Dichotomy of neutralizing antibody, B cell and T cell responses to SARS-CoV-2 vaccination and protection in healthy adults (preprint)

Heterogeneity in SARS-CoV-2 vaccine responses is not understood. Here, we identify four patterns of live-virus neutralizing antibody responses: individuals with hybrid immunity (with confirmed prior infection); rare individuals with low responses (paucity of S1-binding antibodies); and surprisingly, two further groups with distinct serological repertoires. One group - broad responders - neutralize a range of SARS-CoV-2 variants, whereas the other - narrow responders - neutralize fewer, less divergent variants. This heterogeneity does not correlate with Ancestral S1-binding antibody, rather the quality of the serological response. Furthermore, IgDlowCD27-CD137+ B cells and CCR6+ CD4+ T cells are enriched in broad responders before dose 3. Notably, broad responders have significantly longer infection-free time after their third dose. Understanding the control and persistence of these serological profiles could allow personalized approaches to enhance serological breadth after vaccination.

Within-host SARS-CoV-2 viral kinetics informed by complex life course exposures reveals different intrinsic properties of Omicron and Delta variants (preprint)

The emergence of successive SARS-CoV-2 variants of concern (VOC) during 2020-22, each exhibiting increased epidemic growth relative to earlier circulating variants, has created a need to understand the drivers of such growth. However, both pathogen biology and changing host characteristics - such as varying levels of immunity - can combine to influence replication and transmission of SARS-CoV-2 within and between hosts. Disentangling the role of variant and host in individual-level viral shedding of VOCs is essential to inform COVID-19 planning and response, and interpret past epidemic trends. Using data from a prospective observational cohort study of healthy adult volunteers undergoing weekly occupational health PCR screening, we developed a Bayesian hierarchical model to reconstruct individual-level viral kinetics and estimate how different factors shaped viral dynamics, measured by PCR cycle threshold (Ct) values over time. Jointly accounting for both inter-individual variation in Ct values and complex host characteristics - such as vaccination status, exposure history and age - we found that age and number of prior exposures had a strong influence on peak viral replication. Older individuals and those who had at least five prior antigen exposures to vaccination and/or infection typically had much lower levels of shedding. Moreover, we found evidence of a correlation between the speed of early shedding and duration of incubation period when comparing different VOCs and age groups. Our findings illustrate the value of linking information on participant characteristics, symptom profile and infecting variant with prospective PCR sampling, and the importance of accounting for increasingly complex population exposure landscapes when analysing the viral kinetics of VOCs.

Non-hospitalised, vaccinated adults with COVID-19 caused by Omicron BA.1 and BA.2 present with changing symptom profiles compared to those with Delta despite similar viral kinetics (preprint)

Introduction The impact of COVID-19 vaccination on disease in the community has been limited, as a result of both SARS-CoV-2 Variants of Concern that partially escape vaccine-induced immunity. We sought to characterise symptoms and viral loads over the course of COVID-19 infection in otherwise-healthy vaccinated adults, representative of the general population, to assess whether current self-isolation guidance remains justified. Methods In a prospective, observational cohort study, healthy vaccinated UK adults who reported a positive PCR or lateral flow test, self-swabbed on alternate days until day 10. We compared symptoms and viral kinetics between infections caused by VOCs Delta and Omicron (sub-variants BA.1 and BA.2) and investigated applicability of UK NHS isolation guidelines to these newer VOCs. Results 373 infection episodes were reported among 349 participants. Across VOCs, symptom duration was similar, however symptom profiles differed significantly among infections caused by Delta, Omicron BA.1 and BA.2. Anosmia was reported in <10% of participants with BA.1 and BA.2, compared to 42% with Delta infection, coryza fatigue and myalgia predominated. Most notably, viral load trajectories and peaks did not differ between Delta, BA.1 and BA.2, irrespective of symptom severity, VOC or vaccination status. Conclusion COVID-19 isolation guidance should not differ based on symptom severity or febrile illness and must remain under review as new SARS-CoV-2 VOCs emerge and population immunity changes. Our study emphasises the ongoing transmission risk of Omicron sub-variants in vaccinated adults with mild symptoms that may extend beyond current isolation periods.

Emergence of new subgenomic mRNAs in SARS-CoV-2 (preprint)

Two mutations occurred in SARS-CoV-2 early during the COVID-19 pandemic that have come to define circulating virus lineages: first a change in the spike protein (D614G) that defines the B.1 lineage and second, a double substitution in the nucleocapsid protein (R203K, G204R) that defines the B.1.1 lineage, which has subsequently given rise to three Variants of Concern: Alpha, Gamma and Omicron. While the latter mutations appear unremarkable at the protein level, there are dramatic implications at the nucleotide level: the GGG[->]AAC substitution generates a new Transcription Regulatory Sequence (TRS) motif, driving SARS-CoV-2 to express a novel subgenomic mRNA (sgmRNA) encoding a truncated C-terminal portion of nucleocapsid (N.iORF3), which is an inhibitor of type I interferon production. We find that N.iORF3 also emerged independently within the Iota variant, and further show that additional TRS motifs have convergently evolved to express novel sgmRNAs; notably upstream of Spike within the nsp16 coding region of ORF1b, which is expressed during human infection. Our findings demonstrate that SARS-CoV-2 is undergoing evolutionary changes at the functional RNA level in addition to the amino acid level, reminiscent of eukaryotic evolution. Greater attention to this aspect in the assessment of emerging strains of SARS-CoV-2 is warranted.

Anti-inflammatory therapy with nebulised dornase alfa in patients with severe COVID-19 pneumonia (preprint)

Background: SARS-CoV2 infection causes severe, life-threatening pneumonia. Hyper-inflammation, coagulopathy and lymphopenia are associated with pathology and poor outcomes in these patients. Cell-free (cf) chromatin is prominent in COVID-19 patients, amplifies inflammation and promotes coagulopathy and immune dysfunction. We hypothesized that cf-chromatin clearance by nebulised dornase alfa may reduce inflammation and improve disease outcomes. Here, we evaluated the efficacy of nebulized dornase alfa in patients hospitalised with severe COVID-19 pneumonia. Methods: In this randomised controlled single-centre phase 2 proof-of-concept trial, we recruited adult patients admitted to hospital that exhibited stable oxygen saturation ([≥]94%) on supplementary oxygen and a C-reactive protein (CRP) level [≥]30mg/L post dexamethasone treatment. Participants were randomized at a 3:1 ratio to receive twice-daily nebulised dornase alfa in addition to best available care (BAC) or BAC alone for seven days or until hospital discharge. A 2:1 ratio of historical controls to treated individuals (HC, 2:1) were included as the primary endpoint comparators. The primary outcome was a reduction in systemic inflammation measured by blood CRP levels over 7 days post-randomisation, or to discharge if sooner. Secondary and exploratory outcomes included time to discharge, time on oxygen, D-dimer levels, lymphocyte counts and levels of circulating cf-DNA. Results: We screened 75 patients and enrolled 39 participants out of which 30 in dornase alfa arm, and 9 in BAC group. We also matched the recruited patients in the treated group (N=30) to historical controls in the BAC group (N=60). For the the primary outcome, 30 patients in the dornase alfa were compared to 69 patients in the BAC group. Dornase alfa treatment reduced CRP by 33% compared to the BAC group at 7-days (P=0.01). The dornase alfa group least squares mean CRP was 23.23 mg/L (95% CI 17.71 to 30.46) and the BAC group 34.82 mg/L (95% CI 28.55 to 42.47). A significant difference was also observed when only randomised participants were compared. Furthermore, compared to the BAC group, the chance of live discharge was increased by 63% in the dornase alfa group (HR 1.63, 95% CI 1.01 to 2.61, P=0.03), lymphocyte counts were improved (least-square mean: 1.08 vs 0.87, P=0.02) and markers of coagulopathy such as D-dimer were diminished (least-square mean: 570.78 vs 1656.96g/mL, P=0.004). Moreover, the dornase alfa group exhibited lower circulating cf-DNA levels that correlated with CRP changes over the course of treatment. No differences were recorded in the rates and length of stay in the ICU or the time on oxygen between the groups. Dornase alfa was well-tolerated with no serious adverse events reported. Conclusions: In this proof-of-concept study in patients with severe COVID-19 pneumonia, treatment with nebulised dornase alfa resulted in a significant reduction in inflammation, markers of immune pathology and time to discharge. The effectiveness of dornase alfa in patients with acute respiratory infection and inflammation should be investigated further in larger trials. Trial registration number: NCT04359654

Nanocell COVID-19 vaccine elicits iNKT-licensed dendritic cells to produce high affinity antibodies neutralizing Variants of Concern (preprint)

For COVID-19 vaccines, high-affinity antigen-specific antibody, CD8+ T cell and memory B cell responses are essential to maximize protection against Variants of Concern (VOC). We report results in vitro, in mice and human volunteers immunized with bacterially-derived, non-living nanocells (EDVTM) packaged with bacterial plasmid expressing spike protein of SARS-CoV-2 and IFNγ stimulating adjuvant α-galactosylceramide (EDV-COVID-αGC). EDV-COVID-αGC is shown to elicit iNKT-licensed dendritic cell activation/maturation, follicular helper T cell cognate help to B cells to undergo germinal center based somatic hypermutation and production of high affinity antibodies able to neutralize Alpha, Beta, Gamma, Delta, and Omicron VOC including a memory B cell response. Type I and Type II interferon stimulation and S-specific CD8+ T cells was also achieved. EDV-COVID-αGC are lyophilized, stored and transported at room temperature.

Seven Days Treatment With the Angiotensin II Type 2 Receptor Agonist C21 in Hospitalized COVID-19 Patients: A Placebo-Controlled Randomized Phase 2 Trial (preprint)

Background: COVID-19 morbidity and mortality remains high and the need for safe and effective drugs continues despite vaccines. Methods: Double-blind, placebo-controlled, multi-centre, randomized phase 2 trial to evaluate efficacy of oral angiotensin II type 2 receptor agonist C21 in hospitalized patients with COVID-19 and CRP ≥ 50-150 mg/L (NCT04452435). Patients were randomly assigned 100 mg C21 bid or placebo for 7 days in addition to standard of care. Primary endpoint: reduction in CRP. Findings: 106 patients were randomised (51 C21, 55 placebo). There was no significant group difference in CRP (primary endpoint). In a secondary analysis in patients requiring supplemental oxygen at randomisation, CRP was reduced in the C21 group compared to placebo. At the end of the 7-day treatment, 37 (72.5%) and 30 (54.5%) of the patients did not require supplemental oxygen in the C21 and placebo group, respectively (p=0.057). A post hoc analysis showed that at day 14, the proportion of patients still requiring supplemental oxygen was reduced by 90% in the C21 group compared to placebo (p=0.003). Fewer patients required mechanical ventilation (one C21 patient; four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one vs three in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated. Interpretation: Among hospitalised patients with COVID-19 receiving C21 for 7 days there was no reduction in CRP compared to placebo. However, there was a marked reduction of requirement for oxygen at day 14. Funding: Vicore Pharma AB and LifeArc.Clinical Trial Registration Details: The study protocol is available online at ClinicalTrials.gov, NCT04452435.Funding Information: Vicore Pharma AB and LifeArc.Declaration of Interests: Dr. Tornling reports personal fees from Vicore Pharma and Vicore Pharma shares. Dr. Batta reports a grant from LifeArc Medical Research Charity; personal fees from Vicore Pharma; Vicore Pharma stock options; in addition, Dr. Batta has a patent UK2004209.9 pending, a patent UK2009574.1 pending, and a patent US17/113,416 pending. Dr. Porter has nothing to disclose. Dr. Williams has nothing to disclose. Dr. Bengtsson reports consultancy fees from Vicore Pharma. Dr. Parmar reports grants from Vicore Pharma, during the conduct of the study. Dr. Kashiva reports grants from Vicore Pharma, during the conduct of the study. Dr. Hallberg reports personal fees from Vicore Pharma. Anne Katrine Cohrt reports personal fees from Vicore Pharma and Vicore Pharma stock options. Kate Westergaard reports personal fees from Vicore Pharma. Dr. Dalsgaard reports a grant from LifeArc Medical Research Charity, during the conduct of the study; personal fees from Vicore Pharma; Vicore Pharma stocks and stock options; in addition, Dr. Dalsgaard has a patent UK2004209.9 pending, a patent UK2009574.1 pending, and a patent US17/113,416 pending. Dr. Raud reports a grant from LifeArc Medical Research Charity; personal fees from Vicore Pharma; Vicore Pharma stocks and stock options; in addition, Dr. Raud has a patent UK2004209.9 pending, a patent UK2009574.1 pending, and a patent US17/113,416 pending.Ethics Approval Statement: The protocol, patient information, patient consent form and other documents, as required, were approved by properly constituted IECs and by the national regulatory authorities.

Identification of Potential COVID-Related Insider Trading by US Representatives Based on Financial Disclosures (preprint)

Just over a year after the initial COVID-19 shutdown, the United States finds itself as one of the worst-hit nations in the world in terms of COVID infections and deaths per capita. While the cost of delayed action in addressing the pandemic can be debated, one thing that cannot be is when the US Congress learned of the seriousness of the virus. While our previous paper focused on the US Senate, this one focuses on the lower chamber of Congress, the US House of Representatives. Like their senate counterparts, representatives learned of the potential impact of COVID-19 on the US in a closed door meeting in late January, nearly a month-and-a-half before the initial shutdown. As in the previous paper, we sought to find signals of insider trading US Representatives based on this non-public information.Much like the upper chamber, the public also has access to stock transactions of US Representatives thanks to the United States House of Representatives Financial Disclosures database. Using the original source data as well as Quiver Quantitative's cleaned version, Novatero Investments ran three analyses on US Representative stock transactions. These analyses looking for signs of insider trading centered around the late-January closed-door COVID-19 briefing: alterations in transactional volume, significant changes in strategy relative to the US market, and a market timing advantage relative to two baselines. Unlike the clear-cut findings from the Senate analyses, we found 15 representatives whose transaction activity and patterns range from "doubtful" to "strong likelihood" of insider trading, reflective of the myriad of results we've obtained from this data. While there are strong suggestions of insider trading within these results, the data provided can only go so far in terms of solid evidence, and we hope to see a deeper analysis and investigation by those who have access to a more-complete picture of these transactions.

Identification of Potential COVID-Related Insider Trading by US Senators Based on Financial Disclosures (preprint)

The economic impact of the COVID-19 pandemic has been felt around the world. In the United States, the severity and speed of the spread of the virus led to the fastest recession in US market history, going from a historical peak to the recession's (current) low point in less than a month. A vast majority of the public were caught off-guard by this, but a key few knew of the severity of the virus well before the masses. In particular, the US Senate was informed of the severity of COVID-19 in a private briefing on January 24th, 2020. Less than two months later, the SEC issued a warning to four senators on placing trades with nonpublic information, as it is essentially insider trading and a violation of the STOCK Act. Three of the four senators in-question were cleared of any wrongdoing after an astonishingly brief probe by the SEC.Fortunately, the public has access to stock transactions of US Senators thanks to the United States Senate Financial Disclosures database. Using this data via Quiver Quantitative, Novatero Investments carried out three analyses on US Senator stock transactions looking for signs of insider trading centered around the private COVID-19 briefing: alterations in transactional volume, significant changes in strategy relative to the US market, and a market timing advantage relative to two baselines. Based on the results from these analyses, there are suggestions that three senators took advantage of the information obtained in that January briefing to alter their investment strategy: Senators Richard Burr, Kelly Loeffler, and David Perdue. Interestingly, each senator enacted their informational advantage in a different way, making it difficult to detect some of them with a topline glance. While there are strong suggestions of insider trading within these results, the data provided can only go so far in terms of solid evidence, and we hope to see a deeper analysis and investigation by those who have access to a more-complete picture of these transactions.

Renin Angiotensin System Inhibition and Susceptibility and Outcomes from COVID-19: A Systematic Review and Meta-analysis of 69,200 COVID-19 Patients (preprint)

Background: Early observational studies suggested that the use of the renin angiotensin system (RAS) inhibitors, specifically angiotensin converting enzyme inhibitors or angiotensin receptor blockers, may increase the risk of infection with SARS-CoV-2 and adversely affect the prognosis or survival of infected patients. To explore the impact of RAS inhibitor use on the risk of SARS-CoV-2 infection and the prognosis of SARS-CoV-2 infected patients, from all published studies. Methods and Findings: A systematic review and meta-analysis of the use of RAS inhibitors in relation to infection with SARS-CoV-2 and/or the severity and mortality associated with COVID-19 was conducted. English language bibliographic databases PubMed, Web of Science, OVID Embase, Scopus, MedRxiv, BioRxiv, searched from Jan 1st, 2020 to July 20th, 2020. 58 observational studies (69,200 COVID-19 patients and 3,103,335 controls) were included. There was no difference in the susceptibility to SARS-CoV-2 infection between RAS inhibitor users and non-users (unadjusted OR 1.05, 95% CI 0.90 to 1.21), (adjusted OR 0.93, 95% CI 0.85 to 1.02), (adjusted HR 1.07, 95% CI 0.87 to 1.31). There was no significant difference in the severe Covid-19 case rate between RAS inhibitor users and non-users (unadjusted OR 1.05, 95% CI 0.81 to 1.36), (adjusted OR 0.76, 95% CI 0.52 to 1.12), or in mortality due to COVID-19 between RAS inhibitor users and non-users (unadjusted OR 1.12, 95% CI 0.88 to 1.44), (adjusted OR 0.97, 95% CI 0.77 to 1.23), (adjusted HR 0.62, 95% CI 0.34 to 1.14). Conclusions: In the most comprehensive analysis of all available data to date, treatment with RAS inhibitors was not associated with increased risk of infection, severity of disease, or mortality due to COVID-19. The best available evidence suggests that these treatments should not be discontinued on the basis of concern about risk associated with COVID-19.

Determination of Executive Actions for Self-Enrichment (EASE) at the Cost of Corporate Integrity (preprint)

The COVID-19 pandemic and its impact on the US economy led to an unprecedented bailout in the early days of the subsequent recession. Companies lined up for a share of the funds, but many of them were in our estimation unworthy of assistance given risky use of free cashflow for share repurchases, limiting their ability to adjust to an economic downturn. Our research resulted in the creation of the Executive Actions for Self-Enrichment (EASE) score, a quarterly determination of the companies that are working toward long-term business outcomes vis a vis those working towards hollowing out their business in the pursuit of short-term market gains. Scores were determined through the combination of pricing, key financials, and executive stock sales/purchases via SEC Form 4 data. We believe that EASE is able to accurately identify the overleveraging of debt to buy back company shares while executives offload their equity at artificially-induced prices. Conversely, this data also indicates an outsized return effect for the top decile of long-term-focused businesses. Going forward, we expect that EASE will provide a clear window into how companies are being run in a way that is immediately actionable, providing the public with the means to hold companies accountable via their investment decisions and beyond.

Systematic evaluation and external validation of 22 prognostic models among hospitalised adults with COVID-19: An observational cohort study (preprint)

BackgroundThe number of proposed prognostic models for COVID-19, which aim to predict disease outcomes, is growing rapidly. It is not known whether any are suitable for widespread clinical implementation. We addressed this question by independent and systematic evaluation of their performance among hospitalised COVID-19 cases. MethodsWe conducted an observational cohort study to assess candidate prognostic models, identified through a living systematic review. We included consecutive adults admitted to a secondary care hospital with PCR-confirmed or clinically diagnosed community-acquired COVID-19 (1st February to 30th April 2020). We reconstructed candidate models as per their original descriptions and evaluated performance for their original intended outcomes (clinical deterioration or mortality) and time horizons. We assessed discrimination using the area under the receiver operating characteristic curve (AUROC), and calibration using calibration plots, slopes and calibration-in-the-large. We calculated net benefit compared to the default strategies of treating all and no patients, and against the most discriminating predictor in univariable analyses, based on a limited subset of a priori candidates. ResultsWe tested 22 candidate prognostic models among a cohort of 411 participants, of whom 180 (43.8%) and 115 (28.0%) met the endpoints of clinical deterioration and mortality, respectively. The highest AUROCs were achieved by the NEWS2 score for prediction of deterioration over 24 hours (0.78; 95% CI 0.73-0.83), and a novel model for prediction of deterioration <14 days from admission (0.78; 0.74-0.82). Calibration appeared generally poor for models that used probability outcomes. In univariable analyses, admission oxygen saturation on room air was the strongest predictor of in-hospital deterioration (AUROC 0.76; 0.71-0.81), while age was the strongest predictor of in-hospital mortality (AUROC 0.76; 0.71-0.81). No prognostic model demonstrated consistently higher net benefit than using the most discriminating univariable predictors to stratify treatment, across a range of threshold probabilities. ConclusionsOxygen saturation on room air and patient age are strong predictors of deterioration and mortality among hospitalised adults with COVID-19, respectively. None of the prognostic models evaluated offer incremental value for patient stratification to these univariable predictors.

Excess deaths in people with cardiovascular diseases during the COVID-19 pandemic. (preprint)

Background: Cardiovascular diseases(CVD) increase mortality risk from coronavirus infection(COVID-19), but there are concerns that the pandemic has affected supply and demand of acute cardiovascular care. We estimated excess mortality in specific CVDs, both direct, through infection, and indirect, through changes in healthcare. Methods: We used population-based electronic health records from 3,862,012 individuals in England to estimate pre- and post-COVID-19 mortality risk(direct effect) for people with incident and prevalent CVD. We incorporated: (i)pre-COVID-19 risk by age, sex and comorbidities, (ii)estimated population COVID-19 prevalence, and (iii)estimated relative impact of COVID-19 on mortality(relative risk, RR: 1.5, 2.0 and 3.0). For indirect effects, we analysed weekly mortality and emergency department data for England/Wales and monthly hospital data from England(n=2), China(n=5) and Italy(n=1) for CVD referral, diagnosis and treatment until 1 May 2020. Findings: CVD service activity decreased by 60-100% compared with pre-pandemic levels in eight hospitals across China, Italy and England during the pandemic. In China, activity remained below pre-COVID-19 levels for 2-3 months even after easing lockdown, and is still reduced in Italy and England. Mortality data suggest indirect effects on CVD will be delayed rather than contemporaneous(peak RR 1.4). For total CVD(incident and prevalent), at 10% population COVID-19 rate, we estimated direct impact of 31,205 and 62,410 excess deaths in England at RR 1.5 and 2.0 respectively, and indirect effect of 49932 to 99865 excess deaths. Interpretation: Supply and demand for CVD services have dramatically reduced across countries with potential for substantial, but avoidable, excess mortality during and after the COVID-19 pandemic.

Respiratory Failure in Covid19 is associated with increased monocyte expression of complement receptor 3 (preprint)

A key question in COVID-19 infection is why some previously healthy patients develop severe pulmonary failure and some ultimately die. Initial pulmonary failure does not exhibit classical features of ARDS; hypercoagulability is a common laboratory feature, and pulmonary thrombotic microangiopathy has been reported post mortem1,2,3. Biomarkers cannot robustly identify such patients pre-emptively and no specific interventions exist to mitigate clinical deterioration. Mononuclear phagocytic cells are key immune cells and bind fibrinogen through the CD11b/CD18 dimer CR3, whose activated form can initiate microthrombus formation. Accordingly, we profiled circulating monocyte CD11b/CD18 cell surface density from COVID-19 infected adults who were (i) symptomatic but breathless, (ii) requiring ventilatory support, and (iii) recovering following ICU care for hypoxia.

Estimating excess mortality in people with cancer and multimorbidity in the COVID-19 emergency (preprint)

Background: Cancer and multiple non-cancer conditions are considered by the Centers for Disease Control and Prevention (CDC) as high risk conditions in the COVID-19 emergency. Professional societies have recommended changes in cancer service provision to minimize COVID-19 risks to cancer patients and health care workers. However, we do not know the extent to which cancer patients, in whom multi-morbidity is common, may be at higher overall risk of mortality as a net result of multiple factors including COVID-19 infection, changes in health services, and socioeconomic factors. Methods: We report multi-center, weekly cancer diagnostic referrals and chemotherapy treatments until April 2020 in England and Northern Ireland. We analyzed population-based health records from 3,862,012 adults in England to estimate 1-year mortality in 24 cancer sites and 15 non-cancer comorbidity clusters (40 conditions) recognized by CDC as high-risk. We estimated overall (direct and indirect) effects of COVID-19 emergency on mortality under different Relative Impact of the Emergency (RIE) and different Proportions of the population Affected by the Emergency (PAE). We applied the same model to the US, using Surveillance, Epidemiology, and End Results (SEER) program data. Results: Weekly data until April 2020 demonstrate significant falls in admissions for chemotherapy (45-66% reduction) and urgent referrals for early cancer diagnosis (70-89% reduction), compared to pre-emergency levels. Under conservative assumptions of the emergency affecting only people with newly diagnosed cancer (incident cases) at COVID-19 PAE of 40%, and an RIE of 1.5, the model estimated 6,270 excess deaths at 1 year in England and 33,890 excess deaths in the US. In England, the proportion of patients with incident cancer with [≥]1 comorbidity was 65.2%. The number of comorbidities was strongly associated with cancer mortality risk. Across a range of model assumptions, and across incident and prevalent cancer cases, 78% of excess deaths occur in cancer patients with [≥]1 comorbidity. Conclusion: We provide the first estimates of potential excess mortality among people with cancer and multimorbidity due to the COVID-19 emergency and demonstrate dramatic changes in cancer services. To better inform prioritization of cancer care and guide policy change, there is an urgent need for weekly data on cause-specific excess mortality, cancer diagnosis and treatment provision and better intelligence on the use of effective treatments for comorbidities.

Hypertension and renin-angiotensin system blockers are not associated with expression of Angiotensin Converting Enzyme 2 (ACE2) in the kidney (preprint)

Angiotensin converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2) - the cause of COVID-19 disease. It has been hypothesized that use of renin-angiotensin system (RAS) inhibiting medications in patients with hypertension, increases the expression of ACE2 and thereby increases the risk of COVID-19 infection and severe outcomes or death. However, the effect of RAS-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. We examined how hypertension, its major metabolic co-phenotypes and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterised by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. Collectively, our data indicate that neither hypertension nor antihypertensive treatment are likely to alter individual risk of SARS-CoV-2 infection or influence clinical outcomes in COVID-19 through changes of ACE2 expression. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.

Estimating excess 1- year mortality from COVID-19 according to underlying conditions and age in England: a rapid analysis using NHS health records in 3.8 million adults (preprint)

RAPID COMMUNICATION 22 March 2020 Estimating excess 1- year mortality from COVID-19 according to underlying conditions and age in England: a rapid analysis using NHS health records in 3.8 million adults Background: The medical, health service, societal and economic impact of the COVID-19 emergency has unknown effects on overall population mortality. Previous models of population mortality are based on death over days among infected people, nearly all of whom (to date at least) have underlying conditions. Models have not incorporated information on high risk conditions or their longer term background (pre-COVID-19) mortality. We estimated the excess number of deaths over 1 year under different COVID-19 incidence rates and differing mortality impacts. Methods: Using population based linked primary and secondary care electronic health records in England (HDR UK - CALIBER), we report the prevalence of underlying conditions defined by UK Public Health England COVID-19 guidelines (16 March 2020) in 3,862,012 individuals aged [≥]30 years from 1997-2017. We used previously validated phenotypes, openly available (https://caliberresearch.org/portal), for each condition using ICD-10 diagnosis, Read, procedure and medication codes. We estimated the 1-year mortality in each condition, and developed simple models of excess COVID-19-related deaths assuming relative risk (RR) of the impact of the emergency (compared to background mortality) of 1.2, 1.5 and 2.0. Findings: 20.0% of the population are at risk according to current PHE guidelines, of which; 13.7% were age>70 years and 6.3% aged [≤]70 years with [≥]1 underlying condition (cardiovascular disease (2.3%), diabetes (2.2%), steroid therapy (1.9%), severe obesity (0.9%), chronic kidney disease (0.6%) and chronic obstructive pulmonary disease, COPD (0.5%). Multimorbidity (co-occurrence of [≥]2 conditions in an individual) was common (10.1%). The 1-year mortality in the at-risk population was 4.46%, and age and underlying conditions combine to influence background risk, varying markedly across conditions (5.9% in age>70 years, 8.6% for COPD and 13.1% in those with [≥]3 or more conditions). In a suppression scenario (at SARS CoV2 rates of 0.001% of the UK population), there would be minimal excess deaths (3 and 7 excess deaths at relative risk, RR, 1.5 and 2.0 respectively). At SARS CoV2 rates of 10% of the UK population (mitigation) the model estimates the numbers of excess deaths as: 13791, 34479 and 68957 (at RR 1.2, 1.5 and 2.0 respectively). At SARS CoV2 rates of 80% in the UK population (do-nothing), the model estimates the number of excess deaths as 110332, 275,830 and 551,659 (at RR 1.2, 1.5 and 2.0) respectively. Interpretation: We provide the public, researchers and policy makers a simple model to estimate the excess mortality over 1 year from COVID-19, based on underlying conditions at different ages. If the relative mortality impact of COVID-19 were to be about 20% (similar magnitude as the established winter vs summer mortality excess), then the excess deaths would be 0 when 1 in 100 000 (suppression), 13791 when 1 in 10 (mitigation) and 110332 when 8 in 10 are infected (do nothing) scenario. However, the relative impact of COVID-19 is unknown. If the emergency were to double the mortality risk, then we estimate 7, 68957 and 551,659 excess deaths in the same scenarios. These results may inform the need for more stringent suppression measures as well as efforts to target those at highest risk for a range of preventive interventions.