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A letter to the editor is presented about the first case of acute necrotising encephalitis (ANE) in a child associated with the H1N1 virus in Great Britain.

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in variants that can escape neutralization by therapeutic antibodies. Here, we describe AZD3152, a SARS-CoV-2-neutralizing monoclonal antibody designed to provide improved potency and coverage against emerging variants. AZD3152 binds to the back left shoulder of the SARS-CoV-2 spike protein receptor binding domain and prevents interaction with the human angiotensin-converting enzyme 2 receptor. AZD3152 potently neutralized a broad panel of pseudovirus variants, including the currently dominant Omicron variant JN.1 but has reduced potency against XBB subvariants containing F456L. In vitro studies confirmed F456L resistance and additionally identified T415I and K458E as escape mutations. In a Syrian hamster challenge model, prophylactic administration of AZD3152 protected hamsters from weight loss and inflammation-related lung pathologies and reduced lung viral load. In the phase 1 sentinel safety cohort of the ongoing SUPERNOVA study (ClinicalTrials.gov: NCT05648110), a single 600-mg intramuscular injection of AZD5156 (containing 300 mg each of AZD3152 and cilgavimab) was well tolerated in adults through day 91. Observed serum concentrations of AZD3152 through day 91 were similar to those observed with cilgavimab and consistent with predictions for AZD7442, a SARS-CoV-2-neutralizing antibody combination of cilgavimab and tixagevimab, in a population pharmacokinetic model. On the basis of its pharmacokinetic characteristics, AZD3152 is predicted to provide durable protection against symptomatic coronavirus disease 2019 caused by susceptible SARS-CoV-2 variants, such as JN.1, in humans.

Introduction: In the phase 3 TACKLE study, outpatient treatment with AZD7442 (tixagevimab/cilgavimab) was well tolerated and significantly reduced progression to severe disease or death through day 29 in adults with mild-to-moderate coronavirus disease 2019 (COVID-19) at the primary analysis. Here, we report data from the final analysis of the TACKLE study, performed after approximately 15 months' follow-up., Methods: Eligible participants were randomized 1:1 and dosed within 7 days of symptom onset with 600 mg intramuscular AZD7442 (n = 456; 300 mg tixagevimab/300 mg cilgavimab) or placebo (n = 454)., Results: Severe COVID-19 or death through day 29 occurred in 4.4% and 8.8% of participants who received AZD7442 or placebo, a relative risk reduction (RRR) of 50.4% [95% confidence interval (CI) 14.4, 71.3; p = 0.0096]; among participants dosed within 5 days of symptom onset, the RRR was 66.9% (95% CI 31.1, 84.1; p = 0.002). Death from any cause or hospitalization for COVID-19 complications or sequelae through day 169 occurred in 5.0% of participants receiving AZD7442 versus 9.7% receiving placebo, an RRR of 49.2% (95% CI 14.7, 69.8; p = 0.009). Adverse events occurred in 55.5% and 55.9% of participants who received AZD7442 or placebo, respectively, and were mostly mild or moderate in severity. Serious adverse events occurred in 10.2% and 14.4% of participants who received AZD7442 or placebo, respectively, and deaths occurred in 1.8% of participants in both groups. Serum concentration-time profiles recorded over 457 days were similar for AZD7442, tixagevimab, and cilgavimab, and were consistent with the extended half-life reported for AZD7442 (approx. 90 days)., Conclusions: AZD7442 reduced the risk of progression to severe COVID-19, hospitalization, and death, was well tolerated through 15 months, and exhibited predictable pharmacokinetics in outpatients with mild-to-moderate COVID-19. These data support the long-term safety of using long-acting monoclonal antibodies to treat COVID-19., Trial Registration: Clinicaltrials.gov, NCT04723394. ( https://clinicaltrials.gov/study/NCT04723394 ., (© 2024. The Author(s).)

Background: This study aimed to evaluate AZD2816, a variant-updated COVID-19 vaccine expressing the full-length SARS-CoV-2 beta (B.1.351) variant spike protein that is otherwise similar to AZD1222 (ChAdOx1 nCoV-19), and AZD1222 as third-dose boosters., Methods: This phase 2/3, partly double-blinded, randomised, active-controlled study was done at 19 sites in the UK and four in Poland. Adult participants who had received a two-dose AZD1222 or mRNA vaccine primary series were randomly assigned by means of an Interactive Response Technology-Randomisation and Trial Supply Management system (1:1 within each primary-series cohort, stratified by age, sex, and comorbidities) to receive AZD1222 or AZD2816 (intramuscular injection; 5 × 10 10 viral particles). Participants, investigators, and all sponsor staff members involved in study conduct were masked to randomisation. AZD1222 and AZD2816 doses were prepared by unmasked study staff members. The primary objectives were to evaluate safety and humoral immunogenicity (non-inferiority of day-29 pseudovirus neutralising antibody geometric mean titre [GMT] against ancestral SARS-CoV-2: AZD1222 booster vs AZD1222 primary series [historical controls]; margin 0·67; SARS-CoV-2-seronegative participants). This study is registered with ClinicalTrials.gov, NCT04973449, and is completed., Findings: Between June 27 and Sept 30, 2021, 1394 participants of the 1741 screened were randomly assigned to AZD1222 or AZD2816 following an AZD1222 (n=373, n=377) or mRNA vaccine (n=322, n=322) primary series. In SARS-CoV-2-seronegative participants receiving AZD1222 or AZD2816, 78% and 80% (AZD1222 primary series) and 90% and 93%, respectively (mRNA vaccine primary series) reported solicited adverse events to the end of day 8; 2%, 2%, 1%, and 1% had serious adverse events and 12%, 12%, 10%, and 11% had adverse events of special interest, respectively, to the end of day 180. The primary immunogenicity non-inferiority endpoint was met: day-29 neutralising antibody GMT ratios (ancestral SARS-CoV-2) were 1·02 (95% CI 0·90-1·14) and 3·47 (3·09-3·89) with AZD1222 booster versus historical controls (AZD1222 and mRNA vaccine primary series, respectively). Responses against beta were greater with AZD2816 versus AZD1222 (GMT ratios, AZD1222, mRNA vaccine primary series 1·84 [1·63-2·08], 2·22 [1·99-2·47])., Interpretation: Both boosters were well tolerated, with immunogenicity against ancestral SARS-CoV-2 similar to AZD1222 primary-series vaccination. AZD2816 gave greater immune responses against beta versus AZD1222., Funding: AstraZeneca., Competing Interests: Declaration of interests MNR declares institutional support for the study from AstraZeneca. EJK, SS, AC, MK, GTT, JV, PAS, MNP, TV, NM-A, and JAG are, or were, employees of and may hold (or have held) stock or stock options in AstraZeneca. PID declares institutional support for the study from AstraZeneca, and institutional grants from AstraZeneca, Janssen, Moderna, and Atea. RP declares institutional support for the study from AstraZeneca. MA declares support for the study from AstraZeneca and IQVIA to the Clinical Infection Research Group. PKA declares institutional grants to support the conduct of the study from AstraZeneca and the UK Vaccine Taskforce via National Institute for Health Research (NIHR). BJ is an employee of Cytel and is currently on assignment to AstraZeneca. SM is an employee of Exploristics and is currently on assignment to AstraZeneca. TL reports consulting fees from Vaccitech on an unrelated project, an honorarium from Seqirus, grant support from the Vaccine Taskforce for this trial, work-related investments, and is named as an inventor on a patent application for a vaccine against SARS-CoV-2. AJP was a member of WHO's Strategic Advisory Group of Experts on Immunization until January, 2022 and remains chair of the UK Department of Health and Social Care's Joint Committee on Vaccination and Immunisation (JCVI) but does not participate in the JCVI COVID-19 committee; and reports providing advice to Shionogi on COVID-19, and funding from the NIHR, AstraZeneca, the Bill & Melinda Gates Foundation, Wellcome, the Medical Research Council, and the Coalition for Epidemic Preparedness Innovations. Oxford University has entered into a partnership with AstraZeneca for the development of COVID-19 vaccines. VL and SB declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Currently, data on treatment, outcome, and prognostic factors in children with tuberculous meningitis (TBM) in Europe are limited. To date, most existing data on TBM originate from adult studies, or studies conducted in low-resource settings., Methods: We designed a multicenter, retrospective study involving 27 pediatric healthcare institutions in 9 European countries via an established pediatric TB research network, before and after the 2014 revision of World Health Organization (WHO) dosing recommendations., Results: Of 118 children, 39 (33.1%) had TBM grade 1, 68 (57.6%) grade 2, and 11 (9.3%) grade 3. Fifty-eight (49.1%) children received a standard 4-drug treatment regimen; other commonly used drugs included streptomycin, prothionamide, and amikacin. Almost half of the patients (48.3%; 56/116) were admitted to intensive care unit, with a median stay of 10 (interquartile range [IQR] 4.5-21.0) days. Of 104 children with complete outcome data, 9.6% (10/104) died, and only 47.1% (49/104) recovered fully. Main long-term sequelae included spasticity of 1 or more limbs and developmental delay both in 19.2% (20/104), and seizure disorder in 17.3% (18/104). Multivariate regression analyses identified microbiological confirmation of TBM, the need for neurosurgical intervention, and mechanical ventilation as risk factors for unfavorable outcome., Conclusions: There was considerable heterogeneity in the use of TB drugs in this cohort. Despite few children presenting with advanced disease and the study being conducted in a high-resource setting, morbidity and mortality were high. Several risk factors for poor outcome were identified, which may aid prognostic predictions in children with TBM in the future., Competing Interests: Potential conflicts of interest. M. Te. has received QuantiFERON assays at reduced pricing or free of charge for other TB diagnostics projects from the manufacturer (Cellestis/Qiagen) and has received support for conference attendance from Cepheid. B. G.-S. has received diagnostic assays free of charge for other projects from Cepheid, and support for conference attendance from GlaxoSmithKline (GSK). D. B.-G. has received payments as speaker at conferences from MSD and Roche. M. Ts. has received payments from MSD, Pfizer, Sanofi-Pasteur, and GSK for other clinical studies and participation in advisory boards. F. B. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MSD. A. N.-J. reports being supported by Subvencions per a la Intensificació de Facultatius Especialistes (Departament de Salut de la Generalitat de Catalunya, Programa PERIS 2016–2020; ref. SLT008/18/00193). D. B. reports participating at the Qiagen advisory board on IGRAs in children in May 2021. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Following exposure to TB, contacts are screened to target preventive treatment at those at high risk of developing TB. The UK has recently revised its recommendations for screening and now advises a 5 mm tuberculin skin test (TST) cut-off irrespective of age or BCG status. We sought to evaluate the impact of BCG on TST responses in UK children exposed to TB and the performance of different TST cut-offs to predict interferon γ release assay (IGRA) positivity., Methods: Children <15 years old were recruited from 11 sites in the UK between January 2011 and December 2014 if exposed in their home to a source case with sputum smear or culture positive TB. Demographic details were collected and TST and IGRA undertaken. The impact of BCG vaccination on TST positivity was evaluated in IGRA-negative children, as was the performance of different TST cut-offs to predict IGRA positivity., Results: Of 422 children recruited (median age 69 months; IQR: 32-113 months), 300 (71%) had been vaccinated with BCG. BCG vaccination affected the TST response in IGRA-negative children less than 5 years old but not in older children. A 5 mm TST cut-off demonstrated good sensitivity and specificity in BCG-unvaccinated children, and an excellent negative predictive value but was associated with low specificity (62.7%; 95% CI 56.1% to 69.0%) in BCG-vaccinated children. For BCG-vaccinated children, a 10 mm cut-off provided a high negative predictive value (97.7%; 95% CI 94.2% to 99.4%) with the positive predictive value increasing with increasing age of the child., Discussion: BCG vaccination had little impact on TST size in children over 5 years of age. The revised TST cut-off recommended in the recent revision to the UK TB guidelines demonstrates good sensitivity but is associated with impaired specificity in BCG-vaccinated children., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The performance of the Enigma MiniLab assay for influenza A and B viruses and respiratory syncytial virus (RSV) was compared to a centralized laboratory respiratory virus panel. The positive and negative percent agreement for influenza A virus, influenza B virus, and RSV were 79.2% (95% confidence interval [95% CI], 57.8 to 92.9%) and 99.4% (95% CI, 98.4 to 99.9), 100% (95% CI, 47.8 to 100%) and 100% (95% CI, 99.3 to 100%), 98.5% (95% CI, 94.6 to 99.8%) and 94.5% (95% CI, 91.9 to 96.4%), respectively., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Unlabelled: Human parechoviruses (HPeVs) cause a spectrum of disease ranging from self-limiting illness to severe disease and, sometimes, death. We describe the clinical characteristics and outcomes of HPeV infection in infants. The study describes the clinical and laboratory characteristics and outcomes of infants with HPeV infection during 2008-2012, from three paediatric hospitals in London each with a paediatric intensive care unit. The infants were retrospectively identified through laboratory and patient discharge databases and diagnosed through HPeV PCR. Fifty infants were identified. Half required admission to PICU. Infants less than 3 months were more likely to require PICU (16/25: p < 0.01). Clinical signs at presentation were often indistinguishable from those of bacterial sepsis and meningitis, but inflammatory markers were nearly always (95 % of cases) within normal ranges. Brain MRI showed white matter changes in 10/12 infants. Three of 19 infants with follow-up data (16 %) had significant neurological sequelae., Conclusion: HPeV may cause severe disease and long-term neurological sequelae in young infants. HPeV should be considered in infants with clinical features of sepsis/meningitis with normal CSF microscopy. Prospective observational studies are warranted to better define the epidemiology of infection and thus inform future treatment trials.

Purpose: Adenosine deaminase (ADA) deficiency is a systemic disorder of purine metabolism. Deficiency of the purine salvage enzyme ADA leads to the build-up of the toxic metabolites, deoxyadenosine triphosphate and deoxyadenosine. ADA is ubiquitously expressed in all tissues of the body but most profoundly affects lymphocyte development and function leading to severe combined immunodeficiency (SCID). Unlike most other forms of SCID, ADA deficiency also results in non-immunologic manifestations. Associations between ADA deficiency and sensorineural hearing loss, behavioural abnormalities, non-infectious pulmonary disease and skeletal dysplasia are all recognised, and affect the long term outcome for these patients. Identification of new non-immunological manifestations and clinical presentations of ADA deficiency is essential to allow early optimisation of supportive care., Methods and Results: Here we report four patients with ADA deficiency whose presenting feature was haemolytic uremic syndrome (HUS). 3 of 4 patients were diagnosed with ADA deficiency only after developing HUS, and one diagnosis was made post mortem, after a sibling was diagnosed with SCID. Shiga-toxigenic organisms were not isolated from any of the patients. 2 patients made a good recovery from their HUS with supportive treatment and initiation of PEG-ADA. Both remain well on enzyme replacement with mild or no residual renal impairment., Conclusions: Clinicians should be aware of this previously unreported non-immunologic manifestation of ADA deficiency.

Background: The aim of this study is to evaluate vitamin D levels in children with latent and active TB compared to healthy controls of the same age and ethnical background., Methods: A multicenter observational study has been conducted in three tertiary care paediatric centres: Anna Meyer Children's University Hospital, Florence, Italy; Evelina London Children's Hospital, London, United Kingdom and Great Ormond Street Hospital, London, United Kingdom. Vitamin D was considered deficient if the serum level was <25 nmol/L, insufficient between 25 and 50 nmol/L and sufficient for a level >50 nmol/L., Results: The study population included 996 children screened for TB, which have been tested for vitamin D. Forty-four children (4.4%) had active TB, 138 (13.9%) latent TB and 814 (81.7%) were controls. Our study confirmed a high prevalence of hypovitaminosis D in the study population. A multivariate analysis confirmed an increased risk of hypovitaminosis D in children with latent and active TB compared to controls [(P = 0.018; RR = 1.61; 95% CI: 1.086-2.388), (P < 0.0001; RR = 4.587; 95% CI:1.190-9.608)]., Conclusions: Hypovitaminosis D was significantly associated with TB infection in our study. Further studies are needed to evaluate a possible role of vitamin D in the treatment and prevention of tuberculosis in children.

Data are lacking on the performance of interferon-gamma release assays (IGRAs) in children. Although IGRAs are recommended for screening for latent tuberculosis infection (LTBI), many clinicians wish to employ them as a diagnostic test for active tuberculosis (TB). The objective of the present study was to compare the performance of the two commercially available IGRAs and the tuberculin skin test (TST) side-by-side in children with active TB and LTBI. In a prospective study, 209 children were investigated for active (n = 91) or latent TB (n = 118). TST, QuantiFERON-TB Gold In-tube (QFG-IT; Cellestis, Carnegie, Australia) and T-SPOT.TB (Oxford Immunotec, Abingdon, UK) assays were simultaneously used. For culture-confirmed active TB, the sensitivity of the TST was 83%, compared with 80% for QFG-IT and 58% for T-SPOT.TB. IGRAs did not perform significantly better than TST, although QFG-IT was significantly better than T-SPOT.TB. The agreement between QFG-IT and T-SPOT.TB in culture-confirmed TB was poor at 66.7%. In LTBI, the agreement between QFG-IT and T-SPOT.TB was very good (92%) with moderate agreement between TST and T-SPOT.TB (75%) and QFG-IT and TST (77%). A negative interferon-gamma release assay should not dissuade paediatricians from diagnosing and treating presumed active tuberculosis. If used for diagnosis of latent tuberculosis infection, interferon-gamma release assays could significantly reduce the numbers of children receiving chemoprophylaxis. Very good concordance between both tests was found.