ABSTRACT
Within the Innovative Health Initiative (IHI) Inno4Vac CHIMICHURRI project, a regulatory workshop was organised on the development and manufacture of challenge agent strains for Controlled Human Infection Model (CHIM) studies. Developers are often uncertain about which GMP requirements or regulatory guidelines apply but should be guided by the 2022 technical white paper "Considerations on the Principles of Development and Manufacturing Qualities of Challenge Agents for Use in Human Infection Models" (published by hVIVO, Wellcome Trust, HIC-Vac consortium members). Where those recommendations cannot be met, regulators advise following the "Principles of GMP" until definitive guidelines are available. Sourcing wild-type virus isolates is a significant challenge for developers. Still, it is preferred over reverse genetics challenge strains for several reasons, including implications and regulations around genetically modified organisms (GMOs). Official informed consent guidelines for collecting isolates are needed, and the characterisation of these isolates still presents risks and uncertainty. Workshop topics included ethics, liability, standardised clinical endpoints, selection criteria, sharing of challenge agents, and addressing population heterogeneity concerning vaccine response and clinical course. The organisers are confident that the workshop discussions will contribute to advancing ethical, safe, and high-quality CHIM studies of influenza, RSV and C. difficile, including adequate regulatory frameworks.
Subject(s)
Clostridioides difficile , Influenza Vaccines , Influenza, Human , Viruses , Humans , Influenza, Human/prevention & control , Viruses/geneticsABSTRACT
INTRODUCTION: Hyperopia is associated with reduced vision and educational outcomes in schoolchildren. This study explored the impact of clinically significant hyperopia (≥+2.00 D) on visual function in schoolchildren and compared the ability of different screening tests (alone and in combination) to detect this level of hyperopia. METHODS: Vision testing including monocular logMAR visual acuity (VA) measured to threshold (distance [DVA], near [NVA] and DVA through a plus lens [+2.50 D]), stereoacuity and cycloplegic autorefraction (tropicamide 1%) were undertaken on 263 schoolchildren (mean age: 11.76 years ± 3.38) in Queensland, Australia. Vision measures were compared between children with clinically significant hyperopia in at least one meridian (≥+2.00 D) and emmetropia/low hyperopia (>0.00 and <+2.00 D). Receiver operating curve (ROC) analysis was performed to identify optimal pass/fail criteria for each test and the diagnostic accuracy of individual and combinations of tests. RESULTS: Thirty-two children had clinically significant hyperopia and 225 had emmetropia/low hyperopia. DVA and NVA were worse (p < 0.01), while the difference in DVA through a plus lens was less in children with clinically significant hyperopia (p < 0.01). ROC analysis for individual tests resulted in areas under the curve (AUCs) ranging from 0.65 to 0.85. Combining screening tests revealed that failing one or more of the following tests was most effective for detecting hyperopia: DVA, NVA and difference in DVA through a plus lens, resulting in a sensitivity and specificity of 72% and 81%, respectively. CONCLUSION: Significant differences in visual function existed between schoolchildren with clinically significant hyperopia and emmetropia/low hyperopia. Combining measures of DVA and NVA and the difference in DVA through a plus lens demonstrated good discriminative ability for detecting clinically significant hyperopia in this population.
Subject(s)
Hyperopia , Vision Screening , Child , Humans , Hyperopia/diagnosis , Visual Acuity , Vision Tests , Emmetropia , Sensitivity and Specificity , Vision Screening/methodsABSTRACT
Mucosal immunity is important in protecting from upper respiratory tract influenza infection. Human challenge provides a unique model to define correlates of protection with baseline immune responses being correlated to the quantity and length of viral shedding and clinical outcomes. Here, we discuss recent work on mucosal and systemic correlates of protection (R. Bean, L. T. Giurgea, A. Han, L. Czajkowski, et al., mBio 15:e02372-23, 2024, https://doi.org/10.1128/mbio.02372-23) and place it in the context of previous work on mucosal immunity. We also discuss the importance of standardized assays to allow global comparison of relevant immune responses in defining correlates of protection. Correlates of protection are important for designing next-generation broadly protective influenza vaccines.
Subject(s)
Immunity, Mucosal , Influenza A Virus, H1N1 Subtype , Influenza Vaccines , Influenza, Human , Humans , Influenza, Human/prevention & control , Influenza, Human/immunology , Influenza, Human/virology , Influenza Vaccines/immunology , Influenza Vaccines/administration & dosage , Influenza A Virus, H1N1 Subtype/immunology , Virus Shedding , AnimalsABSTRACT
The endemic human coronaviruses (HCoVs) circulate worldwide yet remain understudied and unmitigated. The observation of elevated levels of HCoV reactive antibodies in COVID-19 patients highlights the urgent necessity of better understanding of HCoV specific immunity. Here, we characterized in-depth the de novo SARS-CoV-2 specific antibody responses and the boosting of HCoV-reactive antibodies after SARS-CoV-2 vaccination or infection in individuals up to 98 years old. All the vaccinees were home-dwelling with no documented SARS-CoV-2 infection before receiving the COVID-19 mRNA vaccine (BNT162b2). The first two vaccine doses elicited potent SARS-CoV-2 spike binding antibodies in individuals up to 80 years. The third dose largely boosted the previously low S2 domain binding and neutralizing antibodies in elderly 80-90 years old, but less so in those above 90 years. The endemic betacoronavirus (HKU1 and OC43) reactive antibodies were boosted in all vaccinees, although to a lesser extent in those above 80 years old. COVID-19 patients had potent elevation of alpha- and betacoronavirus (229E, NL63, HKU1 and OC43) reactive antibodies. In both patients and vaccinees, S2 domain specific antibody increases correlated with SARS-CoV-2 neutralizing and HCoV-reactive antibody responses in all ages, indicating S2 domain as a candidate for future universal coronavirus vaccine design.
ABSTRACT
Anxiety symptoms vary moment-to-moment within a day. One factor that may influence these variations is chronotype. Evening chronotypes prefer to engage in activities (e.g., sleep, physical and social activity) later in the day, and evening chronotype is implicated in psychopathology, including anxiety-related disorders. However, it is unknown whether chronotype influences diurnal variation in anxiety symptoms and whether these effects are amplified in individuals with a probable anxiety-related disorder. We examined the diurnal variation in anxiety symptoms and daily activities in morning and evening chronotypes with and without probable generalized anxiety disorder (GAD) or obsessive-compulsive disorder (OCD) in a community sample of adults (N = 410). Evening chronotypes reported higher anxiety symptoms, particularly in the evening hours, and lower engagement in daily activities, predominantly in the morning hours. Evening chronotypes with probable GAD or OCD reported worse anxiety symptoms in the evening. Our findings indicate that anxiety symptoms and engagement in daily activities fluctuate considerably across the day, and these patterns differ depending on chronotype. Evening chronotypes have more anxiety symptoms in the evening, despite preferring this time of day. Personalized treatment approaches that consider chronotype and target certain times of day may be efficient in alleviating peaks in anxiety symptoms.
Subject(s)
Anxiety Disorders , Anxiety , Circadian Rhythm , Humans , Male , Female , Adult , Circadian Rhythm/physiology , Anxiety Disorders/physiopathology , Anxiety Disorders/epidemiology , Anxiety Disorders/psychology , Anxiety/physiopathology , Middle Aged , Obsessive-Compulsive Disorder/physiopathology , Young Adult , Sleep/physiology , Activities of Daily Living , Adolescent , ChronotypeABSTRACT
Given that emotion regulation difficulties confer risk for poor responses to stress, they may predict who is at risk for adverse psychological reactions to major, chronic stressors such as the COVID-19 pandemic. Specific adverse reactions to the pandemic may include more severe traumatic stress, anxiety, and excessive safety behavior use (i.e., hand washing). While emotion regulation difficulties may be a diathesis for adverse reactions to chronic stressors, the context(s) by which they may confer elevated risk is unclear. Accordingly, the present longitudinal study examined the interaction between pre-pandemic emotion regulation difficulties and early pandemic perceived stress in predicting subsequent COVID-related traumatic stress, anxiety, and safety behavior use over 32 weeks of the pandemic. Community adults (N = 145) who completed a measure of emotion regulation in 2016 as part of a larger study were recontacted at the start of the pandemic (March 2020) and assessed every two weeks for 32 weeks. Consistent with a diathesis-stress model, the interaction between difficulties in emotion regulation and perceived stress was significant in predicting COVID-19 anxiety (p = 0.003, d = 0.52) such that at high, but not low, levels of perceived stress, difficulties in emotion regulation in 2016 significantly predicted higher COVID-19 anxiety in 2020. The interaction between difficulties in emotion regulation in 2016 and perceived stress early in 2020 approached significance in predicting COVID-19 traumatic stress (p = 0.073, d = 0.31) and safety behavior use (p = 0.069, d = 0.31). These findings highlight that current perceived stress is an important context that potentiates the effects of preexisting emotion regulation difficulties on the emergence of anxiety-related symptoms during COVID-19, which has important implications for diathesis-stress models of adverse reactions to chronic stressors.
Subject(s)
COVID-19 , Emotional Regulation , Adult , Humans , Prospective Studies , Disease Susceptibility , Pandemics , Longitudinal Studies , Anxiety/psychology , Stress, Psychological/psychologyABSTRACT
Introduction: A substantial proportion of the over 700 million COVID-19 cases world-wide experience long-term symptoms. The objectives of this study were to compare symptom trajectories and risk factors for post-COVID-19 condition after Delta and Omicron infection. Methods: This study consecutively recruited patients with SARS-CoV-2 infection from November 2021 to March 2022. We recorded demographics, comorbidities, vaccination status, sick leave, and 18 symptoms during acute infection and after 4 months. The primary outcome measures were symptoms during acute infection and after 4 months. Secondary outcome measures were work and school absenteeism. Results: We followed a cohort of 1,374 non-hospitalized COVID-19 patients in Bergen, Norway, at three time points. The median age was 39.8 years and 11% were children <16 years. Common acute upper respiratory symptoms waned during follow-up. Fatigue remained common from acute infection (40%) until after 4 months (37%). Four months post-infection, patients reported increased frequencies of dyspnea (from 15% during acute illness to 25% at 4 months, p < 0.001), cognitive symptoms (from 9 to 32%, p < 0.001) and depression (from 1 to 17%, p < 0.001). Patients infected with Omicron reported less dyspnea (22% versus 27%, p = 0.046) and smell/taste problems (5% versus 19%, p < 0.001) at 4 months follow-up than those with Delta infection. Comorbidities and female sex were risk factors for persistent dyspnea and cognitive symptoms. Ten percent reported sick leave after acute illness, and vaccination reduced the risk of absenteeism (adjusted risk ratio: 0.36, 95% confidence interval: 0.15, 0.72, p = 0.008). Conclusion: At 4 months, home-isolated patients infected with Omicron reported overall comparable symptom burden, but less dyspnea and smell/taste problems than Delta infected patients. Several acute symptoms waned during follow-up. It is worrying that dyspnea, neurocognitive symptoms, and particularly depression, increased significantly during the first 4 months after acute infection. Previous vaccination was protective against prolonged sick leave.
Subject(s)
COVID-19 , Child , Humans , Female , Adult , Acute Disease , COVID-19/epidemiology , SARS-CoV-2 , Disease Progression , Norway/epidemiology , DyspneaABSTRACT
Organisms across taxa face stresses including variable temperature, redox imbalance, and xenobiotics. Successfully responding to stress and restoring homeostasis are crucial for survival. Aging is associated with a decreased stress response and alterations in the microbiome, which contribute to disease development. Animals and their microbiota share their environment; however, microbes have short generation time and can rapidly evolve and potentially affect host physiology during stress. Here, we leverage Caenorhabditis elegans and its simplified bacterial diet to demonstrate how microbial adaptation to oxidative stress affects the host's lifespan and stress response. We find that worms fed stress-evolved bacteria exhibit enhanced stress resistance and an extended lifespan. Through comprehensive genetic and metabolic analysis, we find that iron in stress-evolved bacteria enhances worm stress resistance and lifespan via activation of the mitogen-activated protein kinase pathway. In conclusion, our study provides evidence that understanding microbial stress-mediated adaptations could be used to slow aging and alleviate age-related health decline.
Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Animals , Caenorhabditis elegans/metabolism , Longevity/genetics , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolism , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Oxidative Stress , Diet , Bacteria/genetics , Bacteria/metabolismABSTRACT
BACKGROUND: Patients with multiple sclerosis (MS) treated with anti-CD20 therapies such as rituximab may have increased risk of severe COVID-19 disease. Vaccination induces protective immunity, but humoral vaccine response is known to be attenuated in rituximab-treated MS-patients-patients, which has indicated a need for real world data on severe morbidity and mortality from COVID-19 after vaccination. METHODS: Rituximab-treated patients treated at Haukeland University Hospital were identified through the National MS Registry and invited to participate in the study by giving a consent and providing a blood sample 3 weeks or later after ordinary COVID-19- vaccination, i.e. 2 doses given with a standard interval of 3 weeks. Blood samples were analysed with Enzyme-Linked Immunosorbent assay (ELISA) to evaluate humoral vaccine response with screening test against receptor-binding domain (RBD) and confirmatory Spike IgG-specific ELISA. A haemagglutination test (HAT) was performed as a marker of neutralizing antibodies. Patient serum concentration of rituximab were quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS). Registry data from the Norwegian MS registry and information on hospitalization from patient records were collected and linked to laboratory results. RESULTS: 111 patients were included in the study. A total of 7 (6.3%) were hospitalized due to COVID-19 disease during the observation period. No patient was admitted to ICU and there were no deaths. 34.2% did not have detectable titre of SARS CoV-2 Spike IgG antibodies, 72.1% did not have a detectable titre of SARS CoV-2 RBD antibodies, and 88.2% did not have a detectable HAT titre. There was a correlation between hospitalisation and the absence of SARS CoV-2 Spike IgG antibody titre, and between hospitalisation and MS disease duration, as well as between spike IgG antibody titre and CD19 B-cell count, time since last rituximab infusion, cumulative rituximab treatment time and total IgG level in the patients. CONCLUSION: A substantial proportion of rituximab-treated MS-patients-patients did not have detectable humoral vaccine responses after 2 doses of COVID-19 vaccination. Despite this, the cumulative percentage of patients hospitalized with COVID-19 disease throughout the observation period of 22 months was low, and no patients required ICU treatment. The results support that vaccinated MS-patients treated with rituximab have a protective effect against serious Covid-19 infection.
Subject(s)
COVID-19 Vaccines , COVID-19 , Hospitalization , Immunologic Factors , Multiple Sclerosis , Rituximab , Humans , Rituximab/administration & dosage , Rituximab/therapeutic use , Rituximab/pharmacology , Female , Male , Adult , Middle Aged , Multiple Sclerosis/immunology , Multiple Sclerosis/drug therapy , Multiple Sclerosis/blood , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , Immunologic Factors/administration & dosage , Immunologic Factors/pharmacology , Hospitalization/statistics & numerical data , SARS-CoV-2/immunology , Antibodies, Viral/blood , Registries , Immunity, Humoral/drug effects , Immunity, Humoral/immunology , Norway/epidemiologyABSTRACT
Dietary restriction (DR) and hypoxia (low oxygen) extend lifespan in Caenorhabditis elegans through the induction of a convergent downstream longevity gene, fmo-2. Flavin-containing monooxygenases (FMOs) are highly conserved xenobiotic-metabolizing enzymes with a clear role in promoting longevity in nematodes and a plausible similar role in mammals. This makes them an attractive potential target of small molecule drugs to stimulate the health-promoting effects of longevity pathways. Here, we utilize an fmo-2 fluorescent transcriptional reporter in C. elegans to screen a set of 80 compounds previously shown to improve stress resistance in mouse fibroblasts. Our data show that 19 compounds significantly induce fmo-2, and 10 of the compounds induce fmo-2 more than twofold. Interestingly, 9 of the 10 high fmo-2 inducers also extend lifespan in C. elegans. Two of these drugs, mitochondrial respiration chain complex inhibitors, interact with the hypoxia pathway to induce fmo-2, whereas two dopamine receptor type 2 (DRD2) antagonists interact with the DR pathway to induce fmo-2, indicating that dopamine signaling is involved in DR-mediated fmo-2 induction. Together, our data identify nine drugs that each (1) increase stress resistance in mouse fibroblasts, (2) induce fmo-2 in C. elegans, and (3) extend nematode lifespan, some through known longevity pathways. These results define fmo-2 induction as a viable approach to identifying and understanding mechanisms of putative longevity compounds.
Subject(s)
Caenorhabditis elegans , Longevity , Animals , Caenorhabditis elegans/drug effects , Longevity/drug effects , Mice , Oxygenases/metabolism , Oxygenases/genetics , Caloric Restriction , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Fibroblasts/drug effects , Fibroblasts/metabolism , Drug Evaluation, Preclinical/methodsABSTRACT
Underserved and hard-to-reach population groups are under-represented in vaccine trials. Thus, we aimed to identify the challenges of vaccine trial participation of these groups in member countries of the VACCELERATE network. Seventeen National Coordinators (NC), each representing their respective country (15 European countries, Israel, and Turkey), completed an online survey. From 15 eligible groups, those that were more frequently declared underserved/hard-to-reach in vaccine research were ethnic minorities (76.5%), persons experiencing homelessness (70.6%), illegal workers and refugees (64.7%, each). When prioritization for education on vaccine trials was considered, ethnic groups, migrants, and immigrants (5/17, 29.4%) were the groups most frequently identified by the NC as top targets. The most prominent barriers in vaccine trial participation affecting all groups were low levels of health literacy, reluctance to participate in trials due to engagement level, and low levels of trust in vaccines/vaccinations. This study highlighted population groups considered underserved/hard-to-reach in countries contained within the European region, and the respective barriers these groups face when participating in clinical studies. Our findings aid with the design of tailored interventions (within-and across-countries of the European region) and with the development of strategies to overcome major barriers in phase 2 and phase 3 vaccine trial participation.