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Neonatal mortality remains high in many low- and middle-income countries (LMICs), with neonatal sepsis and antimicrobial resistance (AMR) posing significant threats to newborns, particularly in sub-Saharan Africa (SSA). Tanzania is among the countries with the highest neonatal mortality rates, with sepsis being a major contributor. Gut dysbiosis has been identified as a risk factor for neonatal sepsis in high-income countries, due to factors like abundance of pathogenic bacteria, decrease in microbiome diversity, intestinal barrier defects and bacterial translocation. Understanding gut dysbiosis in the local setting and its role in sepsis development may offer new prevention strategies, such as probiotics for high-risk preterm infants. This prospective neonatal cohort, established at Muhimbili National Hospital (MNH) in Dar es Salaam, Tanzania, aims to analyze the gut microbiome of preterm infants and explore associations with neonatal late-onset sepsis (LOS). Additionally, data on bacterial pathogens of bloodstream infections and AMR prevalence will be identified. Secondary endpoints include clinical LOS, sepsis-related death, death from any cause, and hospital discharge outcomes. Eligible preterm neonates (28 + 0 to <34 weeks of gestational age, birth weight ≥ 1000g) will be recruited with maternal consent. Socio-demographic and clinical data, microbiological details of blood pathogens, and a set of fresh frozen fecal samples during the 28 days observation period will be collected. The study targets a sample size of 1350 participants and we expect 72-135 culture-proven LOS during a study period of 18 months. Fecal samples will undergo next-generation sequencing (NGS) to analyze microbial community functions in comparison to matched controls. This collaborative study between universities in Tanzania and Germany, aims to analyze the neonatal microbiome in relation to sepsis development and AMR of blood culture isolates to enhance neonatal sepsis care, improve diagnostics and treatment. The project will offer insights into potential therapeutic strategies for the future, promote academic exchange, capacity building and research on African microbiomes.

Predominantly antibody deficiencies (PAD) are a heterogeneous group of disorders characterized by dysfunctional antibody production, low immunoglobulin levels in serum and impaired vaccine responses. The clinical picture is variable, ranging from mild symptoms to severe complications, which may include autoimmunity, gastrointestinal disease, allergy, and malignancies. If left untreated, PAD patients are at risk of enduring disease progression, irreversible organ damage, and reduced life expectancy. A timely diagnosis has been shown to significantly improve disease prognosis. Here, we report on our experience using targeted gene panel sequencing by employing Agilent’s HaloPlex or SureSelect and Illumina’s MiSeq technologies in a cohort of 291 individuals who presented with low or absent immunoglobulin levels in combination with or without other clinical features. In total, we have detected over 57 novel or previously reported relevant mutations in ADA, ADA2, BTK, CTLA4, LRBA, NFKB1, NFKB2, PIK3CD, STAT3 , and TNFRSF13B . Overall, a genetic diagnosis could be made in 24.7% of the investigated patients. The percentage of coverage for the targeted regions ranged from 90% to 98% in this study. Moreover, functional assays were performed on a defined group of the patients carrying candidate variants in CTLA4 , LRBA , NFKB1 and BTK , which confirmed their deleterious effect on protein expression and/or function. This study reiterates that the immunological heterogeneity of predominantly antibody deficiencies may have a diverse genetic origin, although certain clinical features may hint towards a specific group of defects. Employing targeted sequencing panels proves to be a very time- and cost-efficient, yet reliable, method for the establishment of a genetic diagnosis in individuals with PAD. However, in case of negative panel results, or if functional testing reveals inconspicuous observations in patients with a clear indication for genetic testing, further work-up including whole exome or whole genome sequencing should be considered.

Non-canonical NF-κB-pathway signaling is integral in immunoregulation. Heterozygous mutations in have recently been established as a molecular cause of common variable immunodeficiency (CVID) and DAVID-syndrome, a rare condition combining deficiency of anterior pituitary hormone with CVID. Here, we investigate 15 previously unreported patients with primary immunodeficiency (PID) from eleven unrelated families with heterozygous -mutations including eight patients with the common p.Arg853 nonsense mutation and five patients harboring unique novel C-terminal truncating mutations. In addition, we describe the clinical phenotype of two patients with proximal truncating mutations. Cohort analysis extended to all 35 previously published -cases revealed occurrence of early-onset PID in 46/50 patients (mean age of onset 5.9 years, median 4.0 years). ACTH-deficiency occurred in 44%. Three mutation carriers have deceased, four developed malignancies. Only two mutation carriers were clinically asymptomatic. In contrast to typical CVID, most patients suffered from early-onset and severe disease manifestations, including clinical signs of T cell dysfunction e.g., chronic-viral or opportunistic infections. In addition, 80% of patients suffered from (predominately T cell mediated) autoimmune (AI) phenomena (alopecia > various lymphocytic organ-infiltration > diarrhea > arthritis > AI-cytopenia). Unlike in other forms of CVID, auto-antibodies or lymphoproliferation were not common hallmarks of disease. Immunophenotyping showed largely normal or even increased quantities of naïve and memory CD4 or CD8 T-cells and normal T-cell proliferation. NK-cell number and function were also normal. In contrast, impaired B-cell differentiation and hypogammaglobinemia were consistent features of -associated disease. In addition, an array of lymphocyte subpopulations, such as regulatory T cell, Th17-, cTFH-, NKT-, and MAIT-cell numbers were decreased. We conclude that heterozygous damaging mutations in represent a distinct PID entity exceeding the usual clinical spectrum of CVID. Impairment of the non-canonical NF-κB pathways affects function and differentiation of numerous lymphocyte-subpopulations and thus causes a heterogeneous, more severe form of PID phenotype with early-onset. Further characteristic features are multifaceted, primarily T cell-mediated autoimmunity, such as alopecia, lymphocytic organ infiltration, and in addition frequently ACTH-deficiency.

While genome-wide association studies (GWAS) have linked common genetic variants to COVID-19 susceptibility and severity, rare high-impact variants may also contribute to phenotypic heterogeneity. Inborn errors of type I interferon immunity (IFN-I-IEIs), including X-linked TLR7 deficiency, account for ~ 2% of critical COVID-19 cases. In this study, we investigated rare potentially deleterious variants in IFN-I-IEI and GWAS-prioritized genes in young, severely affected COVID-19 patients from the German National Pandemic Cohort Network (NAPKON). Genome sequencing was performed on 110 hospitalized COVID-19 patients, including 82 males and 28 females, all under 60 years of age and without relevant pre-existing medical conditions. Rare potentially deleterious variants in TLR7 and 25 additional IFN-I-IEI genes, as well as 23 GWAS risk genes for COVID-19 severity, were analyzed based on allele frequency, predicted functional impact, and inheritance pattern models and subsequently classified based on the American College of Medical Genetics and Genomics (ACMG) criteria. Polygenic Risk Scores (PRS) were additionally calculated as an exploratory and case-only analysis to assess the contribution of common variant-derived genetic predisposition for severe COVID-19. Consistent with prior findings from other studies in German cohorts, no candidate variants or large deletions were identified in TLR7 . However, 7 variants of uncertain significance in IFN-I-IEI genes as well as 13 candidate variants of potential deleterious effect in GWAS risk genes were present in 19 individuals (17.3%). We observed nominally significant differences in PRS distributions, with younger individuals (< 40 years) having higher PRS (p = 0.045) compared to older individuals, and carriers of rare variants having lower PRS compared to non-carriers (p = 0.037). These patterns are consistent with an age-dependent contribution of polygenic risk to severe COVID-19 and a potentially lower polygenic burden among rare-variant carriers, although confirmation in larger well-controlled cohorts will be required. The candidate variants identified in IFN-I-IEI and GWAS risk genes represent targets for further functional studies to clarify their potential contribution to disease risk. These findings highlight the need for future integrative genomic approaches to better understand the joint contribution of common and rare variants to COVID-19 severity.

Intermittent preventive treatment (IPT) is a promising strategy for malaria control in infants. We undertook a pooled analysis of the safety and efficacy of IPT in infants (IPTi) with sulfadoxine-pyrimethamine in Africa. We pooled data from six double-blind, randomised, placebo-controlled trials (undertaken one each in Tanzania, Mozambique, and Gabon, and three in Ghana) that assessed the efficacy of IPTi with sulfadoxine-pyrimethamine. In all trials, IPTi or placebo was given to infants at the time of routine vaccinations delivered by WHO's Expanded Program on Immunization. Data from the trials for incidence of clinical malaria, risk of anaemia (packed-cell volume <25% or haemoglobin <80 g/L), and incidence of hospital admissions and adverse events in infants up to 12 months of age were reanalysed by use of standard outcome definitions and time periods. Analysis was by modified intention to treat, including all infants who received at least one dose of IPTi or placebo. The six trials provided data for 7930 infants (IPTi, n=3958; placebo, n=3972). IPTi had a protective efficacy of 30·3% (95% CI 19·8–39·4, p<0·0001) against clinical malaria, 21·3% (8·2–32·5, p=0·002) against the risk of anaemia, 38·1% (12·5–56·2, p=0·007) against hospital admissions associated with malaria parasitaemia, and 22·9% (10·0–34·0, p=0·001) against all-cause hospital admissions. There were 56 deaths in the IPTi group compared with 53 in the placebo group (rate ratio 1·05, 95% CI 0·72–1·54, p=0·79). One death, judged as possibly related to IPTi because it occurred 19 days after a treatment dose, was subsequently attributed to probable sepsis. Four of 676 non-fatal hospital admissions in the IPTi group were deemed related to study treatment compared with five of 860 in the placebo group. None of three serious dermatological adverse events in the IPTi group were judged related to study treatment compared with one of 13 in the placebo group. IPTi with sulfadoxine-pyrimethamine was safe and efficacious across a range of malaria transmission settings, suggesting that this intervention is a useful contribution to malaria control. Bill & Melinda Gates Foundation.

So far, only a few reports about reinfections with SARS-CoV-2 have been published, and they often lack detailed immunological and virological data. We report about a SARS-CoV-2 reinfection with a genetically distinct SARS-CoV-2 variant in an immunocompetent female healthcare worker that has led to a mild disease course. No obvious viral escape mutations were observed in the second virus variant. The infectious virus was shed from the patient during the second infection episode despite the presence of neutralizing antibodies in her blood. Our data indicate that a moderate immune response after the first infection, but not a viral escape, did allow for reinfection and live virus shedding.

The situation of limited data concerning the response to COVID-19 mRNA vaccinations in immunocom-promised children hinders evidence-based recommendations. This prospective observational study investigated humoral and T cell responses after primary BNT162b2 vaccination in secondary immunocompromised and healthy children aged 5–11 years. Participants were categorized as: children after kidney transplantation (KTx, n = 9), proteinuric glomerulonephritis (GN, n = 4) and healthy children (controls, n = 8). Expression of activation-induced markers and cytokine secretion were determined to quantify the T cell response from PBMCs stimulated with peptide pools covering the spike glycoprotein of SARS-CoV-2 Wuhan Hu-1 and Omicron BA.5. Antibodies against SARS-CoV-2 spike receptor-binding domain were quantified in serum. Seroconversion was detected in 56% of KTx patients and in 100% of the GN patients and controls. Titer levels were significantly higher in GN patients and controls than in KTx patients. In Ktx patients, the humoral response increased after a third immunization. No differences in the frequency of antigen-specific CD4+ and CD8+ T cells between all groups were observed. T cells showed a predominant anti-viral capacity in their secreted cytokines; however, this capacity was reduced in KTx patients. This study provides missing evidence concerning the humoral and T cell response in immunocompromised children after COVID-19 vaccination.

Most of the currently known heterozygous pathogenic NFKB1 (Nuclear factor kappa B subunit 1) variants comprise deleterious defects such as severe truncations, internal deletions, and frameshift variants. Collectively, these represent the most frequent monogenic cause of common variable immunodeficiency (CVID) identified so far. NFKB1 encodes the transcription factor precursor p105 which undergoes limited proteasomal processing of its C-terminal half to generate the mature NF-κB subunit p50. Whereas p105/p50 haploinsufficiency due to devastating genetic damages and protein loss is a well-known disease mechanism, the pathogenic significance of numerous NFKB1 missense variants still remains uncertain and/or unexplored, due to the unavailability of accurate test procedures to confirm causality. In this study we functionally characterized 47 distinct missense variants residing within the N-terminal domains, thus affecting both proteins, the p105 precursor and the processed p50. Following transient overexpression of EGFP-fused mutant p105 and p50 in HEK293T cells, we used fluorescence microscopy, Western blotting, electrophoretic mobility shift assays (EMSA), and reporter assays to analyze their effects on subcellular localization, protein stability and precursor processing, DNA binding, and on the RelA-dependent target promoter activation, respectively. We found nine missense variants to cause harmful damage with intensified protein decay, while two variants left protein stability unaffected but caused a loss of the DNA-binding activity. Seven of the analyzed single amino acid changes caused ambiguous protein defects and four variants were associated with only minor adverse effects. For 25 variants, test results were indistinguishable from those of the wildtype controls, hence, their pathogenic impact remained elusive. In summary, we show that pathogenic missense variants affecting the Rel-homology domain may cause protein-decaying defects, thus resembling the disease-mechanisms of p105/p50 haploinsufficiency or may cause DNA-binding deficiency. However, rare variants (with a population frequency of less than 0.01%) with minor abnormalities or with neutral tests should still be considered as potentially pathogenic, until suitable tests have approved them being benign.

During this year's 33rd annual meeting in Leipzig, Germany, the European Society of Paediatric Infectious Diseases (ESPID) jointly together with the European Scientific Working group on Influenza (ESWI), organized a staged debate on the motion of universal annual immunization of children against influenza as a cost-effective health intervention in Europe. Six invited speakers, all experts in the field of influenza vaccination, who were not necessary confident with their given position of pro or contra, battled each other with short oral presentations to convince the audience to vote for or against the motion.

Background. Intermittent preventive antimalarial treatment in infants (IPTi) with sulfadoxine-pyrimethamine reduces falciparum malaria and anemia but has not been evaluated in areas with intense perennial malaria transmission. It is unknown whether an additional treatment in the second year of life prolongs protection. Methods. A randomized, double-blinded, placebo-controlled trial with administration of sulfadoxine-pyrimethamine therapy at 3, 9, and 15 months of age was conducted with 1070 children in an area in Ghana where malaria is holoendemic. Participants were monitored for 21 months after recruitment through active follow-up visits and passive case detection. The primary end point was malaria incidence, and additional outcome measures were anemia, outpatient visits, hospital admissions, and mortality. Stratified analyses for 6-month periods after each treatment were performed. Results. Protective efficacy against malaria episodes was 20% (95% confidence interval [CI], 11%–29%). The frequency of malaria episodes was reduced after the first 2 sulfadoxine-pyrimethamine applications (protective efficacy, 23% [95% CI, 6%–36%] after the first dose and 17% [95% CI, 1%–30%] after the second dose). After the third treatment at month 15, however, no protection was achieved. Protection against the first or single anemia episode was only significant after the first IPTi dose (protective efficacy, 30%; 95% CI, 5%–49%). The number of anemia episodes increased after the last IPTi dose (protective efficacy, -24%; 95% CI, -50% to -2%). Conclusion. In an area of intense perennial malaria transmission, sulfadoxine-pyrimethamine–based IPTi conferred considerably lower protection than reported in areas where the disease is moderately or seasonally endemic. Protective efficacy is age-dependent, and extension of IPTi into the second year of life does not provide any benefit.