Emerging Microbes & Infections

Nicotinamide riboside (NR), a precursor to the essential coenzyme nicotinamide adenine dinucleotide (NAD+), has been extensively studied following oral administration, while the longer-term safety and physiological effects of injectable NR remain less characterized. Following an initial in-clinic phase evaluating repeat intramuscular (IM) and subcutaneous (SC) administration of pharmaceutical-grade NR, participants transitioned to an at-home phase designed to assess the safety, feasibility, and exploratory physiological effects of repeated self-administered SC administration. Participants continued their assigned 50 or 100 mg dose group and self-administered NR subcutaneously 3 times weekly for approximately 90 days. Safety was assessed through adverse event (AE) monitoring, vital signs, and clinical laboratory health measures. Exploratory assessments included markers of mitochondrial bioenergetics, urinary biomarkers of oxidative stress, and participant-reported outcomes related to fatigue, sleep, pain, and quality of life. At-home administration of NR was generally well-tolerated, with no clear dose-dependent safety concerns identified over the study period. Further, participants were able to successfully self-administer repeated SC injections over the study period, demonstrating positive feasibility. Whole-blood NAD+ concentrations remained largely stable over time in both dose groups. MeScreen analysis demonstrated a reduction in GlycoATP at Day 30 and increases in the MitoATP/GlycoATP ratio at Day 30 and Day 90, signifying a preferential shift toward oxidative metabolism. These findings may be indicative of positive metabolic health shifts. Urinary oxidative stress profiling demonstrated heterogeneous temporal responses. Several lipid oxidation markers significantly declined at Day 30 but returned toward baseline at Day 90. Select markers of nucleic acid, nitrative stress, and advanced glycation end-product oxidation demonstrated more sustained reductions. These results for which the majority of measured oxidative stress markers improved suggest that NR injections may exhibit anti-oxidative characteristics. Validated participant-reported sleep and fatigue measures showed improvements. Self-reported facial skin improvement increased descriptively from 11.4% at baseline to 27.8% at Day 30 and 36.8% at Day 90; improvements noticed by others increased from 9.1% to 23.7%, while reported body-skin improvement increased more modestly, from 8.8% to 16.7%. As these outcomes were not designed or powered to establish efficacy or definitive clinical claims, the findings should be considered hypothesis generating and provide preliminary data to inform the selection of outcomes and design considerations for future randomized, placebo-controlled, adequately powered trials of SC NR administration.

Background: The relationship between recent viral infection and subsequent susceptibility to, or protection against, other viruses remains unclear, particularly across ages and symptom status. Methods: A prospective cohort study enrolled participants aged 6 months to 49 years in Washington and Oregon, USA, 2022-2024. Weekly nasal swabs were tested for SARS-CoV-2, respiratory syncytial virus (RSV), and influenza A/B; additional swabs were collected during symptomatic illness and were also tested for parainfluenza (PIV) 1-4, endemic human coronaviruses (hCOV), adenovirus, human metapneumovirus, human rhinovirus (hRV), and enteroviruses. Proportional hazards regression models were used to characterize associations between incident symptomatic infection (illness) and history of recent illness due to other viruses (within 1-7, 8-14, 15-30, 31-60, 61-90, 91-180 days), adjusted for geographic region, age, sex, daycare/school/work attendance, household size, and number of children in the household. For SARS-CoV-2, influenza, and RSV, these analyses were repeated to study incidence of infection (including asymptomatic cases). Findings: Of 3,560 participants, 2,969 (83%) had [≥]1 illness over 4,299 person-years. Adjusted hazard ratios (aHRs) in the short term ([≤]2 weeks) after an illness were predominantly below 1, indicating that recent viral illness was often associated with lower risk of subsequent illness with other viruses. Across age groups, recent hRV illness was associated with lower risk of hCOV, PIV, and RSV illness (aHRs 0.07-0.27). SARS-CoV-2 illness was associated with a higher short-term risk of adenovirus and PIV illness (aHRs 3.20-3.33). In children aged 6 months-4 years, recent influenza illness was associated with higher short-term risk of SARS-CoV-2 illness. Including asymptomatic infections generally attenuated these associations. Interpretation: Some viral illnesses may alter short-term susceptibility to subsequent viral illnesses. Interactions may differ by age and symptom status. Funding: US Centers for Disease Control and Prevention; Washington State Department of Health.

Background: Filoviruses, specifically Ebola virus (EBOV), Bundibugyo virus (BDBV), and Marburg virus (MARV), have been the etiologic agents of multiple outbreaks of severe disease in the Democratic Republic of the Congo (DRC). Two EBOV-specific vaccine regimens have been approved for use in outbreak scenarios, including the Ad26.ZEBOV/MVA-BN-Filo (Zabdeno/Mvabea) two-dose vaccine, where the MVA-BN-Filo booster dose contains EBOV, MARV, and Sudan (SUDV) virus glycoproteins (GPs) and the nucleoprotein from Tai Forest virus. While long-term immunogenicity of up to two years has been found in clinical trial settings, limited real-world data exists. Methods: Using a multiplexed immunoassay, samples (n=698 at baseline) collected in Mbandaka, Equateur province, DRC, between September 2023 and October 2024 were assessed for seroreactivity to six filovirus antigens (1 BDBV, 2 EBOV, 2 MARV, and 1 SUDV) at three distinct periods: baseline/pre-vaccination, 6-8 weeks post-first dose (Zabdeno), at booster administration (Mvabea), and one-year post-boost dose. Results: Substantial filovirus seroreactivity was found at baseline, with 48.7% (n=340/698) of individuals being seroreactive to at least one virus antigen. High baseline seroreactivity was found against BDBV GP (31.1%, n=217/698), with lower baseline seroreactivity to EBOV GP (15.5%, n=106/698), comparatively. Overall EBOV GP seroreactivity increased to 66.8% (n=376/563) at one year-post vaccine boost and 57.6% (n=250/434) of participants were seroreactive. Despite the booster dose inclusion of SUDV GP and MARV GP, there were no substantial increases in reactivity against either antigen at subsequent timepoints. Overall filovirus seroreactivity increased at all timepoints for the entire cohort, although filovirus reactivity decreased over the study period for those who were seroreactive at baseline. Findings: These data highlight detection of significantly elevated seoreactivity to EBOV GP following first-dose administration of Ad26.ZEBOV, which remained relatively stable one-year post-booster dose administration. Additionally, this study identifies high levels of baseline seroreactivity to BDBV GP despite no previous documented outbreaks in this region of DRC. These data suggest that vaccination with the Ad26.ZEBOV-MVA-BN-Filo vaccine induces stable seroreactivity against EBOV GP, but not to other filovirus antigens.

Tick-borne disease risk reflects the combined influence of vector abundance, pathogen prevalence, human exposure, and seasonal activity, yet these components are rarely integrated at the county level. We developed species-specific ecological risk scores for three medically important tick species (Acari: Ixodidae): Amblyomma americanum (L.), Dermacentor variabilis (Say), and Ixodes scapularis Say, across all 102 Illinois counties using data from 2019 to 2022. County-level predicted tick abundance and pathogen prevalence were scaled and combined using equal weights to generate primary vector-level risk scores. Robustness to the equal-weight assumption was evaluated by systematically varying the relative weights assigned to abundance and pathogen prevalence, while a separate sensitivity analysis incorporated reported tick-bite incidence where available. Associations with human disease were evaluated using negative binomial regression of tick-borne disease case counts on the corresponding risk scores, with county population included as an offset. Monthly phenology indicators were constructed by integrating human disease cases, reported tick bites, and sampled tick abundance and were evaluated in relation to temperature and precipitation. Seasonal risk was estimated by combining county-level vector risk with species-specific monthly phenology, generating monthly risk surfaces that were deployed through an interactive R Shiny application. Higher risk scores were significantly associated with greater disease case rates for each tick species. County rankings were highly stable under moderate changes in abundance and prevalence weighting. Seasonal activity differed among species, with A. americanum and D. variabilis showing concentrated warm-season risk and I. scapularis exhibiting a broader seasonal profile. These county-level seasonal risk maps identify where and when relative tick-borne disease risk is elevated in Illinois, supporting targeted prevention, surveillance, and clinical awareness.

Introduction: Acute gastroenteritis (AGE) is a cause of childhood morbidity and may be associated with human adenovirus (HAdV) infection. This study aimed to investigate the occurrence of HAdV in fecal samples from children with AGE in Salvador, Bahia, Brazil, as well as to molecularly characterize the identified strains and evaluate their cytopathic effects in cell culture. Methods: A total of 131 samples were analyzed using the nested polymerase chain reaction (Nested-PCR) technique. Molecular characterization was performed through Sanger sequencing and phylogenetic analysis, while Vero cell cultures were used to investigate the occurrence of cytopathic effects. Results: Of the samples analyzed, 13 (9.9%) tested positive for HAdV, while 118 (90.1%) were negative. The highest detection frequency was observed in children aged three years or younger, particularly those under one year of age. Phylogenetic analysis identified variants related to HAdV-F41 and HAdV-B3, revealing genetic differences and distinct clustering patterns compared with reference sequences. In cell culture, cytopathic effects were observed four days after inoculation, although further analyses are required to confirm productive viral replication. Conclusion: These findings demonstrate the presence of HAdV in the samples studied and contribute to understanding its genetic diversity and circulation in Salvador, highlighting the importance of epidemiological surveillance and further studies on its role in the etiology of childhood AGE.

Importance: Coccidioidomycosis, also known as Valley fever, is a serious fungal disease caused by inhaling Coccidioides spores aerosolized from the soil. Despite rising public health concern, the distribution and incidence of coccidioidomycosis in the US remain poorly characterized as not all states are required to report cases, and case under-ascertainment is presumed to be high, particularly outside of the endemic region. Objective: To estimate monthly, county-level coccidioidomycosis incidence across the US while accounting for widespread under-ascertainment. Design, Setting, and Participants: We integrated multisource data, including human cases diagnosed in electronic health records, serological testing of dogs, and ecological and sociodemographic predictors, in a machine learning model estimating monthly, county-level coccidioidomycosis incidence. The model was trained on surveillance data from Arizona and California from 2013 to 2023, then applied to predict incidence in states across the contiguous US over the same time period. Main Outcomes and Measures: Incidence of coccidioidomycosis at the monthly county level. Results: The model predicted coccidioidomycosis incidence from 2013 to 2023 for 3,108 counties from all states in the contiguous US. The model identified 60 counties in non-reporting states where predicted incidence was [≥]2 cases per 100,000 population (considered moderate to high incidence). In states with mandatory reporting outside of Arizona and California, the model predicted county-level incidence rates that were 28% higher (95% bootstrap interval, 0.1%-69.8%) than those captured in national surveillance, equating to a total of 608 potentially missed cases per year (95% bootstrap interval, 340-964). Conclusions and Relevance: In this cross-sectional study, the model quantified case under-ascertainment for coccidioidomycosis relative to Arizona and California, and highlighted the potential for alternative data sources to fill in gaps in mandatory reporting. Estimating incidence while accounting for under-ascertainment and non-reporting may help efforts to improve public and physician awareness and to detect emergence in new regions.

Introduction: Acute gastroenteritis (AGE) is a global public health problem and a major cause of mortality in low- and lower-middle-income countries. Human bocavirus (HBoV) is among the viral agents associated with this condition. Therefore, investigating the presence of HBoV in cases of AGE in Salvador, Bahia, as well as its prevalence and circulating strains, is important. Objective: To investigate the occurrence of HBoV infection during an AGE outbreak in Salvador. Methods: A total of 178 samples were analyzed for HBoV using nested polymerase chain reaction (nested PCR), and the amplification products were visualized by agarose gel electrophoresis. HBoV was detected in 5.7% of the samples analyzed. Conclusion: This study contributes to the understanding of HBoV epidemiology as a secondary agent associated with acute gastroenteritis during a norovirus outbreak in Salvador. Continued investigation and identification of the etiological agents involved in outbreaks are essential for evaluating the causes of AGE. These findings also highlight the need for broader diagnostic approaches and the importance of phylogenetic analysis for monitoring and controlling viral infections.

Wolbachia-based interventions were less effective in achieving introgression in Rio de Janeiro than other settings. Reduced introgression occurred in locations where dengue was historically high, raising concerns of inequity. We examined factors affecting Wolbachia introgression in Rio through trajectory modeling, spatiotemporal Bayesian models, and Ae. aegypti abundance estimation. During the intervention (2017-2020), Wolbachia introgression was 26% (median; IQR,14-44%), with four distinct trajectories. Despite receiving more releases, densely populated areas with low socioeconomic status had lower introgression. In spatiotemporally explicit multivariable regressions, higher Ae. aegypti abundance, temperature, population density and lower socioeconomic status were associated with reduced introgression. Improved characterization of Ae. aegypti abundance and other structural/environmental predictors of introgression could be used to calibrate release doses to ensure equitable benefits from Wolbachia interventions.

Population genomic studies have revealed strong regional structure in Plasmodium knowlesi across Southeast Asia. To facilitate routine genomic surveillance, we developed a targeted amplicon sequencing panel that preserves the large- and small-scale population genetic structure. We screened published genomes for short, highly polymorphic targets and a 30-SNP barcode. We validated multiplexed amplification and sequencing using a portable Oxford Nanopore Technologies MinION sequencer on 28 clinical infections from four southern Thai provinces collected between 2018-2023. Twenty-seven loci yielded sequence data and 23 infections with data from at least eight loci were retained for analysis. Across the 23 Thai infections and 104 published Malaysian genomes, 586 diverse SNPs were observed. The amplicon panel and 30-SNP barcode retained the major population structure observed in genome-wide data, including a clear distinction between Bornean and Peninsular Malaysian infections and two clusters in Borneo. Across newly sequenced Thai infections, 25 loci were diverse and showed substantial diversity (mean expected heterozygosity = 0.69). All infections were effectively monoclonal. Pairwise identity-by-descent revealed substantial recent relatedness, with 46 of 253 pairs at or above 0.5. Two Thai genetic groups (n = 12 and n = 11) were observed, mirroring previously observed structure in peninsular Malaysia. Groups were not significantly associated with province or collection year. In conclusion, targeted sequencing can reveal geographically informative population structure across scales and thus support surveillance.

Vegetation plays a critical role in shaping fine-scale tick density by structuring local microclimates, habitat resources, and host interactions that largely determine tick survival and activity, with implications for tick-borne disease transmission. Tick burden in the United States continues to increase, with annual reported tick-borne disease cases more than doubling from 2004 through 2019. These trends call for a broader scope of tick-mitigation strategies that go beyond traditional prevention measures that focus on personal protection; and there is an opportunity to inform habitat-level interventions. Here, we quantify fine-scale vegetation structure across 48 subplots at tick surveillance sites in Western Massachusetts to assess local habitat features associated with Ixodes scapularis density and potential for human-tick contact risk. In assessing understory and overstory vegetation attributes, this study identified life stage-specific differences in predicted tick density, with higher adult densities in areas with deeper leaf litter and presence of invasive plant species and nymphs associated with high presence of ferns. Both adult and nymphal Ix. scapularis were predicted at higher densities in relatively low basal area forests (18.9 to 26.9 m2/hectare). This study design provides a simple, low-cost framework for organizations looking to incorporate tick-informed forest measurement ecology into their public health tick surveillance protocols with minimal training.

Brazil experienced its worst dengue epidemic in 2024, with an increase in severe outcomes among elderly individuals, highlighting the need for vaccination strategies informed by population immunity. We reconstructed state- and age-specific immune profiles by fitting an age-structured catalytic model to dengue surveillance data from 2000-2025. This inferred immune profile was incorporated into an SIR-type transmission model to project disease burden and to evaluate the public health impact of vaccine allocation strategies. We observed substantial spatial heterogeneity in accumulated immunity, which was closely associated with projected burden and optimal allocation. Strategies prioritizing states with lower historical incidence and larger susceptible populations yielded greater benefits. Under limited vaccine supply, targeting children resulted in the greatest reductions in DALYs, whereas targeting elderly populations achieved smaller DALY reductions but larger reductions in mortality. We further showed that accelerated vaccine supply markedly increased impact, while allocation choices remained critical when availability was constrained.

Study Objectives: Glucagon-like peptide-1 (GLP-1) receptor agonists raise resting heart rate. We asked whether, after semaglutide initiation, the increase is larger during rapid eye movement (REM) sleep than during non-rapid eye movement (NREM) sleep. Methods: In the Human Phenotype Project, an Israeli cohort of generally healthy adults aged 40 to 70 years, 96 of 494 self-reported semaglutide initiators had a home sleep study (WatchPAT; sleep stages estimated from peripheral arterial tone and actigraphy) before and at least three months after starting. Each was propensity-matched 1:1 to a never-user of GLP-1 drugs measured at the same visits. We estimated the initiators' change minus their controls' change (difference-in-differences). The REM minus NREM contrast was designated primary after an exploratory analysis. Results: Relative to controls (90 to 94 pairs), heart rate rose during nocturnal wake (+3.89 beats per minute [bpm], 95% confidence interval 2.35 to 5.44), NREM sleep (+4.82 bpm, 3.12 to 6.52) and REM sleep (+6.25 bpm, 4.42 to 7.91); the REM increase exceeded the NREM increase by 1.42 bpm (0.98 to 1.89). The excess persisted across matching designs and on a relative scale; the proportion of REM sleep did not change. Never-users with similar weight loss showed no REM sleep heart-rate rise (+0.40 bpm, -0.63 to 1.50). Heart-rate variability decreases disappeared after adjustment for heart rate. Conclusions: Semaglutide initiation was associated with higher heart rate throughout sleep, most during REM sleep, unexplained by weight loss. Clinic measurements may understate this effect. Confirmation with polysomnographic staging is needed.

Japanese encephalitis virus (JEV) is a leading cause of viral encephalitis in humans in Asia. Prior to 2021, only sporadic outbreaks had been detected in Australia's tropical northern extremes. However, during 2021-23, JEV infection was identified in 45 people and in more than 85 piggeries, together with many detections in feral pigs, mosquitoes, and other livestock across Australia, including in the temperate far south. Here we estimated the spatial extent of virus transmission during the outbreak (the realised niche) and the area environmentally suitable for transmission (the potential niche). We collated a national dataset of JEV surveillance and detection in humans, mosquitoes, domestic pigs, feral pigs, and sentinel chickens from 2021-23. We combined these data with (1) previously published predictions of habitat suitability for vertebrate host and vector species, and (2) estimated densities of humans, domestic pigs, and feral pigs, in a multipart assessment of spatial risk. Our model projected broad potential environmental suitability over much of northern and eastern Australia during the outbreak period, but floodplain wetland areas in the north and the inland east of Australia had both the highest estimated environmental suitability for transmission, and the strongest evidence for virus circulation.

Background Influenza vaccines have seen many changes over recent years in terms of both policy recommendations and product types. Immune responses and vaccine effectiveness vary by vaccine strain composition and product type. This study aimed to explore this variation on a regional level through examining spatial and temporal autocorrelations of vaccine uptake of different product types within Michigan from 2017 to 2021. Methods Influenza vaccine administration data from the 2017/18 to 2021/22 seasons were obtained from the Michigan Care Improvement Registry. Population size estimates for 2017 and 2019 were obtained from the Michigan Department of Health and Human Services. Age-standardized and age-stratified vaccination rates were computed. Disparate county-level vaccine uptake clusters were constructed using spatial autocorrelation indicators and spatiotemporal clusters were identified using scan statistics. Linear mixed effect models were used to study the impact of social vulnerability and urbanicity level on seasonal influenza vaccination rate. Results Vaccination incidence rates for adjuvanted, recombinant, and nasal sprays vaccines and for any vaccines increased significantly through the study period. County-level spatiotemporal clusters of type-specific uptake rates were identified. Most notably, we identified an emerging cluster with high uptake of adjuvanted vaccine radiating from Ottawa County, located in suburban Grand Rapids, and the disappearance of high uptake cluster for high-dose vaccine uptake in the area. Vaccination rates by any product type were found to vary seasonally and showed weak negative association with more rural regions. The overall vaccination rates appear to be lower among counties with higher social vulnerability in certain urbanicity levels, but social vulnerability and urbanicity were not significantly associated with overall vaccination rate during the study period. Conclusions Vaccine type-specific uptake was spatially and temporally diverse in Michigan between 2017 and 2022. Mid and Northern Michigan had consistently relatively lower vaccination rate compared to other regions in Michigan.

Aims Rosuvastatin is commonly co-administered with ticagrelor in patients with acute coronary syndrome. Ticagrelor inhibits breast cancer resistance protein (BCRP/ABCG2), increasing rosuvastatin exposure and potentially the risk of rhabdomyolysis. This risk may be further influenced by age and the ABCG2 c.421C>A variant. We aimed to predict optimal rosuvastatin dosing with ticagrelor in elderly patients stratified by ABCG2 genotype using physiologically based pharmacokinetic (PBPK) modelling Methods PBPK models for rosuvastatin and ticagrelor were developed and validated in PK-Sim using clinical data from healthy adults, elderly patients, and individuals with wild-type or homozygous ABCG2 c.421C>A genotypes. Key parameters, including BCRP catalytic activity and age-dependent declines in CYP2C9 and CYP3A4 activity, were optimized. The drug-drug interaction model incorporated competitive BCRP inhibition by ticagrelor. Rosuvastatin steady-state exposure was simulated with half or quarter standard doses during ticagrelor co-administration, and exposure matching approach was used to identify optimal dosing. Results The PBPK models demonstrated good predictive performance across populations and genotypes. In young adults with the wild-type genotype, halving the rosuvastatin dose resulted in an AUC fold change of 1.44, supporting a half-dose strategy. In young homozygous variant carriers, half-dose co-administration produced comparable exposure (AUC fold change 0.78). In elderly wild-type individuals, a four-fold dose reduction achieved comparable exposure (AUC fold change 1.06), whereas elderly variant carriers required only a half-dose reduction (1.12). Conclusions PBPK modelling supported age- and ABCG2 genotype-specific rosuvastatin dosing with ticagrelor. Elderly wild-type patients may require a further dose reduction to minimise toxicity while maintaining therapeutic exposure.

Incidence of ventilator-associated pneumonia (VAP) is increased in patients admitted for brain injury. Staphylococcus aureus appears to be a particularly common pathogen in these respiratory infections. Our aim was to confirm the extent of S. aureus involvement in VAP among patients with neurological injuries. We conducted a retrospective, multicenter study including patients with and without neurological injuries who developed VAP during their ICU stay. Among 15 702 patients admitted in the participant centers during the study period. 407 were finally included in the study. S. aureus was involved in 122 (61.6%) VAP in brain-injured patients and 63 (30.1%) of non-brain-injured patients. In brain-injured patients, multivariate analysis identified age (0.97 [0.95; 0.98]), antibioprophylaxis (0.31 [0.18; 0.53]; p < 0.0001), subarachnoid hemorrhage (2.18 [1.01; 4.68]; p=0.0461), lower Glasgow coma score (0.92 [0.87; 0.97]; p= 0.004) and SAPS II (0.98 [0.97; 1]; p=0.0174) as critical factors associated with the risk of S. aureus in VAP. In the non-brain-injured population, multivariate analysis identified antibioprophylaxis (0.38 [0.22; 0.65]; p=0.0006), age (0.96 [0.95; 0.98]; p<0.0001), SAPS II (0.98 [0.97; 1]; p=0.0265), thoracic surgery (0.21 [0.09; 0.48]; p=0.0002) and peripheral neurosurgery (1.95 [1.2; 3.19]; p=0.0076) as critical factors. A total of 172 patients (42.3%) died during their ICU stay and 90-days mortality was 194 (47.7%). No difference of mortality was noticed function of VAP-associated pathogen.

Brazil has one of the highest dengue burdens globally, with transmission influenced by climate events. Yet, the effects of compound climate extremes on dengue risk and prediction have not been quantified to date. Using a Bayesian spatiotemporal model of monthly dengue cases across 435 health regions from 2010 to 2025, we estimated relative risk associated with interacting long-lag and short-lag drought indicators and temperature anomalies across nine Koppen-Geiger climatic zones, adjusting for absolute temperature and El Nino-Southern Oscillation. Long-lag dry, mid-lag warm and short-lag wet conditions were associated with the highest relative risk in five climatic zones, with temperature anomalies modifying hydrometeorological dynamics more strongly in temperate than tropical areas. Climate covariates improved the prediction of case counts and outbreaks compared to baseline models at lead times of 1, 3, 6 and 12 months, and for the upcoming season 5 months ahead. Improvements were greatest in the Northeast, Southeast, and Midwest. Recent dengue incidence provided the greatest improvement at the 1-month lead, whereas combining incidence with climate information performed best at 3- and 6-month leads. We extended our framework to weekly state-level predictions of the season ahead to align with national public health planning. We proposed a multi-staged dengue forecasting approach to enhance early warning and response across Brazil.

Background: Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and is caused by parasites from the Leishmania donovani complex. VL is endemic in 54 countries, with East Africa (EA) accounting for [~]70% of the global burden. Therefore, there is a pressing need to prioritize VL research in EA. Transcriptomics analysis in rodent models and patients following treatment have shown that immune homeostasis is not restored by the end of treatment. However, comprehensive proteomic studies in VL remain scarce, and the few available studies were conducted outside EA. Methodology/Principal Findings: As a part of ImmStat@cure consortium, we used the Olink Reveal proximity extension assay to profile circulating proteins in VL patients from Ethiopia, Kenya and Sudan. By comparing patients at admission and 17 days after treatment with SSG-PM, we have identified a systemic Th1-cytotoxic inflammatory profile at admission, characterized by high abundance of IFN{gamma}, IL-1B, IL-6, and the granzymes A and B. Chemokines with high abundance included CXCL8/10/11, CCL3, CCL4, CCL8, CXCL8 and CCL20, consistent with the recruitment of monocytes, macrophages, T cells, and NK cells. There were also evidence of immune regulation/exhaustion, with high levels of PD1, PD-L2, IDO1 and KYNU. Although the immune profiles were similar at admission, country specific differences were observed after treatment. Kenyan patients exhibited a sustained inflammatory profile and signatures of myeloid recruitment, characterized by high levels of IL-1B, IL-6 , IL-12A, CXCL8, CCL2, CCL3, CCL4, CCL7 and CEBPB. Sudanese patients showed signatures associated with lymphocyte activation and immune regulation. Conclusions/Significance: These results highlight the complexity of the immune changes associated with VL, identifying both core conserved profiles at admission and country-specific profiles after treatment. The data provided here will provide a valuable resource for future comparative studies across more diverse different geographic regions, for linkage studies that assess the impact of parasite genotype on immune / metabolic response and for use during the evaluation of new therapies against VL.

The World Health Organization has called for malaria vaccines with > 90% efficacy against Plasmodium falciparum (Pf) infection. The live, non-attenuated PfSPZ-CVac (chloroquine) vaccine provides the strongest protection against controlled human malaria infection (CHMI). Its 100% protective efficacy at 12 weeks against genetically distant Pf stems from a highly amplified immune stimulus. After inoculation, each invading sporozoite (SPZ) replicates up to 50,000 times within a hepatocyte. Over six days of development, these parasites express thousands of distinct proteins, presenting a vast and diverse array of antigens to the host immune system. The late liver stage parasites then rupture into the bloodstream, where they are killed by the co-administered drug, chloroquine. To engineer a Pf parasite that develops to the late liver stage like PfSPZ-CVac (chloroquine), but then arrests before transitioning to the blood stage, two genes required for transition from non-pathogenic liver to pathogenic blood stages were identified and deleted, creating late-liver stage arresting, replication-competent (LARC) PfSPZ. In a first-in-human, randomized, double-blind, placebo-controlled clinical trial, we assessed PfSPZ-LARC2 Vaccine in 75 malaria-exposed Burkinabe 1- to 48-year-olds. No vaccine-strain breakthrough blood-stage infections were detected; safety and tolerability profiles were similar in vaccinees and placebo recipients; and the highest immunogenicity was observed in the youngest recipients. Based on these findings, PfSPZ-LARC2 Vaccine has progressed to Phase 2 testing with the goal of rapidly advancing this genetically attenuated whole parasite vaccine to licensure and deployment.

Background. Nigeria's reported Lassa fever case fatality ratio (CFR) rose from 18.9% at week 23 of 2025 to 25.0% in 2026, prompting concerns over failing clinical care. Because surveillance artefacts can also alter CFRs, candidate mechanisms that published data can resolve were identified and evaluated. Methods. This ecological study extracted weekly state-level counts from 474 Nigeria Centre for Disease Control and Prevention situation reports (2017-2026). Per a pre-specified plan, years were compared at phase-matched points, year-on-year CFR changes were decomposed into within-state and between-state components, and tipping-point ascertainment shifts calculated. Weekly incident and cumulative published totals were compared post hoc. Findings. Of 11 candidate mechanisms, 2 could be evaluated fully and 5 in part. On weekly incident counts, 2026 did not differ from 2025 at the phase-matched midpoint (+0.3 percentage points, 95% CI -5.0 to 7.6); within-state (-1.1, 95% CI -4.7 to 3.0) and between-state (+0.5, -2.0 to 2.9) components spanned zero. Conversely, the published cumulative CFR was 5.4 to 6.2 percentage points higher because 70 deaths were added retrospectively by week 36 outside weekly reports. Reconciling cumulative figures would require 279 missed survivors (6% of suspected cases not confirmed). Interpretation. The 2026 CFR rise came from deaths added to cumulative totals outside the weekly counts, and published data cannot attribute it to care. Endemic zoonotic CFRs cannot serve as clinical outcome measures unless testing volumes, deaths added late, and post-mortem sampling are published alongside case counts. Funding. US NSF-NIH-NIFA EEID; UK BBSRC; Birgitta Sintring Fellowship (Uppsala University).