BACKGROUND:Klebsiella pneumoniae causes ~20% of sepsis in neonates, with ~40% crude mortality. A vaccine administered to pregnant women, protecting against ≥70% of K. pneumoniae infections, could avert ~400,000 cases and ~80,000 deaths annually, mostly in Africa and South Asia. Vaccine formulations targeting the capsular polysaccharide (K) or lipopolysaccharide (O) antigens are in development. Global K. pneumoniae populations display extensive K and O diversity, necessitating a polyvalent vaccine targeted to the serotypes associated with neonatal disease in relevant geographical regions. We investigated the prevalence of K and O types associated with neonatal sepsis in Africa and South Asia to inform maternal vaccine design. METHODS AND FINDINGS:We analysed 1,930 K. pneumoniae neonate blood isolates from 13 surveillance studies across 35 sites in 13 countries. We used pathogen whole-genome sequencing to predict K and O serotypes and adjust for local transmission clusters, and Bayesian hierarchical meta-analysis to estimate K and O prevalence overall and per region, treating site as a random effect. Eighty-seven K loci were identified. KL2, KL102, KL25, KL15, and KL62 accounted for 49% of isolates. We estimate that 20 K loci, combining the eight most prevalent per region, could cover 72.9% of all infections (95% credible interval: [69.4%, 76.5%]) and ≥70% in each of Eastern, Western, and Southern Africa and South Asia. Preliminary findings from three sites suggested sufficient temporal stability of K loci to maintain 20-valent K vaccine coverage over 5-10 years, but more longitudinal data are needed to support this prediction. O types were far less diverse (n = 14 types). We estimate the top-5 (O1⍺β,2⍺, O1⍺β,2β, O2⍺, O2β, and O4) would cover 86.2% [82.6, 89.9%] of total infections (76%-92% per region), while the top-10 would cover ~99% of infections in all four regions. The main limitations of our study are the reliance on genome sequences to predict K and O serotypes (as serological typing is not available) and a lack of longitudinal data to explore stability of antigen prevalence over time. CONCLUSIONS:Neonatal sepsis is associated with diverse K and O types, with substantial geographic and temporal variation even after adjusting for localised transmission clusters. Despite this, a single 20-valent K vaccine could theoretically cover ≥70% of infections in all target regions. Locally-targeted vaccines could achieve higher coverage with lower valency, but are less feasible. In principle, very high coverage could be achieved with lower valency O-based vaccines, however, the protective efficacy against disease of antibodies targeting the O antigen remains uncertain. Further research is needed on cross-reactivity, antigen exposure, and stability of antigens over time, to better inform vaccine development.
The hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide. Although most infections are self-limiting, zoonotic genotypes can persist in immunocompromised individuals. Transmitted via the fecal-oral route, HEV has been suggested to directly infect the intestinal epithelium, a tissue with high regenerative capacity. Here, we demonstrate that HEV predominantly infects proliferative transit-amplifying and intestinal stem cells within the crypts of human pluripotent stem cell-derived intestinal organoids (hIOs). Supporting this, we detected HEV RNA in the intestinal crypts of an HEV-infected patient. We further found that HEV infection spreads through cell division and is maintained in hIOs for more than 40 days, contrasting with acute hepatitis A virus, whose infections are rapidly cleared from hIOs. Given the self-renewal ability and metabolic constraints of proliferative intestinal progenitor cells, our findings suggest that intestinal crypts could serve as reservoirs for chronic HEV infection and highlight the intestinal crypt as a primary target for viral infection in the gastrointestinal tract.
Abstract Bacteriophages that infect Salmonella enterica serovar Typhi ( S. Typhi), the cause of typhoid fever, are regarded as specialized, because all previously characterized phages depend on the Vi capsular polysaccharide for infection. Whether capsule-independent infection strategies exist has remained unclear. Here we identify environmental phages that infect S. Typhi both in the presence and absence of Vi. Screening 140 urban wastewater samples from Dhaka, Bangladesh, where typhoid is endemic, we recovered phages infecting a Vi-deficient S. Typhi strain from 41 samples (29%). All 41 phages also infected the isogenic Vi-expressing host, although 28 did so with 10- to 10⁵-fold lower infection efficiency, and suppressing capsule expression increased susceptibility to 23, indicating an inhibitory effect of Vi on infection by many these phages. All 41 phages infected S. Paratyphi A and nine infected a monophasic S. Typhimurium, a broader host range than the Vi-dependent phages, which were restricted to Vi-expressing Typhi. Across 26 circulating genotypes, capsule suppression increased susceptible genotypes per phage by 1.51 on average (Wilcoxon p = 5.76 × 10⁻⁶), though four genotypes remained resistant to all phages tested, indicating additional determinants of susceptibility. Whole-genome sequencing of 27 phages identified three genera in two families, predominantly Teetrevirus (19/27); TerL phylogeny separated these from classical Vi-dependent phage lineages. Together, these findings reveal a broader-host-range component of Typhi phage ecology and show that Vi dependence is not a universal feature of phages capable of infecting S. Typhi. Importance The Vi capsule is a defining surface antigen of Salmonella Typhi and is required for infection by characterized Typhi phages. Here, we show that this dependence is not universal. In a typhoid-endemic setting, we identified environmental phages capable of infecting S. Typhi in the absence of Vi, revealing a previously underrecognized infection strategy. These Vi-independent phages showed broader host ranges than classical Vi-dependent phages, with susceptibility varying across S. Typhi lineages. Genomic characterization identified that these phages were from lineages distinct from Vi-dependent phages. Together, these findings reveal greater diversity in S. Typhi-phage interactions than previously appreciated and suggest that Vi-dependent specialists represent only one component of a broader Typhi-phage ecological landscape. As these phages were identified before the national introduction of the Vi-typhoid conjugate vaccine, they also provide a baseline for future studies examining whether population-level targeting of the Vi capsule is accompanied by changes in Typhi-phage ecology.
Abstract Background Stillbirths and early neonatal deaths remain common in low- and middle-income countries. Maternal infections are likely contributors, but data are extremely limited. We aimed to describe maternal infections at delivery and their association with perinatal death. Methods We investigated maternal infections at delivery in two hospitals in East Africa: in Kilifi County Hospital (2011–2017), Kenya, and Hiwot Fana Comprehensive Specialised Hospital (2019–2020), Ethiopia. We compared 642 mothers delivering stillbirths/newborns dying in the first 24 h after birth (cases) and 855 mothers with newborns surviving ≥ 24 h (controls) from pregnancy cohorts. We tested maternal blood with molecular diagnostic panels (TaqMan Array Cards). In Ethiopia, vagino-rectal swabs and oropharyngeal swabs were also tested, along with conventional microbiological testing (blood cultures for bacteraemia). We tested associations between maternal infection and perinatal death for each site. We did a sensitivity analysis restricted to controls with good pregnancy outcomes in Kenya. Where appropriate, we calculated the population attributable fraction. Results Maternal bacteraemia was associated with increased odds of perinatal death in Ethiopia (adjusted odds ratio aOR3.7 [1.5–9.2]) in hospital deliveries. Maternal bacterial infection (detected molecularly) was associated with perinatal death in Kenya (aOR2.7 [1.2-6.0]), but only in analyses with controls restricted to those with good pregnancy outcomes. From these analyses, for perinatal deaths among hospital deliveries, the PAF for maternal bacterial infection was 6.1% (4.0%-8.2%) in HFCSH and 4.9% (2.6%-7.2%) in KCH. The study was under-powered to identify specific infections. Conclusions Maternal bacterial infection is associated with perinatal death in high-burden settings, and accounted for around 5% of perinatal deaths in hospital deliveries. Improved prevention, and/or detection and treatment of maternal bacterial infection may contribute to reductions in perinatal mortality in hospital deliveries.
Background:Enteric fever, caused by Salmonella Typhi or Paratyphi, is a major public health issue in low- and middle-income countries. Accurate burden estimation is hampered by limited microbiological facilities and low sensitivity of blood-culture tests. Serosurveillance offers a scalable alternative to address these challenges. This study estimated the seroincidence of enteric fever in Bangladesh using cross-sectional rapid serosurveys. Methods:School-based surveys (January-June 2022) were conducted in Chattogram, Dinajpur, Sylhet, Satkhira, and Faridpur, and community-based surveys (July 2019-November 2021) were conducted in Dhaka and Mirzapur. Blood samples (dried blood spots or venous blood) were collected and tested for anti-hemolysin E IgG responses using a kinetic enzyme-linked immunosorbent assay. Seroincidence was estimated using a maximum likelihood approach based on peak antibody titers and decay rates, modeled from blood-culture confirmed enteric fever cases in Bangladesh. Findings:A total of 2969 participants aged 0-22 years were enrolled, with 75.5% aged 5-15 years. Seroincidence rates (per 100 person-years) were highest in Dhaka (33.1; 95% confidence interval [CI], 29.0-37.9), followed by Mirzapur (19.5; 95% CI, 17.4-21.7) and Chattogram (17.1; 95% CI, 15.0-19.4), and the lowest in Faridpur (11.1; 95% CI, 9.6-12.7). The under 5 age group exhibited higher rates in Dhaka (40.3; 95% CI, 32.1-50.7) and Mirzapur (26.1; 95% CI, 21.0-32.4) compared to older age groups. Seroincidence was higher in areas with higher population density. Conclusions:This study highlights a substantial burden of enteric fever infections across Bangladesh. These provide important evidence to guide post-introduction monitoring and optimization of the typhoid conjugate vaccine program in the national immunization schedule.
