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Multiple introductions of NRCS-A Staphylococcus capitis to the neonatal intensive care unit drive neonatal bloodstream infections: a case-control and environmental genomic survey.
Background. The Staphylococcus capitis NRCS-A strain has emerged as a global cause of late-onset sepsis associated with outbreaks in neonatal intensive care units (NICUs) whose transmission is incompletely understood.Methods. Demographic and clinical data for 45 neonates with S. capitis and 90 with other coagulase-negative staphylococci (CoNS) isolated from sterile sites were reviewed, and clinical significance was determined. S. capitis isolated from 27 neonates at 2 hospitals between 2017 and 2022 underwent long-read (ONT) (n=27) and short-read (Illumina) sequencing (n=18). These sequences were compared with S. capitis sequenced from blood culture isolates from other adult and paediatric patients in the same hospitals (n=6), S. capitis isolated from surface swabs (found in 5/150 samples), rectal swabs (in 2/69 samples) in NICU patients and NICU environmental samples (in 5/114 samples). Reads from all samples were mapped to a hybrid assembly of a local sterile site strain, forming a complete UK NRCS-A reference genome, for outbreak analysis and comparison with 826 other S. capitis from the UK and Germany.Results. S. capitis bacteraemia was associated with increased length of NICU stay at sampling (median day 22 vs day 12 for other CoNS isolated; P=0.05). A phylogeny of sequenced S. capitis revealed a cluster comprised of 25/27 neonatal sterile site isolates and 3/5 superficial, 2/2 rectal and 1/5 environmental isolates. No isolates from other wards belonged to this cluster. Phylogenetic comparison with published sequences confirmed that the cluster was NRCS-A outbreak strain but found a relatively high genomic diversity (mean pairwise distance of 84.9 SNPs) and an estimated NRCS-A S. capitis molecular clock of 5.1 SNPs/genome/year (95% credibility interval 4.3-5.9). The presence of S. capitis in superficial cultures did not correlate with neonatal bacteraemia, but both neonates with rectal NRCS-A S. capitis carriage identified also experienced S. capitis bacteraemia.Conclusions. S. capitis bacteraemia occurred in patients with longer NICU admission than other CoNS. Genomic analysis confirms clinically significant infections with the NRCS-A S. capitis strain, distinct from non-NICU clinical samples. Multiple introductions of S. capitis, rather than prolonged environmental persistence, were seen over 5 years of infections.
The impact of antimicrobial stewardship ward rounds on antimicrobial use and predictors of advice, uptake, and outcomes.
OBJECTIVES: To identify the impact of introducing antimicrobial stewardship (AMS) ward rounds. METHODS: We used an interrupted time-series approach to investigate the impact of implementing AMS ward rounds with in-person feedback from a multi-disciplinary team in Hospital-1, also comparing to Hospital-2 in the same city where AMS ward rounds were not yet implemented. Regression models were used to identify predictors of advice given, whether advice was followed, and associations between advice uptake and length of stay. RESULTS: Introducing AMS ward rounds was followed by new or accelerated declines in ceftriaxone, ciprofloxacin, amoxicillin-clavulanate, meropenem and piperacillin-tazobactam use at Hospital-1. Except for ceftriaxone, similar declines were not seen at Hospital-2. Half of reviews (3471/6878; 50%) recommended an intervention; 2003/2726 (73%) subsequently evaluated recommendations were implemented. Senior doctors were more likely than pharmacists or specialist doctors in training to recommend de-escalation/stopping antibiotics and to have their advice followed. The more prior AMS reviews completed, the more likely advice was to be followed. Following advice to de-escalate/stop antimicrobials was associated with a 0.58 day [95%CI 0.22-0.94] reduction in hospital stay. CONCLUSIONS: Multidisciplinary AMS ward rounds reduced antibiotic use and likely reduced length of hospital stay. Senior clinician input and more AMS experience increased advice uptake. DATA SHARING: The datasets analysed during the current study are not publicly available as they contain personal data but are available from the Infections in Oxfordshire Research Database (https://oxfordbrc.nihr.ac.uk/ research-themes-overview/antimicrobial- resistance-and-modernising-microbiology/ infections-in-oxfordshire-research-database-iord/), subject to an application and research proposal meeting the ethical and governance requirements of the Database. For further details on how to apply for access to the data and for a research proposal template please email iord@ndm.ox.ac.uk.
Procalcitonin-guided duration of antibiotic treatment in children hospitalised with confirmed or suspected bacterial infection in the UK (BATCH): a pragmatic, multicentre, open-label, two-arm, individually randomised, controlled trial.
BACKGROUND: Procalcitonin is a rapid response biomarker specific for bacterial infection, which is not routinely used in the UK National Health Service. We aimed to assess whether using a procalcitonin-guided algorithm would safely reduce the duration of antibiotic therapy compared with usual care, in which C-reactive protein is the commonly used biomarker. METHODS: The BATCH trial was a pragmatic, multicentre, open-label, parallel, two-arm, individually randomised, controlled trial conducted in 15 hospitals in England and Wales. Children aged 72 h to 18 years who were admitted to hospital and were being treated with intravenous antibiotics for suspected or confirmed bacterial infection and who were expected to remain on intravenous antibiotics for more than 48 h were enrolled. Participants were randomly assigned (1:1) to receive either current clinical management alone (usual care group) or clinical management with the addition of a procalcitonin test guided algorithm (procalcitonin group). Participants were randomly assigned by minimisation, with site and age group (0-6 months, 6 months to 2 years, 2-5 years, and older than 5 years) as minimisation factors and a random element to reduce predictability. Participants were randomly assigned remotely using a secure 24 h web-based randomisation programme. The coprimary outcomes were duration of intravenous antibiotic use, assessed for superiority, and a composite safety measure, assessed for non-inferiority (non-inferiority margin 5%). The primary analysis sample for each coprimary endpoint included all randomly assigned participants with available outcome data. This trial is registered with the International Standard Randomised Controlled Trial Number registry, ISRCTN11369832. FINDINGS: Between June 11, 2018, and Oct 12, 2022, 15 282 children were screened for eligibility, 1949 of whom were randomly assigned to receive procalcitonin-guided antibiotic therapy (n=977) or usual care (n=972). The median intravenous antibiotic duration was 96·0 h (IQR 59·5-155·5) in the procalcitonin group and 99·7 h (61·2-153·8) in the usual care group (hazard ratio 0·96 [95% CI 0·87-1·05]). 78 (9%) of 917 participants in the procalcitonin group and 85 (9%) of 904 participants in the usual care group had at least one event covered by the composite safety outcome measure (estimated adjusted risk difference -0·81% [95% CI upper bound 1·11]). INTERPRETATION: In children with suspected or confirmed bacterial infection admitted to hospitals in England and Wales for intravenous antibiotic treatment of at least 48 h, the introduction of a procalcitonin-guided algorithm did not reduce duration of intravenous antibiotics treatment and is non-inferior to usual care for safety outcomes. Therefore, evidence does not support the use of procalcitonin-guided algorithms where robust effective paediatric antibiotic stewardship programmes are established. FUNDING: National Institute for Health and Care Research.
Antifungal Drug Usage in European Neonatal Units: A Multicenter Weekly Point Prevalence Study
BACKGROUND: Data on antifungal prescribing in neonatal patients are limited to either single-center or single-country studies or to 1-day recording. Therefore, we assessed antifungal longitudinal usage in neonatal units (NUs) within Europe. METHODS: CALYPSO, a prospective weekly point prevalence study on antifungal drug usage in NUs in 18 hospitals (8 European countries), was conducted in 2020 during a 12-week period. All patients receiving systemic antifungals were included. Ward demographics were collected at the beginning; ward and patient data including indication, risk factors and antifungal regimen were weekly collected prospectively. RESULTS: Among 27 participating NUs, 15 (56%) practiced antifungal prophylaxis for neonates with birth weight <1000 g or <1500 g and additional risk factors. In total, 174 patients received antifungals with a median frequency per week of 10.5% ranging from 6.9% to 12.6%. Indication for antifungal prescribing was prophylaxis in 135/174 (78%) courses and treatment in 22% [39 courses (69% empirical, 10% preemptive, 21% targeted)]. Fluconazole was the most frequent systemic agent used both for prophylaxis (133/135) and treatment (15/39, 39%). Among neonates receiving prophylaxis, the most common risk factors were prematurity (119/135, 88%), mechanical ventilation (109/135, 81%) and central vascular catheters (89/135, 66%). However, gestational age <28 weeks was only recorded in 55/135 (41%) courses and birth weight <1000 g in 48/135 (35%). Most common reason for empirical treatment was late-onset sepsis; all 8 targeted courses were prescribed for invasive candidiasis. CONCLUSION: Antifungal usage in European NUs is driven by prophylaxis and empirical treatment with fluconazole being the most prescribed agent for both indications.
Human infection challenge in the pandemic era and beyond, HIC-Vac annual meeting report, 2022.
HIC-Vac is an international network of researchers dedicated to developing human infection challenge studies to accelerate vaccine development against pathogens of high global impact. The HIC-Vac Annual Meeting (3rd and 4th November 2022) brought together stakeholders including researchers, ethicists, volunteers, policymakers, industry partners, and funders with a strong representation from low- and middle-income countries. The network enables sharing of research findings, especially in endemic regions. Discussions included pandemic preparedness and the role of human challenge to accelerate vaccine development during outbreak, with industry speakers emphasising the great utility of human challenge in vaccine development. Public consent, engagement, and participation in human challenge studies were addressed, along with the role of embedded social science and empirical studies to uncover social, ethical, and regulatory issues around human infection challenge studies. Study volunteers shared their experiences and motivations for participating in studies. This report summarises completed and ongoing human challenge studies across a variety of pathogens and demographics, and addresses other key issues discussed at the meeting.
Inflammation of the nasal mucosa is associated with susceptibility to experimental pneumococcal challenge in older adults.
Streptococcus pneumoniae colonization in the upper respiratory tract is linked to pneumococcal disease development, predominantly affecting young children and older adults. As the global population ages and comorbidities increase, there is a heightened concern about this infection. We investigated the immunological responses of older adults to pneumococcal-controlled human infection by analyzing the cellular composition and gene expression in the nasal mucosa. Our comparative analysis with data from a concurrent study in younger adults revealed distinct gene expression patterns in older individuals susceptible to colonization, highlighted by neutrophil activation and elevated levels of CXCL9 and CXCL10. Unlike younger adults challenged with pneumococcus, older adults did not show recruitment of monocytes into the nasal mucosa following nasal colonization. However, older adults who were protected from colonization showed increased degranulation of cluster of differentiation 8+ T cells, both before and after pneumococcal challenge. These findings suggest age-associated cellular changes, in particular enhanced mucosal inflammation, that may predispose older adults to pneumococcal colonization.
A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis.
Myeloproliferative neoplasms are stem cell-driven cancers associated with a large burden of morbidity and mortality. Most patients present with early-stage disease, but a substantial proportion progress to myelofibrosis or secondary leukemia, advanced cancers with a poor prognosis and high symptom burden. Currently, it remains difficult to predict progression, and therapies that reliably prevent or reverse fibrosis are lacking. A major bottleneck to the discovery of disease-modifying therapies has been an incomplete understanding of the interplay between perturbed cellular and molecular states. Several cell types have individually been implicated, but a comprehensive analysis of myelofibrotic bone marrow is lacking. We therefore mapped the cross-talk between bone marrow cell types in myelofibrotic bone marrow. We found that inflammation and fibrosis are orchestrated by a "quartet" of immune and stromal cell lineages, with basophils and mast cells creating a TNF signaling hub, communicating with megakaryocytes, mesenchymal stromal cells, and proinflammatory fibroblasts. We identified the β-galactoside-binding protein galectin-1 as a biomarker of progression to myelofibrosis and poor survival in multiple patient cohorts and as a promising therapeutic target, with reduced myeloproliferation and fibrosis in vitro and in vivo and improved survival after galectin-1 inhibition. In human bone marrow organoids, TNF increased galectin-1 expression, suggesting a feedback loop wherein the proinflammatory myeloproliferative neoplasm clone creates a self-reinforcing niche, fueling progression to advanced disease. This study provides a resource for studying hematopoietic cell-niche interactions, with relevance for cancer-associated inflammation and disorders of tissue fibrosis.
Thymus development
The thymus is the primary lymphoid organ for the generation of T cells. Its formation during the second half of mouse gestation depends on cellular contributions from all germinal layers. Originating from the third pharyngeal pouch endoderm, the early thymus anlage is populated by neural crest-derived mesenchymal cells, endothelial cells, precursor, and mature hematopoietic cells. Collectively, these cell populations create a microenvironment able to generate functionally competent naïve T cells. Spontaneous and engineered gain- and loss-of-function mutations in mice combined with cell fate mapping and single-cell transcriptomic analyses have revealed the molecular mechanisms that govern the fate commitment, differentiation, position, state, and function of a large number of separate, cell populations resident in the embryonic thymus. This information provides to date a comprehensive, albeit yet still incomplete, understanding of how the thymus is formed and how its function is established during embryogenesis.
The recent landscape of RSV vaccine research.
Respiratory syncytial virus (RSV) causes a significant burden of acute respiratory illness across all ages, particularly for infants and older adults. Infants, especially those born prematurely or with underlying health conditions, face a high risk of severe RSV-related lower respiratory tract infections (LRTIs). Globally, RSV contributes to millions of LRTI cases annually, with a disproportionate burden in low- and middle-income countries (LMICs). The RSV virion outer capsule contains glycoproteins G and F which are essential for viral entry into respiratory epithelial cells and represent key targets for therapeutics development. The F-glycoprotein has several highly conserved antigenic sites that have proven useful targets for the development of monoclonal antibodies (mAbs) against RSV. Historically, prevention in infants was limited to the mAb palivizumab, which, despite its efficacy, was costly and inaccessible in many regions. Recent advancements include nirsevimab, a long-acting mAb that has shown substantial efficacy in reducing medically attended RSV-related disease in infants, in phase III clinical trials, early regional and national real-world data. In addition, three new vaccines have been approved: two protein subunit vaccines and a messenger RNA vaccine. The vaccines are all licenced for use in older adults, with one also approved as a maternal vaccine. Promising candidates in development include the mAb clesrovimab, which has an extended half-life and high levels in the nasal epithelial lining and high safety and efficacy profiles in late-stage trials. There are also a wide range of vaccine candidates currently in late-stage clinical trials. These developments signify a major advancement in RSV prevention strategies, offering improved protection for high-risk populations. With the ongoing rollout of the recently licenced vaccines and mAbs internationally, the landscape of RSV care is rapidly changing. We also must ensure these advances reach those in LMICs who need these therapies most.
The Epidemiology and Clinical Burdens of Human Parainfluenza Virus Infections Amongst Hospitalized Children Under 5 Years of Age in Jordan: A National Multi-Center Cross-Sectional Study
Human parainfluenza virus (HPIV) is a major cause of respiratory illnesses in children under five years, with clinical manifestations ranging from mild upper respiratory tract infections to severe lower respiratory tract diseases. This multi-center, cross-sectional study investigated the burden, clinical features, and predictors of respiratory viral infections in hospitalized children across four sites in Jordan. Nasopharyngeal specimens from 1000 eligible children were analyzed. In this article, we focused on HPIV infections. The overall HPIV positivity rate was 22.6%, with HPIV-3 accounting for 90.3% of cases. Significant geographic variability was observed, with higher positivity rates in the southern region. HPIV-positive cases frequently presented with symptoms like nasal congestion, tachypnea, and poor feeding. Co-infections with respiratory syncytial virus (RSV) or influenza were associated with worse outcomes, including an increased need for invasive ventilation. The logistic regression identified male gender, asthma, and respiratory acidosis as predictors of complications. Geographic differences in HPIV prevalence and severity were notable, emphasizing the influence of environmental and socioeconomic factors. These findings underscore the urgent need for enhanced HPIV surveillance, targeted public health interventions, and vaccine development to mitigate the disease burden. This study provides critical insights that guide healthcare strategies and improve outcomes in young children at risk of severe HPIV infections.
The Epidemiology and Health Burdens of Influenza Infections Amongst Hospitalized Children Under 5 Years of Age in Jordan: A National Multi-Center Cross-Sectional Study.
BACKGROUND/OBJECTIVES: Seasonal influenza is a significant global health concern, causing substantial morbidity and mortality, particularly among high-risk groups such as children under five years old. There is scarce local evidence from developing countries such as Jordan on the burden of influenza, which has limited preventive measures. This multi-center national cross-sectional study aimed to assess the epidemiological and clinical burden of influenza among hospitalized children under five years old in Jordan. METHODS: Data were collected from 1000 participants across four hospitals between November 2022 and April 2023. Nasopharyngeal specimens were analyzed using multiplex RT-PCR to determine positivity for influenza A and B. RESULTS: We found a 9.9% positivity rate, predominantly influenza A (8.4%), while influenza B was positive among 1.5% of the participants. Positivity rates were higher in older age groups, particularly children older than 2 years. Influenza-positive cases exhibited longer fever durations and higher rates of sore throat. There were no positive influenza cases among participants if they or any of their family members received the influenza vaccine, highlighting the vaccine's protective role. Logistic regression analysis identified maternal smoking during pregnancy as a significant predictor of influenza positivity. CONCLUSIONS: The findings of this study underscore the need for enhanced vaccination efforts and public health policies targeting young children and pregnant women in Jordan. Expanding vaccination uptake could significantly mitigate the burden of influenza and its complications in this vulnerable population.
A community-based intervention (the Omama Project) improves neurodevelopment in impoverished 2-year-old Roma children: a quasi-experimental observational study.
UNLABELLED: High rates of childhood neurodisability are reported among the Roma, Europe's largest ethnic minority community. Interventions targeting early child development (ECD) during the first 2 years of life can improve neurodevelopmental outcomes in vulnerable children; however, evidence from Roma preschoolers is scarce. In a quasi-experimental observational study, we compared neurodevelopmental outcomes at age 2 years, measured on the INTERGROWTH-21st Project Neurodevelopmental Assessment (INTER-NDA), between Roma children receiving a community-based ECD intervention (RI, n = 98), and age- and sex-matched Roma and non-Roma children (RC, n = 99 and NRC, n = 54, respectively) who did not receive the intervention in Eastern Slovakia. The intervention was delivered between 3 weeks and 20 months in weekly home-based sessions by trained Roma women from matched settlements to RIs. Compared with RC, RI had higher 2-year cognitive (B = 0.15; 95% CI, 0.04, 0.25), language (B = 0.25; 95% CI, 0.11, 0.38) and fine motor (B = 0.08; 95% CI, 0.01, 0.16) scores. After adjustment for covariates, cognitive delay decreased by 88% in RI compared with RC (aOR, 0.12; 95% CI, 0.03, 0.53). Linear growth at 24 months was a key predictor of developmental scores for both groups (range, B = 0.04-0.14; 95% CI, 0.01, 0.07 and 0.09, 0.20). CONCLUSIONS: Our results highlight that, without directly intervening on nutritional and poverty status, a community-based ECD intervention, delivered by trained Roma women to Roma children, can significantly improve neurodevelopmental outcomes at age 2 years. WHAT IS KNOWN: • The Roma are Europe's largest ethnic minority. High rates of neurodisability, malnutrition and poverty are reported in Roma preschoolers. • Optimal early child development (ECD) is foundational to lifecourse health and wellbeing. Early interventions improve ECD outcomes in vulnerable children; however, evidence from Roma communities is limited. WHAT IS NEW: • The Omama project is a community-based ECD intervention, delivered by trained Roma women to Roma children aged 3 weeks to 20 months living in impoverished settlements in Eastern Slovakia. • Roma children receiving the intervention had (i) higher cognitive, language and fine motor scores and (ii) lower rates of cognitive delay compared with controls.
Early neurophysiological markers of aberrant auditory processing associated with increased risk of autism spectrum disorder: A systematic review
Importance: There is a lack of reliable early diagnostic criteria for autism spectrum disorder (ASD), despite earlier diagnosis leading to better outcomes. Objective: To evaluate the association of aberrant auditory processing (AAP) as a potential early marker of ASD risk in children under 2 years old. Methods: A systematic review of studies published between 1985 and September 2024 was conducted by searching PubMed and Web of Science. Results: The review encompassed 18 studies with 140 231 participants, and a majority (76%) of these studies found evidence that early neurophysiological changes in auditory processing are associated with later ASD risk. Specifically, prolonged auditory brainstem response (ABR) latency, reduced social stimuli selectivity, and poorer auditory brain connectivity were correlated with ASD status in later childhood. Notably, auditory habituation did not differ significantly with ASD risk. It's important to recognize that the evidence was somewhat limited by heterogeneity, small sample sizes, and inadequate reporting. Interpretation: This review identified three early neurophysiological AAP markers associated with ASD risk: ABR latency, social stimuli selectivity, and auditory brain coherence. These markers show potential for aiding in earlier ASD risk assessment in young children, potentially leading to earlier interventions. However, to fully establish the association of these AAP markers with ASD as a reliable screening tool during early childhood, future research should focus on standardized experimental protocols and adequately powered prospective cohort studies.
Safety and humoral immunogenicity of the ChAdOx1 nCoV-19 vaccine administered as a fourth dose booster following two doses of ChAdOx1 nCoV-19 and a third dose of BNT162b2 (COV009): A prospective cohort study.
OBJECTIVES: Evaluation of the safety and humoral immunogenicity of ChAdOx1 nCoV-19 as a fourth dose booster in individuals who have had two initial doses of the vaccine and a third dose of BNT162b2. METHODS: COV009 is a safety follow-up study of volunteers enroled in the pivotal pre-licensure ChAdOx1 nCoV-19. In this sub-study, 149 eligible participants were given a fourth dose of ChAdOx1 nCoV-19. Primary outcomes were reactogenicity, safety, and humoral immunogenicity. Anti-spike IgG and pseudo-neutralising antibody against multiple variants were measured from pre-first dose to 28 days post-second and post-fourth dose (third dose samples were unavailable). RESULTS: A fourth dose of ChAdOx1 nCoV-19 had an acceptable safety profile with no vaccine-related serious adverse events. Humoral responses against various SARS CoV-2 variants post-fourth dose were significantly increased compared with the responses after the second dose (7- to 9-fold increase for anti-spike IgG responses across variants, all p<0.05). Those with lower antibody levels prior to the 4th dose had stronger responses to a 4th dose booster. Seropositivity by anti-nucleocapsid, or higher antibody responses pre-fourth dose correlated with lower infection risks six months thereafter (OR: 0.16, 95% CI: 0.05, 0.50). CONCLUSIONS: The ChAdOx1 nCoV-19 fourth dose is well tolerated and boosts humoral immunity; this was evident as an increased humoral response across multiple variants of concern. These data support its use as a booster dose against SARS-CoV-2 infection.
Predictors of severity of SARS-CoV-2 infections in Brazil: Post hoc analyses of a randomised controlled trial.
OBJECTIVES: To identify demographic, clinical and immunological factors associated with adverse COVID-19 outcomes. METHODS: A large randomised controlled trial of ChAdOx1 nCoV-19 was undertaken in Brazil. Participants were randomised 1:1 either to receive ChAdOx1 nCov-19 or to a control group. COVID-19 infections were confirmed by nucleic acid amplification test (NAAT) and classified using the WHO clinical progression scale. Anti-spike antibody responses and serum neutralising activity were measured 28 days after second vaccination in some participants. Exploratory analyses were conducted into factors associated with COVID-19 infection severity and hospitalisation, using logistic regression models adjusted for demographic and clinical factors. RESULTS: 10,416 participants were enrolled; 1790 had NAAT-positive COVID-19 infection; 63 cases required hospitalisation. More severe infection was associated with greater body-mass index (BMI) (odds ratio [OR] = 1.06 [95 %CI: 1.01-1.10], p = 0.01) and diabetes (OR = 3.67 [1.59-8.07], p = 0.003). Hospitalisation risk increased with greater age (OR = 1.06 [1.03-1.08], p 180 days after last vaccination. In the fully vaccinated subgroup (n = 841), only greater age predicted hospitalisation (OR = 1.07 [1.03-1.12], p
Ebola disease: bridging scientific discoveries and clinical application.
The west Africa Ebola disease epidemic (2014-16) marked a historic change of course for patient care during emerging infectious disease outbreaks. The epidemic response was a failure in many ways-a slow, cumbersome, and disjointed effort by a global architecture that was not fit for purpose for a rapidly spreading outbreak. In the most affected countries, health-care workers and other responders felt helpless-dealing with an overwhelming number of patients but with few, if any, tools at their disposal to provide high-quality care. These inadequacies, however, led to attention and innovation. The decade since then has seen remarkable achievements in clinical care for Ebola disease, including the approval of the first vaccines and treatments. In this paper, the first in a two-part Series, we reflect on this progress and provide expert summary of the modern landscape of Ebola disease, highlighting the priorities and ongoing activities aimed at further improving patient survival and wellbeing in the years ahead.
Safety and efficacy of the blood-stage malaria vaccine RH5.1/Matrix-M in Burkina Faso: interim results of a double-blind, randomised, controlled, phase 2b trial in children.
BACKGROUND: Two pre-erythrocytic vaccines (R21/Matrix-M and RTS,S/AS01) are now approved for Plasmodium falciparum malaria. However, neither induces blood-stage immunity against parasites that break through from the liver. RH5.1/Matrix-M, a blood-stage P falciparum malaria vaccine candidate, was highly immunogenic in Tanzanian adults and children. We therefore assessed the safety and efficacy of RH5.1/Matrix-M in Burkinabe children. METHODS: In this double-blind, randomised, controlled, phase 2b trial, RH5.1/Matrix-M was given to children aged 5-17 months in Nanoro, Burkina Faso, a seasonal malaria transmission setting. Children received either three intramuscular vaccinations with 10 μg RH5.1 protein with 50 μg Matrix-M adjuvant or three doses of rabies control vaccine, Rabivax-S, given either in a delayed third-dose (0, 1, and 5 month) regimen (first cohort) or a 0, 1, and 2 month regimen (second cohort). Vaccinations were completed part way through the malaria season. Children were randomly assigned 2:1 within each cohort to receive RH5.1/Matrix-M or Rabivax-S. Participants were assigned according to a random allocation list generated by an independent statistician using block randomisation with variable block sizes. Participants, their families, and the study teams were masked to group allocation; only pharmacists who prepared the vaccines were unmasked. Vaccine safety, immunogenicity, and efficacy were evaluated. The coprimary outcomes assessed were: first, the safety and reactogenicity of RH5.1/Matrix-M; and second, the protective efficacy of RH5.1/Matrix-M against clinical malaria (measured as time to first episode of clinical malaria, using a Cox regression model) from 14 days to 6 months after the third vaccination in the per-protocol sample. This ongoing trial is registered with ClinicalTrials.gov (NCT05790889). FINDINGS: From April 6 to 13 and July 3 to 7, 2023, 412 children aged 5-17 months were screened, and 51 were excluded. A total of 361 children were enrolled in this study. In the first cohort, 119 were assigned to the RH5.1/Matrix-M delayed third-dose group, and 62 to the equivalent rabies control group. The second cohort included 120 children in the monthly RH5.1/Matrix-M group and 60 in the equivalent rabies control group. The final vaccination was administered to all groups from Sept 4 to 21, 2023. RH5.1/Matrix-M in both cohorts had a favourable safety profile and was well tolerated. Most adverse events were mild, with the most common being local swelling and fever. No serious adverse events were reported. Comparing the RH5.1/Matrix-M delayed third-dose regimen with the pooled control groups resulted in a vaccine efficacy of 55% (95% CI 20 to 75%; p=0·0071). The same analysis showed a vaccine efficacy of 40% (-3 to 65%; p=0·066) when comparing the monthly regimen with the pooled control groups. Participants vaccinated with RH5.1/Matrix-M in both cohorts showed high concentrations of anti-RH5.1 serum IgG antibodies 14 days after the third vaccination, and the purified IgG showed high levels of in vitro growth inhibition activity against P falciparum; these responses were higher in patients who received the RH5.1/Matrix-M vaccine delayed third-dose regimen, as opposed to monthly regimen (growth inhibition activity 79·0% [SD 14·3] vs 74·2% [SD 15·9]; p=0·016). INTERPRETATION: RH5.1/Matrix-M appears safe and highly immunogenic in African children and shows promising efficacy against clinical malaria when given in a delayed third-dose regimen. This trial is ongoing to further monitor efficacy over time. FUNDING: The European and Developing Countries Clinical Trials Partnership, the UK Medical Research Council, the National Institute for Health and Care Research Oxford Biomedical Research Centre, the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, the US Agency for International Development, and the Wellcome Trust.
Immunogenicity and safety of beta variant COVID-19 vaccine AZD2816 and AZD1222 (ChAdOx1 nCoV-19) as primary-series vaccination for previously unvaccinated adults in Brazil, South Africa, Poland, and the UK: a randomised, partly double-blinded, phase 2/3 non-inferiority immunobridging study.
BACKGROUND: AZD2816 is a variant-adapted COVID-19 vaccine that expresses the full-length SARS-CoV-2 beta variant spike protein but is otherwise similar to AZD1222 (ChAdOx1 nCoV-19). This study aimed to evaluate the safety and immunogenicity of AZD1222 or AZD2816 (or both) primary-series vaccination in a cohort of adult participants who were previously unvaccinated. METHODS: In this phase 2/3, randomised, multinational, active-controlled, non-inferiority, immunobridging study, adult participants previously unvaccinated for COVID-19 were enrolled at 16 study sites in Brazil, South Africa, Poland, and the UK. Participants were stratified by age, sex, and comorbidity and randomly assigned 5:5:5:2 to receive a primary series of AZD1222 (AZD1222 group), AZD2816 (AZD2816 [4-week] group), or AZD1222-AZD2816 (AZD1222-AZD2816 group) at 4-week dosing intervals, or AZD2816 at a 12-week interval (AZD2816 [12-week] group) and evaluated for safety and immunogenicity through 180 days after dose 2. Primary outcomes were safety (rates of solicited adverse events occurring during 7 days and unsolicited adverse events occurring during 28 days after each dose) and immunogenicity (non-inferiority of pseudovirus neutralising antibody geometric mean titre [GMT], GMT ratio margin of 0·67, and seroresponse rate, rate difference margin of -10%, recorded 28 days after dose 2 with AZD2816 [4-week interval] against beta vs AZD1222 against ancestral SARS-CoV-2) in participants who were seronegative at baseline. This trial is registered with ClinicalTrials.gov, NCT04973449, and is completed. FINDINGS: Between July 7 and Nov 12, 2021, 1449 participants were assigned to the AZD1222 group (n=413), the AZD2816 (4-week) group (n=415), the AZD1222-AZD2816 group (n=412), and the AZD2816 (12-week) group (n=209). Ten (2·6%) of 378 participants who were seronegative at baseline in the AZD1222 group, nine (2·4%) of 379 in the AZD2816 (4-week) group, eight (2·1%) of 380 in the AZD1222-AZD2816 group, and 11 (5·8%) of 191 in the AZD2816 (12-week) group had vaccine-related unsolicited adverse events. Serious adverse events were recorded in one (0·3%) participant in the AZD1222 group, one (0·3%) in the AZD2816 (4-week) group, two (0·5%) in the AZD1222-AZD2816 group, and none in the AZD2816 (12-week) group. Co-primary immunogenicity endpoints were met: neutralising antibody GMT (ratio 1·19 [95% CI 1·08-1·32]; lower bound greater than 0·67) and seroresponse rate (difference 1·7% [-3·1 to 6·5]; lower bound greater than -10%) at 28 days after dose 2 were non-inferior in the AZD2816 (4-week) group against beta versus in the AZD1222 group against ancestral SARS-CoV-2. Seroresponse rates were highest with AZD2816 against beta (12-week interval 94·3% [95% CI 89·4-97·3]; 4-week interval 85·7% [81·5-89·2]) and with AZD1222 (84·6% [80·3-88·2]) against ancestral SARS-CoV-2. INTERPRETATION: Primary series of AZD1222 and AZD2816 were well tolerated, with no emergent safety concerns. Both vaccines elicited robust immunogenicity against beta and ancestral SARS-CoV-2 with greater responses demonstrated when testing against SARS-CoV-2 strains that matched those targeted by the respective vaccine. These findings demonstrate the continued importance of ancestral COVID-19 vaccines in protecting against severe COVID-19 and highlight the feasibility of using the ChAdOx1 platform to develop COVID-19 vaccines against future SARS-CoV-2 variants. FUNDING: AstraZeneca.