Previous research has shown that immune development during the first week of life, i.e. ontogeny, is progressive, consistent and robust, involving large numbers of differentially expressed genes at each sampled time point. To obtain more granular detail about conserved and population-specific ontogeny, the influence of day of life on blood gene expression and cell type composition was examined in two distinct neonatal populations, from The Gambia and Papua New Guinea, employing block randomization strategies to minimize batch effects. This enabled more detailed conclusions about ontogenic program differences between the two cohorts. Population-specific ontogeny revealed mechanistic insights likely to contribute to inherent population-based heterogeneity in the efficiency of neonatal immune responses, including cell cycle, kinesins, and DAP12 signaling in Papua New Guinea, and antigen presentation, clathrin-mediated endocytosis and alpha-defensins in The Gambia. Differences between populations interconnect using protein:protein interaction networks of population-specific genes and pathinkR-based pathway networks and heat maps, thus fitting the concept of pathway/network remodeling. In addition to the population-specific changes, there is a profound core ontogenic gene-expression program involving ~18% of all expressed genes with remarkable 88-96% conservation at each day of life, revealing new contributors to this shared early-life ontogenic program.

We investigated the genetic and epigenetic regulation of the UBASH3A gene and its association with early-onset sepsis. Using matched whole blood DNA methylation, gene expression, genotypes, and immune cell counts from the EPIC-HIPC newborn cohort, we report that promoter methylation was negatively correlated (Pearson r = −0.5, P < 2.2 × 10−16) with ontogenetic changes in UBASH3A gene expression and circulating CD3+ T-cell numbers. Higher promoter methylation at birth was associated with lower UBASH3A expression and reduced early-onset sepsis risk (odds ratio, 0.26; P = .015). Genetic variation significantly influenced variations in baseline UBASH3A methylation (132 cis-meQTL, false discovery rate <0.05).

Background:Protection of newborns from infection can be achieved through maternal or vaccine-induced antibodies, but the factors influencing vaccine protection (correlate of protection) and subsequent infant immunity remain insufficiently understood. Further investigation is essential to optimize early-life vaccination strategies. Objective:We sought to evaluate the impact of timing and sequence of hepatitis B vaccine (HBV) and Bacille Calmette-Guérin (BCG) vaccine within the first week of life on infant HBV immunogenicity and its relationship with maternal antibodies. Methods:This was an exploratory analysis of a US National Institutes of Health-supported prospective, randomized study of systems biology signatures predictive of HBV immunogenicity in 2 geographically distinct cohorts in The Gambia (GAM; N = 720) and Papua New Guinea (PNG, N = 101) (clinicaltrials.gov NCT03246230). Healthy, hepatitis B surface antigen (anti-HBs)-negative mothers and their infants were enrolled and randomized into 4 vaccine groups: HBV alone, BCG alone, HBV + BCG, or no vaccination (delayed until no later than day of life [DOL]7). Blood samples were collected at birth (DOL0) and on a randomly assigned day (either DOL1, DOL3, or DOL7) with a maximum of 2 blood draws in the first week of life per ethics approval. All infants received catch-up vaccination within DOL7 and the recommended oral polio vaccine within 10 days of birth. Additional blood samples were collected at DOL30 and DOL128 to measure anti-HBs titers and assess immunogenicity. Results:Demographic and clinical characteristics were balanced across vaccine groups, suggesting successful randomization in both cohorts. Similar infant growth trajectories and longitudinal anti-HBs titer trends were observed across all vaccine groups in both cohorts over the first 128 days of life. Maternal and neonatal baseline anti-HBs titers were strongly correlated (GAM: r = 0.98; PNG: r = 0.99). DOL0 titers predicted DOL30 titers (GAM: R 2 = 0.56; PNG: R 2 = 0.945) but not DOL128 titers. Exploratory pairwise comparisons showed that Gambian infants receiving BCG at birth and HBV at DOL7 had higher DOL30 titers than those vaccinated with HBV at DOL1 (Wilcoxon P = .046), whereas in PNG, infants in the HBV + BCG group and the delayed group had higher DOL128 titers than those in the HBV group (Wilcoxon P = .046; Wilcoxon P = .019, respectively). Conclusions:This study demonstrates the feasibility of conducting large-scale neonatal immunogenicity studies in resource-constrained settings. Our observations underscore the importance of vaccine timing and maternal antibodies in shaping early-life vaccine-induced immunogenicity, offering valuable insights for neonatal vaccination schedules.

Sickle cell trait (SCT) is a genetic condition characterized by a heterozygous A-T substitution (Glu to Val) in 1 copy of the β-globin (HBB) gene on chromosome 11. Although often asymptomatic, individuals with SCT can experience complications under stress, such as hypoxia, dehydration, and extreme exertion, leading to vaso-occlusion, organ damage, and impaired immune defenses. Understanding the impact of SCT on the immune system may aid in preventing clinical complications. We genotyped 720 newborns from The Gambia, West Africa, an area in which people are prone to have sickle cell disorders, using RNA-sequencing reads mapped to the HBB gene to identify those with SCT and investigate immune development using single-omics and multiomics approaches. We identified 118 newborns (~17%) with SCT and 4 (0.6%) with sickle cell disease (SCD). Newborns with SCT demonstrated distinct molecular signatures across day of life (DOL) 0, 1, 3, and 7, compared with those without, including reduction of DOL 3 plasma proteins (eg, cysteine-rich secretory protein-3, inter-α-trypsin inhibitor 1, tetranectin, and cadherin-5). Additionally, we observed enrichment of pathways previously associated with SCD, such as the Jison sickle cell pathway, along with those linked to hematologic (chronic leukemia), hepatic (liver cancer), and renal (aging kidney) functions and disorders. These SCT-based associations were validated in an independent cohort of 45 neonates. Despite the absence of overt early clinical phenotypes, SCT-associated changes manifest in the first week of life at the molecular level. Monitoring and characterizing these associations may enable the identification of future disease risks and the development of preventive strategies. This trial was registered at www.clinicaltrials.gov as #NCT03246230.

Abstract Introduction The plasma metabolome changes markedly over the first week of life yet little is known regarding how these trajectories might differ across geographically distinct populations. Methods To gain insight into potential differences in ontogeny between geographic sites, newborn participants were enrolled in The Gambia (n = 45) and Papua New Guinea (n = 45). All participants had samples collected at birth and were randomized to have their second sample collected either on the first, third, or seventh day following birth. Global untargeted plasma metabolomics employed ultra-performance liquid chromatography mass spectrometry (Metabolon). Principal Component Analysis (PCA), regression methods, and enrichment analysis were used to identify significant differences in metabolite profiles between time points (p < 0.01, adjusted for multiple comparisons). Results PCA showed plasma metabolites clustering by day of sample collection and by site. The majority (62%) of metabolite features showed a significant difference based on time point: 46% of these were lipids and 17% were amino acids. Temporal dynamics revealed dramatic changes during the first week of life, with the most pronounced shifts occurring between D1 and D3. The most significant temporal changes were consistent across the two geographic sites, suggesting that the underlying biological processes are robust. Additionally, 24% of the metabolite features showed a significant difference between sites, with the most common being lipids (28.2%). Xenobiotics including caffeine and food metabolites were distinct in GAM vs. PNG, suggesting differences in maternal diet and environmental factors. Conclusion The plasma metabolome undergoes marked changes during the first week of human life, with distinct features across geographic locations, and warrants further exploration with respect to potential correlations to immune status and clinical outcomes, with particular emphasis on lipid pathways. Funding Source National Institute Of Allergy And Infectious Diseases of the U.S. National Institutes of Health under Awards Human Immunology Project Consortium (HIPC; U19AI118608) Topic Categories Computational and Systems Immunology (COMP)

Dynamic molecular changes in early life follow a robust ontogeny as the infant immune system adapts to the demands of its new environment. Studies of plasma immunomodulatory cytokines and chemokines have previously demonstrated ontogenetic patterns of immune development across the first week of life. However, how plasma cytokine and chemokines concentrations evolve over the first 4 months of life remains unknown. In this study, we examined plasma cytokine and chemokine concentrations in a longitudinal cohort of infants in Papua New Guinea (Oceania; n = 87) across the first four months of life. Using a multiplex assay, concentration of 41 cytokines and chemokines in peripheral blood plasma samples collected at Day of Life (DOL) 0 (i.e., birth), -7, -30, and - 128 were measured. Several cytokines and chemokines that shape cellular immunity demonstrated a statistically significant increase in concentration over the first four months of life, including CXCL10 (5.5-fold), IFNγ (8.8-fold), and IL-2 (1.7-fold). In contrast, other cytokines and chemokines significantly diminished with age, including CCL2 (0.12-fold), CXCL8 (0.35-fold), IL-6 (0.38-fold), and TGFα (0.43-fold). Plasma cytokine and chemokine concentrations appeared to be minimally affected by demographic factors such as birth season, gestational age, sex, or maternal age. The patterns and directionality of these observations largely mirrored those reported in previous cohorts, suggesting universal patterns of plasma cytokine and chemokine trajectories in early life. Overall, understanding early life trajectories of plasma cytokines and chemokines provides insight into human immune development and supports future studies analyzing cytokine trajectories in relation to health and disease.

Tick bites and tick-related diseases are on the rise. Diagnostic tests that identify well-characterised tick-borne pathogens (TBPs) possess limited capacity to address the causation of symptoms associated with poorly characterised tick-related illnesses, such as debilitating symptom complexes attributed to ticks (DSCATT) in Australia. Identification of local signals in tick-bitten skin that can be detected systemically in blood would have both clinical (diagnostic or prognostic) and research (mechanistic insight) utility, as a blood sample is more readily obtainable than tissue biopsies. We hypothesised that blood samples may reveal signals which reflect relevant local (tissue) events and that the time course of these signals may align with local pathophysiology. As a first step towards testing this hypothesis, we compared molecular signatures in skin biopsies taken from the tick-bite location of human participants, as published in our previous study, together with peripheral blood signatures obtained concurrently. This approach captures differentially expressed molecules across multiple omics datasets derived from peripheral blood (including cellular and cell-free transcriptomics, proteomics, metabolomics, and DNA methylation), and skin biopsies (spatial transcriptomics). Our original data revealed that extracellular matrix organisation and platelet degranulation pathways were upregulated in the skin within 72 h of a tick bite. The same signals appeared in blood, where they then remained elevated for three months, displaying longitudinally consistent alterations of biological functions. Despite the limited sample size, these data represent proof-of-concept that molecular events in the skin following a tick bite can be detectable systemically. This underscores the potential value of blood samples, akin to a liquid biopsy, to capture biomarkers reflecting local tissue processes.

Acute Rheumatic Fever (ARF) is a systemic inflammatory condition triggered by Group A Streptococcus infection, with timely diagnosis critical to prevent Rheumatic Heart Disease. ARF pathogenesis is poorly understood and diagnosis is based on clinical criteria. Here, we compared ARF cases and well-defined controls from two Uganda cohorts. We identified a 5-protein signature that discriminates ARF patients from clinically-similar conditions (receiver operating characteristic-area under the curve (ROC-AUC)=1.0, n=18 definite ARF vs n=9 known alternate diagnosis; ROC-AUC=0.97, n=18 definite ARF vs n=13 unknown alternate diagnosis), which retained very good diagnostic value in a validation cohort (ROC-AUC=0.83 n=26 definite ARF vs n=13 unknown alternate diagnosis). Pathway analysis identified the epithelial-mesenchymal transition pathway as highly-associated with acute ARF, suggesting that tissue damage and repair is central to ARF pathogenesis. Our findings require further validation, yet highlight the potential for proteomics to identify clinically useful diagnostic biomarkers that would revolutionise ARF diagnosis and treatment.

Type 1 interferons (T1IFNs) are typically expressed in low concentrations under homeostatic conditions, but upon pathogenic insult or perturbation of the pathway, these critical immune signaling molecules can become either protectors from or drivers of pathology. While essential for initiating antiviral defense and modulating inflammation, dysregulation of T1IFN signaling can contribute to immunopathology, making it and its associated pathways prime targets for immune evasion and disruption by pathogens. This review focuses on the changes in T1IFN signaling across the lifespan, with particular emphasis on the role of the Stimulator of Interferon Genes (STING) pathway in autoimmune and infectious disease susceptibility, especially in the context of viral infections. Aging is associated with diminished T1IFN responsiveness, partially resulting from chronic stimulation of the STING pathway, which contributes to increased susceptibility and impaired viral clearance. Conversely, neonates and young children also show increased vulnerability to certain viral infections, but whether this is driven by T1IFN differences or another mechanism remains incompletely understood. Despite growing interest in T1IFN-based immunotherapies, pediatric and elderly populations remain underrepresented in clinical trials. Here, we advocate for a deeper molecular and systems understanding of how the interferon response evolves across the human lifespan, to inform age-tailored therapeutic approaches and more inclusive study designs, thereby improving outcomes in both the youngest and oldest patients.

Tick-associated diseases present challenges due to tridirectional interactions among host-specific responses, tick toxins and salivary proteins as well as microbes. We aimed to uncover molecular mechanisms in tick-bitten skin samples (cases) and contralateral skin samples (controls) collected simultaneously from the same participants, using spatial transcriptomics. Cases and controls analysed using NanoString GeoMx Digital Spatial Profiler identified 274 upregulated and 840 downregulated differentially expressed genes (DEGs), revealing perturbations in keratinization and immune system regulation. Samples of skin biopsies taken within 72 h post tick-bite DEGs had changes in protein metabolism and viral infection pathways as compared to samples taken 3 months post tick-bite, which instead displayed significant perturbations in several epigenetic regulatory pathways, highlighting the temporal nature of the host response following tick bites. Within-individual signatures distinguished tick-bitten samples from controls and identified between-individual signatures, offering promise for future biomarker discovery to guide prognosis and therapy.

Understanding of newborn immune ontogeny in the first week of life will enable age-appropriate strategies for safeguarding vulnerable newborns against infectious diseases. Here we conducted an observational study exploring the immunological profile of infants longitudinally throughout their first week of life. Our Expanded Program on Immunization - Human Immunology Project Consortium (EPIC-HIPC) studies the epigenetic regulation of systemic immunity using small volumes of peripheral blood samples collected from West African neonates on days of life (DOL) 0, 1, 3, and 7. Genome-wide DNA methylation and single nucleotide polymorphism markers are examined alongside matched transcriptomic and flow cytometric data. Integrative analysis reveals that a core network of transcription factors mediates dynamic shifts in neutrophil-to-lymphocyte ratios (NLR), which are underpinned by cell-type specific methylation patterns in the two cell types. Genetic variants are associated with lower NLRs at birth, and healthy newborns with lower NLRs at birth are more likely to subsequently develop sepsis. These findings provide valuable insights into the early-life determinants of immune system development.

The first few days of life are characterized by rapid external and internal changes that require substantial immune system adaptations. Despite growing evidence of the impact of this period on lifelong immune health, this period remains largely uncharted. To identify factors that may impact the trajectory of immune development, we conducted stringently standardized, high-throughput phenotyping of peripheral white blood cell (WBC) populations from 796 newborns across two distinct cohorts (The Gambia, West Africa; Papua New Guinea, Melanesia) in the framework of a Human Immunology Project Consortium (HIPC) study. Samples were collected twice from each newborn during the first week of life, first at Day of Life 0 (at birth) and then subsequently at Day of Life 1, 3, or 7 depending on the randomization group the newborn belongs to. The subsequent analysis was conducted at an unprecedented level of detail using flow cytometry and an unbiased automated gating algorithm. The results showed that WBC composition in peripheral blood changes along patterns highly conserved across populations and environments. Changes across days of life were most pronounced in the innate myeloid compartment. Breastfeeding, and at a smaller scale neonatal vaccination, were associated with changes in peripheral blood neutrophil and monocyte cell counts. Our results suggest a common trajectory of immune development in newborns and possible association with timing of breastfeeding initiation, which may contribute to immune-mediated protection from infection in early life. These data begin to outline a specific window of opportunity for interventions that could deliberately direct WBC composition, and with that, immune trajectory and thus ontogeny in early life. This trial is registered with NCT03246230.

BACKGROUND:Neonatal sepsis is a deadly disease with non-specific clinical signs, delaying diagnosis and treatment. There remains a need for early biomarkers to facilitate timely intervention. Our objective was to identify neonatal sepsis gene expression biomarkers that could predict sepsis at birth, prior to clinical presentation. METHODS:Among 720 initially healthy full-term neonates in two hospitals (The Gambia, West Africa), we identified 21 newborns who were later hospitalized for sepsis in the first 28 days of life, split into early-onset sepsis (EOS, onset ≤7 days of life) and late-onset sepsis (LOS, onset 8-28 days of life), 12 neonates later hospitalized for localized infection without evidence of systemic involvement, and 33 matched control neonates who remained healthy. RNA-seq was performed on peripheral blood collected at birth when all neonates were healthy and also within the first week of life to identify differentially expressed genes (DEGs). Machine learning methods (sPLS-DA, LASSO) identified genes expressed at birth that predicted onset of neonatal sepsis at a later time. FINDINGS:Neonates who later developed EOS already had ∼1000 DEGs at birth when compared to control neonates or those who later developed a localized infection or LOS. Based on these DEGs, a 4-gene signature (HSPH1, BORA, NCAPG2, PRIM1) for predicting EOS at birth was developed (training AUC = 0.94, sensitivity = 0.93, specificity = 0.92) and validated in an external cohort (validation AUC = 0.72, sensitivity = 0.83, and specificity = 0.83). Additionally, during the first week of life, EOS disrupted expression of >1800 genes including those influencing immune and metabolic transitions observed in healthy controls. INTERPRETATION:Despite appearing healthy at birth, neonates who later developed EOS already had distinct whole blood gene expression changes at birth, which enabled the development of a 4-gene predictive signature for EOS. This could facilitate early recognition and treatment of neonatal sepsis, potentially mitigating its long-term sequelae. FUNDING:CIHR and NIH/NIAID.

Maternal immunisation, a low cost and high efficacy intervention is recommended for its pathogen specific protection. Evidence suggests that maternal immunisation has another significant impact: reduction of preterm birth (PTB), the single greatest cause of childhood morbidity and mortality globally. Our overarching question is: how does maternal immunisation modify the immune system in pregnant women and/or their newborn to reduce adverse pregnancy outcomes and enhance the newborn infant’s capacity to protect itself from infectious diseases during early childhood? To answer this question we are conducting a multi-site, prospective observational cohort study collecting maternal and infant biological samples at defined time points during pregnancy and post-partum from nulliparous women. We aim to enrol 400 women and determine the immune trajectory in pregnancy and the impact of maternal immunisation (including influenza, pertussis and/or COVID-19 vaccines) on this trajectory. The results are expected to identify areas that can be targeted for future intervention studies.

Background:Accumulating evidence indicates that an early, robust type 1 interferon (IFN) response to SARS-CoV-2 is important in determining COVID-19 outcomes, with an inadequate IFN response associated with disease severity. Our objective was to examine the prophylactic potential of IFN administration to limit viral transmission. Methods:A cluster randomised open label clinical trial was undertaken to determine the effects of pegylated IFNβ-1a administration on SARS-CoV-2 household transmission between December 3rd, 2020 and June 29th, 2021. Index cases were identified from databases of confirmed SARS-CoV-2 individuals in Santiago, Chile. Households were cluster randomised (stratified by household size and age of index cases) to receive 3 doses of 125 μg subcutaneous pegylated IFNβ-1a (172 households, 607 participants), or standard care (169 households, 565 participants). The statistical team was blinded to treatment assignment until the analysis plan was finalised. Analyses were undertaken to determine effects of treatment on viral shedding and viral transmission. Safety analyses included incidence and severity of adverse events in all treatment eligible participants in the standard care arm, or in the treatment arm with at least one dose administered. Clinicaltrials.gov identifier: NCT04552379. Findings:5154 index cases were assessed for eligibility, 1372 index cases invited to participate, and 341 index cases and their household contacts (n = 831) enrolled. 1172 participants in 341 households underwent randomisation, with 607 assigned to receive IFNβ-1a and 565 to standard care. Based on intention to treat (ITT) and per protocol (PP) analyses for the primary endpoints, IFNβ-1a treatment did not affect duration of viral shedding in index cases (absolute risk reduction = -0.2%, 95% CI = -8.46% to 8.06%) and transmission of SARS-CoV-2 to household contacts (absolute risk reduction = 3.87%, 95% CI = -3.6% to 11.3%). Treatment with IFNβ-1a resulted in significantly more treatment-related adverse events, but no increase in overall adverse events or serious adverse events. Interpretation:Based upon the primary analyses, IFNβ-1a treatment did not affect duration of viral shedding or the probability of SARS-CoV-2 transmission to uninfected contacts within a household. Funding:Biogen PTY Ltd. Supply of interferon as 'Plegridy (peginterferon beta-1a).' The study was substantially funded by BHP Holdings Pty Ltd.

Importance Evidence suggests that early, robust type 1 interferon responses to SARS-CoV-2 are critical determinants for COVID-19 disease outcomes, accelerating viral clearance and limiting viral shedding. Objective We undertook a ring prophylaxis study to determine whether pegylated IFNβ-1α could reduce SARS-CoV-2 household transmission. Design A cluster randomized clinical trial of pegylated IFNβ-1α conducted in Santiago, Chile. Recruitment was conducted between December 4th 2020, and 31st May 2021, with the last follow-up completed June 29th 2021. Setting The study was conducted across 341 households in the metropolitan area of Santiago, Chile. Participants Index cases were identified from databases of those with confirmed SARS-CoV-2 from COVID-19 clinics and emergency room visits in Santiago, Chile. 5,154 index cases were assessed for eligibility, 1,372 index cases were invited to participate, and 341 index cases and their household contacts (n = 831) were enrolled in the study. Intervention Households were cluster randomized to receive 125µg subcutaneous pegylated IFNβ-1α (n = 172 households, 607 participants), or standard care (n = 169 households, 565 participants). Main Outcome(s) and Measure(s) Frequentist and Bayesian analyses were undertaken to determine the effects of treatment on (i) reducing viral shedding in index cases and (ii) reducing viral transmission to treatment-eligible household contacts. Four secondary outcomes were assessed including duration of viral shedding, effects on viral transmission and seroconversion, incidence of hospitalization, and incidence and severity of reported adverse events. A post-hoc ‘at risk population’ was defined as households where the index case was positive at the start of the study and there was at least one treatment eligible contact in a household who tested negative for SARS-CoV-2. Results In total, 1172 participants in 341 households underwent randomization, with 607 assigned to receive IFNβ-1α and 565 to standard care. Based on intention to treat and per protocol analyses, IFNβ-1α treatment was ineffective. However, in the ‘at risk’ population, the relative risk of infection was reduced by 23% in treated individuals and that there was a 95% probability that IFNβ-1α reduced household transmission Conclusions and Relevance Ring prophylaxis with IFNβ-1α reduces the probability of SARS-CoV-2 transmission within a household. Trial Registration [Clinicaltrials.gov][1] identifier: [NCT04552379][2] ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04552379 ### Clinical Protocols <https://pubmed.ncbi.nlm.nih.gov/34388972/> ### Funding Statement This study was funded by: BHP Holdings Pty Ltd Biogen ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Pontifical Catholic University of Chile. Ethics approval granted I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: http://Clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04552379&atom=%2Fmedrxiv%2Fearly%2F2022%2F06%2F24%2F2022.06.13.22276369.atom

In Australia, there is a paucity of data about the extent and impact of zoonotic tick-related illnesses. Even less is understood about a multifaceted illness referred to as Debilitating Symptom Complexes Attributed to Ticks (DSCATT). Here, we describe a research plan for investigating the aetiology, pathophysiology, and clinical outcomes of human tick-associated disease in Australia. Our approach focuses on the transmission of potential pathogens and the immunological responses of the patient after a tick bite. The protocol is strengthened by prospective data collection, the recruitment of two external matched control groups, and sophisticated integrative data analysis which, collectively, will allow the robust demonstration of associations between a tick bite and the development of clinical and pathological abnormalities. Various laboratory analyses are performed including metagenomics to investigate the potential transmission of bacteria, protozoa and/or viruses during tick bite. In addition, multi-omics technology is applied to investigate links between host immune responses and potential infectious and non-infectious disease causations. Psychometric profiling is also used to investigate whether psychological attributes influence symptom development. This research will fill important knowledge gaps about tick-borne diseases. Ultimately, we hope the results will promote improved diagnostic outcomes, and inform the safe management and treatment of patients bitten by ticks in Australia.

A single birth-dose of Hepatitis B vaccine (HepB) can protect newborns from acquiring Hepatitis B infection through vertical transmission, though several follow-up doses are required to induce long-lived protection. In addition to stimulating antibodies, a birth-dose of HepB might also induce polyfunctional CD4 + T-cells, which may contribute to initial protection. We investigated whether vaccination with HepB in the first week of life induced detectable antigen-specific CD4 + T-cells after only a single dose and following completion of the entire HepB vaccine schedule (3 doses). Using HBsAg- stimulated peripheral blood mononuclear cells from 344 infants, we detected increased populations of antigen-specific polyfunctional CD154 + IL-2 + TNFα + CD4 + T-cells following a single birth-dose of HepB in a proportion of infants. Frequencies of polyfunctional T-cells increased following the completion of the HepB schedule but increases in the proportion of responders as compared to following only one dose was marginal. Polyfunctional T-cells correlated positively with serum antibody titres following the birth dose (day30) and completion of the 3-dose primary HepB vaccine series (day 128). These data indicate that a single birth dose of HepB provides immune priming for both antigen-specific B- and T cells

The BCG vaccine has long been recognized for reducing the risk to suffer from infectious diseases unrelated to its target disease, tuberculosis. Evidence from human trials demonstrate substantial reductions in all-cause mortality, especially in the first week of life. Observational studies have identified an association between BCG vaccination and reduced risk of respiratory infectious disease and clinical malaria later in childhood. The mechanistic basis for these pathogen-agnostic benefits, also known as beneficial non-specific effects (NSE) of BCG have been attributed to trained immunity, or epigenetic reprogramming of hematopoietic cells that give rise to innate immune cells responding more efficiently to a broad range of pathogens. Furthermore, within trained immunity, the focus so far has been on enhanced monocyte function. However, polymorphonuclear cells, namely neutrophils, are not only major constituents of the hematopoietic compartment but functionally as well as numerically represent a prominent component of the immune system. The beneficial NSEs of the BCG vaccine on newborn sepsis was recently demonstrated to be driven by a BCG-mediated numeric increase of neutrophils (emergency granulopoiesis (EG)). And experimental evidence in animal models suggest that BCG can modulate neutrophil function as well. Together, these findings suggest that neutrophils are crucial to at least the immediate beneficial NSE of the BCG vaccine. Efforts to uncover the full gamut of mechanisms underpinning the broad beneficial effects of BCG should therefore include neutrophils at the forefront.