A Randomised -Controlled Phase 2 trial of Molnupiravir in Unvaccinated and Vaccinated Individuals with Early SARS-CoV-2

BackgroundMolnupiravir was licensed for treating high-risk patients with COVID-19 based on data from unvaccinated adults. AGILE CST-2 (NCT04746183) Phase II reports safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals. MethodsAdult out-patients with PCR-confirmed SARS-CoV-2 infection within five days of symptom onset were randomly assigned 1:1 to receive molnupiravir (800mg twice daily for five days) or placebo. The primary outcome was time to swab PCR-negativity, compared using a Bayesian model for estimating the probability of a superior virological response (Hazard Ratio>1) for molnupiravir over placebo. Secondary outcomes included change in viral titre at day 5, safety and tolerability, clinical progression and patient reported outcome measures. We analysed outcomes after the last participant reached day 29. FindingsOf 180 participants randomised (90 molnupiravir, 90 placebo), 50% were vaccinated. Infections with SARS-CoV-2 variants Delta (40%), Alpha (21%), Omicron (21%) and EU1 (16%) were represented. The median time to negative-PCR was 8 versus 11 days for molnupiravir and placebo (HR=1{middle dot}30, 95% CrI 0{middle dot}92-1{middle dot}71, p=0{middle dot}07 by Logrank and p=0{middle dot}03 by Breslow-Gehan tests). Although small numbers precluded subgroup analysis, no obvious differences were observed between vaccinated and unvaccinated participants. Using a two-point prior the probability of molnupiravir being superior to placebo (HR>1) was 75{middle dot}4%, which was just below our defined threshold of 80% for establishing superiority. Using an uninformative continuous prior, the probability of HR>1 was 94{middle dot}7%. As an exploratory analysis, the change in viral titre on day 5 (end of treatment) was significantly greater with molnupiravir compared with placebo. A total of 4 participants reported severe adverse events (grade 3+), 3 of whom were in the placebo arm. InterpretationWe found molnupiravir to be well-tolerated, with evidence for high probability of antiviral efficacy in a population of vaccinated and unvaccinated individuals infected with a broad range of viral variants. FundingFunded by Ridgeback Biotherapeutics and UK National Institute for Health and Care Research infrastructure funding. The AGILE platform infrastructure is supported by the Medical Research Council (grant number MR/V028391/1) and the Wellcome Trust (grant number 221590/Z/20/Z).

Scottish COVID CAncer iMmunity Prevalence (SCCAMP) - a longitudinal study of patients with cancer receiving active anti-cancer treatment during the COVID-19 pandemic

BackgroundCancer and systemic anti-cancer treatment (SACT) have been identified as possible risk factors for infection and related severe illness associated with SARS-CoV-2 virus as a consequence of immune suppression. The Scottish COVID CAncer iMmunity Prevalence (SCCAMP) study aims to characterise the incidence and outcomes of SARS-Cov-2 infection in patients undergoing active anti-cancer treatment during the COVID-19 pandemic and their antibody response following vaccination. Patients and MethodsEligible patients were those attending secondary care for active anti-cancer treatment for a solid tumour. Blood samples were taken for total SARS-CoV-2 antibody assay (Siemens) at baseline and after 1.5, 3, 6 and 12 months. Data on COVID-19 infection, vaccination, cancer type, treatment and outcome was obtained from routine electronic health records. ResultsThe study recruited 766 eligible participants between 28th May 2020 and 31st October 2021. The median age was 62.7 years, and 66.5% were female. Most received cytotoxic chemotherapy (79%), with the remaining 14% receiving immunotherapy and 7% receiving another form of anti-cancer therapy (radiotherapy, other systemic anti-cancer treatment). 48 (6.3%) tested positive for SARS-CoV-2 by PCR during the study period. The overall infection rate matched that of the age-matched local general population until May 2021, after which population levels appeared higher. Antibody testing detected additional evidence of infection prior to vaccination, taking the total number to 58 (7.6%). There was no significant difference in SARS-CoV-2 PCR positive test rates based on type of anti-cancer treatment. Mortality proportion was similar between those who died within 90 days of a positive SARS-CoV-2 PCR and those with no positive PCR (10.4% vs 10.6%). Death from all causes was lowest among vaccinated patients, and of the patients who had a positive SARS-CoV-2 PCR at any time, all of those who died during the study period were unvaccinated. Multivariate analysis correcting for age, gender, socioeconomic status, comorbidities and number of previous medications revealed that vaccination was associated with a significantly lower infection rate regardless of treatment with chemotherapy or immunotherapy with hazard ratios of 0.307 (95% CI 0.144-0.6548) or 0.314 (95% CI 0.041-2.367) in vaccinated patients respectively. Where antibody data was available, 96.3% of patients successfully raised SARS-CoV-2 antibodies at a time point after vaccination. This was unaffected by treatment type. ConclusionSCCAMP provides real-world evidence that patients with cancer undergoing SACT have a high antibody response and protection from SARS-CoV-2 infection following COVID-19 vaccination. Highlights- The SCCAMP dataset represents the largest longitudinal study of patients with cancer undergoing anti-cancer treatment during the COVID-19 pandemic - Rates of infection in the cancer cohort mirrored those of the local age adjusted population - Vaccination was effective in patients with cancer undergoing active treatment in terms of antibody response and SARS-CoV-2 PCR rates - Treatment type did not impact the rate of SARS-CoV-2 antibody response

Advancement of antigen-specific immunotherapy: knowledge transfer between allergy and autoimmunity.

Targeted restoration of immunological tolerance to self-antigens or innocuous environmental allergens represents the ultimate aim of treatment options in autoimmune and allergic disease. Antigen-specific immunotherapy (ASI) is the only intervention that has proven disease-modifying efficacy as evidenced by induction of long-term remission in a number of allergic conditions. Mounting evidence is now indicating that specific targeting of pathogenic T cells in autoinflammatory and autoimmune settings enables effective restoration of immune homeostasis between effector and regulatory cells and alters the immunological course of disease. Here, we discuss the key lessons learned during the development of antigen-specific immunotherapies and how these can be applied to inform future interventions. Armed with this knowledge and current high-throughput technology to track immune cell phenotype and function, it may no longer be a matter of 'if' but 'when' this ultimate aim of targeted tolerance restoration is realised.

Trends in excess cancer and cardiovascular deaths in Scotland during the COVID-19 pandemic 30 December 2019 to 20 April 2020

Understanding the trends in causes of death for different diseases during the current COVID-19 pandemic is important to determine whether there are excess deaths beyond what is normally expected. Using the most recent report from National Records Scotland (NRS) on 29 April 2020, we examined the percentage difference in crude numbers of deaths in 2020 compared to the average for 2015-2019 by week of death within calendar year. To determine if trends were similar, suggesting underreporting/underdiagnosed COVID-19 related deaths, we also looked at the trends in % differences for cardiovascular disease deaths. From the first 17 weeks of data, we found a peak in excess deaths at week 14 of 2020, about four weeks after the first case in Scotland was detected on 1 March 2020-- but by week 17 these excesses had returned to normal levels, 4 weeks after lockdown in the UK began. Similar observations were seen for cardiovascular disease-related deaths. These observations suggest that the short-term increase in excess cancer and cardiovascular deaths might be associated with undetected/unconfirmed deaths related to COVID-19. Both of these conditions make patients more susceptible to infection and lack of widespread access to testing for COVID-19 are likely to have resulted in under-estimation of COVID-19 mortality. These data further suggest that the cumulative toll of COVID-19 on mortality is likely undercounted. More detailed analysis is needed to determine if these excesses were directly or indirectly related to COVID-19. Disease specific mortality will need constant monitoring for the foreseeable future as changes occur in increasing capacity and access to testing, reporting criteria, changes to health services and different measures are implemented to control the spread of the COVID-19. Multidisciplinary, multi-institutional, national and international collaborations for complementary and population specific data analysis is required to respond and mitigate adverse effects of the COVID-19 pandemic and to inform planning for future pandemics.

Availability, diversification and versatility explain human selection of introduced plants in Ecuadorian traditional medicine.

Globally, a majority of people use plants as a primary source of healthcare and introduced plants are increasingly discussed as medicine. Protecting this resource for human health depends upon understanding which plants are used and how use patterns will change over time. The increasing use of introduced plants in local pharmacopoeia has been explained by their greater abundance or accessibility (availability hypothesis), their ability to cure medical conditions that are not treated by native plants (diversification hypothesis), or as a result of the introduced plants' having many different simultaneous roles (versatility hypothesis). In order to describe the role of introduced plants in Ecuador, and to test these three hypotheses, we asked if introduced plants are over-represented in the Ecuadorian pharmacopoeia, and if their use as medicine is best explained by the introduced plants' greater availability, different therapeutic applications, or greater number of use categories. Drawing on 44,585 plant-use entries, and the checklist of >17,000 species found in Ecuador, we used multi-model inference to test if more introduced plants are used as medicines in Ecuador than expected by chance, and examine the support for each of the three hypotheses above. We find nuanced support for all hypotheses. More introduced plants are utilized than would be expected by chance, which can be explained by geographic distribution, their strong association with cultivation, diversification (except with regard to introduced diseases), and therapeutic versatility, but not versatility of use categories. Introduced plants make a disproportionately high contribution to plant medicine in Ecuador. The strong association of cultivation with introduced medicinal plant use highlights the importance of the maintenance of human-mediated environments such as homegardens and agroforests for the provisioning of healthcare services.

PKCθ links proximal T cell and Notch signaling through localized regulation of the actin cytoskeleton.

Notch is a critical regulator of T cell differentiation and is activated through proteolytic cleavage in response to ligand engagement. Using murine myelin-reactive CD4 T cells, we demonstrate that proximal T cell signaling modulates Notch activation by a spatiotemporally constrained mechanism. The protein kinase PKCθ is a critical mediator of signaling by the T cell antigen receptor and the principal costimulatory receptor CD28. PKCθ selectively inactivates the negative regulator of F-actin generation, Coronin 1A, at the center of the T cell interface with the antigen presenting cell (APC). This allows for effective generation of the large actin-based lamellum required for recruitment of the Notch-processing membrane metalloproteinase ADAM10. Such enhancement of Notch activation is critical for efficient T cell proliferation and Th17 differentiation. We reveal a novel mechanism that, through modulation of the cytoskeleton, controls Notch activation at the T cell:APC interface thereby linking T cell receptor and Notch signaling pathways.