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The Oxford Vaccine Group is an independent multi-disciplinary clinical trials and epidemiology group based at the Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford. OVG works towards the goal of developing new and improved vaccines for the prevention of infection in adults and children.
Salmonella Typhi gut invasion drives hypoxic immune subsets associated with disease outcomes.
Salmonella Typhi (S. Typhi), the causative agent of typhoid disease, remains a major public health concern. Owing to the human-restricted nature of S. Typhi, studies of typhoid pathogenesis in animal models are limited to a murine non-typhoidal pathogen. More recently, human challenge models have been conducted, providing insight into immune correlates of infection outcomes, which are still incompletely understood. Here, we performed an integrated single-cell analysis of immune responses from the human S. Typhi challenge model and mouse model of typhoid disease, to associate biological mechanism with human infection outcome. Most prominent, we revealed immune subsets with a hypoxia-related signature in the blood of individuals who developed disease in the human challenge model. This signature was also evident in the mouse model in activated macrophages infiltrating into the Peyer's patches, but not during infection with a mutant strain impaired for gut invasion. We further identified hypoxia-related signature as a general immune correlate of disease outcome in other infection-and inflammatory-related diseases. Collectively, we identified a hypoxia-associated immune signature that correlates with disease outcomes in humans. Using a mouse model, we demonstrated that this signature is driven by bacterial invasion to the Peyer's patches, implicating a causal role in the pathogenesis of typhoid fever.
Nipah virus vaccines evaluated in pigs as a 'One Health' approach to protect public health.
Nipah virus (NiV) causes a severe neurological disease in humans. The first NiV outbreak, in Malaysia, involved pig-to-human transmission, that resulted in significant economic losses to the local pig industry. Despite the risk NiV poses to pig-dense regions, no licensed vaccines exist. This study therefore assessed three NiV vaccine candidates in pigs: (1) adjuvanted soluble NiV (s)G protein, (2) adjuvanted pre-fusion stabilised NiV (mcs)F protein, and (3) adenoviral vectored NiV G (ChAdOx1 NiV G). NiV sG induced the strongest neutralising antibody response, NiV mcsF induced antibodies best able to neutralise cell-cell fusion, whereas ChAdOx1 NiV G elicited CD8+ T-cell responses. Despite differences in immunogenicity, prime-boost immunisation with all candidates conferred a high degree of protection against NiV infection. Follow-up studies demonstrated longevity of immune responses and broadly comparable immune responses in Bangladeshi pigs under field conditions. These studies provide a platform for developing a NiV vaccine for pigs.
Understanding the interaction of upper respiratory tract infection with respiratory syncytial virus and Streptococcus pneumoniae using a human challenge model: a multicenter, randomized controlled study protocol.
BACKGROUND: Streptococcus pneumoniae (pneumococcus) and respiratory syncytial virus (RSV) are major causes of respiratory infections globally. Viral and bacterial co-infections are commonly observed in respiratory infections and there is evidence that these pathogens interact synergistically to evade host responses and lead to more severe disease. Notably, RSV seasonal outbreaks are associated with increased hospitalization and a subsequent peak in invasive pneumococcal disease cases, particularly in pediatric populations. Here, we summarize a protocol for a controlled human infection model aiming to evaluate pathogen interaction dynamics and immune responses in a combined pneumococcus and RSV model. The primary objective is to determine whether primary RSV challenge increases the risk of secondary pneumococcal colonization. METHODS: This is an open-label, multi-center, randomized controlled human co-infection study, inclusive of a pilot phase. Individuals will be randomized to primary inoculation with either pneumococcus (serotype 6B) or RSV (subtype RSV-A) intra-nasally on day 0 followed by a reciprocal challenge on day 7. During pilot phase A up to 10 participants will be monitored in an in-patient facility for 7-10 days following RSV-A challenge. If there are no safety concerns, we will then progress to an outpatient phase where participants will self-isolate at home. Clinical samples to be taken from participants include nasal swabs and washes for pathogen detection; and nasal cells, nasal lining fluid, and blood samples to examine mucosal and systemic immune responses. DISCUSSION: This work will lead to important scientific knowledge on the interaction and dynamics between pneumococcus and RSV. This knowledge could help inform pneumococcal and RSV vaccination strategies, particularly for groups at risk of developing severe pneumococcal and RSV disease. TRIAL REGISTRATION: The study is registered on ISRCTN (The UKs Clinical Study Registry). DOI https://doi.org/10.1186/ISRCTN12036902.
Defining the genetic determinants of CD8+ T cell receptor repertoire in the context of immune checkpoint blockade.
The relationship between genetic variation and CD8+ T cell receptor (TCR) repertoire usage in patients receiving immune checkpoint blockade (ICB) therapy for cancer is unexplored. We have conducted a genome-wide and human leukocyte antigen (HLA)-focused analysis of CD8+ TCR repertoire to identify genetic determinants of variable gene (V-gene) and CDR3 K-nucleotide oligomer usage from samples taken before and after ICB (n = 250). We identify 11 cis and 10 trans V-gene associations, primarily to the MHC, that meet genome-wide significance. TCR clones containing HLA associated V-genes were less stable across treatment, while, at the single-cell level, genetically associated clones demonstrate subset enrichment and increased tumor reactivity expression profiles. Notably, patients with HLA-matched TCR clones demonstrate improved overall survival. Our work indicates a complex relationship between genotype and TCR repertoire in the context of ICB treatment, with implications for understanding factors relating to therapeutic response and patient outcomes.
Neonatal Antifungal Consumption Is Dominated by Prophylactic Use; Outcomes From The Pediatric Antifungal Stewardship: Optimizing Antifungal Prescription Study.
BACKGROUND: Diagnostic challenges combined with the vulnerability of neonates to develop invasive candidiasis (IC) may lead to antifungal administration in the absence of IC. A modified point-prevalence study was performed to obtain an improved insight and understanding of antifungal prescribing in this specific patient population. METHODS: Neonates and infants ≤90 days of age receiving systemic antifungals from 12 centers in England were included. Data were collected prospectively during 26 consecutive weeks and entered into an online REDCap database. RESULTS: Two hundred eighty neonates and infants were included, the majority ≤1 month of age (68.2%). Prematurity was the commonest underlying condition (68.9%). Antifungals were prescribed for prophylactic reason in 79.6%; of those, 64.6% and 76.3% were extreme low birth weight infants and prematurely born neonates, respectively. Additional risk factors were present in almost all patients, but only 44.7% had ≥3 risk factors rendering them more susceptible to develop IC. Nonpremature and non extremely low birth weight premature infants only scored ≥3 risk factors in 32.6% and 15%, respectively. Fluconazole was the most common antifungal used (76.7% of all prescriptions), and commonly underdosed as treatment. The number of microbiologic proven IC was low, 5.4%. CONCLUSIONS: Neonatal antifungal prophylaxis is commonly prescribed outside the recommendations based on known risk profiles. Fluconazole is the main antifungal prescribed in neonates and infants, with underdosing frequently observed when prescribed for treatment. Number of proven IC was very low. These observations should be taken into consideration to develop a national pediatric Antifungal Stewardship program aiming to guide rational prescribing.
Case Report: Disseminated, rifampicin resistant Mycobacterium bovis (BCG) infection in an immunocompromised child
<ns4:p><ns4:bold>Background: </ns4:bold><ns4:italic>Bacillus Calmette–Guérin</ns4:italic> (BCG) is a live-attenuated vaccine used world-wide for prevention of tuberculosis disease. In some immunocompromised hosts it has the potential to cause disease. As with other members of the <ns4:italic>M. tuberculosis </ns4:italic>complex it has the potential for acquiring drug resistance.</ns4:p><ns4:p> <ns4:bold>Methods: </ns4:bold>We reviewed 10 years of paediatric clinical BCG strains referred to our clinical microbiology laboratory in Oxford where they underwent whole genome sequencing. We present a case series comparing clinical, pathogen genetic and pathogen phenotypic data, and consider the clinical implications.</ns4:p><ns4:p> <ns4:bold>Results: </ns4:bold>We identified 15 BCG isolates from 8 children under 16 years old. Only one child had clinical disease with the other seven reported as local inoculation-site reactions. Case 1 suffered disseminated disease secondary to an undiagnosed IL-12/IFNγ receptor defect and the BCG isolates evolved two different rifampicin resistance mutations. Across all 15 isolates, phenotypic resistance to each first line drug was seen. </ns4:p><ns4:p> <ns4:bold>Conclusions: </ns4:bold>BCG is a safe and effective vaccine in children. Most clinical specimens in our series were not related to disease. However, in the context of rare pathogen-specific immunocompromise, BCG can cause pathology and acquire drug resistance under selection from therapy.</ns4:p>
Simultaneous Viral Whole-Genome Sequencing and Differential Expression Profiling in Respiratory Syncytial Virus Infection of Infants.
Targeted metagenomics using strand-specific libraries with target enrichment is a sensitive, generalized approach to pathogen sequencing and transcriptome profiling. Using this method, we recovered 13 (76%) complete human respiratory syncytial virus (RSV) genomes from 17 clinical respiratory samples, reconstructed the phylogeny of the infecting viruses, and detected differential gene expression between two RSV subgroups, specifically, a lower expression of the P gene and a higher expression of the M2 gene in RSV-A than in RSV-B. This methodology can help to relate viral genetics to clinical phenotype and facilitate ongoing population-level RSV surveillance and vaccine development.
Real-world uptake of nirsevimab, RSV maternal vaccine, and RSV vaccines for older adults: a systematic review and meta-analysis.
BACKGROUND: In clinical trials, recently introduced respiratory syncytial virus (RSV) immunisation products have shown high efficacy in preventing severe RSV outcomes. Implementing successful immunisation programmes is however key to realising these benefits in real-world settings. We aimed to investigate uptake of the long-acting monoclonal antibody nirsevimab, the RSV maternal vaccine, and RSV vaccines for older adults in countries where immunisation programmes have been introduced, and to explore how uptake varies between countries and population subgroups. METHODS: In this systematic review and meta-analysis, we carried out four monthly searches in Medline, Embase, and Global Health databases for studies reporting uptake of nirsevimab, the RSV maternal vaccine, and RSV vaccines for older adults. We included population-based studies published between December 1, 2022 and February 5, 2025. Two independent reviewers screened studies, extracted data, and completed a risk of bias assessment using the Joanna Briggs Institute (JBI) Critical Appraisal Tools. We assessed uptake stratified by country and socio-demographic and clinical subgroups. Meta-analyses were conducted using random-effects modelling. PROSPERO registration number: CRD42025643585. FINDINGS: We screened a total of 1267 studies, 43 of which met the inclusion criteria reporting data on over 1.38 million individuals from six countries. Nirsevimab uptake data were reported in 34 studies: 16 from Spain, eight from the United States, seven from France, one with combined data from Andorra and Spain, and one from each of Italy and Luxembourg. Our pooled estimates showed that nirsevimab uptake on population level was 90.1% (95% confidence interval (CI): 86.4-92.9) in Spain and 51.2% (95% CI: 29.3-72.7) in the United States during the 2023/24 RSV season. Uptake data for the RSV maternal vaccine and RSV vaccines for older adults were reported in five and eight studies, respectively, all from the United States. Meta-analysis showed population-level uptake of 30.5% (95% CI: 20.6-42.6) and 18.2% (95% CI: 10.8-28.9), respectively. Uptake varied across subgroups. INTERPRETATION: Uptake of nirsevimab varied substantially between the countries that have implemented infant RSV immunisation programmes. Despite the limited number of studies and the lack of more accurate data at national level the low uptake estimates for RSV maternal vaccine and RSV vaccines for older adults are concerning. National, clinical, and public health initiatives are needed to increase uptake of RSV immunisation products and ensure maximum benefit to people currently at risk of severe RSV outcomes. FUNDING: Health Data Research UK, Inflammation and Immunity Driver Programme.
T cells, more than antibodies, may prevent symptoms developing from respiratory syncytial virus infections in older adults.
INTRODUCTION: The immune mechanisms supporting partial protection from reinfection and disease by the respiratory syncytial virus (RSV) have not been fully characterized. In older adults, symptoms are typically mild but can be serious in patients with comorbidities when the infection extends to the lower respiratory tract. METHODS: This study formed part of the RESCEU older-adults prospective-cohort study in Northern Europe (2017-2019; NCT03621930) in which a thousand participants were followed over an RSV season. Peripheral-blood samples (taken pre-season, post-season, during illness and convalescence) were analyzed from participants who (i) had a symptomatic acute respiratory tract infection by RSV (RSV-ARTI; N=35) or (ii) asymptomatic RSV infection (RSV-Asymptomatic; N=16). These analyses included evaluations of antibody (Fc-mediated-) functional features and cell-mediated immunity, in which univariate and machine-learning (ML) models were used to explore differences between groups. RESULTS: Pre-RSV-season peripheral-blood biomarkers were predictive of symptomatic RSV infection. T-cell data were more predictive than functional antibody data (area under receiver operating characteristic curve [AUROC] for the models were 99% and 76%, respectively). The pre-RSV season T-cell phenotypes which were selected by the ML modelling and which were more frequent in RSV-Asymptomatic group than in the RSV-ARTI group, coincided with prominent phenotypes identified during convalescence from RSV-ARTI (e.g., IFN-γ+, TNF-α+ and CD40L+ for CD4+, and IFN-γ+ and 4-1BB+ for CD8+). CONCLUSION: The evaluation and statistical modelling of numerous immunological parameters over the RSV season suggests a primary role of cellular immunity in preventing symptomatic RSV infections in older adults.
Immunological and inflammatory biomarkers of susceptibility and severity in adult respiratory syncytial virus infections
BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in young infants. However, it is also a significant pathogen in older adults. Validated biomarkers of RSV disease severity would benefit diagnostics, treatment decisions, and prophylactic interventions. This review summarizes knowledge of biomarkers for RSV disease in adults. METHODS: A literature review was performed using Ovid Medline, Embase, Global health, Scopus, and Web of Science for articles published 1946-October 2016. Nine articles were identified plus 9 from other sources. RESULTS: From observational studies of natural infection and challenge studies in volunteers, biomarkers of RSV susceptibility or disease severity in adults were: (1) lower anti-RSV neutralizing antibodies, where neutralizing antibody (and local IgA) may be a correlate of susceptibility/severity; (2) RSV-specific CD8+ T cells in bronchoalveolar lavage fluid preinfection (subjects with higher levels had less severe illness); and (3) elevated interleukin-6 (IL-6), IL-8, and myeloperoxidase levels in the airway are indicative of severe infection. CONCLUSIONS: Factors determining susceptibility to and severity of RSV disease in adults have not been well defined. Respiratory mucosal antibodies and CD8+ T cells appear to contribute to preventing infection and modulation of disease severity. Studies of RSV pathogenesis in at-risk populations are needed.
Targeted metagenomics reveals association between severity and pathogen co-detection in infants with respiratory syncytial virus.
Respiratory syncytial virus (RSV) is the leading cause of hospitalisation for respiratory infection in young children. RSV disease severity is known to be age-dependent and highest in young infants, but other correlates of severity, particularly the presence of additional respiratory pathogens, are less well understood. In this study, nasopharyngeal swabs were collected from two cohorts of RSV-positive infants <12 months in Spain, the UK, and the Netherlands during 2017-20. We show, using targeted metagenomic sequencing of >100 pathogens, including all common respiratory viruses and bacteria, from samples collected from 433 infants, that burden of additional viruses is common (111/433, 26%) but only modestly correlates with RSV disease severity. In contrast, there is strong evidence in both cohorts and across age groups that presence of Haemophilus bacteria (194/433, 45%) is associated with higher severity, including much higher rates of hospitalisation (odds ratio 4.25, 95% CI 2.03-9.31). There is no evidence for association between higher severity and other detected bacteria, and no difference in severity between RSV genotypes. Our findings reveal the genomic diversity of additional pathogens during RSV infection in infants, and provide an evidence base for future causal investigations of the impact of co-infection on RSV disease severity.
How to use…respiratory viral studies.
Viral respiratory tract infections are the most common infections of childhood. They result in clinical syndromes ranging from mild upper respiratory tract infection to severe lower respiratory tract disease requiring intensive care. Respiratory viruses are most commonly identified from a respiratory swab or nasopharyngeal aspirate by real-time PCR, which has a very high sensitivity and specificity. In this article, we review when and how children should be tested for viral respiratory tract infections and how to interpret the result in context of the clinical picture.
Dexamethasone in hospitalized patients with Covid-19 — preliminary report
Background: Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. Methods: In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the preliminary results of this comparison. Results: A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55). Conclusions: In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936. opens in new tab; ISRCTN number, 50189673. opens in new tab.)