Clinically meaningful improvements in patient-reported outcomes in mitapivat-treated patients with pyruvate kinase deficiency.

Clinically meaningful benefits in the signs, symptoms, and impacts of #PKDeficiency as assessed by disease-specific patient-reported outcome measures were observed in mitapivat-treated adult patients in two phase 3 clinical trials.

Motivation to participate in structured physical activity for autistic youth: A systematic scoping review.

LAY ABSTRACT: Autistic youth participate less in physical education classes and organised sport than their neurotypical peers. We conducted a review of existing studies to investigate what is known about what motivates (and does not motivate) autistic youth to take part in structured physical activities. We systematically searched electronic databases and found 18 publications that met the criteria to be included in this review. Data from these studies were extracted and mapped to the self-determination theory to identify factors that support (or undermine) motivation for autistic youth. We also discussed the findings with autistic individuals and other relevant stakeholders to discover how the review related to their experiences. Our results found competence (youth feeling competent in their athletic and social skills and abilities) to be the most reported psychological need impacting motivation for autistic youth. Intrinsic motivation (participating for enjoyment and satisfaction) was the most common facilitator of motivation. Autism-specific themes outside of the self-determination theory were mapped inductively, and we found that the sensory environment was a prominent theme reported to influence the motivation of autistic youth not covered by the self-determination theory. The findings of this review suggest that supporting the psychological needs of autistic youth can foster motivation to engage in physical activity, although how these needs are met can differ from their neurotypical peers. Future research should examine motivational factors that support engagement in structured physical activities through the lens of autistic youth and their experiences.

The Acute Effects of Ball Pressure on Anticipation Timing Following a Series of Purposeful Headers in Adult Football (Soccer) Players.

The purpose of this study is to investigate the acute effects of ball pressure on anticipation timing following a series of purposeful headers in adult football (soccer) players. There is evidence to suggest acute neurophysiological changes to the brain following purposeful heading; this may lead to altered anticipation timing as a result, potentially having future safety implications for players. A repeated measures crossover design was used. Seventeen participants aged between 20 and 30 years performed (i) 20 rotational headers with a lower-pressure match ball (58.6 kPa; 8.5 psi), (ii) 20 rotational headers with a higher-pressure match ball (103.4 kPa; 15 psi), or (iii) 20 non-headers (kicks) as a control each on separate days. The effect of ball pressure on anticipation timing accuracy, measured as absolute, constant, and variable errors, was assessed before and immediately after each intervention session using an anticipation timing task. Differences between group means were compared using repeated measures ANOVA and linear mixed effects models, with p-values of <0.05 considered statistically significant. No significant differences in anticipation timing accuracy across interventions were detected between control, occluded, and non-occluded trials. This finding differs from the previous literature regarding the measurable, acute effects of purposeful heading. The anticipation timing task may lack sensitivity for detecting the effects of repeated heading on brain function.

Early-life pulmonary viral infection leads to long-term functional and lower airway structural changes in the lungs.

Early-life respiratory virus infections have been correlated with enhanced development of childhood asthma. In particular, significant numbers of respiratory syncytial virus (RSV)-hospitalized infants go on to develop lung disease. It has been suggested that early-life viral infections may lead to altered lung development or repair that negatively impacts lung function later in life. Our data demonstrate that early-life RSV infection modifies lung structure, leading to decreased lung function. At 5 wk postneonatal RSV infection, significant defects are observed in baseline pulmonary function test (PFT) parameters consistent with decreased lung function as well as enlarged alveolar spaces. Lung function changes in the early-life RSV-infected group continue at 3 mo of age. The altered PFT and structural changes induced by early-life RSV were mitigated in TSLPR-/- mice that have previously been shown to have reduced immune cell accumulation associated with a persistent Th2 environment. Importantly, long-term effects were demonstrated using a secondary RSV infection 3 mo following the initial early-life RSV infection and led to significant additional defects in lung function, with severe mucus deposition within the airways, and consolidation of the alveolar spaces. These studies suggest that early-life respiratory viral infection leads to alterations in lung structure/repair that predispose to diminished lung function later in life.NEW & NOTEWORTHY These studies outline a novel finding that early-life respiratory virus infection can alter lung structure and function long-term. Importantly, the data also indicate that there are critical links between inflammatory responses and subsequent events that produce a more severe pathogenic response later in life. The findings provide additional data to support that early-life infections during lung development can alter the trajectory of airway function.

A real-world observational study assessing relationships between excessive daytime sleepiness and patient satisfaction in obstructive sleep apnea.

OBJECTIVES/BACKGROUND: To estimate prevalence and severity of excessive daytime sleepiness among patients with obstructive sleep apnea (OSA) who were prescribed treatment; assess perception and satisfaction of OSA-related care; describe relationships between excessive daytime sleepiness, treatment adherence, and patient satisfaction. PATIENTS/METHODS: A national population-based cross-sectional sample of US adults with clinician-diagnosed OSA was surveyed in January 2021 via Evidation Health's Achievement App. Patients completed the Epworth Sleepiness Scale, rated satisfaction with healthcare provider and overall OSA care, and reported treatment adherence. Covariates affecting excessive daytime sleepiness (average weekly sleep duration, treatment adherence, sleepiness-inducing medications, age, sex, body mass index, nasal congestion, smoking status, and comorbidities) were adjusted in multivariate regression models. RESULTS: In 2289 participants (50.3 % women; 44.8 ± 11.1 years), EDS was highly prevalent (42 %), and was experienced by 36 % of patients with high positive airway pressure (PAP) therapy adherence. Each additional hour of nightly PAP use was associated with improved sleepiness (a 0.28-point lower Epworth score; p < 0.001). Excessive daytime sleepiness was associated with lower patient satisfaction with healthcare providers and overall care (OR [95 % CI] 0.62 [0.48-0.80] and 0.50 [0.39-0.64], respectively; p < 0.0001), whereas PAP adherence was associated with higher patient satisfaction (OR [95 % CI] 2.37 [1.64-3.43] and 2.91 [2.03-4.17]; p < 0.0001), after adjusting for confounders. CONCLUSIONS: In a real-world population-based study of patients with OSA, excessive daytime sleepiness was highly prevalent and associated with poor patient satisfaction ratings. Better patient-centered care among patients with OSA may require interventions aimed at addressing excessive daytime sleepiness and treatment adherence.

Individualized Treatment Patterns for Patients with Narcolepsy Treated with Oxybate: A Clinical Practice Perspective.

Purpose: Real-world data regarding divided nightly dosing of oxybate and individualized prescribing in patients with narcolepsy are limited. Study objectives were to understand oxybate prescribing practices, including optimizing dose regimens and adjusting dosing per occasional changes in patients' routines, and physician recommendations for representative patient scenarios. Patients and Methods: A cross-sectional, web- and audio-based survey of physicians treating ≥2 patients with narcolepsy, prescribed nightly oxybate (sodium oxybate) dosing for ≥6 months, was conducted. Physicians were surveyed on patients' usual oxybate dosing regimens, frequency of and reasons for oxybate dosing-related discussions, and preferred methods for and perceptions of adjusting oxybate dosing. Physicians provided dosing-related guidance for 4 representative scenarios. Results: Participating physicians (N=25) were neurologists (52%), psychiatrists (44%), and neuropsychiatrists (4%). Individualized oxybate prescribing practices were reflected by the variability of physicians' reporting of the percentage of their patients being prescribed once-nightly, twice-nightly, and thrice-nightly dosing regimens. Most physicians (68%) reported discussing adjusting individualized treatment to accommodate occasional changes to patients' routines; the most common reasons were consuming contraindicated beverages (alcohol; 65%) and travel (59%). Adjusting total nightly dose (68%) and dose timing (68%) were preferred adjustment methods. Most physicians (88%) felt the ability to individualize oxybate dosing was important and had a positive impact on ability to provide care. For each representative scenario, physicians provided several dose-adjustment recommendations, and physician responses encouraged patient participation in treatment decision-making. Conclusion: Physicians provided guidance supportive of oxybate dose adjustments to accommodate occasional changes in patients' routines, and perceived individualized dosing as important in providing care.

ChAdOx1 COVID vaccines express RBD open prefusion SARS-CoV-2 spikes on the cell surface.

Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been proven to be an effective means of decreasing COVID-19 mortality, hospitalization rates, and transmission. One of the vaccines deployed worldwide is ChAdOx1 nCoV-19, which uses an adenovirus vector to drive the expression of the original SARS-CoV-2 spike on the surface of transduced cells. Using cryo-electron tomography and subtomogram averaging, we determined the native structures of the vaccine product expressed on cell surfaces in situ. We show that ChAdOx1-vectored vaccines expressing the Beta SARS-CoV-2 variant produce abundant native prefusion spikes predominantly in one-RBD-up conformation. Furthermore, the ChAdOx1-vectored HexaPro-stabilized spike yields higher cell surface expression, enhanced RBD exposure, and reduced shedding of S1 compared to the wild type. We demonstrate in situ structure determination as a powerful means for studying antigen design options in future vaccine development against emerging novel SARS-CoV-2 variants and broadly against other infectious viruses.

A steroid-resistant cockroach allergen model is associated with lung and cecal microbiome changes.

The pathogenesis of asthma has been partially linked to lung and gut microbiome. We utilized a steroid-resistant chronic model of cockroach antigen-induced (CRA) asthma with corticosteroid (fluticasone) treatment to examine lung and gut microbiome during disease. The pathophysiology assessment demonstrated that mucus and airway hyperresponsiveness were increased in the chronic CRA with no alteration in the fluticasone (Flut)-treated group, demonstrating steroid resistance. Analysis of mRNA from lungs showed no decrease of MUC5AC or Gob5 in the Flut-treated group. Furthermore, flow-cytometry in lung tissue showed eosinophils and neutrophils were not significantly reduced in the Flut-treated group compared to the chronic CRA group. When the microbiome profiles were assessed, data showed that only the Flut-treated animals were significantly different in the gut microbiome. Finally, a functional analysis of cecal microbiome metabolites using PiCRUSt showed several biosynthetic pathways were significantly enriched in the Flut-treated group, with tryptophan pathway verified by ELISA with increased kynurenine in homogenized cecum samples. While the implications of these data are unclear, they may suggest a significant impact of steroid treatment on future disease pathogenesis through microbiome and associated metabolite pathway changes.

Childhood Outcomes in Children with and without Cardiac Echogenic Foci: An Electronic Birth Cohort Study in Wales, UK.

There is uncertainty about outcomes associated with cardiac echogenic foci (CEF) seen at the midtrimester ultrasound scan because of limited population-based follow-up data. This can lead to unnecessary invasive testing and significant parental anxiety. We analysed data from a cohort study, The Welsh Study of Mothers and Babies, to examine whether children with CEF had more adverse outcomes during childhood compared with children without CEF. Children born between 1 January 2009 and 31 December 2011 were followed until 31 January 2018, migration out of Wales, or death. The primary outcome was cardiac hospital admissions, defined a priori by an expert steering group. Secondary outcomes included congenital cardiac anomalies, and hospital admissions for other causes. There was no evidence of an association between isolated CEF and cardiac hospital admissions (hazard ratio 0.87, 95% confidence interval [CI] 0.33-2.25, p value 0.768), or with congenital cardiac anomalies. There was a small increased risk of a respiratory admission with isolated CEF (hazard ratio 1.27, 95% CI 1.04-1.54, p value 0.020). Further research is needed on features of CEF, such as location or number, to fully understand the clinical significance of these findings.

Sex-associated early-life viral innate immune response is transcriptionally associated with chromatin remodeling of type-I IFN-inducible genes.

This study investigates sex-associated systemic innate immune differences by examining bone marrow-derived dendritic cells (BMDCs). BMDC grown from 7-day-old mice show enhanced type-I interferon (IFN) signaling in female compared to male BMDC. Upon respiratory syncytial virus (RSV) infection of 7-day-old mice, a significantly altered phenotype of BMDC at 4 weeks post-infection is observed in a sex-dependent manner. The alterations include heightened Ifnb/ interleukin (Il12a) and enhanced IFNAR1+ expression in BMDC from early-life RSV-infected female mice that leads to increased IFN-γ production by T cells. Phenotypic differences were verified upon pulmonary sensitization whereby EL-RSV male-derived BMDC promoted enhanced T helper 2/17 responses and exacerbated disease upon RSV infection while EL-RSV/F BMDC sensitization was relatively protective. Assay for transposase-accessible chromatin using sequencing analysis (ATAC-seq) demonstrated that EL-RSV/F BMDC had enhanced chromatin accessibility near type-I immune genes with JUN, STAT1/2, and IRF1/8 transcription factors predicted to have binding sites in accessible regions. Importantly, ATAC-seq of human cord blood-derived monocytes displayed a similar sex-associated chromatin landscape with female-derived monocytes having more accessibility in type-I immune genes. These studies enhance our understanding of sex-associated differences in innate immunity by epigenetically controlled transcriptional programs amplified by early-life infection in females via type-I immunity.

Adenoviral vectored vaccination protects against Crimean-Congo Haemorrhagic Fever disease in a lethal challenge model.

BACKGROUND: The tick-borne bunyavirus, Crimean-Congo Haemorrhagic Fever virus (CCHFV), can cause severe febrile illness in humans and has a wide geographic range that continues to expand due to tick migration. Currently, there are no licensed vaccines against CCHFV for widespread usage. METHODS: In this study, we describe the preclinical assessment of a chimpanzee adenoviral vectored vaccine (ChAdOx2 CCHF) which encodes the glycoprotein precursor (GPC) from CCHFV. FINDINGS: We demonstrate here that vaccination with ChAdOx2 CCHF induces both a humoral and cellular immune response in mice and 100% protection in a lethal CCHF challenge model. Delivery of the adenoviral vaccine in a heterologous vaccine regimen with a Modified Vaccinia Ankara vaccine (MVA CCHF) induces the highest levels of CCHFV-specific cell-mediated and antibody responses in mice. Histopathological examination and viral load analysis of the tissues of ChAdOx2 CCHF immunised mice reveals an absence of both microscopic changes and viral antigen associated with CCHF infection, further demonstrating protection against disease. INTERPRETATION: There is the continued need for an effective vaccine against CCHFV to protect humans from lethal haemorrhagic disease. Our findings support further development of the ChAd platform expressing the CCHFV GPC to seek an effective vaccine against CCHFV. FUNDING: This research was supported by funding from the Biotechnology and Biological Sciences Research Council (UKRI-BBSRC) [BB/R019991/1 and BB/T008784/1].

Immunization with matrix-, nucleoprotein and neuraminidase protects against H3N2 influenza challenge in pH1N1 pre-exposed pigs.

There is an urgent need for influenza vaccines providing broader protection that may decrease the need for annual immunization of the human population. We investigated the efficacy of heterologous prime boost immunization with chimpanzee adenovirus (ChAdOx2) and modified vaccinia Ankara (MVA) vectored vaccines, expressing conserved influenza virus nucleoprotein (NP), matrix protein 1 (M1) and neuraminidase (NA) in H1N1pdm09 pre-exposed pigs. We compared the efficacy of intra-nasal, aerosol and intra-muscular vaccine delivery against H3N2 influenza challenge. Aerosol prime boost immunization induced strong local lung T cell and antibody responses and abrogated viral shedding and lung pathology following H3N2 challenge. In contrast, intramuscular immunization induced powerful systemic responses and weak local lung responses but also abolished lung pathology and reduced viral shedding. These results provide valuable insights into the development of a broadly protective influenza vaccine in a highly relevant large animal model and will inform future vaccine and clinical trial design.

Hormone replacement therapy (conjugated oestrogens plus bazedoxifene) for post-menopausal women with symptomatic hand osteoarthritis: primary report from the HOPE-e randomised, placebo-controlled, feasibility study.

Background: Symptomatic hand osteoarthritis is more common in women than in men, and its incidence increases around the age of menopause, implicating oestrogen deficiency. No randomised controlled trials of hormone replacement therapy (HRT) have been done in people with hand osteoarthritis. We aimed to determine the feasibility and acceptability of a form of HRT (conjugated oestrogens plus bazedoxifene) in post-menopausal women with painful hand osteoarthritis. Methods: The HOPE-e feasibility study was a randomised, double-blind, placebo-controlled trial, for which we recruited women aged 40-65 years, for whom 1-10 years had passed after their final menstrual period, with definite hand osteoarthritis and at least two painful hand joints. Participants were recruited across three primary or secondary care sites and from the community and were randomly assigned (1:1) to receive conjugated oestrogens plus bazedoxifene or placebo, orally once every day for 24 weeks, before weaning for 4 weeks until the end of the study. The primary feasibility outcomes were rates of identification, recruitment, randomisation, retention, and compliance of eligible participants, and the likelihood of unmasking. The secondary objective was to generate proof-of-concept quantitative and qualitative data on the acceptability of proposed clinical outcomes for a full trial and adverse events. We used an intention-to-treat analysis, and criteria for progression to a full trial were pre-defined as recruitment of at least 30 participants across all sites in 18 months; a dropout rate of less than or equal to 30% of randomised individuals; and acceptability to the majority of participants, including acceptable rates of adverse events. Due to the COVID-19 pandemic, the recruitment window was reduced to 12-15 months. A proportionately reduced minimum sample size of 22 was judged to be sufficient to test feasibility. This trial was registered at ISRCTN, ISRCTN12196200. Findings: From May 9, 2019 to Dec 31, 2020, 434 enquiries or referrals were received. We did 96 telephone pre-screens; of the 35 eligible participants, seven were excluded as ineligible at the telephone or face-to-face screening and 28 (80% [95% CI 63-92]) were randomly assigned. Of the 406 who were not randomly assigned, 250 (62%) were ineligible (with contraindicated medications accounting for 50 [20%] of these), 101 (25%) did not respond to further enquiries, and 55 (14%) chose not to proceed (with the most common reason being not wanting to take a hormone-based drug). All 28 randomised participants completed all follow-up assessments with high compliance and outcome measure completeness. All three adverse event-related treatment withdrawals were in the placebo group. No serious adverse events were reported. Participants and investigators were successfully masked (participant Bang's blinding index placebo group 0·50 [95% CI 0·25-0·75]). The trial met the prespecified criteria for progression to a full trial. Interpretation: This first-ever feasibility study of a randomised controlled trial of HRT for post-menopausal women with painful hand osteoarthritis met its progression criteria, although it was not powered to detect a clinical effect. This outcome indicates that a full trial of an HRT in this population is feasible and acceptable and identifies potential refinements with regard to the design of such a trial. Funding: Research for Patient Benefit programme, National Institute for Health Research.

Production of a high purity, C-tagged hepatitis B surface antigen fusion protein VLP vaccine for malaria expressed in Pichia pastoris under cGMP conditions.

Virus-like particles (VLPs) induce strong humoral and cellular responses and have formed the basis of some currently licensed vaccines. Here, we present the method used for the production of R21, a VLP-based anti-sporozoite malaria vaccine, under current Clinical Good Manufacturing Practice regulations (cGMP). Previous preclinical studies in BALB/c mice showed that R21 produced almost complete protection against sporozoite challenge with transgenic Plasmodium berghei parasites. Here, we have modified the preclinical production process to enable the production of sufficient quantities of highly pure, clinical-grade material for use in human clinical trials. The R21 construct was re-engineered to include a C-tag to allow affinity-based separation from the major contaminant alcohol oxidase 1 (AOX 1, ~74 kDa). To our knowledge, this is the first use of C-tag technology to purify a VLP vaccine candidate for use in human clinical trials. The R21 vaccine has shown high-level efficacy in an African Phase IIb trial, and multiple clinical trials are underway to assess the safety and efficacy of the vaccine. Our findings support the future use of C-tag platform technologies to enable cGMP-compliant biomanufacturing of high purity yeast-expressed VLP-based vaccines for early phase clinical trials when clinical grade material is required in smaller quantities in a quick time frame.

Validation of the Pediatric Narcolepsy Screening Questionnaire (PNSQ): A cross-sectional, observational study.

OBJECTIVE/BACKGROUND: This study evaluated psychometric properties of the Pediatric Narcolepsy Screening Questionnaire (PNSQ), developed in response to the difficulty of identifying pediatric narcolepsy. PATIENTS/METHODS: The initial PNSQ was updated following debriefing interviews with parents of children with suspected/diagnosed narcolepsy. Subsequently, newly recruited caregivers were categorized into groups: clinician-confirmed narcolepsy, other sleep problems (OSP), and no sleep problems (controls). Caregivers completed the 11-item PNSQ assessing narcolepsy symptomatology. PNSQ psychometric properties were evaluated; mean PNSQ Total Score (TS) was compared inter-group using analysis of variance. RESULTS: The analysis population (N = 158) included patients with narcolepsy (n = 49), OSP (n = 55), and controls (n = 54); mean ± SD age was 13.8 ± 2.8, 10.2 ± 4.3, and 10.0 ± 3.8 years, respectively. Inter-item Pearson correlations (range, 0.22-0.75) indicated good construct validity. Principal component analysis confirmed unidimensionality. Item discriminative power was high for narcolepsy vs control (range, 0.693-0.936) and lower for narcolepsy vs OSP (range, 0.584-0.729). The latent trait was well covered (separation index = 0.868). Item 7 (vivid dreams/nightmares), having low discriminative power and specificity, was removed. Cronbach's alpha (final PNSQ) indicated high internal consistency reliability (raw alpha = 0.88). Mean ± SD PNSQ TS (range, 0-50) in the narcolepsy, OSP, and control groups were 34.98 ± 7.98, 25.20 ± 9.43, and 9.54 ± 9.38, respectively (nominal P < 0.0001). Classification by PNSQ TS was defined: PNSQ+ (likely narcolepsy, TS ≥ 29), PNSQ 0 (likely OSP, TS 19-28), and PNSQ- (narcolepsy unlikely, TS ≤ 18); patients with narcolepsy were classified as PNSQ+ (79.6%), PNSQ 0 (18.4%), and PNSQ- (2.0%). CONCLUSIONS: The PNSQ demonstrated good psychometric properties and excellent performance discriminating narcolepsy, OSP, and control groups.

Motor evoked potentials versus Macrostimulation in predicting the postoperative motor threshold in STN Deep brain stimulation.

INTRODUCTION: Accuracy is crucial in Deep Brain Stimulation (DBS). Electrophysiological and image-based techniques are used to avoid suboptimal positioning. Macrostimulation is the gold standard to delineate the therapeutic window intraoperatively. Despite this, electrode revision rates due to malpositioning are as high as 17%. The goal was to compare motor evoked potentials (MEPs) with the gold standard of Macrostimulation. We assessed accuracy and precision as well as the correlation in predicting motor side effects at the initial mapping 4 weeks postoperatively. METHODS: In this prospective study intraoperative MEPs from 94 contacts in 16 patients undergoing STN DBS under local anesthesia were correlated to the postoperative threshold for stimulation-induced motor side effects and compared to intraoperative Macrostimulation. Analysis of accuracy, precision and correlation (Pearson) was performed. RESULTS: MEPs of the upper extremity had a mean percentage error of 25% (SD 38.8%) and correlated significantly with the motor threshold at postoperative mapping (R=0.235). Macrostimulation was less accurate and precise with a mean percentage error of - 68% (SD 78.8%) but had a higher correlation (R=0.388). MEPs rarely (3%) overestimated the threshold by maximally 1 mA. In contrast, Macrostimulation overestimated the threshold by over 1 mA in 69% leading to a false sense of security. CONCLUSION: MEPs are feasible in an awake setting during Deep Brain Stimulation in the STN for PD patients. MEPs of the upper extremity are more accurate and precise predicting the motor threshold and avoid a false sense of security in comparison to the gold standard of Macrostimulation.

Vaccines based on the replication-deficient simian adenoviral vector ChAdOx1: Standardized template with key considerations for a risk/benefit assessment.

Replication-deficient adenoviral vectors have been under investigation as a platform technology for vaccine development for several years and have recently been successfully deployed as an effective COVID-19 counter measure. A replication-deficient adenoviral vector based on the simian adenovirus type Y25 and named ChAdOx1 has been evaluated in several clinical trials since 2012. The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) was formed to evaluate the safety and other key features of new platform technology vaccines. This manuscript reviews key features of the ChAdOx1-vectored vaccines. The simian adenovirus Y25 was chosen as a strategy to circumvent pre-existing immunity to common human adenovirus serotypes which could impair immune responses induced by adenoviral vectored vaccines. Deletion of the E1 gene renders the ChAdOx1 vector replication incompetent and further genetic engineering of the E3 and E4 genes allows for increased insertional capability and optimizes vaccine manufacturing processes. ChAdOx1 vectored vaccines can be manufactured in E1 complementing cell lines at scale and are thermostable. The first ChAdOx1 vectored vaccines approved for human use, against SARS-CoV-2, received emergency use authorization in the UK on 30th December 2020, and is now approved in more than 180 countries. Safety data were compiled from phase I-III clinical trials of ChAdOx1 vectored vaccines expressing different antigens (influenza, tuberculosis, malaria, meningococcal B, prostate cancer, MERS-CoV, Chikungunya, Zika and SARS-CoV-2), conducted by the University of Oxford, as well as post marketing surveillance data for the COVID-19 Oxford-AstraZeneca vaccine. Overall, ChAdOx1 vectored vaccines have been well tolerated. Very rarely, thrombosis with thrombocytopenia syndrome (TTS), capillary leak syndrome (CLS), immune thrombocytopenia (ITP), and Guillain-Barre syndrome (GBS) have been reported following mass administration of the COVID-19 Oxford-AstraZeneca vaccine. The benefits of this COVID-19 vaccination have outweighed the risks of serious adverse events in most settings, especially with mitigation of risks when possible. Extensive immunogenicity clinical evaluation of ChAdOx1 vectored vaccines reveal strong, durable humoral and cellular immune responses to date; studies to refine the COVID-19 protection (e.g., via homologous/heterologous booster, fractional dose) are also underway. New prophylactic and therapeutic vaccines based on the ChAdOx1 vector are currently undergoing pre-clinical and clinical assessment, including vaccines against viral hemorrhagic fevers, Nipah virus, HIV, Hepatitis B, amongst others.

The ChAdOx1 vectored vaccine, AZD2816, induces strong immunogenicity against SARS-CoV-2 beta (B.1.351) and other variants of concern in preclinical studies.

BACKGROUND: There is an ongoing global effort to design, manufacture, and clinically assess vaccines against SARS-CoV-2. Over the course of the ongoing pandemic a number of new SARS-CoV-2 virus isolates or variants of concern (VoC) have been identified containing mutations in key proteins. METHODS: In this study we describe the generation and preclinical assessment of a ChAdOx1-vectored vaccine (AZD2816) which expresses the spike protein of the Beta VoC (B.1.351). FINDINGS: We demonstrate that AZD2816 is immunogenic after a single dose. When AZD2816 is used as a booster dose in animals primed with a vaccine encoding the original spike protein (ChAdOx1 nCoV-19/ [AZD1222]), an increase in binding and neutralising antibodies against Beta (B.1.351), Gamma (P.1) and Delta (B.1.617.2) is observed following each additional dose. In addition, a strong and polyfunctional T cell response was measured all booster regimens. INTERPRETATION: Real world data is demonstrating that one or more doses of licensed SARS-CoV-2 vaccines confer reduced protection against hospitalisation and deaths caused by divergent VoC, including Omicron. Our data support the ongoing clinical development and testing of booster vaccines to increase immunity against highly mutated VoC. FUNDING: This research was funded by AstraZeneca with supporting funds from MRC and BBSRC.

Test-retest reliability of the Epworth Sleepiness Scale in clinical trial settings.

The present analysis examined the test-retest reliability of the Epworth Sleepiness Scale in participants with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea in three clinical trials. Intraclass correlation coefficient estimates for Epworth Sleepiness Scale scores from two solriamfetol 12-week placebo-controlled trials (one narcolepsy, one obstructive sleep apnea) and one long-term open-label extension trial (narcolepsy or obstructive sleep apnea) were calculated using postbaseline time-point pairs for the overall population in each trial, by treatment, and by primary obstructive sleep apnea therapy adherence. In the 12-week narcolepsy trial, intraclass correlation coefficients (95% confidence intervals) were 0.83 (0.79, 0.87) for weeks 4 and 8 (n = 199), 0.87 (0.83, 0.90) for weeks 8 and 12 (n = 196), and 0.81 (0.76, 0.85) for weeks 4 and 12 (n = 196). In the 12-week obstructive sleep apnea trial, intraclass correlation coefficients (95% confidence intervals) were 0.74 (0.69, 0.78) (n = 416), 0.80 (0.76, 0.83) (n = 405), and 0.74 (0.69, 0.78) (n = 405), respectively. In the open-label extension trial, intraclass correlation coefficients (95% confidence intervals) were 0.82 (0.79, 0.85) for weeks 14 and 26/27 (n = 495), 0.85 (0.82, 0.87) for weeks 26/27 and 39/40 (n = 463), and 0.78 (0.74, 0.81) for weeks 14 and 39/40 (n = 463). Placebo/solriamfetol treatment or adherence to primary obstructive sleep apnea therapy did not affect reliability. In conclusion, across three large clinical trials of participants with narcolepsy or obstructive sleep apnea, Epworth Sleepiness Scale scores demonstrated a robust acceptable level of test-retest reliability in evaluating treatment response over time.

ER stress protein PERK promotes inappropriate innate immune responses and pathogenesis during RSV infection.

The activation of dendritic cells (DC) during respiratory viral infections is central to directing the immune response and the pathologic outcome. In these studies, the effect of RSV infection on development of ER stress responses and the impact on innate immunity was examined. The upregulation of ER stress was closely associated with the PERK pathway through the upregulation of CHOP in RSV infected DC. The inhibition of PERK corresponded with decreased EIF2a phosphorylation but had no significant effect on Nrf2 in DC, two primary pathways regulated by PERK. Subsequent studies identified that by blocking PERK activity in infected DC an altered ER stress response and innate cytokine profile was observed with the upregulation of IFNß and IL-12, coincident to the down regulation of IL-1ß. When mitochondria respiration was assessed in PERK deficient DC there were increased dysfunctional mitochondria after RSV infection that resulted in reduced oxygen consumption rates (OCR) and ATP production indicating altered cellular metabolism. Use of a CD11c targeted genetic deleted murine model, RSV infection was characterized by reduced inflammation and diminished mucus staining as well as reduced mucus-associated gene gob5 expression. The assessment of the cytokine responses showed decreased IL-13 and IL-17 along with diminished IL-1ß in the lungs of PERK deficient infected mice. When PERK-deficient animals were assessed in parallel for lung leukocyte numbers, animals displayed significantly reduced myeloid and activated CD4 and CD8 T cell numbers. Thus, the PERK activation pathway may provide a rational target for altering the severe outcome of an RSV infection through modifying immune responses.