Bringing Peer Review To Early COVID-19 Research, More News

August 18, 2020 | New insights into the SARS-CoV-2 spike protein, a daily aerosol protectant, a look a death rates in 1918 and now, and a journal dedicated to publishing COVID-19 research with visible peer review. Plus new funding from NIH and the American Heart Association to enable further research on SARS-CoV-2 and COVID-19.

Research Updates

Using nanometer-level simulations, Northwestern University researchers have discovered a positively charged site (known as the polybasic cleavage site) located 10 nanometers from the actual binding site on the SARS-CoV-2 spike protein. The positively charged site allows strong bonding between the virus protein and the negatively charged human-cell receptors. Leveraging this discovery, the researchers designed a negatively charged molecule to bind to the positively charged cleavage site. Blocking this site inhibits the virus from bonding to the host cell. The work was published in ACS Nano. DOI: 10.1021/acsnano.0c04798

UC San Francisco scientists have devised a novel approach to halting the spread of SARS-CoV-2: a completely synthetic, production-ready molecule that straitjackets the crucial SARS-CoV-2 machinery that allows the virus to infect our cells. As reported in a new paper, now available on the preprint server bioRxiv, experiments using live virus show that the molecule is among the most potent SARS-CoV-2 antivirals yet discovered. In an aerosol formulation they tested, dubbed “AeroNabs” by the researchers, these molecules could be self-administered with a nasal spray or inhaler. Used once a day, AeroNabs could provide powerful, reliable protection against SARS-CoV-2 until a vaccine becomes available, they say. The research team is in active discussions with commercial partners to ramp up manufacturing and clinical testing of AeroNabs. If these tests are successful, the scientists aim to make AeroNabs widely available as an inexpensive, over-the-counter medication to prevent and treat COVID-19. Preprint DOI: 10.1101/2020.08.08.238469

Researchers from Harvard, Yale, and Emory compared the estimated excess deaths in New York during the peak of the 1918 influenza pandemic with above-average deaths during the early period of the COVID-19 outbreak in a new research letter published in JAMA Network Open. During the peak of the 1918 H1N1 influenza outbreak in New York City, a total of 31,589 all-cause deaths occurred among 5,500,000 residents, yielding an incident rate of 287.17 deaths per 100,000 person-months. During the early period of the COVID-19 outbreak in New York City, 33,465 all-cause deaths occurred among 8,280,000 residents, yielding an incident rate of 202.08 deaths per 100,000 person-months. These findings suggest that the mortality associated with COVID-19 during the early phase of the New York City outbreak was comparable to the peak mortality observed during the 1918 H1N1 influenza pandemic, the authors write. DOI: 10.1001/jamanetworkopen.2020.17527

A preliminary analysis of an ongoing study of more than 300 COVID-19 patients treated with convalescent plasma therapy at Houston Methodist suggests the treatment is safe and effective. The results appear in The American Journal of Pathology. The study compared 316 transfused patients to controls and preliminary analysis showed a significant reduction in mortality within 28 days, specifically in patients transfused within 72 h of admission with plasma with an anti-spike protein receptor binding domain titer of ≥1:1350. DOI: 10.1016/j.ajpath.2020.08.001

A team from Yale conducted a retrospective cohort study of 1827 patients with confirmed COVID‐19 who were hospitalized within the Yale‐New Haven Health System (YNHHS) between March 14, 2020 and April 23, 2020 and published their findings in Hepatology. They analyzed liver tests at three time points (pre‐infection baseline, admission, peak hospitalization), and hospitalization outcomes (severe COVID‐19, ICU admission, mechanical ventilation, death). Abnormal liver tests were commonly observed in hospitalized patients with COVID‐19, both at admission and peak hospitalization. A significant proportion of these patients had abnormal liver tests pre‐hospitalization. Multivariate analysis revealed an association between abnormal liver tests and severe COVID‐19, including ICU admission, mechanical ventilation, and death. DOI: 10.1002/hep.31487

An online national survey of 4, 351 adolescents and young adults aged 13–24 years was conducted in May 2020 and used to assess relationships among COVID-19 and e-cigarettes and cigarettes. Researchers from Stanford found that COVID-19 was five times more likely among ever-users of e-cigarettes only, seven times more likely among ever-dual-users, and 6.8 times more likely among past 30-day dual-users. The team published their findings in the Journal of Adolescent Health and concluded that COVID-19 is associated with youth use of e-cigarettes only and dual use of e-cigarettes and cigarettes, suggesting the need for screening and education. DOI: 10.1016/j.jadohealth.2020.07.002

Researchers from Harvard and Washington University have constructed chimeric forms of vesicular stomatitis virus (VSV) bearing the fusion proteins of Zaire ebolavirus (ZEBOV) or SARS coronavirus 2 (SARS-CoV-2) and shown that two small-molecule inhibitors of an endosomal lipid kinase (PIKfyve) inhibit viral infection by preventing release of the viral contents from endosomes. The findings suggest the potential for targeting PIKfyve kinase when developing small-molecule antivirals against SARS-CoV-2. The results were published in PNAS. DOI: 10.1073/pnas.2007837117

By applying the renewal theory in probability to reduce recall bias in initial case reports, scientists from NIH, Peking University, and the Chinese Center for Disease Control and Prevention have come up with a new estimate for the incubation period of COVID-19. Their mean estimate of 7.76 days, longer than previous estimates of 4 to 5 days, is based on 1,084 confirmed cases of COVID-19 that had known histories of travel or residency in Wuhan, China. The results were published in Science Advances, and the authors caution that their approach relies on several assumptions and may not apply to later cases where the virus may have mutated. DOI: 10.1126/sciadv.abc1202

Last month, a team from McMaster University analyzed gene expression datasets from airway epithelial cells of 515 healthy subjects, gene promoter activity analysis using the FANTOM5 dataset containing 120 distinct sample types, single cell RNA sequencing (scRNAseq) of 10 healthy subjects, proteomic datasets, immunoblots on multiple airway epithelial cell types, and immunohistochemistry on 98 human lung samples. Their findings, published in the European Respiratory Journal, suggest the presence of a mechanism dynamically regulating ACE2 expression in human lung, perhaps in periods of SARS-CoV-2 infection, and also suggest that alternate receptors for SARS-CoV-2 exist to facilitate initial host cell infection. DOI: 10.1183/13993003.01123-2020 Later in July, a group from Uppsala University came to a similar conclusion in a paper published in Molecular Systems Biology. In the respiratory system, the expression of ACE2 was limited, with no or only low expression in a subset of cells in a few individuals, observed by one antibody only, the Swedish group writes. DOI: 10.15252/msb.20209610

To compare disease trends in adults and children during the first wave of the coronavirus pandemic in England between January and May 2020, UK researchers reviewed COVID-19 test result data for this period. The data included NHS and Public Health England (PHE) test results plus those carried out by family doctors at 300 general practices contributing to the Royal College of General Practitioners monitoring system for flu-like illness—35,200 children under the age of 16. Around 24% of all those tested had the virus, and children accounted for 1% of the total. 4% of the 35,200 tests carried out on children were positive compared to 19%-35% of adults. Their findings are published in BJM. DOI: 10.1136/archdischild-2020-320042.

Evidence has revealed that SARS-CoV-2 infection caused taste loss at a rate higher than that of influenza. ACE2, the entry receptor of SARS-CoV-2, has been identified in the oral epithelium; however, it is unclear at what developmental stage ACE2 expression emerges and whether ACE2 is expressed in taste buds. To identify the specific developmental stage, researchers from the University of Georga analyzed RNA-Seq data from embryonic, newborn, and adult mouse oral tissue. They found that when applied across species, nongustatory papilla epithelial cells are the prime targets for SARS-CoV-2 infection in the tongue; thus, taste loss in COVID-19 patients is likely not caused by a direct infection of SARS-CoV-2 to taste bud cells. Additionally, fetuses at different stages of development may have distinct susceptibility to SARS-CoV-2 infection. Their results are published in ACS Pharmacology and Translational Science. DOI: 10.1021/acsptsci.0c00062

In Annals of Internal Medicine, researchers from Garibaldi Hospital in Italy describe what they believe are the first 3 reported cases of AChR antibody–positive myasthenia gravis after COVID-19. Their observations are consistent with reports of other infections that induce autoimmune disorders, they say, as well as with the growing evidence of other neurologic disorders with presumed autoimmune mechanisms after COVID-19 onset. The team notes that symptoms of myasthenia gravis appeared within 5 to 7 days after fever onset in all 3 patients, and the time from presumed infection with SARS-CoV-2 to the beginning of myasthenia gravis symptoms is consistent with the time from infection to symptoms in other neurologic disorders triggered by infections. DOI: 10.7326/L20-0845

Industry Updates

MIT Press and the University California, Berkeley have launched an open access journal—Rapid Reviews: COVID-19 (RR:C19)—in an effort to reduce misinformation and to elevate noteworthy and useful research for scientists, public health officials, journalists, and the public. The first issue posted peer reviews of eight COVID-19 preprint studies. More than 20,000 preprints have been made available on preprint servers, including medRxiv, bioRxiv, and SSRN. The RR:C19 editorial team believes there is an urgent need for scholarly peer review to validate—or debunk—information before it is widely circulated. Press release.

The American Heart Association has awarded an additional $400,000 in research grants focused on the cardiovascular impact of COVID-19. The awards go to four more teams who submitted proposals for the COVID-19 and Its Cardiovascular Impact Rapid Response Grants during the original submission process in March. The winning teams come from Cleveland Clinic, Johns Hopkins University, Cedars-Sinai Medical Center, and New York-Presbyterian/Columbia University Irving Medical Center. Press release.

The National Institutes of Health has awarded a grant of $1.2 million to the Mouse Biology Program at the University of California, Davis, to create mice that are susceptible to the COVID-19 virus, and to distribute them to researchers. Mice and rats are not naturally infected by SARS-CoV-2, the virus that causes COVID-19. The virus enters human cells by attaching to a protein called ACE2. Lloyd's team plans to create "humanized" laboratory mice by using CRISPR-Cas9 technology to precisely replace the genetic code for the mouse equivalent of ACE2 with the code for human ACE2. Press release.

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