Mortality Data For 25-44 Year Olds, Characteristics of High and Low Viral Cases: COVID-19 Updates
December 18, 2020 | Human “helper proteins” aiding the virus, genes linked with disease severity, the potency of neutralizing antibodies, and AI system identifying drugs. Plus: PacBio and Labcorp generate 65,000 genomes and funding from Germany and DARPA.
Editor’s Note: The COVID-19 research roundups will be taking off for the upcoming holidays. We’ll return in January.
Researchers have discovered numerous genetic variants that influence the amount or function of human “helper proteins” that support or facilitate SARS-CoV-2. The gene variants reveal potential target structures for new drugs. The researchers have now published their results in Nature Communications. The team examined 179 proteins known to be involved in SARS-CoV-2 infection for their naturally occurring variants. They discovered 38 targets for existing drugs as well as evidence that certain proteins that interact with the virus influence the immune system. DOI: 10.1038/s41467-020-19996-z
In JAMA, researchers examined all-cause excess mortality and COVID-19–related mortality during the early pandemic period among adults aged 25 to 44 years. Because unintentional drug overdoses are the usual leading cause of death in this demographic, COVID-19 deaths were compared with unintentional opioid deaths. From March 1, 2020, to July 31, 2020, a total of 76,088 all-cause deaths occurred among US adults aged 25 to 44 years, which was 11,899 more than expected. Among adults aged 25 to 44 years, 4,535 COVID-19 deaths were recorded, accounting for 38% of the measured excess mortality. Although the remaining excess deaths are unexplained, the authors write, inadequate testing in this otherwise healthy demographic likely contributed. These results suggest that COVID-19–related mortality may have been underdetected in this population. DOI: 10.1001/jama.2020.24243
In data published in Nature Communications, Massachusetts General Hospital researchers analyzed autopsy specimens from 24 patients who succumbed to SARS-CoV-2 infection using a combination of different RNA and protein analytical platforms to characterize inter-patient and intra-patient heterogeneity of pulmonary virus infection. There is a spectrum of high and low virus cases associated with duration of disease, they write. High viral cases have high activation of interferon pathway genes and a predominant M1-like macrophage infiltrate. Low viral cases are more heterogeneous, likely reflecting inherent patient differences in the evolution of host response, but there is consistent indication of pulmonary epithelial cell recovery based on napsin A immunohistochemistry and RNA expression of surfactant and mucin genes. Using a digital spatial profiling platform, the team found the virus corresponds to distinct spatial expression of interferon response genes demonstrating the intra-pulmonary heterogeneity of SARS-CoV-2 infection. DOI: 10.1038/s41467-020-20139-7
Scientists at the Ragon Institute of MGH, MIT and Harvard, publishing in the journal Cell, show that the potency of neutralizing antibodies which developed in COVID-19 patients was significantly reduced in those with severe or fatal disease compared to patients with milder infections. The group developed an automated assay that could measure the potency of neutralizing antibodies in hundreds of COVID-19 patient samples at a time. They used this technology to examine samples from 113 COVID-19 patients, comparing milder cases to severe and fatal ones to understand the nuances of the antibody response. They discovered that patients with severe or fatal COVID-19 had significantly less effective neutralizing antibodies than patients with milder cases. In fact, a model they built suggested that measuring the potency of these neutralizing antibodies could predict patient outcomes. DOI: 10.1016/j.cell.2020.12.015
British researchers have developed two versions of a unique five plex RT-qPCR test, termed CoV2-ID, that allows the detection of three viral target genes, a human internal control for confirming the presence of human cells in a sample and a control artificial RNA for quality assessment and potential quantification. In their publication in Scientific Reports, they propose using multiple cycle fluorescence detection, rather than real-time PCR to reduce significantly the time taken to complete the assay as well as assuage the misunderstandings underlying the use of quantification cycles. They also developed an assay to identify mutant genotypes, noting that all of the samples locally gathered have a mutant genotype while a sample originating elsewhere has the wild type. DOI: 10.1038/s41598-020-79233-x
A study published in mBio shows that endothelial cells (ECs) which line capillaries lack ACE2 receptors for SARS-CoV-2 attachment and suggests that SARS-CoV-2 indirectly activates endothelial cell linked disease mechanisms that direct coagulation and inflammation associated with severe Covid-19 disease. As a result, for Covid-19 patients with serious lung disease, targeting endothelial cells may be a novel approach restoring normal lung function. DOI: 10.1128/mBio.03185-20
Molecular markers in the blood that are predictive of severe COVID-19 outcomes have been identified in a study by a Chinese research team published in The EMBO Journal. The group studied peripheral blood and plasma samples of 66 COVID‐19‐infected patients experiencing a range of disease severities and 17 healthy controls. Chronic activation of neutrophils, IFN‐I signaling, and a high level of inflammatory cytokines were observed in patients with severe disease progression. In contrast, COVID‐19‐infected patients experiencing milder disease symptoms showed robust T‐cell responses. DOI: 10.15252/embj.2020105896
Researchers from the University of Edinburgh have identified five genes associated with the most severe COVID-19 illness: IFNAR2, TYK2, OAS1, DPP9 and CCR2. Their results are published in Nature. They studied the DNA of 2,700 patients in 208 intensive care units (ICUs) in the UK. Researchers from the GenOMICC consortium—a global collaboration to study genetics in critical illness—compared those data with samples provided by healthy volunteers from other studies, such as UK Biobank, Generation Scotland and 100,000 Genomes. The team found key differences in five genes of the ICU patients compared with samples provided by healthy volunteers. The results identify robust genetic signals relating to key host antiviral defense mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs, they write, though the authors close their abstract with a caveat: Large-scale randomized clinical trials will be essential before any change to clinical practice. DOI: 10.1038/s41586-020-03065-y
A team from the National University of Singapore used their platform known as 'IDentif.AI' (Optimising Infectious Disease Combination Therapy with Artificial Intelligence) to investigate 12 potential drug candidates for COVID-19, representing over 530,000 possible drug combinations. Their results showed that the optimal drug therapy was a combination of the drugs remdesivir, ritonavir, and lopinavir at specific doses. The study was completed within 2 weeks, with a three‐order of magnitude reduction in the number of tests needed. IDentif.AI independently mirrored clinical trial outcomes to date without any data from these trials. They published their findings in AIChE. DOI: 10.1002/btm2.10196
Using PacBio’s Single Molecule, Real-Time (SMRT) Sequencing platform, Labcorp has generated more than 6,500 high-resolution complete genomes from people infected with the SARS-CoV-2 virus who were sampled in the United States during the early phase of the pandemic (approximately March-May 2020). The viral sequencing assay developed by Labcorp makes use of 1.2 kb overlapping amplicons multiplexed at a cost-effective level of 600-1,000 patient samples per SMRT Cell. These initial findings come from the company’s research collaboration with Labcorp that is focused on SARS-CoV-2 and the related immune response to COVID-19. The two companies are collaborating to develop a production-scale assay for sequencing the complete genome of thousands of SARS-CoV-2 viruses from de-identified positive patient samples using the PacBio Sequel II System. Labcorp is currently using this information to shed light on viral evolution during the early pandemic, mutations arising in different geographic regions, and the implications for disease severity and outcomes. Press release.
A team of scientists from The Wistar Institute, INOVIO, AstraZeneca, the Perelman School of Medicine at the University of Pennsylvania, and Indiana University has received a $37.6 million award over two years from the Defense Advanced Research Projects Agency (DARPA) and the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) for rapid preclinical development and translational studies of DNA-encoded monoclonal antibodies (DMAbs) as countermeasures for COVID-19. In addition to their high specificity for the target, DMAbs have important advantages of rapid manufacturing, low cost of production, and temperature-stable storage and distribution. Press release.
A new online calculator for estimating individual and community-level risk of dying from COVID-19 has been developed by researchers at the Johns Hopkins Bloomberg School of Public Health. The researchers who developed the calculator expect it to be useful to public health authorities for assessing mortality risks in different communities, and for prioritizing certain groups for vaccination as COVID-19 vaccines become available. The algorithm underlying the calculator uses information from existing large studies to estimate risk of COVID-19 mortality for individuals based on age, gender, sociodemographic factors and a variety of different health conditions. The risk estimates apply to individuals in the general population who are currently uninfected, and captures factors associated with both risk of future infection and complications after infection. Press release.
The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) has made its first decisions in the new COVID-19 Focus Funding instrument. These decisions will enable 33 projects to immediately begin research on immunity, host susceptibility and pathomechanisms of infection with SARS-CoV-2. A total of €3.6 million will be provided for a maximum of one year, including the standard program allowance for indirect project costs. The 33 projects that have now been approved address topics such as questions of immune response and the mechanisms of different immune cell populations against SARS-CoV-2, which they are investigating in model systems and with patient material. There are also investigations into molecular pathomechanisms at the general cellular level and in various organ systems such as the lungs, gastrointestinal tract, liver and nervous system. Further topics include analysing the pathogenicity of the virus, conducting evolution analyses and influencing the pathogenicity of the virus. Press release.