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Identifying and reducing risks of neurological complications associated with vaccination.
Vaccines protect against many infectious diseases, including some that can directly or indirectly cause nervous system damage. Serious neurological consequences of immunization are typically extremely rare, although they have the potential to jeopardize vaccination programmes, as demonstrated most recently during the COVID-19 pandemic. Neurologists have an important role in identifying safety signals at population and individual patient levels, as well as providing advice on the benefit-risk profile of vaccination in cohorts of patients with diverse neurological conditions. This article reviews the links between vaccination and neurological disease and considers how emerging signals can be evaluated and their mechanistic basis identified. We review examples of neurotropic infections with live attenuated vaccines, as well as neuroimmunological and neurovascular sequelae of other types of vaccines. We emphasize that such risks are typically dwarfed by neurological complications associated with natural infection and discuss how the risks can be further mitigated. The COVID-19 pandemic has highlighted the need to rapidly identify and minimize neurological risks of vaccination, and we review the structures that need to be developed to protect public health against these risks in the future.
Implementation and adherence to regular asymptomatic testing in a COVID-19 vaccine trial.
BACKGROUND: For pathogens which cause infections that present asymptomatically, evaluating vaccine efficacy (VE) against asymptomatic infection is important for understanding a vaccine's potential epidemiological impact. Regular testing for subclinical infections is a potentially valuable strategy but its success hinges on participant adherence and minimising false positives. This paper describes the implementation and adherence to weekly testing in a COVID-19 vaccine trial. METHODS: COV002 was a phase 2/3 trial assessing the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2. Asymptomatic infections were detected using weekly self-administered swabs for RT-PCR testing. We analysed adherence using mixed-effects regression models and estimated the probability of true and false positive asymptomatic infections using estimates of adherence and testing characteristics. FINDINGS: 356,551 tests were self-administered by 10,811 participants during the 13-month follow-up. Median adherence was 75.0% (IQR 42·6-90·9), which translated to a 74·5% (IQR 50·9-78·8) probability of detecting a positive asymptomatic infection during the swabbing period, and between 21 and 96 false positives during VE evaluation. The odds of returning a swab declined by 8% per week and further after testing positive and unblinding. Adherence was higher in older age groups, females and non-healthcare workers. INTERPRETATION: The COV002 trial demonstrated the feasibility of running a long-term regular asymptomatic testing strategy. This information could be valuable for designing future phase III vaccine trials in which infection is an outcome. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, AstraZeneca.
What defines an efficacious COVID-19 vaccine? A review of the challenges assessing the clinical efficacy of vaccines against SARS-CoV-2.
The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused more than 1 million deaths in the first 6 months of the pandemic and huge economic and social upheaval internationally. An efficacious vaccine is essential to prevent further morbidity and mortality. Although some countries might deploy COVID-19 vaccines on the strength of safety and immunogenicity data alone, the goal of vaccine development is to gain direct evidence of vaccine efficacy in protecting humans against SARS-CoV-2 infection and COVID-19 so that manufacture of efficacious vaccines can be selectively upscaled. A candidate vaccine against SARS-CoV-2 might act against infection, disease, or transmission, and a vaccine capable of reducing any of these elements could contribute to disease control. However, the most important efficacy endpoint, protection against severe disease and death, is difficult to assess in phase 3 clinical trials. In this Review, we explore the challenges in assessing the efficacy of candidate SARS-CoV-2 vaccines, discuss the caveats needed to interpret reported efficacy endpoints, and provide insight into answering the seemingly simple question, "Does this COVID-19 vaccine work?"
Multi-omics analysis reveals COVID-19 vaccine induced attenuation of inflammatory responses during breakthrough disease.
The immune mechanisms mediating COVID-19 vaccine attenuation of COVID-19 remain undescribed. We conducted comprehensive analyses detailing immune responses to SARS-CoV-2 virus in blood post-vaccination with ChAdOx1 nCoV-19 or a placebo. Samples from randomised placebo-controlled trials (NCT04324606 and NCT04400838) were taken at baseline, onset of COVID-19-like symptoms, and 7 days later, confirming COVID-19 using nucleic amplification test (NAAT test) via real-time PCR (RT-PCR). Serum cytokines were measured with multiplexed immunoassays. The transcriptome was analysed with long, short and small RNA sequencing. We found attenuation of RNA inflammatory signatures in ChAdOx1 nCoV-19 compared with placebo vaccinees and reduced levels of serum proteins associated with COVID-19 severity. KREMEN1, a putative alternative SARS-CoV-2 receptor, was downregulated in placebo compared with ChAdOx1 nCoV-19 vaccinees. Vaccination ameliorates reductions in cell counts across leukocyte populations and platelets noted at COVID-19 onset, without inducing potentially deleterious Th2-skewed immune responses. Multi-omics integration links a global reduction in miRNA expression at COVID-19 onset to increased pro-inflammatory responses at the mRNA level. This study reveals insights into the role of COVID-19 vaccines in mitigating disease severity by abrogating pro-inflammatory responses associated with severe COVID-19, affirming vaccine-mediated benefit in breakthrough infection, and highlighting the importance of clinically relevant endpoints in vaccine evaluation.
Evaluating the Impact of the BioFire FilmArray in Childhood Meningitis: An Observational Cohort Study.
BACKGROUND: Multiplex polymerase chain reaction assays have the potential to reduce antibiotic use and shorten length of inpatient stay in children with suspected central nervous system infection by obtaining an early microbiological diagnosis. The clinical impact of the implementation of the BioFire FilmArray Meningitis/Encephalitis Panel on the management of childhood meningitis was evaluated at the John Radcliffe Hospital in Oxford and Children's Health Ireland at Temple Street in Dublin. METHODS: Children who had lumbar punctures performed as part of a septic screen were identified retrospectively through clinical discharge coding and microbiology databases from April 2017 to December 2018. Anonymized clinical and laboratory data were collected. Comparison of antibiotic use, length of stay and outcome at discharge was made with a historical cohort in Oxford (2012-2016), presenting before implementation of the FilmArray. RESULTS: The study included 460 children who had a lumbar puncture as part of an evaluation for suspected central nervous system infection. Twelve bacterial cases were identified on the FilmArray that were not detected by conventional bacterial culture. Bacterial culture identified one additional case of bacterial meningitis, caused by Escherichia coli , which had not been identified on the FilmArray. Duration of antibiotics was shorter in children when FilmArray was used than before its implementation; enterovirus meningitis (median: 4 vs. 5 days), human parechovirus meningitis (median: 4 vs. 4.5 days) and culture/FilmArray-negative cerebrospinal fluid (median: 4 vs. 6 days). CONCLUSIONS: The use of a FilmArray can identify additional bacterial cases of meningitis in children that had been negative by traditional culture methods. Children with viral meningitis and culture-negative meningitis received shorter courses of antibiotics and had shorter hospital stays when FilmArray was used. Large studies to evaluate the clinical impact and cost effectiveness of incorporating the FilmArray into routine testing are warranted.
Management of neonatal central nervous system viral infections: Knowledge gaps and research priorities.
Congenital CMV, enteroviruses, human parechovirus and herpes simplex virus are all common causes of severe central nervous system (CNS) infection in neonates. The introduction of screening (i.e. newborn hearing screening programme), integration of molecular syndromic testing (i.e. multiplex polymerase chain reaction assays) and increase in sexually transmitted infections (i.e. anogenital herpes) have contributed to increases in each of these infections over the last decade. However, therapeutic options are highly limited in part due to the lack of epidemiological data informing trials. This review will describe our current understanding of the clinical burden and epidemiology of these severe neonatal CNS infections, outline the novel antiviral and vaccines in the pipeline and suggest future research studies which could help develop new therapeutics.
Changes in preterm birth and stillbirth during COVID-19 lockdowns in 26 countries.
Preterm birth (PTB) is the leading cause of infant mortality worldwide. Changes in PTB rates, ranging from -90% to +30%, were reported in many countries following early COVID-19 pandemic response measures ('lockdowns'). It is unclear whether this variation reflects real differences in lockdown impacts, or perhaps differences in stillbirth rates and/or study designs. Here we present interrupted time series and meta-analyses using harmonized data from 52 million births in 26 countries, 18 of which had representative population-based data, with overall PTB rates ranging from 6% to 12% and stillbirth ranging from 2.5 to 10.5 per 1,000 births. We show small reductions in PTB in the first (odds ratio 0.96, 95% confidence interval 0.95-0.98, P value <0.0001), second (0.96, 0.92-0.99, 0.03) and third (0.97, 0.94-1.00, 0.09) months of lockdown, but not in the fourth month of lockdown (0.99, 0.96-1.01, 0.34), although there were some between-country differences after the first month. For high-income countries in this study, we did not observe an association between lockdown and stillbirths in the second (1.00, 0.88-1.14, 0.98), third (0.99, 0.88-1.12, 0.89) and fourth (1.01, 0.87-1.18, 0.86) months of lockdown, although we have imprecise estimates due to stillbirths being a relatively rare event. We did, however, find evidence of increased risk of stillbirth in the first month of lockdown in high-income countries (1.14, 1.02-1.29, 0.02) and, in Brazil, we found evidence for an association between lockdown and stillbirth in the second (1.09, 1.03-1.15, 0.002), third (1.10, 1.03-1.17, 0.003) and fourth (1.12, 1.05-1.19, <0.001) months of lockdown. With an estimated 14.8 million PTB annually worldwide, the modest reductions observed during early pandemic lockdowns translate into large numbers of PTB averted globally and warrant further research into causal pathways.
Resurgence of congenital syphilis: new strategies against an old foe.
Congenital syphilis is a major global cause of fetal loss, stillbirth, neonatal death, and congenital infection. In 2020, the global rate of congenital syphilis was 425 cases per 100 000 livebirths-substantially higher than WHO's elimination target of 50 cases per 100 000 livebirths. Case rates are rising in many high-income countries, but remain low compared with those in low-income and middle-income settings. This Review aims to summarise the current epidemiology and knowledge on transmission and treatment of syphilis in pregnancy, and proposes measures to reduce the rising incidence seen worldwide. We also describe emerging diagnostic and treatment tools to prevent vertical transmission and improve management of congenital syphilis. Finally, we outline a programme of public health priorities, which include research, clinical, and preventive strategies.
Indirect effects of cytomegalovirus infection: Implications for vaccine development.
Development of a cytomegalovirus (CMV) vaccine is a high priority due to its significant global impact-contributing to mortality in immunosuppressed individuals, neurodevelopmental delay in infected neonates and non-genetic sensorineural hearing loss. The impact of CMV on the general population has been less well studied; however, a wide range of evidence indicates that CMV may increase the risk of atherosclerosis, cancer, immunosenescence, and progression of tuberculosis (TB) and human immunodeficiency virus. Due to the high seroprevalence of CMV worldwide, any modulation of risk by CMV is likely to have a significant impact on the epidemiology of these diseases. This review will evaluate how CMV may cause morbidity and mortality outside of the neonatal and immunosuppressed populations and consider the potential impact of a CMV vaccine on these outcomes.
Vestibular and balance dysfunction in children with congenital CMV: a systematic review.
OBJECTIVE: This systematic review evaluates vestibular and balance dysfunction in children with congenital cytomegalovirus (cCMV), makes recommendations for clinical practice and informs future research priorities. DESIGN: MEDLINE, Embase, EMCARE, BMJ Best Practice, Cochrane Library, DynaMed Plus and UpToDate were searched from inception to 20 March 2021 and graded according to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria. PATIENTS: Children with cCMV diagnosed within 3 weeks of life from either blood, saliva and/or urine (using either PCR or culture). INTERVENTION: Studies of vestibular function and/or balance assessments. MAIN OUTCOME MEASURES: Vestibular function and balance. RESULTS: 1371 studies were identified, and subsequently 16 observational studies were eligible for analysis, leading to an overall cohort of 600 children with cCMV. All studies were of low/moderate quality. In 12/16 studies, vestibular function tests were performed. 10/12 reported vestibular dysfunction in ≥40% of children with cCMV. Three studies compared outcomes for children with symptomatic or asymptomatic cCMV at birth; vestibular dysfunction was more frequently reported in children with symptomatic (22%-60%), than asymptomatic cCMV (0%-12.5%). Two studies found that vestibular function deteriorated over time: one in children (mean age 7.2 months) over 10 months and the other (mean age 34.7 months) over 26 months. CONCLUSIONS: Vestibular dysfunction is found in children with symptomatic and asymptomatic cCMV and in those with and without hearing loss. Audiovestibular assessments should be performed as part of neurodevelopmental follow-up in children with cCMV. Case-controlled longitudinal studies are required to more precisely characterise vestibular dysfunction and help determine the efficacy of early supportive interventions. PROSPERO REGISTRATION: CRD42019131656.
Pulmonary Cystic Echinococcosis in a Child Presenting in the United Kingdom with Fever and Chest Pain: A Brief Report and Discussion on Management.
Cystic echinococcosis is a zoonosis caused by the larvae of Echinococcus granulosus . Pulmonary disease may be asymptomatic until the cyst ruptures or becomes secondarily infected. We report a case of pulmonary cystic echinococcosis presenting in the United Kingdom, with discussion on management: optimum antihelminthic agent, length of treatment and type of operative intervention. Treatment should be individualized to the clinical scenario.
Molecular epidemiology and antimicrobial resistance phenotype of paediatric bloodstream infections caused by Gram-negative bacteria.
BACKGROUND: Gram-negative organisms are common causes of bloodstream infection (BSI) during the neonatal period and early childhood. Whilst several large studies have characterised these isolates in adults, equivalent data (particularly incorporating whole genome sequencing) is lacking in the paediatric population. METHODS: We perform an epidemiological and sequencing based analysis of Gram-negative bloodstream infections (327 isolates (296 successfully sequenced) from 287 patients) in children <18 years old between 2008 and 2018 in Oxfordshire, UK. RESULTS: Here we show that the burden of infection lies predominantly in neonates and that most infections are caused by Escherichia coli, Klebsiella spp. and Enterobacter hormaechei. There is no evidence in our setting that the proportion of antimicrobial resistant isolates is increasing in the paediatric population although we identify some evidence of sub-breakpoint increases in gentamicin resistance. The population structure of E. coli BSI isolates in neonates and children mirrors that in adults with a predominance of STs 131/95/73/69 and the same proportions of O-antigen serotypes. In most cases in our setting there is no evidence of transmission/point-source acquisition and we demonstrate the utility of whole genome sequencing to refute a previously suspected outbreak. CONCLUSIONS: Our findings support continued use of current empirical treatment guidelines and suggest that O-antigen targeted vaccines may have a role in reducing the incidence of neonatal sepsis.
LARP1 haploinsufficiency is associated with an autosomal dominant neurodevelopmental disorder.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and metabolic plasticity. Using lymphocytes collected and immortalized from an index proband who carries a truncating variant in one allele of LARP1, we demonstrated that lower cellular levels of LARP1 protein cause reduced rates of aerobic respiration and glycolysis. As expression of LARP1 increases during neurodevelopment, with higher levels in neurons and astrocytes, we propose that LARP1 haploinsufficiency contributes to ASD or related NDDs through attenuated metabolic activity in the developing fetal brain.
Development and Evaluation of Machine Learning in Whole-Body Magnetic Resonance Imaging for Detecting Metastases in Patients With Lung or Colon Cancer: A Diagnostic Test Accuracy Study.
OBJECTIVES: Whole-body magnetic resonance imaging (WB-MRI) has been demonstrated to be efficient and cost-effective for cancer staging. The study aim was to develop a machine learning (ML) algorithm to improve radiologists' sensitivity and specificity for metastasis detection and reduce reading times. MATERIALS AND METHODS: A retrospective analysis of 438 prospectively collected WB-MRI scans from multicenter Streamline studies (February 2013-September 2016) was undertaken. Disease sites were manually labeled using Streamline reference standard. Whole-body MRI scans were randomly allocated to training and testing sets. A model for malignant lesion detection was developed based on convolutional neural networks and a 2-stage training strategy. The final algorithm generated lesion probability heat maps. Using a concurrent reader paradigm, 25 radiologists (18 experienced, 7 inexperienced in WB-/MRI) were randomly allocated WB-MRI scans with or without ML support to detect malignant lesions over 2 or 3 reading rounds. Reads were undertaken in the setting of a diagnostic radiology reading room between November 2019 and March 2020. Reading times were recorded by a scribe. Prespecified analysis included sensitivity, specificity, interobserver agreement, and reading time of radiology readers to detect metastases with or without ML support. Reader performance for detection of the primary tumor was also evaluated. RESULTS: Four hundred thirty-three evaluable WB-MRI scans were allocated to algorithm training (245) or radiology testing (50 patients with metastases, from primary 117 colon [n = 117] or lung [n = 71] cancer). Among a total 562 reads by experienced radiologists over 2 reading rounds, per-patient specificity was 86.2% (ML) and 87.7% (non-ML) (-1.5% difference; 95% confidence interval [CI], -6.4%, 3.5%; P = 0.39). Sensitivity was 66.0% (ML) and 70.0% (non-ML) (-4.0% difference; 95% CI, -13.5%, 5.5%; P = 0.344). Among 161 reads by inexperienced readers, per-patient specificity in both groups was 76.3% (0% difference; 95% CI, -15.0%, 15.0%; P = 0.613), with sensitivity of 73.3% (ML) and 60.0% (non-ML) (13.3% difference; 95% CI, -7.9%, 34.5%; P = 0.313). Per-site specificity was high (>90%) for all metastatic sites and experience levels. There was high sensitivity for the detection of primary tumors (lung cancer detection rate of 98.6% with and without ML [0.0% difference; 95% CI, -2.0%, 2.0%; P = 1.00], colon cancer detection rate of 89.0% with and 90.6% without ML [-1.7% difference; 95% CI, -5.6%, 2.2%; P = 0.65]). When combining all reads from rounds 1 and 2, reading times fell by 6.2% (95% CI, -22.8%, 10.0%) when using ML. Round 2 read-times fell by 32% (95% CI, 20.8%, 42.8%) compared with round 1. Within round 2, there was a significant decrease in read-time when using ML support, estimated as 286 seconds (or 11%) quicker ( P = 0.0281), using regression analysis to account for reader experience, read round, and tumor type. Interobserver variance suggests moderate agreement, Cohen κ = 0.64; 95% CI, 0.47, 0.81 (with ML), and Cohen κ = 0.66; 95% CI, 0.47, 0.81 (without ML). CONCLUSIONS: There was no evidence of a significant difference in per-patient sensitivity and specificity for detecting metastases or the primary tumor using concurrent ML compared with standard WB-MRI. Radiology read-times with or without ML support fell for round 2 reads compared with round 1, suggesting that readers familiarized themselves with the study reading method. During the second reading round, there was a significant reduction in reading time when using ML support.
The association between ibuprofen administration in children and the risk of developing or exacerbating asthma: a systematic review and meta-analysis.
BACKGROUND: Ibuprofen is one of the most commonly used analgesic and antipyretic drugs in children. However, its potential causal role in childhood asthma pathogenesis remains uncertain. In this systematic review, we assessed the association between ibuprofen administration in children and the risk of developing or exacerbating asthma. METHODS: We searched MEDLINE, Embase, Cochrane Library, CINAHL, Web of Science, and Scopus from inception to May 2022, with no language limits; searched relevant reviews; and performed citation searching. We included studies of any design that were primary empirical peer-reviewed publications, where ibuprofen use in children 0-18 years was reported. Screening was performed in duplicate by blinded review. In total, 24 studies met our criteria. Data were extracted according to PRISMA guidelines, and the risk of bias was assessed using RoB2 and NOS tools. Quantitative data were pooled using fixed effect models, and qualitative data were pooled using narrative synthesis. Primary outcomes were asthma or asthma-like symptoms. The results were grouped according to population (general, asthmatic, and ibuprofen-hypersensitive), comparator type (active and non-active) and follow-up duration (short- and long-term). RESULTS: Comparing ibuprofen with active comparators, there was no evidence of a higher risk associated with ibuprofen over both the short and long term in either the general or asthmatic population. Comparing ibuprofen use with no active alternative over a short-term follow-up, ibuprofen may provide protection against asthma-like symptoms in the general population when used to ease symptoms of fever or bronchiolitis. In contrast, it may cause asthma exacerbation for those with pre-existing asthma. However, in both populations, there were no clear long-term follow-up effects. CONCLUSIONS: Ibuprofen use in children had no elevated risk relative to active comparators. However, use in children with asthma may lead to asthma exacerbation. The results are driven by a very small number of influential studies, and research in several key clinical contexts is limited to single studies. Both clinical trials and observational studies are needed to understand the potential role of ibuprofen in childhood asthma pathogenesis.
A Randomized Trial Assessing the Immunogenicity and Reactogenicity of Two Hexavalent Infant Vaccines Concomitantly Administered With Group B Meningococcal Vaccine.
BACKGROUND: Three hexavalent (DTaP-IPV-Hib-HepB) vaccines are licensed in Europe, only one of which (Vaxelis, Hex-V), uses a meningococcal outer membrane protein complex as a carrier protein for Hemophilus influenza type b (Hib), creating potential interactions with the meningococcal vaccine 4CMenB. METHODS: In this single-center open-label randomized trial, infants were randomized in a 1:1 ratio to receive Hex-V or an alternative hexavalent vaccine (Infanrix-Hexa, Hex-IH) at 2, 3, and 4 months with 4CMenB (2, 4, and 12 months) in the UK routine immunization schedule. The primary outcome was noninferiority of geometric mean concentrations (GMCs) of anti-PRP (Hib) IgG at 5 months of age. Secondary outcomes included safety, reactogenicity, and immunogenicity of other administered vaccines measured at 5 and 13 months of age. RESULTS: Of the 194 participants enrolled, 96 received Hex-V and 98 Hex-IH. Noninferiority of anti-PRP IgG GMCs at 5 months of age in participants receiving Hex-V was established; GMCs were 23-times higher following three doses of Hex-V than three doses of Hex-IH (geometric mean ratio (GMR) 23.25; one-sided 95% CI 16.21, -). 78/85 (92%) of Hex-V recipients and 43/87 (49%) of Hex-IH recipients had anti-PRP antibodies ≥1.0 µg/mL. At 5 months of age serum, bactericidal activity titers against MenB strain 5/99 were higher following Hex-V than Hex-IH (GMR 1.56; 95% CI, 1.13-2.14). The reactogenicity profile was similar in both groups. CONCLUSIONS: These data support flexibility in the use of either Hex-IH or Hex-V in infant immunization schedules containing 4CMenB, with the possibility that Hex-V may enhance protection against Hib.