10%. The GMC and seroresponse rates to serotypes 6A and 19A, which are not in PHiD-CV, were compared with those of the serotype in PHiD-CV that had the lowest seroresponse rate. Non-inferiority of the immune responses to antigens in the co-administered Expanded Programme on Immunization (EPI) vaccines (objective 3) was declared if the lower bound of the 95% CI for the difference between SIIPL-PCV and PHiD-CV in seroresponse rates, or GMC ratios for pertussis antigens, was greater than -10% (or 0·5 for pertussis antigens) for all vaccine antigens. Safety data were assessed according to treatment received at the first visit in infants who received at least one dose of study vaccine and for whom at least some post-vaccination safety data were available. The primary immunogenicity analysis was in the per-protocol immunogenicity population, which included infants who received all study vaccines and had immunogenicity measurements after vaccination and no major protocol deviations. This trial is registered at ClinicalTrials.gov (NCT03197376). FINDINGS: Between June 21, 2017, and Jan 29, 2018, 2250 infants were enrolled and randomly assigned to receive SIIPL-PCV (n=1503; 502 to lot 1, 501 to lot 2, and 500 to lot 3) or PHiD-CV (n=747). 1458 (97·0%) infants assigned to SIIPL-PCV and 724 (96·9%) assigned to PHiD-CV were included in the per-protocol primary immunogenicity analysis. Lot-to-lot equivalence was shown, with the lowest lower bound of the 95% CI for the GMC ratio being 0·52 (for serotype 6B in lot 2 vs lot 3) and the highest upper bound being 1·69 (for serotype 6B in lot 1 vs lot 2). SIIPL-PCV was non-inferior to PHiD-CV in terms of immunogenicity: the lower bound of the 97·5% CI for the GMC ratio was greater than 0·5 (the lowest being 0·67 for serotype 19F) and the lower bound of the 97·5% CI for the difference in seroresponse rate was greater than -10% (the lowest being -2·2% for serotype 6B) for all ten serotypes in SIIPL-PCV. The lowest seroresponse rate after PHiD-CV was to serotype 6B (76·7% [95% CI 73·4-79·7]). This serotype was therefore used for the comparisons with serotype 6A and 19A in SIIPL-PCV. Non-inferiority of immune responses to the EPI vaccines after co-administration with SIIPL-PCV compared with after co-administration with PHiD-CV was shown for all vaccine antigens included in the primary series. The lowest lower bound of the 95% CI for the difference in seroresponse rates was -7·1% for rotavirus antibody and for the GMC ratio for pertussis antigens was 0·62 for anti-pertussis toxoid. 1131 (75·2%) of 1503 infants in the SIIPL-PCV group and 572 (76·6%) of 747 in the PHiD-CV group had at least one unsolicited adverse event. 36 (2·4%) participants in the SIIPL-PCV group and 18 (2·4%) in the PHiD-CV group had a serious adverse event; none were considered related to vaccination. In infants who were selected to have solicited adverse events recorded, injection-site induration after primary vaccinations occurred in 27 (4·9%) of 751 infants who received SIIPL-PCV versus 34 (9·4%) of 364 who received PHiD-CV (p=0·0032). There were no other notable differences in the safety profiles of the two vaccines. One infant in the SIIPL-PCV group and two in the PHiD-CV group died during the study. The deaths were not considered to be related to study vaccination or study participation. INTERPRETATION: The immunogenicity of SIIPL-PCV was non-inferior to that of PHiD-CV, for which efficacy and effectiveness data against pneumococcal disease are available. The vaccine is safe and can be co-administered with routine EPI vaccines. The data generated in this trial have supported the licensure and pre-qualification of SIIPL-PCV, making the vaccine available for introduction into national immunisation programmes. Generating post-implementation data confirming vaccine impact remains important. FUNDING: Bill & Melinda Gates Foundation.

Estimating the impact of pneumococcal conjugate vaccines on childhood pneumonia in sub-Saharan Africa: A systematic review.

Background: This study aimed to summarise the evidence on the impact of routine administration of 10-valent and 13-valent pneumococcal conjugate vaccines on pneumonia in children under five years of age in sub-Saharan Africa. Methods: A systematic search of the literature was conducted including primary research reporting on the impact of 10- or 13-valent pneumococcal vaccines on childhood pneumonia in a sub-Saharan African country. Case-control, cohort, pre-post and time-series study designs were eligible for inclusion. Thematic narrative synthesis was carried out to summarise the findings. Results: Eight records were included in the final analysis, 6 records were pre-post or time-series studies, 1 was a case-control study and 1 report combined pre-post and case-control studies. Vaccine impact on clinical pneumonia measured as percentage reduction in risk (%RR) was mostly non-significant. The reduction in risk was more consistent in radiological and pneumococcal pneumonia. Conclusions: Evidence of the positive impact of routine infant pneumococcal vaccination on clinical pneumonia incidence in sub-Saharan Africa is inconclusive. Ongoing surveillance and further research is required to establish the long term trend in pneumonia epidemiology and aetiology after PCV introduction. PROSPERO registration: CRD42019142369 30/09/19.

Tracking coverage, dropout and multidimensional equity gaps in immunisation systems in West Africa, 2000-2017.

BACKGROUND: Several West African countries are unlikely to achieve the recommended Global Vaccine Action Plan (GVAP) immunisation coverage and dropout targets in a landscape beset with entrenched intra-country equity gaps in immunisation. Our aim was to assess and compare the immunisation coverage, dropout and equity gaps across 15 West African countries between 2000 and 2017. METHODS: We compared Bacille Calmette Guerin (BCG) and the third dose of diphtheria-tetanus-pertussis (DTP3) containing vaccine coverage between 2000 and 2017 using the WHO and Unicef Estimates of National Immunisation Coverage for 15 West African countries. Estimated subregional median and weighted average coverages, and dropout (DTP1-DTP3) were tracked against the GVAP targets of ≥90% coverage (BCG and DTP3), and ≤10% dropouts. Equity gaps in immunisation were assessed using the latest disaggregated national health survey immunisation data. RESULTS: The weighted average subregional BCG coverage was 60.7% in 2000, peaked at 83.2% in 2009 and was 65.7% in 2017. The weighted average DTP3 coverage was 42.3% in 2000, peaked at 70.3% in 2009 and was 61.5% in 2017. As of 2017, 46.7% of countries (7/15) had met the GVAP targets on DTP3 coverage. Average weighted subregional immunisation dropouts consistently reduced from 16.4% in 2000 to 7.4% in 2017, meeting the GVAP target in 2008. In most countries, inequalities in BCG, and DTP3 coverage and dropouts were mainly related to equity gaps of more than 20% points between the wealthiest and the poorest, high coverage regions and low coverage regions, and between children of mothers with at least secondary education and those with no formal education. A child's sex and place of residence (urban or rural) minimally determined equity gaps. CONCLUSIONS: The West African subregion made progress between 2000 and 2017 in ensuring that its children utilised immunisation services, however, wide equity gaps persist.

Anaesthetic and surgical management of airway penetrating injuries in children in resource-poor setting: Case reports.

INTRODUCTION: Impacted penetrating foreign body (FB) in the airway especially the postnasal space presents with management challenges. The challenges are worsened by lack of modern equipment in resource-poor settings. Two suchlike cases were managed in this report. PRESENTATION OF CASES: Case 1: A 4-year-old girl who fell on a metal rod in her mouth while playing alone. Examination revealed an agitated child in open mouth posture, with a silvery straight metallic object impacted on the hard palate and projecting from the mouth. X-ray of the post nasal space showed a radiopaque object through the hard palate impinging on the skull base. Case 2: A 5-year-old male presented with swollen neck and difficulty in breathing following a fall on a sharp pencil while at play in school. The object which pierced through the neck was immediately removed by an attendant. Examination revealed a child in obvious respiratory distress with swollen neck, face and eyes with a slit measuring 2cm over the crico-thyroid membrane (subcutaneous emphysema). DISCUSSION: With no available fibre-optic laryngoscope, classical Macintosh laryngoscopy was infeasible. With refusal of tracheostomy, the authors employed three-man intubation technique to successfully secure the airway for excision of the FB in first patient. The second was induced with IV ketamine since he could not tolerate the supine position and facemask. Due to falling oxygen saturation, an orotracheal intubation was done before a successful mid-level emergency tracheostomy was sited. CONCLUSION: Penetrating airway injuries in children pose serious management challenges. Careful anticipation and quick intervention are helpful.

Sexual activity among Nigerian women following successful obstetric fistula repair.

OBJECTIVE: To evaluate post-operative sexual activity among women who have undergone obstetric fistula repair. METHODS: The present descriptive cross-sectional study recruited married women who had undergone successful obstetric fistula repair who were attending reunion activities at Bingham University Teaching Hospital, Jos, Nigeria, between March 13 and March 15, 2014. Participants were interviewed regarding penetrative vaginal intercourse after surgery, and any changes in sexual desire, arousal, orgasm, sexual satisfaction, and the presence of coital pain compared with before they experienced obstetric fistula. RESULTS: There were 102 patients who participated in interviews; 23 (22.5%) reported not being able to engage in penetrative vaginal intercourse and 12 (52%) of these patients ascribed this to a "tight" or "narrow" vagina. Compared with the pre-fistula period, 63 (61.7%) patients reported reduced sexual desire, 57 (55.9%) reported lack of or inadequate lubrication during intercourse, 12 (11.8%) reported anorgasmia, and 60 (58.8%) reported reduced attainment of orgasm. Dyspareunia was reported by 48 (47.1%) patients; 43 (90%) experienced superficial or deep dyspareunia, and 5 (10%) experienced both. A lack of and lower sexual satisfaction were reported by 20 (19.6%) and 40 (39.2%) patients, respectively. CONCLUSION: Following obstetric fistula repair, many women experienced difficulty engaging in penetrative vaginal intercourse and reported sexual dysfunction. Management of sexual dysfunction should be part of fistula rehabilitation programs.