Background Typhoid fever remains a major cause of morbidity and mortality in low- and middle-income settings. In the last 10 years, several reports have described the reemergence of typhoid fever in southern and eastern Africa, associated with multidrug-resistant H58 Salmonella Typhi. Here, we identify risk factors for pediatric typhoid fever in a large epidemic in Blantyre, Malawi. Methods A case-control study was conducted between April 2015 and November 2016. Cases were recruited at a large teaching hospital, and controls were recruited from the community, matched by residential ward. Stepwise variable selection and likelihood ratio testing were used to select candidate risk factors for a final logistic regression model. Results Use of river water for cooking and cleaning was highly associated with risk of typhoid fever (odds ratio [OR], 4.6 [95% confidence interval {CI}, 1.7–12.5]). Additional risk factors included protective effects of soap in the household (OR, 0.6 [95% CI, .4–.98]) and >1 water source used in the previous 3 weeks (OR, 3.2 [95% CI, 1.6–6.2]). Attendance at school or other daycare was also identified as a risk factor (OR, 2.7 [95% CI, 1.4–5.3]) and was associated with the highest attributable risk (51.3%). Conclusions These results highlight diverse risk factors for typhoid fever in Malawi, with implications for control in addition to the provision of safe drinking water. There is an urgent need to improve our understanding of transmission pathways of typhoid fever, both to develop tools for detecting S. Typhi in the environment and to inform water, sanitation, and hygiene interventions.

Invasive pneumococcal disease is a leading cause of human immunodeficiency virus (HIV)-associated mortality in sub-Saharan African children. Defective T-cell-mediated immunity partially explains this high disease burden, but there is an increased risk of invasive pneumococcal disease even in the context of a relatively preserved percentage of CD4 cells. We hypothesized that impaired B-cell immunity to this pathogen further amplifies the immune defect. We report a shift in the B-cell compartment toward an apoptosis-prone phenotype evident early in HIV disease progression. We show that, although healthy HIV-uninfected and minimally symptomatic HIV-infected children have similar numbers of isotype-switched memory B cells, numbers of pneumococcal protein antigen-specific memory B cells were lower in HIV-infected than in HIV-uninfected children. Our data implicate defective naturally acquired B-cell pneumococcal immunity in invasive pneumococcal disease causation in HIV-infected children and highlight the need to study the functionality and duration of immune memory to novel pneumococcal protein vaccine candidates in order to optimize their effectiveness in this population.

SummaryObjectiveDespite CD4+ count restoration and viral load suppression with antiretroviral therapy (ART), HIV-infected children remain at increased risk of life-threatening infections including invasive pneumococcal disease (IPD). We therefore investigated whether persistent susceptibility to IPD following ART is associated with incomplete recovery of B-cell function.Methods41 HIV-infected Malawian children commencing ART were followed-up for a 1 year period during which time blood samples were collected at 0, 3, 6 and 12 months for comprehensive immunophenotyping and pneumomococcal-specific Memory B-cell Enzyme-Linked Immunospot assays. In addition, nasopharyngeal swab samples were cultured to determine pneumococcal carriage rates.ResultsNormalization of major lymphocyte subsets such as CD4+ percentages was evident following 3 months of ART. The proportions of mature naïve B cells (CD19+ CD10− CD27− CD21hi) and resting memory B cells (CD19+ CD27+ CD21hi) increased and apoptosis-prone mature activated B cells (CD19+ CD21lo CD10−) decreased markedly by 12 months. However, in the context of high nasopharyngeal pneumococcal carriage rates (83%), restoration of pneumococcal protein antigen-specific B-cell memory was more delayed.ConclusionsThese data show that, in chronically HIV-infected children receiving ART, improvement in B-cell memory profiles and function is slower than CD4+ T-cells. This supports early initiation of ART and informs research into optimal timing of immunization with pneumococcal vaccines.

Background Diverse environmental exposures and risk factors have been implicated in the transmission of Salmonella Typhi, however, the dominant transmission pathways through the environment to susceptible humans remain unknown. Here, we utilize spatial, bacterial genomic, and hydrological data to refine our view of Typhoid transmission in an endemic setting. Methods 546 patients presenting to Queen Elizabeth Central Hospital in Blantyre, Malawi with blood culture-confirmed typhoid fever between April 2015 and January 2017 were recruited to a cohort study. The households of a subset of these patients were geolocated, and 256 S. Typhi isolates were whole genome sequenced. Pairwise single nucleotide variant (SNV) distances were incorporated into a geostatistical modeling framework using multidimensional scaling. Results Typhoid fever was not evenly distributed across Blantyre, with estimated minimum incidence ranging across the city from less than 15 to over 100 cases/100,000/year. Pairwise SNV distance and physical household distances were significantly correlated (p=0.001). We evaluated the ability of river catchment to explain the spatial patterns of genomics observed, finding that it significantly improved the fit of the model (p=0.003). We also found spatial correlation at a smaller spatial scale, of households living <192 meters apart. Conclusions These findings reinforce the emerging view that hydrological systems play a key role in the transmission of typhoid fever. By combining genomic and spatial data, we show how multi-faceted data can be used to identify high incidence areas, understand the connections between them, and inform targeted environmental surveillance, all of which will be critical to shape local and regional typhoid control strategies.