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Researchers from the University of Oxford have published further data from the Phase I/II clinical trials of the ChAdOx1 nCoV-19 coronavirus vaccine, evidencing the decision to move to a two-dose regimen in ongoing phase III trials, and how ChAdOx1 nCov-19 induces broad antibody and T cell functions.
Examining the role of community champions to promote vaccine uptake in under-served communities in the United Kingdom: Lessons from the COVID-19 pandemic
The COVID-19 pandemic has highlighted how ethnic minority groups are disproportionally affected by health crises and the potential for community engagement to provide equitable public health information and services. Policymakers, practitioners, and academics have presented community engagement as a way to improve the access and uptake of health services, including vaccination, but the role of community members for health promotion is rarely questioned. We examine ‘community vaccine champions’, who have been acting as advocates, promoting engagement among ethnic minority groups for COVID-19 vaccination in different communities across the United Kingdom. Our research explores how champions working with minoritised groups have experienced and confronted the challenges brought on by the pandemic. Participants were invited to participate in this study as they worked with or for the Black or South Asian community (i.e., community leader, faith leader, or a public or allied health professional) and were working or had worked to increase COVID-19 vaccine uptake. From April 2021 until May 2022, we conducted 12 semi-structured interviews lasting 45–60 min via video call. The interviews were inductively coded and analysed following a discourse approach to health communication, where a focus is made to draw out underlying messages and talking points. Our findings highlight the range of different types of champions, who have a variety of roles within their respective community groups. Champions proved adaptive in taking on new positions to promote vaccination, with limited training and preparation, and found that being ‘grassroots’ actors positioned them well to both address local needs and to help build trust between authorities and their communities. A major issue that champions found was the use of ethnic minority classifications and how to address misinformation. Classifications were seen as a problem in how relevant data was collected, as well as in assigning blame to certain groups. Champions also stressed the influence of media and social media misinformation on vaccine decision-making. Still, our informants cautioned taking action based on simplistic assumptions about how misinformation negatively affects vaccine uptake. We conclude by setting out the need for ongoing community support for health issues and the challenges of community engagement for vaccine promotion in a pandemic setting.
Safety, tolerability, viral kinetics, and immune correlates of protection in healthy, seropositive UK adults inoculated with SARS-CoV-2: a single-centre, open-label, phase 1 controlled human infection study.
BACKGROUND: A SARS-CoV-2 controlled human infection model (CHIM) has been successfully established in seronegative individuals using a dose of 1×101 50% tissue culture infectious dose (TCID50) pre-alpha SARS-CoV-2 virus. Given the increasing prevalence of seropositivity to SARS-CoV-2, a CHIM that could be used for vaccine development will need to induce infection in those with pre-existing immunity. Our aim was to find a dose of pre-alpha SARS-CoV-2 virus that induced infection in previously infected individuals. METHODS: Healthy, UK volunteers aged 18-30 years, with proven (quantitative RT-PCR or lateral flow antigen test) previous SARS-CoV-2 infection (with or without vaccination) were inoculated intranasally in a stepwise dose escalation CHIM with either 1×101, 1×102, 1×10³, 1×104, or 1×105 TCID50 SARS-CoV-2/human/GBR/484861/2020, the same virus used in the seronegative CHIM. Post-inoculation, volunteers were quarantined in functionally negative pressure rooms (Oxford, UK) for 14 days and until 12-hourly combined oropharyngeal-nasal swabs were negative for viable virus by focus-forming assay. Outpatient follow-up continued for 12 months post-enrolment, with additional visits for those who developed community-acquired SARS-CoV-2 infection. The primary objective was to identify a safe, well tolerated dose that induced infection (defined as two consecutive SARS-CoV-2 positive PCRs starting 24 h after inoculation) in 50% of seropositive volunteers. This study is registered with ClinicalTrials.gov (NCT04864548); enrolment and follow-up to 12 months post-enrolment are complete. FINDINGS: Recruitment commenced on May 6, 2021, with the last volunteer enrolled into the dose escalation cohort on Nov 24, 2022. 36 volunteers were enrolled, with four to eight volunteers inoculated in each dosing group from 1×101 to 1×105 TCID50 SARS-CoV-2. All volunteers have completed quarantine, with follow-up to 12 months complete. Despite dose escalation to 1×105 TCID50, we were unable to induce sustained infection in any volunteers. Five (14%) of 36 volunteers were considered to have transient infection, based on the kinetic of their PCR-positive swabs. Transiently infected volunteers had significantly lower baseline mucosal and systemic SARS-CoV-2-specific antibody titres and significantly lower peripheral IFNγ responses against a CD8+ T-cell SARS-CoV-2 peptide pool than uninfected volunteers. 14 (39%) of 36 volunteers subsequently developed breakthrough infection with the omicron variant after discharge from quarantine. Most adverse events reported by volunteers in quarantine were mild, with fatigue (16 [44%]) and stuffy nose (16 [44%]) being the most common. There were no serious adverse events. INTERPRETATION: Our study demonstrates potent protective immunity induced by homologous vaccination and homologous or heterologous previous SARS-CoV-2 infection. The community breakthrough infections seen with the omicron variant supports the use of newer variants to establish a model with sufficient rate of infection for use in vaccine and therapeutic development. FUNDING: Wellcome Trust and Department for Health and Social Care.
Safety and immunogenicity of ChAdOx1 nCoV-19 (AZD1222) vaccine in adults in Kenya: a phase 1/2 single-blind, randomised controlled trial.
BackgroundThere are limited data on the immunogenicity of coronavirus disease 2019 (COVID-19) vaccines in African populations. Here we report the immunogenicity and safety of the ChAdOx1 nCoV-19 (AZD1222) vaccine from a phase 1/2 single-blind, randomised, controlled trial among adults in Kenya conducted as part of the early studies assessing vaccine performance in different geographical settings to inform Emergency Use Authorisation.MethodsWe recruited and randomly assigned (1:1) 400 healthy adults aged ≥18 years in Kenya to receive ChAdOx1 nCoV-19 or control rabies vaccine, each as a two-dose schedule with a 3-month interval. The co-primary outcomes were safety, and immunogenicity assessed using total IgG enzyme-linked immunosorbent assay (ELISA) against SARS-CoV-2 spike protein 28 days after the second vaccination.ResultsBetween 28 th October 2020 and 19 th August 2021, 400 participants were enrolled and assigned to receive ChAdOx1 nCoV-19 (n=200) or rabies vaccine (n=200). Local and systemic adverse events were self-limiting and mild or moderate in nature. Three serious adverse events were reported but these were deemed unrelated to vaccination. The geometric mean anti-spike IgG titres 28 days after second dose vaccination were higher in the ChAdOx1 group (2773 ELISA units [EU], 95% CI 2447, 3142) than in the rabies vaccine group (61 EU, 95% CI 45, 81) and persisted over the 12 months follow-up. We did not identify any symptomatic infections or hospital admissions with respiratory illness and so vaccine efficacy against clinically apparent infection could not be measured. Vaccine efficacy against asymptomatic SARS-CoV-2 infection was 38.4% (95% CI -26.8%, 70.1%; p=0.188).ConclusionsThe safety, immunogenicity and efficacy against asymptomatic infection of ChAdOx1 nCoV-19 among Kenyan adults was similar to that observed elsewhere in the world, but efficacy against symptomatic infection or severe disease could not be measured in this cohort.Pan-african clinical trials registrationPACTR202005681895696 (11/05/2020).
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.
Respiratory Syncytial Virus Consortium in Europe (RESCEU) Birth Cohort Study: Defining the Burden of Infant Respiratory Syncytial Virus Disease in Europe.
BACKGROUND:Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants worldwide. Although prematurity and cardiopulmonary disease are risk factors for severe disease, the majority of infants hospitalized with RSV are previously healthy. Various vaccines and therapeutics are under development and expected to be available in the near future. To inform the use of these new vaccines and therapeutics, it is necessary to determine the burden of RSV disease in Europe. We will prospectively follow-up a birth cohort to obtain incidence data on RSV acute respiratory tract infection (ARTI). METHODS:Multicenter prospective study of a birth cohort consisting of 10 000 healthy infants, recruited during 3 consecutive years. RSV associated hospitalization in the first year of life will be determined by questionnaires and hospital chart reviews. A nested cohort of 1000 infants will be actively followed. In case of ARTI, a respiratory sample will be collected for RSV molecular diagnosis. RESULTS:The primary outcome is the incidence rate of RSV-associated hospitalization in the first year of life. In the active cohort the primary outcome is RSV associated ARTI and MA-ARTI. CONCLUSIONS:We will provide key information to fill the gaps in knowledge about the burden of RSV disease in healthy infants. CLINICAL TRIALS REGISTRATION:NCT03627572.
Presumed Risk Factors and Biomarkers for Severe Respiratory Syncytial Virus Disease and Related Sequelae: Protocol for an Observational Multicenter, Case-Control Study From the Respiratory Syncytial Virus Consortium in Europe (RESCEU).
Respiratory syncytial virus (RSV) is the leading viral pathogen associated with acute lower respiratory tract infection and hospitalization in children < 5 years of age worldwide. While there are known clinical risk factors for severe RSV infection, the majority of those hospitalized are previously healthy infants. There is consequently an unmet need to identify biomarkers that predict host response, disease severity, and sequelae. The primary objective is to identify biomarkers of severe RSV acute respiratory tract infection (ARTI) in infants. Secondary objectives include establishing biomarkers associated with respiratory sequelae following RSV infection and characterizing the viral load, RSV whole-genome sequencing, host immune response, and transcriptomic, proteomic, metabolomic and epigenetic signatures associated with RSV disease severity. Six hundred thirty infants will be recruited across 3 European countries: the Netherlands, Spain, and the United Kingdom. Participants will be recruited into 2 groups: (1) infants with confirmed RSV ARTI (includes upper and lower respiratory tract infections), 500 without and 50 with comorbidities; and (2) 80 healthy controls. At baseline, participants will have nasopharyngeal, blood, buccal, stool, and urine samples collected, plus complete a questionnaire and 14-day symptom diary. At convalescence (7 weeks ± 1 week post-ARTI), specimen collection will be repeated. Laboratory measures will be correlated with symptom severity scores to identify corresponding biomarkers of disease severity. CLINICAL TRIALS REGISTRATION:NCT03756766.
Low Sensitivity of BinaxNOW RSV in Infants.
BACKGROUND:Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants. Early detection of RSV can optimize clinical management and minimize use of antibiotics. BinaxNOW RSV (BN) is a rapid antigen detection test that is widely used. We aimed to validate the sensitivity of BN in hospitalized and nonhospitalized infants against the gold standard of molecular diagnosis. METHODS:We evaluated the performance of BN in infants with acute respiratory tract infections with different degrees of disease severity. Diagnostic accuracy of BN test results were compared with molecular diagnosis as reference standard. RESULTS:One hundred sixty-two respiratory samples from 148 children from October 2017 to February 2019 were studied. Sixty-six (40.7%) samples tested positive for RSV (30 hospitalizations, 31 medically attended episodes not requiring hospitalization, and 5 nonmedically attended episodes). Five of these samples tested positive with BN, leading to an overall sensitivity of BN of 7.6% (95% confidence interval [CI], 3.3%-16.5%) and a specificity of 100% (95% CI, 96.2%-100%). Sensitivity was low in all subgroups. CONCLUSIONS:We found a low sensitivity of BN for point-of-care detection of RSV infection. BinaxNOW RSV should be used and interpreted with caution.
Development and preclinical analysis of lipopolysaccharide-based glycoconjugate vaccine candidates against Coxiella burnetti
Q fever is a zoonosis caused by the Gram-negative bacterium Coxiella burnetii. Currently, there is only one licensed human vaccine for Q fever, but its high level of reactogenicity necessitates the urgent need for developing a safer and efficacious alternative. Prior research has highlighted the utility of anti-C. burnetii phase I (smooth form) lipopolysaccharide (LPS) IgG antibodies in conferring protection against Q fever. Drawing on this foundation, this thesis describes the generation and evaluation of novel LPS-based glycoconjugate vaccine candidates aimed at combating Q fever. The initial phase of the work involved synthesising the vaccine candidates using LPS extracted from inactivated C. burnetii. Purified LPS was conjugated with carrier proteins including tetanus toxoid heavy chain (TThc) and CRM197, using two different chemistries. The selection of carrier proteins and conjugation chemistries was informed by their scalability and potential for clinical development. As a result, this work led to the development of two LPS-based glycoconjugate vaccine candidates, QCON-CT and QCON-ET. The capacity of these vaccine candidates to induce a functional immune response was subsequently evaluated using a mouse model. Both vaccine candidates were capable of eliciting a serum anti-C. burnetii phase I LPS IgG response. In particular, QCON-CT, when formulated with Alum adjuvant, induced significantly higher anti-LPS IgG titres compared with an existing licensed inactivated veterinary vaccine. In addition, a comprehensive in silico pipeline was developed using a dataset generated from a randomised, phase 2b, typhoid fever controlled human infection model (CHIM) study to evaluate molecular signatures post-vaccination. In this study, a plain polysaccharide-based vaccine was compared with a glycoconjugate vaccine containing the same polysaccharide antigen. This in turn provides a large dataset for transcriptomic analysis development. Methods were developed to contrast immunological profiles of the two vaccine types, quantifying various metrics including differential gene expression, T cell-dependent functions induced by the glycoconjugate vaccine, and likely antigen-specific antibody clonotype abundances. Establishing this pipeline not only aided the understanding of typhoid fever by identifying the very first molecular markers associated with vaccine-induced protection, but also enabled RNA-Seq data generated from the Q fever mouse study to be leveraged by transcriptomic analyses. Using this in silico pipeline, it was determined that both glycoconjugate vaccine candidates against Q fever induced a convergent humoral response, characterised by the upregulation of several likely LPS-specific B cell receptor (BCR) clonotypes. These findings, in alignment with the in vitro readouts, indicate the promising effectiveness that can be achieved by the LPS-based glycoconjugate vaccine approach. Overall, a path towards further clinical development of the Q fever glycoconjugate vaccine candidates is delineated by the results generated in this thesis, highlighting their potential in addressing global public health needs by facilitating the control and prevention of Q fever outbreaks worldwide. The mechanistic insights and methodologies developed herein not only provide a framework for future vaccine research, but also hold promise for application in combating many other infectious diseases.
Feasibility and utility of a combined nasogastric-tube-and-string-test device for bacteriologic confirmation of pulmonary tuberculosis in young children.
For microbiological confirmation of pediatric pulmonary tuberculosis (PTB), gastric aspirates (GA) are often operationally unfeasible without hospitalization, and the encapsulated orogastric string test is not easily swallowed in young children. The Combined-NasoGastric-Tube-and-String-Test (CNGTST) enables dual collection of GA and string specimens. In a prospective cohort study in Kenya, we examined its feasibility in children under five with presumptive PTB and compared the bacteriological yield of string to GA. Paired GA and string samples were successfully collected in 95.6 % (281/294) of children. Mycobacterium tuberculosis was isolated from 7.0 % (38/541) of GA and 4.3 % (23/541) of string samples, diagnosing 8.2 % (23/281) of children using GA and 5.3 % (15/281) using string. The CNGTST was feasible in nearly all children. Yield from string was two-thirds that of GA despite a half-hour median dwelling time. In settings where the feasibility of hospitalisation for GA is uncertain, the string component can be used to confirm PTB.
Clinical trial capacity building in a pandemic—outcome of a rapid site readiness project in Latin America
BackgroundLatin America (Latam) has a tradition of large-scale vaccine trials. Because of fluctuating demand, many sites have downsized their infrastructure. Therefore, BMGF launched a clinical trial site-readiness initiative early in the coronavirus-2019 (COVID-19) pandemic including Latam countries between August and September 2020. This survey evaluated clinical development performance measures pre/post initiative (September 2022).Results20/21 prequalified sites participated in COVID-19 vaccine/drug development trials. 156 clinical trials (140 COVID-19 vaccine/drug trials) were initiated in the 2 years since prequalification, compared to 176 in the 5 years before. 33,428/37,810 participants were included in COVID-19 programs. The number of enrolled subjects/day across sites quadrupled from 15 (1–35) to 63 (5–300). The dropout rate was 6.8%. Study approval timelines were reduced from 60 (12–120) to 35 (5–90) days. Mean qualified staff was increased from 24 (6–80) to 88 (22–180).ConclusionClinical trial sites across Latam were successfully prequalified to participate in COVID-19 developments. For the 100 days mission of vaccine availability in a new pandemic sufficient and well-trained clinical trial sites readily available are essential. This is only achievable if sites—especially in low/middle-income countries—are maintained active through a constant flow of vaccine studies.
Plasma Protein Biomarkers Distinguish Multisystem Inflammatory Syndrome in Children From Other Pediatric Infectious and Inflammatory Diseases.
BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious hyperinflammatory complication following infection with severe acute respiratory syndrome coronavirus 2. The mechanisms underpinning the pathophysiology of MIS-C are poorly understood. Moreover, clinically distinguishing MIS-C from other childhood infectious and inflammatory conditions, such as Kawasaki disease or severe bacterial and viral infections, is challenging due to overlapping clinical and laboratory features. We aimed to determine a set of plasma protein biomarkers that could discriminate MIS-C from those other diseases. METHODS: Seven candidate protein biomarkers for MIS-C were selected based on literature and from whole blood RNA sequencing data from patients with MIS-C and other diseases. Plasma concentrations of ARG1, CCL20, CD163, CORIN, CXCL9, PCSK9 and ADAMTS2 were quantified in MIS-C (n = 22), Kawasaki disease (n = 23), definite bacterial (n = 28) and viral (n = 27) disease and healthy controls (n = 8). Logistic regression models were used to determine the discriminatory ability of individual proteins and protein combinations to identify MIS-C and association with severity of illness. RESULTS: Plasma levels of CD163, CXCL9 and PCSK9 were significantly elevated in MIS-C with a combined area under the receiver operating characteristic curve of 85.7% (95% confidence interval: 76.6%-94.8%) for discriminating MIS-C from other childhood diseases. Lower ARG1 and CORIN plasma levels were significantly associated with severe MIS-C cases requiring inotropes, pediatric intensive care unit admission or with shock. CONCLUSION: Our findings demonstrate the feasibility of a host protein biomarker signature for MIS-C and may provide new insight into its pathophysiology.
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.
Nasopharyngeal Carriage of Pneumococcus in Children in England up to 10 Years After 13-Valent Pneumococcal Conjugate Vaccine Introduction: Persistence of Serotypes 3 and 19A and Emergence of 7C.
<h4>Background</h4>Monitoring changes in pharyngeal carriage of pneumococcus in children following 13-valent pneumococcal conjugate vaccine (PCV13) introduction in the United Kingdom in 2010 informs understanding of patterns of invasive pneumococcal disease (IPD) incidence.<h4>Methods</h4>Nasopharyngeal swabs from healthy children vaccinated with PCV13 according to schedule (2, 4, and 12 months) were cultured and serotyped. Results for children aged 13-48 months were compared between 2014-2015 and 2017-2019 and with children aged 6-12 months (2017-2020). Blood was obtained from a subset of children for pneumococcal serotype-specific immunoglobulin G (IgG).<h4>Results</h4>Total pneumococcal carriage at 13-48 months was 47.9% (473/988) in 2014-2015 and 51.8% (412/795) in 2017-2019 (P = .10); at age 6-12 months this value was 44.6% (274/615). In 2017-2019, 2.9% (95% confidence interval, 1.8%-4.3%) of children aged 13-48 months carried PCV13 serotypes (mainly 3 [1.5%] and 19A [0.8%]) and >20% carried the additional 20-valent PCV (PCV20) serotypes. Similar proportions of children had IgG ≥0.35 IU/mL for each serotype in 2014-2015 and 2017-2019. Serotype 7C carriage increased significantly (P < .01) between 2014-2015 and 2017-2019. Carriage of PCV20 serotypes 8 and 12F, both major causes of IPD, was rare.<h4>Conclusions</h4>Introduction of PCV20, if licensed for children, could significantly change the composition of pneumococcal serotypes carried in the pharynx of UK children.<h4>Clinical trials registration</h4>NCT03102840.
Serum HCoV-spike specific antibodies do not protect against subsequent SARS-CoV-2 infection in children and adolescents.
SARS-CoV-2 infections in children are generally asymptomatic or mild and rarely progress to severe disease and hospitalization. Why this is so remains unclear. Here we explore the potential for protection due to pre-existing cross-reactive seasonal coronavirus antibodies and compare the rate of antibody decline for nucleocapsid and spike protein in serum and oral fluid against SARS-CoV-2 within the pediatric population. No differences in seasonal coronaviruses antibody concentrations were found at baseline between cases and controls, suggesting no protective effect from pre-existing immunity against seasonal coronaviruses. Antibodies against seasonal betacoronaviruses were boosted in response to SARS-CoV-2 infection. In serum, anti-nucleocapsid antibodies fell below the threshold of positivity more quickly than anti-spike protein antibodies. These findings add to our understanding of protection against infection with SARS-CoV-2 within the pediatric population, which is important when considering pediatric SARS-CoV-2 immunization policies.
Intravenous immunoglobulin treatment for encephalitis in children aged 6 months to 16 years: the IgNiTE RCT
Background There are data suggesting that intravenous immunoglobulin treatment has some benefit for certain forms of encephalitis but robust evidence from large randomised controlled trials in children with all-cause encephalitis is lacking. Objective To evaluate whether intravenous immunoglobulin treatment improves neurological outcomes in childhood encephalitis when given early in the illness. Design Phase 3b, investigator-initiated, randomised, double-blind, placebo-controlled trial of intravenous immunoglobulin for the treatment of encephalitis in children. Setting Twenty-one NHS Hospitals in the UK. Participants Children aged 6 months to 16 years with a diagnosis of acute or sub-acute encephalitis. Intervention Two doses (1 g/kg/dose) of either intravenous immunoglobulin or matching placebo, given 24–36 hours apart, in addition to standard treatment. Main outcome measure Participants were followed up for 12 months (+/– 4 weeks) after randomisation. The primary outcome measure was a ‘good recovery’ defined as a score of ≤ 2 on the Paediatric Glasgow Outcome Score Extended at 12 months after randomisation. Secondary outcomes The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and intravenous immunoglobulin safety data. Results We planned to recruit 308 children over a 42-month period. After enrolment of 18 participants (8 male; 44%) over 21 months (from December 2015 to September 2017), funding was withdrawn due to slow recruitment and the study was terminated. Ten participants were randomised to the intravenous immunoglobulin group, and eight to the placebo group, and all 18 participants were included in the analysis. At 12 months after randomisation, 9 participants [50%; intravenous immunoglobulin n = 5 (50%), placebo n = 4 (50%)] made good recovery and 5 participants [28%; intravenous immunoglobulin n = 3 (30%), placebo n = 2 (25%)] made a poor recovery. Three participants in the placebo group (43%) experienced a total of 10 serious adverse events compared with none in the intravenous immunoglobulin group but none of the adverse events were judged to be related to the study treatment. No deaths occurred during the study period. Conclusion ImmunoglobuliN in the Treatment of Encephalitis (IgNiTE) was halted prematurely due to slow recruitment. Given the small sample size, the study was underpowered to evaluate the effect of intravenous immunoglobulin when compared with placebo in childhood encephalitis. The study findings, albeit from a small sample size, support existing evidence that encephalitis results in poor neurological outcomes for many children. Lessons learned from the ImmunoglobuliN in the Treatment of Encephalitis trial would be valuable for the success of future trials set up to address the efficacy of early treatment with intravenous immunoglobulin in all-cause encephalitis in children. Study limitations and future work The study was underpowered to evaluate the efficacy of intravenous immunoglobulin in the treatment of childhood encephalitis due to the small sample size achieved. Future trials should seek to address this important question. Trial registration This trial is registered as Clinical Trials.gov (NCT02308982) and ISRCTN15791925. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/212/15) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 6. See the NIHR Funding and Awards website for further award information.
Decision to self-isolate during the COVID-19 pandemic in the UK: a rapid scoping review.
OBJECTIVE: Testing for COVID-19 was a key component of the UK's response to the COVID-19 pandemic. This strategy relied on positive individuals self-isolating to reduce transmission, making isolation the lynchpin in the public health approach. Therefore, we scoped evidence to systematically identify and categorise barriers and facilitators to compliance with self-isolation guidance during the COVID-19 pandemic in the UK, to inform public health strategies in future pandemics. DESIGN: A rapid scoping review was conducted. SEARCH STRATEGY: Key terms were used to search literature databases (PubMed, Scopus and the WHO COVID-19 Research Database, on 7 November 2022), Google Scholar and stakeholder-identified manuscripts, ultimately including evidence published in English from UK-based studies conducted between 2020 and 2022. DATA EXTRACTION AND SYNTHESIS: Data were extracted and synthesised into themes, organised broadly into capability, opportunity and motivation, and reviewed with key stakeholders from the UK Health Security Agency (UKHSA). RESULTS: We included 105 sources, with 63 identified from UKHSA and used to inform their decision-making during the pandemic. Influences on the decision to comply with isolation guidance were categorised into six themes: perceived ability to isolate; information and guidance; logistics; social influences, including trust; perceived value; and perceived consequences. Individuals continuously assessed these factors in deciding whether or not to comply with guidance and self-isolate. CONCLUSIONS: Decisions to self-isolate after a positive test were influenced by multiple factors, including individuals' beliefs, concerns, priorities and personal circumstances. Future testing strategies must facilitate meaningful financial, practical and mental health support to allow individuals to overcome the perceived and actual negative consequences of isolating. Clear, consistent communication of the purpose and procedures of isolating will also be critical to support compliance with self-isolation guidance, and should leverage people's perceived value in protecting others. Building public trust is also essential, but requires investment before the next pandemic starts.
A Genome-Wide Association Study of Respiratory Syncytial Virus Infection Severity in Infants.
BACKGROUND: Respiratory syncytial virus (RSV) is a significant cause of infant morbidity and mortality worldwide. Most children experience at least one 1 RSV infection by the age of two 2 years, but not all develop severe disease. However, the understanding of genetic risk factors for severe RSV is incomplete. Consequently, we conducted a genome-wide association study of RSV severity. METHODS: Disease severity was assessed by the ReSVinet scale, in a cohort of 251 infants aged 1 week to 1 year. Genotyping data were collected from multiple European study sites as part of the RESCEU Consortium. Linear regression models were used to assess the impact of genotype on RSV severity and gene expression as measured by microarray. RESULTS: While no SNPs reached the genome-wide statistical significance threshold (P < 5 × 10-8), we identified 816 candidate SNPs with a P-value of <1 × 10-4. Functional annotation of candidate SNPs highlighted genes relevant to neutrophil trafficking and cytoskeletal functions, including LSP1 and RAB27A. Moreover, SNPs within the RAB27A locus significantly altered gene expression (false discovery rate, FDR P < .05). CONCLUSIONS: These findings may provide insights into genetic mechanisms driving severe RSV infection, offering biologically relevant information for future investigations.