Project description:mRNA vaccines have the potential to tackle many unmet medical needs that are unable to be addressed with conventional vaccine technologies. A potent and well-tolerated delivery technology is integral to fully realizing the potential of mRNA vaccines. Pre-clinical and clinical studies have demonstrated that mRNA delivered intramuscularly (IM) with first-generation lipid nanoparticles (LNPs) generates robust immune responses. Despite progress made over the past several years, there remains significant opportunity for improvement, as the most advanced LNPs were designed for intravenous (IV) delivery of siRNA to the liver. Here, we screened a panel of proprietary biodegradable ionizable lipids for both expression and immunogenicity in a rodent model when administered IM. A subset of compounds was selected and further evaluated for tolerability, immunogenicity, and expression in rodents and non-human primates (NHPs). A lead formulation was identified that yielded a robust immune response with improved tolerability. More importantly for vaccines, increased innate immune stimulation driven by LNPs does not equate to increased immunogenicity, illustrating that mRNA vaccine tolerability can be improved without affecting potency.
Project description:Accurate detection of acute kidney injury (AKI) in clinical trials is important. Using a 'baseline' creatinine from trial enrolment may not be ideal for understanding a participant's true baseline kidney function. We aimed to determine if a 'pre-trial baseline creatinine' resulted in comparable creatinine concentrations to a 'trial baseline creatinine', and how the timing of baseline creatinine affected the incidence of AKI in the Combination Antibiotic therapy for MEthicillin Resistant Staphylococcus aureus (CAMERA2) randomised trial. Study sites retrospectively collected a pre-trial baseline creatinine from up to 1 year before CAMERA2 trial enrolment ideally when the patient was medically stable. Baseline creatinine from CAMERA2 (the 'trial baseline creatinine'), was the highest creatinine measurement in the 24 h preceding trial randomisation. We used Wilcoxon sign rank test to compare pre-trial and trial baseline creatinine concentrations. We included 217 patients. The median pre-trial baseline creatinine was significantly lower than the median trial baseline creatinine (82 μmol/L [IQR 65-104 μmol/L] versus 86 μmol/L [IQR 66-152 μmol/L] p = <0.001). Using pre-trial baseline creatinine, 48 of 217 patients (22%) met criteria for an AKI at CAMERA2 enrolment and only 5 of these patients met criteria for an AKI using the CAMERA2 study protocol (using baseline creatinine from trial entry). Using a baseline creatinine from the time of trial enrolment failed to detect many patients with AKI. Trial protocols should consider the optimal timing of baseline creatinine and the limitations of using a baseline creatinine during an acute illness.
Project description:It is striking that all marketed SARS-CoV-2 vaccines are developed for intramuscular administration designed to produce humoral and cell mediated immune responses, preventing viremia and the COVID-19 syndrome. They have a high degree of efficacy in humans (70-95%) depending on the type of vaccine. However, little protection is provided against viral replication and shedding in the upper airways due to the lack of a local sIgA immune response, indicating a risk of transmission of virus from vaccinated individuals. A range of novel nasal COVID-19 vaccines are in development and preclinical results in non-human primates have shown a promising prevention of replication and shedding of virus due to the induction of mucosal immune response (sIgA) in upper and lower respiratory tracts as well as robust systemic and humoral immune responses. Whether these results will translate to humans remains to be clarified. An IM prime followed by an IN booster vaccination would likely result in a better well-rounded immune response, including prevention (or strong reduction) in viral replication in the upper and lower respiratory tracts.
Project description:With vaccines for coronavirus disease 2019 (COVID-19) being introduced in countries across the world, policy makers are facing many practical considerations about how best to implement a vaccination programme. The supply of vaccines is insufficient for the global population, so decisions must be made as to which groups are prioritised for any vaccination and when. Furthermore, the aims of vaccination programmes will differ between countries, with some prioritising economic benefits that could stem from the relaxation of non-pharmaceutical interventions and others seeking simply to reduce the number of COVID-19 cases or deaths. This paper aims to share the experiences and lessons learned from conducting economic evaluations in Singapore and Thailand on hypothetical COVID-19 vaccines to provide a basis for other countries to develop their own contextualised economic evaluations, with particular focus on the key uncertainties, technical challenges, and characteristics that modellers should consider in partnership with key stakeholders. Which vaccines, vaccination strategies, and policy responses are most economically beneficial remains uncertain. It is therefore important for all governments to conduct their own analyses to inform local policy responses to COVID-19, including the implementation of COVID-19 vaccines in both the short and the long run. It is essential that such studies are designed, and ideally conducted, before vaccines are introduced so that policy decisions and implementation procedures are not delayed.
Project description:Spasticity of the upper extremity can result in severe pain, along with many complications that can impair a patient's activities of daily living. Failure to treat patients with spasticity of the upper limb can result in a decrease in the range of motion of joints and contracture development, leading to further restriction in daily activities. We aimed to investigate the practice patterns of Canadian physicians who utilize Botulinum toxin type-A (BoNT-A) injections in the management of shoulder spasticity. 50 Canadian Physical Medicine and Rehabilitation (PM&R) physicians completed a survey with an estimated completion rate of (36.23%). The demographics of the survey participants came from a variety of provinces, clinical settings, and patient populations. The most common muscle injected for shoulder adduction and internal rotation spasticity was the pectoralis major, this was followed by latissimus dorsi, pectoralis minor, subscapularis and teres major. Injection of BoNT-A for problematic post-stroke shoulder spasticity was common, with (81.48%) of participants responding that it was always or often used in their management of post-stroke spasticity (PSS). Dosing of BoNT-A demonstrated variability for the muscle injected as well as the type of toxin used. The goals of the patients, caregivers, and practitioners were used to help guide the management of these patients. As a result, the practice patterns of Canadian physicians who treat shoulder spasticity are varied, due to numerous patient factors. Future studies are needed to analyze optimal treatment patterns, and the development of algorithms to standardize care.
Project description:INTRODUCTION:In children with brachial plexus birth injury (BPBI), denervation of the shoulder muscles leads to bony deformity in the first months of life, reducing active and passive range of motion (ROM) and causing activity limitation. The aim of this multicentre randomised controlled trial is to evaluate the effectiveness of botulinum toxin injections (BTI) in the shoulder internal rotator muscles of 12-month-old babies in limiting the progression of posterior subluxation of the glenohumeral joint, compared with a sham procedure mimicking BTI. The secondary aims are to evaluate the effectiveness of BTI in (1) limiting the progression of glenoid retroversion and three-dimensional (3D) deformity and (2) improving shoulder ROM and upper limb function, as well as to confirm the tolerance of BTI. METHODS AND ANALYSIS:Sixty-two babies with unilateral BPBI and a risk of posterior humeral head subluxation will be included. Only those with at least 7% posterior subluxation of the humeral head compared with the contralateral shoulder on the MRI will be randomised to one of two groups: 'BTI' and 'Sham'. The BTI group will receive BOTOX injections at the age of 12 months in the internal shoulder rotator muscles (8 UI/kg). The sham group will undergo a sham BTI procedure. Both groups will undergo repeated shoulder MRI at 18 months of age to quantify changes in the percentage of posterior migration of the humeral head (primary outcome), glenoid version and 3D bone deformity. Clinical evaluations (passive shoulder ROM, active movement scale) will be carried out at baseline and 15 and 18 months of age. The mini-assisting hand assessment will be rated between 10 and 11 months and at 18 months of age. Adverse events will be recorded at least monthly for each child. ETHICS AND DISSEMINATION:Full ethical approval for this study has been obtained. The findings will be disseminated in peer-reviewed publications. TRIAL REGISTRATION NUMBER:EudraCT: 2015-001402-34 in European Clinical Trial database; NCT03198702 in Clinical Trial database; Pre-results.
Project description:Chromosome duplication normally initiates via the assembly of replication fork complexes at defined origins. DNA synthesis by any one fork is thought to cease when it meets another travelling in the opposite direction, at which stage the replication machinery may simply dissociate before the nascent strands are finally ligated. But what actually happens is not clear. Here we present evidence consistent with the idea that every fork collision has the potential to trigger re-replication of the already replicated DNA, thus posing a threat to genomic integrity. In Escherichia coli this threat is kept at bay by the RecG DNA translocase. Without RecG, replication initiates where forks meet, establishing new forks with the potential to sustain cell growth and division in the absence of an active origin. The studies reported raise the question of how eukaryotic and archaeal cells are able to exploit multiple origins for the duplication of each chromosome without any apparent ill effect from the consequent multiple fork collisions.
Project description:Platycodin D (PD) is a potent adjuvant with dual Th1 and Th2 potentiating activity, but its mechanisms of action remain unclear. Here, the C2C12 myoblast cell line and mice were used as in vitro and in vivo models to identify potential signaling pathways involved in the adjuvant activity of PD. PD induced a transient cytotoxicity and inflammatory response in the C2C12 cells and in mouse quadricep muscles. A comparative analysis of microarray data revealed that PD induced similar gene expression profiles in the C2C12 cells and in the quadricep muscles, and triggered rapid regulation of death, immune, and inflammation-related genes, both in vivo and in vitro. It was further demonstrated that caspase-1-dependent pyroptosis was involved in the PD-induced cytotoxicity and inflammatory response in the C2C12 cells via the Ca2+-c-jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK)-NLR family pyrin domain containing 3 (NLRP3) inflammasome signaling pathway. Consistently, the in vivo analysis revealed that a local blockage of NLRP3 and caspase-1 inhibited PD-induced cytokine production and immune cell recruitment at the injection site, and impaired the adjuvant activity of PD on antigen-specific immune responses to model antigen ovalbumin (OVA) in mice. These findings identified the caspase-1-dependent adjuvanticity of PD and expanded the current knowledge on the mechanisms of action of saponin-based adjuvants.
Project description:IntroductionThe summary of product characteristics of vaccines administered intramuscularly, including the vaccine for coronavirus SARS-CoV-2 (COVID-19) and Influenza, warned for risks of bleeding in patients treated with oral anticoagulants. We aimed to estimate the incidence of major bleeding events in this setting and to compare these risks against other vaccination routes.MethodsThis systematic review included all prospective and retrospective studies enrolling anticoagulated patients that received intramuscular vaccination, published until December 2020 in CENTRAL, MEDLINE and EMBASE. The outcomes of interest were major bleeding and haematoma related with vaccination. The incidence of the outcomes was estimated through a random-effects meta-analysis using the Freeman-Turkey transformation. The results are expressed in percentages, with 95%-confidence intervals (95%CI), limited between 0 and 100%. When studies compared intramuscular vaccination vs. other route, the data were compared and pooled using random-effects meta-analysis. Risk ratios (RR) with 95%CI were reported.ResultsOverall 16 studies with 642 patients were included. No major bleeding event was reported. The pooled incidence of haematomas following vaccination (mostly against Influenza) in patients treated with oral anticoagulants (mostly warfarin; no data with DOACs / NOACs) was 0.46% (95%CI 0-1.53%). Three studies evaluated the intramuscular vs. subcutaneous route of vaccination. Intramuscular vaccines did not increase the risk of haematoma (RR 0.53, 95%CI 0.10-2.82) compared with subcutaneous route.ConclusionsIntramuscular vaccination in anticoagulated patients is safe with very low incidence of haematomas and the best available evidence suggests that using the intramuscular route does not increase the risk of haematomas compared with the subcutaneous route.