Pneumonia, Meningitis, and Septicemia in Adults and Older Children in Rural Gambia: 8 Years of Population-Based Surveillance.

BACKGROUND: Representative data describing serious infections in children aged ≥5 years and adults in Africa are limited. METHODS: We conducted population-based surveillance for pneumonia, meningitis, and septicemia in a demographic surveillance area in The Gambia between 12 May 2008 and 31 December 2015. We used standardized criteria to identify, diagnose, and investigate patients aged ≥5 years using conventional microbiology and radiology. RESULTS: We enrolled 1638 of 1657 eligible patients and investigated 1618. Suspected pneumonia, septicemia, or meningitis was diagnosed in 1392, 135, and 111 patients, respectively. Bacterial pathogens from sterile sites were isolated from 105 (7.5%) patients with suspected pneumonia, 11 (8.1%) with suspected septicemia, and 28 (25.2%) with suspected meningitis. Streptococcus pneumoniae (n = 84), Neisseria meningitidis (n = 16), and Staphylococcus aureus (n = 15) were the most common pathogens. Twenty-eight (1.7%) patients died in hospital and 40 (4.1%) died during the 4 months after discharge. Thirty postdischarge deaths occurred in patients aged ≥10 years with suspected pneumonia. The minimum annual incidence was 133 cases per 100 000 person-years for suspected pneumonia, 13 for meningitis, 11 for septicemia, 14 for culture-positive disease, and 46 for radiological pneumonia. At least 2.7% of all deaths in the surveillance area were due to suspected pneumonia, meningitis, or septicemia. CONCLUSIONS: Pneumonia, meningitis, and septicemia in children aged ≥5 years and adults in The Gambia are responsible for significant morbidity and mortality. Many deaths occur after hospital discharge and most cases are culture negative. Improvements in prevention, diagnosis, inpatient, and follow-up management are urgently needed.

Insights Into Pneumococcal Pneumonia Using Lung Aspirates and Nasopharyngeal Swabs Collected From Pneumonia Patients in The Gambia.

BACKGROUND: We investigated the pathogenesis of pneumococcal pneumonia using clinical specimens collected for pneumonia surveillance in The Gambia. METHODS: Lung aspirates and nasopharyngeal swabs from 31 patients were examined by culture, quantitative polymerase chain reaction (qPCR), whole genome sequencing, serotyping, and reverse-transcription qPCR. RESULTS: Five lung aspirates cultured pneumococci, with a matching strain identified in the nasopharynx. Three virulence genes including ply (pneumolysin) were upregulated >20-fold in the lung compared with the nasopharynx. Nasopharyngeal pneumococcal density was higher in pediatric pneumonia patients compared with controls (P < .0001). CONCLUSIONS: Findings suggest that changes in pneumococcal gene expression occurring in the lung environment may be important in pathogenesis.

Staphylococcus aureus Bacteremia in Children of Rural Areas of The Gambia, 2008-2015.

Staphylococcus aureus bacteremia is a substantial cause of childhood disease and death, but few studies have described its epidemiology in developing countries. Using a population-based surveillance system for pneumonia, sepsis, and meningitis, we estimated S. aureus bacteremia incidence and the case-fatality ratio in children <5 years of age in 2 regions in the eastern part of The Gambia during 2008-2015. Among 33,060 children with suspected pneumonia, sepsis, or meningitis, we performed blood culture for 27,851; of 1,130 patients with bacteremia, 198 (17.5%) were positive for S. aureus. S. aureus bacteremia incidence was 78 (95% CI 67-91) cases/100,000 person-years in children <5 years of age and 2,080 (95% CI 1,621-2,627) cases/100,000 person-years in neonates. Incidence did not change after introduction of the pneumococcal conjugate vaccine. The case-fatality ratio was 14.1% (95% CI 9.6%-19.8%). Interventions are needed to reduce the S. aureus bacteremia burden in The Gambia, particularly among neonates.

Impact of the change in WHO's severe pneumonia case definition on hospitalized pneumonia epidemiology: case studies from six countries.

OBJECTIVE: To quantify the impact of the change in definition of severe pneumonia on documented pneumonia burden. METHODS: We reviewed existing data acquired during observational hospitalized pneumonia studies, before the introduction of the pneumococcal conjugate vaccine, in infants aged 2-23 months from Fiji, Gambia, Lao People's Democratic Republic, Malawi, Mongolia and Viet Nam. We used clinical data to calculate the percentage of all-cause pneumonia hospitalizations with severe pneumonia, and with primary end-point consolidation, according to both the 2005 or 2013 World Health Organization (WHO) definitions. Where population data were available, we also calculated the incidence of severe pneumonia hospitalizations according to the different definitions. FINDINGS: At six of the seven sites, the percentages of all-cause pneumonia hospitalizations due to severe pneumonia were significantly less (P < 0.001) according to the 2013 WHO definition compared with the 2005 definition. However, the percentage of severe pneumonia hospitalizations, according to the two definitions of severe pneumonia, with primary end-point consolidation varied little within each site. The annual incidences of severe pneumonia hospitalizations per 100 000 infants were significantly less (all P < 0.001) according to the 2013 definition compared with the 2005 definition, ranging from a difference of -301.0 (95% confidence interval, CI: -405.2 to -196.8) in Fiji to -3242.6 (95% CI: -3695.2 to -2789.9) in the Gambia. CONCLUSION: The revision of WHO's definition of severe pneumonia affects pneumonia epidemiology, and hence the interpretation of any pneumonia intervention impact evaluation.

Vaccine wastage in The Gambia: a prospective observational study.

BACKGROUND: Vaccination is a cost-effective and life-saving intervention. Recently several new, but more expensive vaccines have become part of immunization programmes in low and middle income countries (LMIC). Monitoring vaccine wastage helps to improve vaccine forecasting and minimise wastage. As the costs of vaccination increases better vaccine management is essential. Many LMIC however do not consistently monitor vaccine wastage. METHODS: We conducted two surveys in health facilities in rural and urban Gambia; 1) a prospective six months survey in two regions to estimate vaccine wastage rates and type of wastage for each of the vaccines administered by the Expanded programme on Immunization (EPI) and 2) a nationwide cross sectional survey of health workers from randomly selected facilities to assess knowledge, attitude and practice on vaccine waste management. We used WHO recommended forms and standard questionnaires. Wastage rates were compared to EPI targets. RESULTS: Wastage rates for the lyophilised vaccines BCG, Measles and Yellow Fever ranged from 18.5-79.0%, 0-30.9% and 0-55.0% respectively, mainly through unused doses at the end of an immunization session. Wastage from the liquid vaccines multi-dose/ single dose vials were minimal, with peaks due to expiry or breakage of the vaccine diluent. We interviewed 80 health workers and observed good knowledge. Batching children for BCG was uncommon (19%) whereas most health workers (73.4%) will open a vial as needed. CONCLUSION: National projected wastage targets were met for the multi-dose/single dose vials, but for lyophilised vaccines, the target was only met in the largest major health facility.

Comparative Genomic Analysis and In Vivo Modeling of Streptococcus pneumoniae ST3081 and ST618 Isolates Reveal Key Genetic and Phenotypic Differences Contributing to Clonal Replacement of Serotype 1 in The Gambia.

Streptococcus pneumoniae serotype 1 is one of the leading causes of invasive pneumococcal disease (IPD) in West Africa, with ST618 being the dominant cause of IPD in The Gambia. Recently however, a rare example of clonal replacement was observed, where the ST3081 clone of serotype 1 replaced the predominant ST618 clone as the main cause of IPD. In the current study, we sought to find the reasons for this unusual replacement event. Using whole-genome sequence analysis and clinically relevant models of in vivo infection, we identified distinct genetic and phenotypic characteristics of the emerging ST3081 clone. We show that ST3081 is significantly more virulent than ST618 in models of invasive pneumonia, and is carried at higher densities than ST618 during nasopharyngeal carriage. We also observe sequence type-specific accessory genes and a unique sequence type-specific fixed mutation in the pneumococcal toxin pneumolysin, which is associated with increased hemolytic activity in ST3081 and may contribute to increased virulence in this clone. Our study provides evidence that, within the same serotype 1 clonal complex, biological properties differ significantly from one clone to another in terms of virulence and host invasiveness, and that these differences may be the result of key genetic differences within the genome.

Standardization of Clinical Assessment and Sample Collection Across All PERCH Study Sites.

BACKGROUND.: Variable adherence to standardized case definitions, clinical procedures, specimen collection techniques, and laboratory methods has complicated the interpretation of previous multicenter pneumonia etiology studies. To circumvent these problems, a program of clinical standardization was embedded in the Pneumonia Etiology Research for Child Health (PERCH) study. METHODS.: Between March 2011 and August 2013, standardized training on the PERCH case definition, clinical procedures, and collection of laboratory specimens was delivered to 331 clinical staff at 9 study sites in 7 countries (The Gambia, Kenya, Mali, South Africa, Zambia, Thailand, and Bangladesh), through 32 on-site courses and a training website. Staff competency was assessed throughout 24 months of enrollment with multiple-choice question (MCQ) examinations, a video quiz, and checklist evaluations of practical skills. RESULTS.: MCQ evaluation was confined to 158 clinical staff members who enrolled PERCH cases and controls, with scores obtained for >86% of eligible staff at each time-point. Median scores after baseline training were ≥80%, and improved by 10 percentage points with refresher training, with no significant intersite differences. Percentage agreement with the clinical trainer on the presence or absence of clinical signs on video clips was high (≥89%), with interobserver concordance being substantial to high (AC1 statistic, 0.62-0.82) for 5 of 6 signs assessed. Staff attained median scores of >90% in checklist evaluations of practical skills. CONCLUSIONS.: Satisfactory clinical standardization was achieved within and across all PERCH sites, providing reassurance that any etiological or clinical differences observed across the study sites are true differences, and not attributable to differences in application of the clinical case definition, interpretation of clinical signs, or in techniques used for clinical measurements or specimen collection.

Morbidity and Mortality Due to Bordetella pertussis: A Significant Pathogen in West Africa?

In the absence of specific surveillance platforms for pertussis and availability of suitable diagnostics at the hospital level, reliable data that describe morbidity and mortality from pertussis are difficult to obtain in any setting, as is the case in West Africa. Here, we summarize the available evidence of the burden of pertussis in the region, given historical data, and describe recent and ongoing epidemiological studies that offer opportunities for additional data collection. The available seroepidemiological data provide evidence of ongoing circulation of Bordetella pertussis in the region. Due to the lack of systematic and targeted surveillance with laboratory confirmation of B. pertussis infection, we cannot definitively conclude that pertussis disease is well controlled in West Africa. However, based on observations by clinicians and ongoing demographic surveillance systems that capture morbidity and mortality data in general terms, currently there is no evidence that pertussis causes a significant burden of disease in young children in West Africa.

Population structure, epidemiology and antibiotic resistance patterns of Streptococcus pneumoniae serotype 5: prior to PCV-13 vaccine introduction in Eastern Gambia.

BACKGROUND: Streptococcus pneumoniae serotype 5 is among the most common serotypes causing invasive pneumococcal disease (IPD) in The Gambia. We anticipate that introduction of the 13-valent pneumococcal conjugate vaccine (PCV-13) into routine vaccination in The Gambia will reduce serotype 5 IPD. However, the emergence of new clones that have altered their genetic repertoire through capsular switching or genetic recombination after vaccination with PCV-13 poses a threat to this public health effort. In order to monitor for potential genetic changes post-PCV-13 vaccination, we established the baseline population structure, epidemiology, and antibiotic resistance patterns of serotype 5 before the introduction of PCV-13. METHODS: Fifty-five invasive S. pneumoniae serotype 5 isolates were recovered from January 2009 to August 2011 in a population-based study in the Upper River Region of The Gambia. Serotyping was done by latex agglutination and confirmed by serotype-specific Polymerase Chain Reaction (PCR). Genotyping was undertaken using Multilocus Sequence Typing (MLST). Antimicrobial sensitivity was done using disc diffusion. Contingency table analyses were conducted using Pearson's Chi(2) and Fisher's exact test. Clustering was performed using Bionumerics version 6.5. RESULTS: MLST resolved S. pneumoniae serotype 5 isolates into 3 sequence types (ST), namely ST 289(6/55), ST 3339(19/55) and ST 3404(30/55). ST 289 was identified as the major clonal complex. ST 3339, the prevalent genotype in 2009 [84.6% (11/13)], was replaced by ST 3404 [70.4% (19/27)] in 2010 as the dominant ST. Interestingly, ST 3404 showed lower resistance to tetracycline and oxacillin (P < 0.001), an empirical surrogate to penicillin in The Gambia. CONCLUSIONS: There has been an emergence of ST 3404 in The Gambia prior to the introduction of PCV-13. Our findings provide important background data for future assessment of the impact of PCV-13 into routine immunization in developing countries, such as The Gambia.

The economic burden of childhood pneumococcal diseases in The Gambia.

BACKGROUND: Streptococcus pneumoniae is a common cause of child death. However, the economic burden of pneumococcal disease in low-income countries is poorly described. We aimed to estimate from a societal perspective, the costs incurred by health providers and families of children with pneumococcal diseases. METHODS: We recruited children less than 5 years of age with outpatient pneumonia, inpatient pneumonia, pneumococcal sepsis and bacterial meningitis at facilities in rural and urban Gambia. We collected provider costs, out of pocket costs and productivity loss for the families of children. For each disease diagnostic category, costs were collected before, during, and for 1 week after discharge from hospital or outpatient visit. RESULTS: A total of 340 children were enrolled; 100 outpatient pneumonia, 175 inpatient pneumonia 36 pneumococcal sepsis, and 29 bacterial meningitis cases. The mean provider costs per patient for treating outpatient pneumonia, inpatient pneumonia, pneumococcal sepsis and meningitis were US$8, US$64, US$87 and US$124 respectively and the mean out of pocket costs per patient were US$6, US$31, US$44 and US$34 respectively. The economic burden of outpatient pneumonia, inpatient pneumonia, pneumococcal sepsis and meningitis increased to US$15, US$109, US$144 and US$170 respectively when family members' time loss from work was taken into account. CONCLUSION: The economic burden of pneumococcal disease in The Gambia is substantial, costs to families was approximately one-third to a half of the provider costs, and accounted for up to 30 % of total societal costs. The introduction of pneumococcal conjugate vaccine has the potential to significantly reduce this economic burden in this society.

The large contribution of twins to neonatal and post-neonatal mortality in The Gambia, a 5-year prospective study.

BACKGROUND: A high twinning rate and an increased risk of mortality among twins contribute to the high burden of infant mortality in Africa. This study examined the contribution of twins to neonatal and post-neonatal mortality in The Gambia, and evaluated factors that contribute to the excess mortality among twins. METHODS: We analysed data from the Basse Health and Demographic Surveillance System (BHDSS) collected from January 2009 to December 2013. Demographic and epidemiological variables were assessed for their association with mortality in different age groups. RESULTS: We included 32,436 singletons and 1083 twins in the analysis (twining rate 16.7/1000 deliveries). Twins represented 11.8 % of all neonatal deaths and 7.8 % of post-neonatal deaths. Mortality among twins was higher than in singletons [adjusted odds ratio (AOR) 4.33 (95 % CI: 3.09, 6.06) in the neonatal period and 2.61 (95 % CI: 1.85, 3.68) in the post-neonatal period]. Post-neonatal mortality among twins increased in girls (P for interaction = 0.064), being born during the dry season (P for interaction = 0.030) and lacking access to clean water (P for interaction = 0.042). CONCLUSION: Mortality among twins makes a significant contribution to the high burden of neonatal and post-neonatal mortality in The Gambia and preventive interventions targeting twins should be prioritized.

Spatial analysis of under-5 mortality and potential risk factors in the Basse Health and Demographic Surveillance System, the Gambia.

OBJECTIVES: To describe the spatial pattern in under-5 mortality rates in the Basse Health and Demographic Surveillance System (BHDSS) and to test for associations between under-5 deaths and biodemographic and socio-economic risk factors. METHODS: Using data on child survival from 2007 to 2011 in the BHDSS, we mapped under-5 mortality by km(2) . We tested for spatial clustering of high or low death rates using Kulldorff's spatial scan statistic. Associations between child death and a variety of biodemographic and socio-economic factors were assessed with Cox proportional hazards models, and deviance residuals from the best-fitting model were tested for spatial clustering. RESULTS: The overall death rate among children under 5 was 0.0195 deaths per child-year. We found two spatial clusters of high death rates and one spatial cluster of low death rates; children in the two high clusters died at a rate of 0.0264 and 0.0292 deaths per child-year, while in the low cluster, the rate was 0.0144 deaths per child-year. We also found that children born to Fula mothers experienced, on average, a higher hazard of death, whereas children born in the households in the upper two quintiles of asset ownership experienced, on average, a lower hazard of death. After accounting for the spatial distribution of biodemographic and socio-economic characteristics, we found no residual spatial pattern in child mortality risk. CONCLUSION: This study demonstrates that significant inequality in under-5 death rates can occur within a relatively small area (1100 km(2) ). Risks of under-5 mortality were associated with mother's ethnicity and household wealth. If high mortality clusters persist, then equity concerns may require additional public health efforts in those areas.

Pneumococcal carriage in rural Gambia prior to the introduction of pneumococcal conjugate vaccine: a population-based survey.

OBJECTIVE: To evaluate pneumococcal colonisation before and after the introduction of pneumococcal conjugate vaccine (PCV) in eastern Gambia. METHODS: Population-based cross-sectional survey of pneumococcal carriage between May and August 2009 before the introduction of PCV into the Expanded Program on Immunization. Nasopharyngeal swabs were collected from all household members, but in selected households, only children aged 6-10 years were swabbed. This age group participated in an earlier trial of a nine-valent PCV between 2000 and 2004. RESULTS: The prevalence of nasopharyngeal pneumococcal carriage in 2933 individuals was 72.0% in underfives (N = 515), 41.6% in children aged 5-17 (N = 1508) and 13.0% in adults ≥18 (N = 910) years. The age-specific prevalence of serotypes included in PCV7, PCV10 and PCV13 was 24.7%, 26.6% and 46.8% among children <5 years of age; 8.5%, 9.2% and 17.7% among children 5-17 years; and 2.5%, 3.3% and 5.5% among adults ≥18 years. The most common serotypes were 6A (13.1%), 23F (7.6%), 3 (7.3%), 19F (7.1%) and 34 (4.6%). There was no difference in the overall carriage of pneumococci between vaccinated and unvaccinated children 8 years after the primary vaccination with three doses of PCV (48.3% vs. 41.1%). CONCLUSION: Before the introduction of PCV, serotypes included in PCV13 accounted for about half the pneumococcal serotypes in nasopharyngeal carriage. Thus, the potential impact of PCV13 on pneumococcal disease in the Gambia is substantial.

Discovery and validation of biomarkers to guide clinical management of pneumonia in African children.

BACKGROUND: Pneumonia is the leading cause of death in children globally. Clinical algorithms remain suboptimal for distinguishing severe pneumonia from other causes of respiratory distress such as malaria or distinguishing bacterial pneumonia and pneumonia from others causes, such as viruses. Molecular tools could improve diagnosis and management. METHODS: We conducted a mass spectrometry-based proteomic study to identify and validate markers of severity in 390 Gambian children with pneumonia (n = 204) and age-, sex-, and neighborhood-matched controls (n = 186). Independent validation was conducted in 293 Kenyan children with respiratory distress (238 with pneumonia, 41 with Plasmodium falciparum malaria, and 14 with both). Predictive value was estimated by the area under the receiver operating characteristic curve (AUC). RESULTS: Lipocalin 2 (Lpc-2) was the best protein biomarker of severe pneumonia (AUC, 0.71 [95% confidence interval, .64-.79]) and highly predictive of bacteremia (78% [64%-92%]), pneumococcal bacteremia (84% [71%-98%]), and "probable bacterial etiology" (91% [84%-98%]). These results were validated in Kenyan children with severe malaria and respiratory distress who also met the World Health Organization definition of pneumonia. The combination of Lpc-2 and haptoglobin distinguished bacterial versus malaria origin of respiratory distress with high sensitivity and specificity in Gambian children (AUC, 99% [95% confidence interval, 99%-100%]) and Kenyan children (82% [74%-91%]). CONCLUSIONS: Lpc-2 and haptoglobin can help discriminate the etiology of clinically defined pneumonia and could be used to improve clinical management. These biomarkers should be further evaluated in prospective clinical studies.

Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis.

BACKGROUND: The annual number of hospital admissions and in-hospital deaths due to severe acute lower respiratory infections (ALRI) in young children worldwide is unknown. We aimed to estimate the incidence of admissions and deaths for such infections in children younger than 5 years in 2010. METHODS: We estimated the incidence of admissions for severe and very severe ALRI in children younger than 5 years, stratified by age and region, with data from a systematic review of studies published between Jan 1, 1990, and March 31, 2012, and from 28 unpublished population-based studies. We applied these incidence estimates to population estimates for 2010, to calculate the global and regional burden in children admitted with severe ALRI in that year. We estimated in-hospital mortality due to severe and very severe ALRI by combining incidence estimates with case fatality ratios from hospital-based studies. FINDINGS: We identified 89 eligible studies and estimated that in 2010, 11·9 million (95% CI 10·3-13·9 million) episodes of severe and 3·0 million (2·1-4·2 million) episodes of very severe ALRI resulted in hospital admissions in young children worldwide. Incidence was higher in boys than in girls, the sex disparity being greatest in South Asian studies. On the basis of data from 37 hospital studies reporting case fatality ratios for severe ALRI, we estimated that roughly 265,000 (95% CI 160,000-450,000) in-hospital deaths took place in young children, with 99% of these deaths in developing countries. Therefore, the data suggest that although 62% of children with severe ALRI are treated in hospitals, 81% of deaths happen outside hospitals. INTERPRETATION: Severe ALRI is a substantial burden on health services worldwide and a major cause of hospital referral and admission in young children. Improved hospital access and reduced inequities, such as those related to sex and rural status, could substantially decrease mortality related to such infection. Community-based management of severe disease could be an important complementary strategy to reduce pneumonia mortality and health inequities. FUNDING: WHO.

Is the absolute requirement for informed consent before HIV testing a barrier to public health? A case report and management challenges.

Clinicians in sub-Saharan Africa are faced with a major challenge of parental refusal to test their children for HIV. We present a case of a nine-month-old child with a clinical presentation suggestive of HIV infection whose mother persistently declined HIV testing of the child or herself. The case illustrates the difficulties faced by the clinicians caring for the child in an isolated location in West Africa. While not eliminating these difficulties, an opt-out approach to paediatric HIV testing in sub-Saharan Africa may increase the proportion of children who access treatment when they need it, particularly when this is backed by the development of more effective national and regional clinical and legislative frameworks for HIV testing in children.

Two assumptions of the prior event rate ratio approach for controlling confounding can be evaluated by self-controlled case series and dynamic random intercept modeling.

OBJECTIVES: The prior event rate ratio (PERR) is a recently developed approach for controlling confounding by measured and unmeasured covariates in real-world evidence research and observational studies. Despite its rising popularity in studies of safety and effectiveness of biopharmaceutical products, there is no guidance on how to empirically evaluate its model assumptions. We propose two methods to evaluate two of the assumptions required by the PERR, specifically, the assumptions that occurrence of outcome events does not alter the likelihood of receiving treatment, and that earlier event rate does not affect later event rate. STUDY DESIGN AND SETTING: We propose using self-controlled case series (SCCS) and dynamic random intercept modeling (DRIM), respectively, to evaluate the two aforementioned assumptions. A nonmathematical introduction of the methods and their application to evaluate the assumptions are provided. We illustrate the evaluation with secondary analysis of deidentified data on pneumococcal vaccination and clinical pneumonia in The Gambia, West Africa. RESULTS: SCCS analysis of data on 12,901 vaccinated Gambian infants did not reject the assumption of clinical pneumonia episodes had no influence on the likelihood of pneumococcal vaccination. DRIM analysis of 14,325 infants with a total of 1719 episodes of clinical pneumonia did not reject the assumption of earlier episodes of clinical pneumonia had no influence on later incidence of the disease. CONCLUSION: The SCCS and DRIM methods can facilitate appropriate use of the PERR approach to control confounding. PLAIN LANGUAGE SUMMARY: The prior event rate ratio is a promising approach for analysis of real-world data and observational studies. We propose two statistical methods to evaluate the validity of two assumptions it is based on. They can facilitate appropriate use of the prior even rate ratio.

Pneumococcal conjugate vaccination schedules in infants-acquisition, immunogenicity, and pneumococcal conjugate and yellow fever vaccine co-administration study: statistical analysis plan.

RATIONALE: The effectiveness of immunisation with pneumococcal conjugate vaccine (PCV) has been demonstrated in many countries. However, the global impact of PCV is limited by its cost, which has prevented its introduction in some countries. Reducing the cost of PCV programmes will facilitate further vaccine introductions and improve the sustainability of PCV in low-income countries when they transition from subsidised vaccine supply. We are conducting a large, population-level, cluster-randomised field trial (PVS) of an alternative reduced-dose schedule of PCV compared to the standard schedule. We are also conducting a nested sub-study at the individual level to investigate the immunogenicity of the two schedules and their effects on pneumococcal carriage acquisition (PVS-AcqImm). METHODS AND DESIGN: PVS-AcqImm is a prospective, cluster-randomised trial of an alternative schedule of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months compared to the standard of three primary doses scheduled at 6, 10, and 14 weeks of age. Sub-groups within the alternative schedule group receive yellow fever vaccine separately or co-administered with PCV at 9 months of age. The primary endpoints are (a) concentrations of vaccine-type anti-pneumococcal IgG at 18 months of age, (b) proportions with yellow fever neutralising antibody titre ≥ 1:8 4 weeks after separate or co-administration of PCV and yellow fever vaccines, and (c) rate of nasopharyngeal vaccine-type pneumococcal acquisition from 10-14 months of age. Participants and field staff are not masked to group allocation while measurement of the laboratory endpoints is masked. Approximately equal numbers of participants are resident in each of 28 randomly allocated geographic clusters (14 clusters in each group); 784 enrolled for acquisition measurements and 336 for immunogenicity measurements. PURPOSE: This statistical analysis plan (SAP) describes the PVS-AcqImm cohort and follow-up criteria to be used in different analyses. The SAP defines the endpoints and describes how adherence to the interventions will be presented. We describe the approach to analyses and how we will account for the effect of clustering. Defining the SAP prior to the conduct of analysis will avoid bias in analyses that may arise from prior knowledge of trial findings. TRIAL REGISTRATION: ISRCTN, ISRCTN7282161328. Registered on 28 November 2019. https://www.isrctn.com/ISRCTN72821613 . PROTOCOL: MRCG SCC number 1670, LSHTM Ref 17683. Current protocol version: 6.0, 24 May 2021. Version: 1.0 (5 April 2023); SAP revisions-none.

Impact of pneumococcal conjugate vaccination on pneumococcal nasopharyngeal carriage in the Gambia: Population-based cross-sectional surveys.

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.

Ochrobactrum anthropi sepsis in a 15-month-old child: A case report.

Key Clinical Message: Ochrobactrum anthropi (O. anthropi), a rare opportunistic pathogen, caused sepsis in a malnourished 15-month-old African child. Early detection and appropriate antibiotics led to full recovery, highlighting the importance of robust surveillance for emerging pathogens in vulnerable populations. Abstract: While rarely causing infections, O. anthropi, a non-fermenting, obligately aerobic, flagellated gram-negative bacillus, demonstrates oxidase positivity and indole negativity. Traditionally, Ochrobactrum spp is considered a low threat due to its environmental abundance and mild virulence. It is, however, a multidrug-resistant bacteria known for causing opportunistic infections in humans. O. anthropi is typically associated with catheter-related bloodstream infections. The first documented case was in 1998; most cases have been reported in developed countries. We present a case of O. anthropi sepsis in a malnourished child in sub-Saharan Africa. We report a case involving a 15-month-old African female who presented with symptoms and signs of protein-energy malnutrition and sepsis. The blood culture revealed O.anthropi. We treated the child with the empirical first-line antibiotics per the national guidelines, intravenous ampicillin and gentamicin for a week, and the child fully recovered. This report describes a rare case of O. anthropi sepsis with malnutrition in an African female child. O. anthropi is an emerging pathogen causing opportunistic infections in both immunocompetent and immunocompromised patients. We report that early bacterial detection, appropriate antibiotic susceptibility and antimicrobial management based on local antibiogram data may be essential for excellent patient outcomes. Additionally, we recommend more robust surveillance to detect such rare emerging pathogens.