A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe ARDS From COVID-19.

RATIONALE: There are limited therapeutic options for patients with COVID-19-related acute respiratory distress syndrome (ARDS) with inflammation-mediated lung injury. Mesenchymal stromal cells offer promise as immunomodulatory agents. OBJECTIVES: Evaluation of efficacy and safety of allogeneic mesenchymal cells in mechanically-ventilated patients with moderate or severe COVID-induced respiratory failure. METHODS: Patients were randomized to two infusions of 2 million cells/kg or sham infusions, in addition to standard of care. We hypothesized that cell therapy would be superior to sham-control for the primary endpoint of 30-day mortality. The key secondary endpoint was ventilator-free survival within 60 days, accounting for deaths and withdrawals in a ranked analysis. MEASUREMENTS AND MAIN RESULTS: At the third interim analysis, the Data and Safety Monitoring Board recommended that the trial halt enrollment as the pre-specified mortality reduction from 40% to 23% was unlikely to be achieved (n=222 out of planned 300). Thirty-day mortality was 37.5% (42/112) in cell recipients versus 42.7% (47/110) in control patients (RR 0.88;95% CI 0.64,1.21;p=0.43). There were no significant differences in days alive off ventilation within 60 days (median rank 117.3 [IQR:60.0,169.5] in cell patients and 102.0 [IQR:54.0,162.5] in controls; higher is better). Resolution or improvement of ARDS at 30-days was observed in 51/104 (49.0%) cell recipients and 46/106 (43.4%) of control patients (OR 1.36;95% CI 0.57, 3.21). There were no infusion-related toxicities and overall serious adverse events over 30 days were similar. CONCLUSIONS: Mesenchymal cells, while safe, did not improve 30-day survival or 60-day ventilator-free days in patients with moderate/severe COVID-related acute respiratory distress syndrome. Clinical trial registration available at www. CLINICALTRIALS: gov, ID:NCT04371393. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

A numerical analysis of skin-PPE interaction to prevent facial tissue injury.

The use of close-fitting PPE is essential to prevent exposure to dispersed airborne matter, including the COVID-19 virus. The current pandemic has increased pressure on healthcare systems around the world, leading to medical professionals using high-grade PPE for prolonged durations, resulting in device-induced skin injuries. This study focuses on computationally improving the interaction between skin and PPE to reduce the likelihood of discomfort and tissue damage. A finite element model is developed to simulate the movement of PPE against the face during day-to-day tasks. Due to limited available data on skin characteristics and how these vary interpersonally between sexes, races and ages, the main objective of this study was to establish the effects and trends that mask modifications have on the resulting subsurface strain energy density distribution in the skin. These modifications include the material, geometric and interfacial properties. Overall, the results show that skin injury can be reduced by using softer mask materials, whilst friction against the skin should be minimised, e.g. through use of micro-textures, humidity control and topical creams. Furthermore, the contact area between the mask and skin should be maximised, whilst the use of soft materials with incompressible behaviour (e.g. many elastomers) should be avoided.

A COVID-19 vaccine candidate using SpyCatcher multimerization of the SARS-CoV-2 spike protein receptor-binding domain induces potent neutralising antibody responses.

There is need for effective and affordable vaccines against SARS-CoV-2 to tackle the ongoing pandemic. In this study, we describe a protein nanoparticle vaccine against SARS-CoV-2. The vaccine is based on the display of coronavirus spike glycoprotein receptor-binding domain (RBD) on a synthetic virus-like particle (VLP) platform, SpyCatcher003-mi3, using SpyTag/SpyCatcher technology. Low doses of RBD-SpyVLP in a prime-boost regimen induce a strong neutralising antibody response in mice and pigs that is superior to convalescent human sera. We evaluate antibody quality using ACE2 blocking and neutralisation of cell infection by pseudovirus or wild-type SARS-CoV-2. Using competition assays with a monoclonal antibody panel, we show that RBD-SpyVLP induces a polyclonal antibody response that recognises key epitopes on the RBD, reducing the likelihood of selecting neutralisation-escape mutants. Moreover, RBD-SpyVLP is thermostable and can be lyophilised without losing immunogenicity, to facilitate global distribution and reduce cold-chain dependence. The data suggests that RBD-SpyVLP provides strong potential to address clinical and logistic challenges of the COVID-19 pandemic.

Evaluation of the immunogenicity of prime-boost vaccination with the replication-deficient viral vectored COVID-19 vaccine candidate ChAdOx1 nCoV-19.

Clinical development of the COVID-19 vaccine candidate ChAdOx1 nCoV-19, a replication-deficient simian adenoviral vector expressing the full-length SARS-CoV-2 spike (S) protein was initiated in April 2020 following non-human primate studies using a single immunisation. Here, we compared the immunogenicity of one or two doses of ChAdOx1 nCoV-19 in both mice and pigs. Whilst a single dose induced antigen-specific antibody and T cells responses, a booster immunisation enhanced antibody responses, particularly in pigs, with a significant increase in SARS-CoV-2 neutralising titres.