No Cytokine Storm, ‘Bursty’ Disease Spread: Biomarkers For Elevated Risk: COVID-19 Updates

September 10, 2020

September 11, 2020 | Japanese researchers argue there is no cytokine storm, computer-designed protective proteins, ELISA test for antibodies, COVID-19’s impact on Black and Hispanic communities, a “burstier” model of disease spread, and new biomarkers for elevated risk. Plus, the International Vaccine Institute preps with Gates money, 3M funds vaccine researcher, and more.

Research Updates

Computer-designed small proteins have now been shown to protect lab-grown human cells from SARS-CoV-2, the coronavirus that causes COVID-19. The work, conducted by Institute for Protein Design researchers at the University of Washington School of Medicine, was published in Science. The team used computers to originate new proteins that bind tightly to SARS-CoV-2 Spike protein and obstruct it from infecting cells. Beginning in January, more than two million candidate Spike-binding proteins were designed on the computer. Over 118,000 were then produced and tested in the lab. The lead antiviral candidate, named LCB1, rivaled the best-known SARS-CoV-2 neutralizing antibodies in its protective actions. LCB1 is currently being evaluated in rodents. DOI: 10.1126/science.abd9909

In collaboration with Penn State, University of Texas at Austin and U.S. Army Medical Research Institute of Infectious Diseases, physician scientists at Houston Methodist, sought to find alternatives to measuring virus neutralization (VN) titers, which is the gold standard of COVID-19 antibody testing, as VN antibodies in the blood correlate with immunity. This kind of antibody testing, however, is not widely available, because it's technically complex, requires days to set up, run and interpret, and needs to be performed in a biosafety level 3 laboratory. The team instead developed ELISA antibody tests for SARS-CoV-2 and looked at the relationship of anti-spike ectodomain (ECD) and anti-receptor binding domain (RBD) IgG bloodstream antibody titers. In assessing the correlation between VN antibody levels and anti-RBD and anti-ECD ELISA protein titer data, the researchers found that the ELISA tests had an 80% probability or greater of comparable antibody level to VN titers at or above the FDA-recommended levels for COVID-19 convalescent plasma. These results affirm that all three types of tests could potentially serve as a quantitative target for therapeutic and prophylactic treatments. Their results are published in the Journal of Clinical Investigation. DOI: 10.1172/JCI141206

A recent study by researchers from Syracuse University shows that the average daily increase in rural COVID-19 mortality rates has been significantly higher in counties with the largest percentages of Black and Hispanic residents. The study was published in the Journal of Rural Health. The authors suggest that we increase access to free COVID-19 testing in rural areas generally, but especially in rural areas with vulnerable population groups, and that local governments work with trusted community-based organizations, including the faith-based community, to help educate, conduct testing and contact tracing, and provide necessary personal protective resources to Black and Hispanic residents. DOI: 10.1111/jrh.12511

Researchers reporting in ACS' Journal of Proteome Research compared lipoproteins and metabolites in the blood of COVID-19 patients and healthy subjects, revealing signs of multi-organ damage in patients that could someday help diagnose and treat COVID-19. The breadth of the disturbed pathways indicates a systemic signature of SARS-CoV-2 positivity that includes elements of liver dysfunction, dyslipidaemia, diabetes, and coronary heart disease risk that are consistent with recent reports that COVID-19 is a systemic disease affecting multiple organs and systems, they write. DOI: 10.1021/acs.jproteome.0c00519

Using a diffusion model based on interpersonal contact networks, researchers at the University of California, Irvine, have modeled the spread of COVID-19. Taking into account spatial heterogeneity, the spread of COVID-19 is much “burstier” than in standard epidemiological models, with substantial local disparities in timing and severity and long lags between local outbreaks, they report in a paper in PNAS. They show that spatial heterogeneity may produce dramatic differences in social exposures to those with the illness and may stress health care delivery systems in ways that are not well captured by standard SIR-like models. DOI: 10.1073/pnas.2011656117

In the Journal of Clinical Investigation, a German team proposed a mechanism behind why older people and people with underlying medical conditions are at particular risk of severe COVID-19. Higher patient age and comorbidity index correlated with increased frequencies of CoV-2 specific CD4+ T-cells, harboring higher portions of IL-2- but lower portions of IFNγ secreting cells. The data suggest a link between individual patient predisposition with respect to age and comorbidity and impairment of CoV-2 specific Th1-type cellular immunity, the authors write, thereby supporting a concept of altered T-cell function in patients at risk. DOI: 10.1172/JCI140965

A Brigham and Women’s team has tracked the rate of nosocomial COVID-19 transmission in their own hospital over a 12-week period. Of 8,370 patients with non-COVID-19 hospitalizations, 11 tested positive within 14 days of admission. Only one case was deemed hospital-acquired. The analysis reveals that a multifaceted infection control program based on US Centers for Disease Control and Prevention guidance may be associated with minimized risk of nosocomial transmission of SARS-CoV-2 infection, the authors note. They published their results in JAMA. DOI: 10.1001/jamanetworkopen.2020.20498.

Ferritin could be a marker of severity of COVID-19 according to an Israeli team. They reviewed data from 39 hospitalized patients from two hospitals and found that a significant increase in ferritin levels was demonstrated in patients with moderate and severe disease, compared to patients with mild disease. Severe patients had significantly higher levels of ferritin than non-severe patients. They published their findings in the Israel Medical Association Journal. PMID: 32812717

Radboud University Medical Center researchers propose in a JAMA letter that there is no COVID-19 cytokine storm. They measured three cytokines in patients with COVID-19 who met the criteria for a severe acute respiratory infection (ARDS), patients with bacterial septic shock (with and without ARDS), and patients who had been admitted to the ICU after a cardiac arrest or severe trauma. The cytokines were measured using the same methods for each of the groups of patients. Although IL-6 levels are elevated in severe COVID-19, they are lower than levels usually observed in (non–COVID-19) acute respiratory distress syndrome (ARDS), the authors write. The severe disease observed in critically ill COVID-19 patients is therefore not explained by strongly elevated levels of inflammatory proteins in the blood, they conclude. “This means that critically ill COVID-19 patients likely will not benefit from specific anti-cytokine therapies." DOI: 10.1001/jama.2020.17052

Alternatively, researchers from the Institute for Genetic Medicine (IGM) at Hokkaido University argue that weakening or preventing the cytokine storm would drastically reducing the overall mortality to COVID-19. The Japanese team reviewed the existing research on macrophage activation syndrome (MAS) and argue that existing therapies for MAS have shown initial success in ameliorating severe COVID-19 cases. They published their results in Inflammation and Regeneration. DOI: 10.1186/s41232-020-00131-w

A team at Massachusetts General Hospital noted that patients with high levels of blood clotting protein factor V are at elevated risk for serious injury from blood clots such as deep vein thrombosis or pulmonary embolism. In addition, within this severe COVID‐19 cohort, factor V activity was associated with SARS‐CoV‐2 viral load in a sex‐dependent manner. Their findings are published in the American Journal of Hematology. DOI: 10.1002/ajh.25979.

French researchers have identified another biomarker of severe COVID-19 disease: changes in unconventional T cells. Their work is published in the Journal of Experimental Medicine (JEM). Circulating unconventional T cells of COVID-19 patients presented with a profound and persistent phenotypic alteration. Expression of the CD69 activation marker on blood iNKT and MAIT cells of COVID-19 patients on admission was predictive of clinical course and disease severity. DOI: 10.1084/jem.20200872

In a paper published in eClinical Medicine, researchers at the University of Texas Health Science Center at San Antonio describe the presentation and outcomes of children diagnosed with multisystem inflammatory syndrome in children (MIS-C), also known as pediatric inflammatory multisystem syndrome. With data gathered from database review and screened by two authors, the team determined that multisystem inflammatory syndrome is a new pediatric disease associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is dangerous and potentially lethal. Among the more concerning findings was that children could still develop MIS-C despite an asymptomatic course of coronavirus 2019 disease. The literature reports that MIS-C typically manifests 3–4 weeks after SARS-CoV-2 infection. An added matter of trepidation was that 52% of individuals who developed the inflammatory syndrome did not have any underlying medical conditions. DOI: 10.1016/j.eclinm.2020.100527

Researchers at Karolinska Institute in Sweden have identified an alpaca-derived single domain antibody fragment, Ty1, that specifically targets the receptor binding domain (RBD) of the SARS-CoV-2 spike, directly preventing ACE2 engagement. Ty1 binds the RBD with high affinity, occluding ACE2. The researchers believe this nanobody has the potential to be developed as an antiviral treatment against COVID-19. The results are published in the journal Nature Communications. DOI: 10.1038/s41467-020-18174-5  

University of Washington researchers posit that that varying immune responses to SARS-CoV-2 due to age and sex may depend on viral load and the time-course of infection. Researchers extracted and sequenced viral RNA from swabs collected from 430 COVID-19 positive cases and 54 negative controls. The scientists then analyzed the hosts' antiviral and immune responses across infection status, viral load, age and sex. They found antiviral response is characterized by type I and II interferon induction, which wanes with time and is correlated with viral load. They also found evidence of transcriptional repression by SARS-CoV-2. Differences in immune responses may underlie disparities in outcomes for 2 higher-risk groups, males and the elderly, they write in PLOS Biology. DOI: 10.1371/journal.pbio.3000849

Beth Israel Deaconess Medical Center immunologists have tested a vaccine candidate and demonstrated that it elicited robust immune response in Syrian golden hamsters and prevented severe clinical disease including weight loss, pneumonia and death. They published their findings in Nature Medicine. Pending clinical trial outcomes, the Ad26.COV2.S vaccine is on track to start a phase 3 efficacy trial in up to 60,000 participants in September 2020. DOI: 10.1038/s41591-020-1070-6

In Cell Reports, researchers from Cornell and the German Center for Neurodegenerative Diseases (DZNE) map the expression of 28 human genes dubbed "SCARFs"—SARS-Cov-2 and Coronavirus-Associated Receptors and Factors—in a variety of human tissues to develop a comprehensive profile of the molecular factors that both facilitate and restrict SARS-CoV2 infection. The study indicates alternate entry paths for how the virus could enter the lungs, central nervous system and heart. Their research also supports emerging clinical data that shows SARS-CoV-2 also infects the intestines, kidney and placenta. They noted that specific groups of cells within the prostate and testes are likely to be permissive for SARS-CoV-2 and may help explain male-specific vulnerabilities. DOI: 10.1016/j.celrep.2020.108175

Industry Updates 

The International Vaccine Institute (IVI) has announced that the Bill & Melinda Gates Foundation awarded close to $1.5M to IVI to support clinical trial site preparedness in four African and Asian countries to potentially support future COVID-19 Phase III efficacy vaccine trials. Following successful completion of early-stage clinical trials of COVID-19 vaccine candidates, it will be essential to transition to efficacy trials at different sites around the world with high disease burden, including those in resource-limited settings. To ensure these sites are prepared for efficacy trials with the necessary technical capability, trained staff, sufficient trial participants, and a thorough assessment of prevailing COVID-19 burden, IVI aims to bolster in-country capacity at select sites by the fourth quarter of 2020. Press release

3M has awarded $400,000 to the Shmunis School of Biomedicine and Cancer Research at Tel Aviv University (TAU) to develop a receptor-binding motif (RBM)-based vaccine. In order for the virus to infect someone, viral RBM, a tiny but highly complex structure, must detect ACE2, bind to it and mediate infection. A vaccine that exclusively targets the RBM should be extremely potent in affording maximal protection against SARS CoV2 by stimulating our immune system in the most efficient and cost-effective way, says Prof. Jonathan Gershoni who will be leading the research. His team has developed a novel patented technology to 'surgically' isolate the RBM from the rest of the spike protein. The technology will be a starting point for a vaccine. Press release

Insilico Medicine has launched a new system for COVID-19 basic and clinical research. COVIDomic is a cloud-based platform that uses AI approaches to identify risk factors associated with severe disease progression. The bioinformatics and Artificial Intelligence (AI) tools can be applied in many ways, starting with better stratifying COVID-19 patients, understanding the disease trajectory and identifying relevant disease pathways and targets. COVIDomic is built using massive multi-omics data sets, sophisticated dimensionality reduction algorithms and deep learning systems. This amount of computing will rely on Intel Xeon processors. The development team is inviting scientists globally to contribute to the development of the system and engage in active research collaborations. Press release

ADMA Biologics has launched COVID-19 ImmunoRank Neutralization MICRO-ELISA, a proprietary, fully-validated ELISA assay for the detection of SARS-CoV-2 neutralizing antibodies in plasma developed in collaboration with Leinco Technologies. ImmunoRank is intended to help identify individuals who produce an adaptive immune response to SARS-CoV-2, indicating recent or prior infection, and specifically for the detection of circulating SARS-CoV-2 neutralizing antibodies in human plasma of all immune globulin classes. ImmunoRank is designed to test up to 90 samples per test kit with 99.8% specificity. The assay procedure takes approximately 80 minutes. An Emergency Use Authorization (EUA) submission is currently being prepared for review and potential approval by the FDA. Press release.