New Rhesus Macaque Model, Six SARS-CoV-2 Strains, the Structure of Dexamethasone with Serum Albumin: COVID-19 Updates

November 13, 2020 | A look at how COVID-19 patients fare after recovery, Mount Sinai’s new ML model analyzes EHRs, overlapping genes in viruses, conferred immunity from other coronaviruses, and a picture of RNA-RNA interactions. Plus a new Intel system at LLNL for COVID-19 research, Baylor’s coronavirus curriculum, and a recommended vaccine distribution framework.

Research Updates

Researchers from the Chinese Academy of Medical Sciences & Peking Union Medical College have published a new rhesus macaque animal mod el that recapitulates the clinical and pathological manifestations of coronavirus disease 2019 (COVID-19) observed in humans by mimicking natural infection via the nasal route. The model is published in PLOS Pathogens. DOI: 10.1371/journal.ppat.1008949

In PNAS, a Taiwanese research team reports that the genome of SARS-CoV-2 to date can be classified in six major types characterized by 14 signature single nucleotide variations (SNVs). In particular, type VI, that was first reported in China and spread to different countries, has become the major type (more than 95% among data collected after mid-May 2020). The signature SNVs for this strain type, C241T (5′UTR), C3037T (nsp3 F924F), C14408T (nsp12 P4715L), and A23403G (S protein D614G), exhibit high pairwise allelic associations, and the haplotype 241T-3037T-14408T-23403G has the highest frequency. DOI: 10.1073/pnas.2007840117

Dexamethasone, a widely used corticosteroid, has recently been reported as the first drug to increase the survival chances of patients with severe COVID-19. Therapeutic agents, including dexamethasone, are mostly transported through the body by binding to serum albumin. In a paper published in the Journal of the International Union of Crystallography, a team from the University of Virginia—using the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science User Facility at DOE's Argonne National Laboratory—determined the structure of serum albumin in complex with dexamethasone. Dexamethasone binds to drug site 7, which is also the binding site for commonly used nonsteroidal anti-inflammatory drugs and testosterone, suggesting potentially problematic binding competition. DOI: 10.1107/S2052252520012944

Researchers at the University of Michigan interviewed 488 COVID-19 patients by phone around 60 days after their hospitalization and categorized their health statuses. They've published their findings in the Annals of Internal Medicine. More than 39% of the patients interviewed said they hadn't gotten back to normal activities yet, two months after leaving the hospital. Twelve percent of the patients said they couldn't carry out basic care for themselves anymore, or as well as before. Nearly 23% said they became short of breath just climbing a flight of stairs. One-third had ongoing COVID-like symptoms, including many who still had problems with taste or smell. The patients listed many financial and emotional impacts as well. DOI: 10.7326/M20-5661

Spain's annual life expectancy at birth dropped by 0.9 years between 2019 and the annual period up until July 2020 due to the COVID-19 pandemic, according to a new study published this week in the open-access journal PLOS ONE by researchers at the Center for Demographic Studies, Spain. Researchers used daily death count data from the Spanish Daily Mortality Monitoring System (MoMo) as well as information on death, population and demographic information from the Spanish National Statistics Institute. The team estimated weekly and annual life expectancies at birth for 2019 and the annual period up until July 2020. The weekly life expectancies at birth in Spain were lower in weeks 11 through 20 of 2020—spanning early March through early May—compared to the same weeks in 2019. Likewise, the annual life expectancy for the country as a whole declined by 0.9 years between 2019 and the annual period up until July 2020, for both men and women. DOI: 10.1371/journal.pone.0241952

Researchers at Karolinska Institutet in Sweden have explored all COVID-19 research published during the initial phase of the pandemic. To obtain an overview of the more than 60,000 publications on COVID-19 in PubMed, the team used a machine learning technique that enables them to map key areas of a research field and track the development over time. The present study, published in the Journal of Medical Internet Research, includes 16,670 scientific papers on COVID-19 published from 14 February to 1 June 2020, divided into 14 different topics. The most common research topics were health care response, clinical manifestations, and psychosocial impact. Some topics, like health care response, declined over time, while others, such as clinical manifestations and protective measures, showed a growing trend of publications. Protective measures, immunology, and clinical manifestations were the research topics published in journals with the highest average scientific ranking. The countries that accounted for the majority of publications (the USA, China, Italy and the UK) were also amongst the ones hardest hit by the pandemic. DOI: 10.2196/21559

Mount Sinai researchers have developed machine learning models that analyze the electronic health records (EHRs) of patients who tested positive for COVID-19 to predict the likelihood of critical events and mortality within clinically relevant time windows. They share their newest models in the Journal of Medical Internet Research. They used Extreme Gradient Boosting (XGBoost) and baseline comparator models to predict in-hospital mortality and critical events at time windows of 3, 5, 7, and 10 days from admission. The models could aid clinical practitioners at Mount Sinai and across the world in the care and management of COVID-19 patients, they write. DOI: 10.2196/24018

A team in the Netherlands used whole genome sequencing to investigate outbreaks on 16 mink farms and the humans living or working on these farms. They found that the virus was initially introduced from humans and has since evolved, most likely reflecting widespread circulation among mink in the beginning of the infection period several weeks prior to detection. Despite enhanced biosecurity, early warning surveillance and immediate culling of infected farms, transmission occurred between mink farms in three big transmission clusters with unknown modes of transmission. Sixty-eight percent (68%) of the tested mink farm residents, employees and/or contacts had evidence of SARS-CoV-2 infection. They published their findings in Science. DOI: 10.1126/science.abe5901

Overlapping genes (OLGs) are common in viruses and have been associated with pandemics but are still widely overlooked. A collaboration between researchers in Taiwan and the American Museum of Natural History has identified and characterized ORF3d, a novel OLG in SARS-CoV-2 that is also present in Guangxi pangolin-CoVs but not other closely related pangolin-CoVs or bat-CoVs. The team documented evidence of ORF3d translation, characterize its protein sequence, and conduct an evolutionary analysis at three levels: between taxa, between human hosts, and within human hosts. ORF3d has been independently identified and shown to elicit a strong antibody response in COVID-19 patients, they write, in the work published in eLife. DOI: 10.7554/eLife.59633

A European team performed RNA structure probing to obtain single-base resolution secondary structure maps of the full SARS-CoV-2 coronavirus genome both in vitro and in living infected cells. Probing data recapitulate the previously described coronavirus RNA elements (5′ UTR and s2m), and reveal new structures. Of these, about 10% show significant covariation among SARS-CoV-2 and other coronaviruses, hinting at their functionally-conserved role. Secondary structure-restrained 3D modeling of these segments further allowed for the identification of putative druggable pockets. The work is published in Nucleic Acids Research. DOI: 10.1093/nar/gkaa1053

Researchers at the Francis Crick Institute and University College London have found that some antibodies, created by the immune system during infection with common cold coronaviruses, can also target SARS-CoV-2 and may confer a degree of protection against the new viral strain. Their work, published in Science, shows that some people, notably children, have antibodies reactive to SARS-CoV-2 in their blood, despite not ever having been infected with the virus. These antibodies are likely the result of exposure to other coronaviruses, which cause a common cold and which have structural similarities with SARS-CoV-2. DOI: 10.1126/science.abe1107

Children and adults produce different types and amounts of antibodies in response to infection with the new coronavirus, SARS-CoV-2, a new Nature Immunology study from researchers at Columbia University Vagelos College of Physicians and Surgeons has found. Adult COVID-19 cohorts had anti-spike (S) IgG, IgM and IgA antibodies, as well as anti-nucleocapsid (N) IgG antibody, while children with and without MIS-C had reduced breadth of anti-SARS-CoV-2-specific antibodies, predominantly generating IgG antibodies specific for the S protein but not the N protein. Moreover, children with and without MIS-C had reduced neutralizing activity as compared to both adult COVID-19 cohorts, indicating a reduced protective serological response. The differences in antibodies suggest the course of the infection and immune response is distinct in children and most children easily clear the virus from their bodies. DOI: 10.1038/s41590-020-00826-9

An enzyme that helps COVID-19 infect the body also plays a role in inflammation and patient outcomes in inflammatory bowel disease (IBD), according to a new study led by Cedars-Sinai. Angiotensin-converting enzyme 2 (ACE2), the host receptor for SARS-CoV-2, is highly expressed in small bowel (SB). Reduced SB, but elevated colonic ACE2 levels in IBD are associated with inflammation and severe disease but normalized following anti-cytokine therapy suggesting compartmentalization of ACE2-related biology in SB and colonic inflammation. The restoration of ACE2 expression with anti-cytokine therapy may be important in the context of SARS-CoV-2 infection and potentially explain reports of reduced morbidity from COVID-19 in IBD patients treated with anti-cytokines. The findings were published in Gastroenterology. DOI: 10.1053/j.gastro.2020.10.041

Existing compounds can inhibit both the main protease (M^pro), a key viral protein required for SARS-CoV-2 replication inside human cells, and the lysosomal protease cathepsin L, a human protein important for viral entry into host cells according to researchers at the University of South Florida. They published their findings in Science Advances. The team solved X-ray crystal structures of M^pro in complex with calpain inhibitors II and XII, and three analogs of GC-376. Interestingly, the structure of calpain inhibitor XII revealed an unexpected, inverted binding pose. Taken together, the biochemical, computational, structural, and cellular data presented herein provide new directions for the development of dual inhibitors as SARS-CoV-2 antivirals. DOI: 10.1126/sciadv.abe0751

In PLOS Biology, two Penn State researchers recommend that samples from COVID-19 vaccine clinical trials be used to assess the likelihood that the vaccines being tested will drive resistance evolution and determine viral titer to assess transmissibility. For example, blood samples can be used to assess the redundancy of immune protection generated by candidate vaccines by measuring the types and amounts of antibodies and T-cells that are present. DOI: 10.1371/journal.pbio.3001000

Neoleukin Therapeutics has published research in Science describing novel molecules designed to treat or prevent infection by SARS-CoV-2. The company created de novo protein decoys specifically designed to bind the SARS-CoV-2 spike protein with high affinity, preventing its association with the viral receptor hACE2, which is required for infection. Their computational design strategy avoided incorporating elements of hACE2 that are known (or predicted) to be biologically active, such as the catalytic site. CTC-445.2d, the best decoy, potently neutralizes SARS-CoV-2 infection of cells in vitro and a single intranasal prophylactic dose of decoy protected Syrian hamsters from a subsequent lethal SARS-CoV-2 challenge. DOI: 10.1126/science.abe0075

A team from the University of Pittsburgh describe the identification of nanobodies that efficiently neutralize SARS-CoV-2. They used camelid immunization and proteomics to identify a large repertoire of highly potent neutralizing nanobodies (Nbs) to the SARS-CoV-2 spike (S) protein receptor-binding domain (RBD). The nanobodies bind tightly to the spike and efficiently neutralize SARS-CoV-2 in cells, and the thermostable nanobodies they developed can be rapidly produced in bulk from microbes. DOI: 10.1126/science.abe4747

Scientists at the University of Cambridge, in collaboration with Justus-Liebig University, Germany, uncovered the entire structure of the SARS-CoV-2 genome inside the host cell, revealing a network of RNA-RNA interactions spanning very long sections of the genome. Different functional parts along the genome need to work together despite the great distance between them, and the new structural data shows how this is accomplished to enable the coronavirus life cycle and cause disease. They published their work in Molecular Cell. DOI: 10.1016/j.molcel.2020.11.004

Using genetic screening and cryo-EM, a Yale team has shown that nonstructural protein 1, Nsp1, is one of SARS-CoV-2's most pathogenic viral proteins. In human lung cells, it can drastically alter host cell gene expression and essentially form a plug that prevents the ribosome from receiving genetic instructions for new proteins encoded in messenger RNA. This process affects protein production in many parts of the body, and high levels of Nsp1 may help explain why some people fare poorly after infection by the virus. The work is in pre-proof at Molecular Cell. DOI: 10.1016/j.molcel.2020.10.034

Tohoku University scientists have found that human editing enzymes are likely behind a type of mutation in the COVID-19 virus that stimulates the release of pro-inflammatory molecules called cytokines by immune cells in the body. The finding is published in the journal Scientific Reports. The team investigated the genome sequences of almost 8,000 SARS-CoV-2 viruses from an international database. They specifically looked for 'point mutations', in which a nucleotide base within the virus's RNA is switched to another base. Their analyses found that virus strains that had evolved from the original one isolated in Wuhan, China had a disproportionate number of cytosine bases that were switched to uracil, in addition to a number of other nucleotide base switches. Further analyses of the nucleotide bases preceding and following these point mutations suggested they were caused by two types of human editing deaminase enzymes, called APOBECs and ADARs. DOI: 10.1038/s41598-020-74843-x

Industry Updates

Lawrence Livermore National Laboratory (LLNL) will leverage Intel Xeon Scalable processors in its latest high-performance computing cluster, “Ruby.” The Ruby system will be used for unclassified programmatic work in support of the National Nuclear Security Administration’s (NNSA) stockpile stewardship mission, researching therapeutic drugs and designer antibodies against SARS-CoV-2, the virus that causes COVID-19, and for other open science work at LLNL. Ruby was built in collaboration with Intel, LLNL, Supermicro and Cornelis Networks. The system consists of more than 1,500 nodes, each outfitted with Intel Xeon Scalable processors and features 192 gigabytes (GB) of memory. Ruby will deliver 6 petaFLOPs of peak performance and is expected to rank among the Top 100 most powerful supercomputers in the world. Press release.

Baylor College of Medicine today released a curriculum for teachers that specifically focuses on the COVID-19 pandemic. The curriculum, which includes lesson plans and activities for students in grades K-12, is available for free through BioEdOnline. The COVID-19 curriculum is written by scientists and educators and reviewed by Baylor infectious diseases experts. The program is called COVID HACKS (Healthy Actions, Community, Knowledge and Science). In total, there will be about 30 lesson plans. The lesson plans address questions such as: What are viruses? How big are they? What do they look like? What is COVID-19? What are the symptoms of the infection? How can social distancing slow the spread of viruses? Why 6 feet? Why are face masks important? What are vaccines and how can they protect us? Press release.

Regenstrief Institute, Indiana Clinical and Translational Sciences Institute (CTSI) and Datavant are supporting the National COVID Cohort Collaborative (N3C). Supported by a contract from the NIH, Regenstrief will serve as the national project's Honest Data Broker, using specialized technologies and processes to create more complete and informative data sets. Specifically, the Honest Data Broker will handle requests for data and manage a process referred to as "privacy-preserving record linkage" (PPRL) using technologies and approaches that help ensure N3C data are shared safely, securely and privately, all in compliance with HIPAA standards. Such de-identified linkages of N3C data will help to address the challenges of securely assembling patient-level data that is traditionally fragmented and difficult to use across large-scale clinical research efforts. Datavant provides the privacy-preserving record linkage (PPRL) technology which underpins de-identified data contributions to the NIH COVID-19 Data Warehouse, including the N3C, ensuring patient records are shared safely, securely, and privately in compliance with de-identification standards. Press release.

TFF Pharmaceuticals and Augmenta Bioworks announced a worldwide Joint Development and Collaboration Agreement to develop novel commercial products incorporating Augmenta’s human-derived monoclonal antibodies (mAbs) for potential COVID-19 therapeutics. Under the terms of the Agreement, both companies will collaborate in a Joint Development Project to develop one or more commercial therapeutics based on, derived from, and/or incorporating Augmenta’s human monoclonal antibodies to potentially treat patients with COVID-19. These products will be developed using TFF Pharmaceuticals’ Thin-Film Freezing technology to manufacture dry powder formulations of these specific mAbs for inhalation delivery directly to the lungs of patients. The agreement also includes the development of formulations suitable for parenteral administration, where the Thin Film Freezing dry powder formulations can be reconstituted, potentially mitigating the impacts of cold-chain storage and handling. TFF Pharmaceuticals will also have the option to develop two additional Augmenta mAbs for indications other than COVID-19. Press release.