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Xiang Y, Nambulli S, Xiao Z, et al. Versatile and multivalent nanobodies efficiently neutralize SARS-CoV-2. Science 05 Nov 2020. Full-text: https://doi.org/10.1126/science.abe4747
An early inhalation of nanobodies – the future treatment? VHH antibodies or nanobodies (Nbs) are minimal, monomeric antigen-binding domains derived from camelid single-chain antibodies. Unlike IgG antibodies, Nbs are small, highly soluble and stable, readily bioengineered into bi/multivalent forms, and are amenable to low-cost, efficient microbial production. They can also be administered by inhalation, making their use against the respiratory viruses very appealing. The authors discovered several Nbs with picomolar to femtomolar affinities that inhibit viral infection at sub-ng/ml concentration and determined a structure of one of the most potent in complex with RBD. Multivalent Nb constructs achieved ultrahigh neutralization potency and may prevent mutational escape. While the research is still preliminary, it is hoped that Nbs might someday be the key ingredient in an antiviral drug that could be easily delivered via nasal spray.
Schoof M, Faust B, Saunders RA, et al. An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike. Science 05 Nov 2020. Full-text: https://doi.org/10.1126/science.abe3255
Michael Schoof and colleagues from San Francisco focused on such an ultrapotent Nb. Nb6 binds Spike in a fully inactive conformation with its receptor binding domains (RBDs) locked into their inaccessible down-state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.
Linsky TW, Vergara R, Codina N, et al. De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2. Science 05 Nov 2020. Full-text: https://doi.org/10.1126/science.abe0075
Another new way to combat COVID-19. Thomas W. Linsky and colleagues from Seattle and other US cities developed a computational protein design strategy that enables the rapid and accurate design of hyperstable de novo protein “decoys”. The decoys replicate the protein receptor interface that a virus binds to in order to infect a cell. Thus, they outcompete viral interaction with the cell. The best ACE2 decoy, CTC-445.2, did bind with low nanomolar affinity and high specificity to the RBD of the spike protein. Because the decoy replicates the spike protein target interface in hACE2, it is intrinsically resilient to viral mutational escape. A bivalent decoy, CTC-445.2d, showed 10-fold improvement in binding. CTC-445.2d 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.
Zilla M, Wheeler BJ, Keetch C, et al. Variable Performance in 6 Commercial SARS-CoV-2 Antibody Assays May Affect Convalescent Plasma and Seroprevalence Screening. American Journal of Clinical Pathology, aqaa228. Full-text: https://doi.org/10.1093/ajcp/aqaa228
Megan Zilla and colleagues from Pittsburgh have compared six SARS-CoV-2 antibody assays, namely Beckman Coulter, Euroimmun (IgG, IgA), Roche, and Siemens (Centaur, Vista). Assays were assessed for specificity (n=184), sensitivity (n=154), and seroconversion in a defined cohort with clinical correlates and molecular SARS-CoV-2 results. Assay specificity was 99% or greater for all assays except the Euroimmun IgA (95%). Sensitivity at more than 21 days from symptom onset were 84%, 95%, 72%, 98%, 67%, and 96% for Beckman Coulter, Centaur, Vista, Roche, Euroimmun IgA, and Euroimmun IgG, respectively. These finding raises concerns that seroprevalence studies may vary significantly based on the serologic assay utilized, even when the assays are from reliable manufacturers with proven methodologies and have similar targets and initial specificity and sensitivity measures.
Santos-Ferreira D, Tomás R, Dores H. Return-to-Play Guidelines for Athletes After COVID-19 Infection. JAMA Cardiol. November 4, 2020. Full-text: https://doi.org/10.1001/jamacardio.2020.5345
What to do with athletes after recovery? The clinical implications of asymptomatic to mild COVID-19 still remain undetermined. Pulmonary and cardiac fibrosis are potentially the most relevant for athletes, which may lead to reduced lung capacity or cardiac dysfunction, malignant arrhythmias, and sudden death. Complications from the disease must be excluded prior to returning to play. According to the authors, those with suspected or confirmed COVID-19 (including mild or complicated disease) or presenting with suggestive signs or symptoms should undergo additional investigations according to presentation and disease severity. These may include blood tests, electrocardiography, echocardiography, 24-hour and/or 48-hour Holter monitoring, exercise testing, or lung function tests.
Smilowitz NR, Jethani N, Chen J, et al. Myocardial Injury in Adults Hospitalized with COVID-19. Circulation 5 Nov 2020. Full-text: https://doi.org/10.1161/CIRCULATIONAHA.120.050434
Nathaniel R. Smilowitz and colleagues have analyzed myocardial injury at admission and during hospitalization in a large cohort of 2163 patients with COVID-19 from a high-volume health care system in New York. Nearly a third (32%) had myocardial injury at presentation, and nearly half had injury detected during the course of their hospitalization. Regardless of when it was first detected, myocardial injury was associated with increased odds of mortality and critical illness, with higher cardiac Troponin (cTn) measurements associated with worse outcomes.
Rentsch CT, De Vito NJ, MacKenna B, et al. Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform. Lancet Neurology, November 05, 2020. Full-text: https://doi.org/10.1016/S2665-9913(20)30378-7
This population-based cohort study using national primary care data and linked death registrations in the OpenSAFELY platform, which covers approximately 40% of the general population in England, UK. Between September 1, 2019, and March 1, 2020, of 194,637 people with rheumatoid arthritis or systemic lupus erythematosus, 30,569 (16%) received two or more prescriptions of HCQ. Between March 1 and July 13, 2020, there were 547 COVID-19 deaths, 70 among HCQ users. Estimated standardized cumulative COVID-19 mortality was 0.23% among users and 0.22% among non-users. These findings are not surprising given the mounting body of literature suggesting no clinical benefit for HCQ. However, this study is the largest to date and adds further evidence to the lack of any preventive effect.
Woodworth KR, Olsen EO, Neelam V, et al. Birth and Infant Outcomes Following Laboratory-Confirmed SARS-CoV-2 Infection in Pregnancy — SET-NET, 16 Jurisdictions, March 29–October 14, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1635–1640. Full-text: http://dx.doi.org/10.15585/mmwr.mm6944e2
The Surveillance for Emerging Threats to Mothers and Babies Network (SET-NET) collects information on pregnancy and infant outcomes in 16 US jurisdictions. Among 3,912 infants with known gestational age born to women with SARS-CoV-2 infection, 12.9% were preterm (<37 weeks), higher than a national estimate of 10.2%. Among 610 (21.3%) infants with testing results, 2.6% had positive SARS-CoV-2 results, primarily those born to women with infection at delivery. Among the infants with positive test results, one half were born preterm, which might reflect higher rates of screening in the ICU.
Zambrano LD, Ellington S, Strid P, et al. Update: Characteristics of Symptomatic Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status — United States, January 22–October 3, 2020. MMWR Morb Mortal Wkly Rep 2020;69:1641–1647. Full-text: http://dx.doi.org/10.15585/mmwr.mm6944e3
In an analysis of approximately 400,000 women aged 15–44 years with symptomatic COVID-19, the absolute risks for severe COVID-19–associated outcomes among women were low. However, pregnant women were at significantly higher risk for severe outcomes: Compared with nonpregnant women, pregnant women more frequently were admitted to an ICU (10.5 versus 3.9 per 1,000 cases; aRR = 3.0; 95% CI = 2.6–3.4), received invasive ventilation (2.9 versus 1.1 per 1,000 cases; aRR = 2.9; 95% CI = 2.2–3.8) and received ECMO (0.7 versus 0.3 per 1,000 cases; aRR = 2.4; 95% CI = 1.5–4.0). Thirty-four deaths (1.5 per 1,000 cases) were reported among 23,434 symptomatic pregnant women, and 447 (1.2 per 1,000 cases) were reported among 386,028 nonpregnant women, reflecting a 70% increased risk for death associated with pregnancy (aRR = 1.7; 95% CI = 1.2–2.4).