Profile of T Cells, Broadly Neutralizing Antibodies, Anti-Viral Targets: COVID-19 Updates

January 29, 2021

January 29, 2021 I COVID-19 may become seasonal, severe infection associated with myeloid immune cells, potential Achilles heel of coronaviruses identified, melatonin synthesized in lungs could have protective effect, and plitidepsin outperforms remdesivir in preclinical trials. Plus: NSAID use during COVID-19 is time-dependent on its harm or benefit and NAU to test Allarity drug against Coronavirus Variant B117.


Research News

COVID-19 may be seasonal, like the flu, suggests a new paper published in Evolutionary Bioinformatics. Authors of the paper show that COVID-19 cases and mortality rates, among other epidemiological metrics, are significantly correlated with temperature and latitude across 221 countries. They also explain that our own immune systems could be partially responsible for the pattern of seasonality. For example, our immune response to the flu can be influenced by temperature and nutritional status, including vitamin D, a critical nutrient to our immune defenses. The researchers add that it is, however, too soon to say how seasonality and our immune systems interact in the case of COVID-19. DOI:10.1177/1176934321989695

SARS-CoV-2 independently entered Russia at least 67 times, primarily at the end of February and beginning of March 2020, according to a new study published in Nature Communications. Researchers of the study used 211 virus genomes, which were sequenced at Smorodintsev Research Institute of Influenza, and all genomes had been obtained from patients from 25 Russian regions during mid-March to April 2020. They determined that the vast majority of introductions came from European countries, and no cases of introduction from China were registered, which they attribute to the timely closure of borders with the country. Currently, nine local virus lineages are circulating in Russia, which are not present elsewhere in the world. DOI:10.1038/s41467-020-20880-z

Research led at Vanderbilt University Medical Center has discovered a “proofreading” exoribonuclease, called nsp14-ExoN, which can correct errors in the RNA sequence that occur during replication, when copies of a virus are generated. They believe that this may be the Achilles’ heel of the coronavirus, a finding that could help close the door on COVID-19 and possibly head off future pandemics. Using cutting-edge technologies and novel bioinformatics approaches, the researchers discovered that this ExoN also regulates the rate of recombination, which is the ability of the coronavirus to shuffle parts of its genome and even pull genetic material from other viral strains while it replicates in order to gain evolutionary advantage. These patterns of recombination are conserved across multiple coronaviruses, including SARS-CoV-2. They believe that the coronavirus ExoN is therefore a conserved, important target for inhibition and attenuation in the ongoing pandemic. This research is published in PLOS Pathogens. DOI:10.1371/journal.ppat.1009226

Also at Vanderbilt University Medical Center (VUMC),  researchers have identified genetic factors that increase the risk for developing pneumonia to help identify patients with COVID-19 at greatest risk for this life-threatening complication. The researchers conducted genome-wide association studies (GWAS) of more than 85,000 patients whose genetic information is stored in VUMC’s BioVU biobank. They identified nearly 9,000 cases of pneumonia in patients of European ancestry and 1,710 cases in patients of African ancestry. After further analysis, the research team linked the gene that causes cystic fibrosis (CF) and European ancestry and the mutation that causes sickle cell disease (SCD) in patients of African ancestry as the strongest pneumonia associations. After removing patients with CF and SCD, they then pinpointed a pneumonia-associated variation in a gene called R3HCC1L in patients of European ancestry, and one near a gene called UQCRFS1 in patients of African ancestry. They believe these findings could be applied to identifying patients with high risk of severe pneumonia to enable early interventions. They have published this work in the American Journal of Human Genetics. DOI:10.1016/j.ajhg.2020.12.010

Melatonin produced in the lungs acts as a barrier against SARS-CoV-2, blocking the expression of genes that encode proteins in cells serving as viral entry points, finds researchers at the University of São Paulo (USP). The hormone, therefore, prevents infection of these cells by the virus and inhibits the immune response so that the virus remains in the respiratory tract for a few days and then leaves the host, say the researchers. They used RNA sequencing data to quantify the level of expression of 212 COVID-19 signature genes in 288 samples from healthy human lungs. The researchers correlated these gene expression levels with a gene index that estimated the capacity of the lungs to synthesize melatonin (MEL-index). They then were able to determine that when the MEL-index was high, the entry points for the virus in the lungs were closed, and vice-versa. The research team suggests the potential for nasal administration of melatonin to prevent disease from developing in pre-symptomatic COVID-19 patients. This study is published in Melatonin Research. DOI:10.32794/mr11250090

In a new study, published in Cell Reports Medicine, La Jolla Institute for Immunology (LJI) researchers suggest that T cells can mount attacks against many SARS-CoV-2 targets, beyond the key sites on the virus’s spike protein. They believe that by attacking the virus from many angles, the body is equipped to potentially recognize different SARS-CoV-2 variants. The researchers examined T cells from 100 people who had recovered from COVID-19 to take a closer look at the genetic sequence of the virus to separate the potential epitopes from the epitopes that these T cells would recognize. Their analysis revealed that not all parts of the virus induce the same strong immune response in everyone, and T cells can recognize dozens of epitopes on SARS-CoV-2 that vary from person to person. They determined that each study participant had the ability to recognize about 17 CD8+ T cell epitopes and 19 CD4+ T cell epitopes. DOI:10.1016/j.xcrm/2021/100202

John Hopkins Medicine researchers, in collaboration with Immunoscape, have published a complete profile of the response of T cells in people who have recovered from SARS-CoV-2 infection. The paper, published in The Journal of Clinical Investigation, better defines which T cells interact with which specific portion of the SARS-CoV-2 virus and how those interactions can provide long-lasting immunity against COVID-19. The researchers collected blood samples from 30 convalescent patients who had recovered from mild cases of COVID-19 and the Immunoscape team, a U.S.-Singapore biotechnology company, used its highly sensitive human leukocyte antigen (HLA)-SARS-CoV-2 tetramers to tag and identify the types of virus-recognizing CD8+ T cells. The researchers found that as levels of neutralizing antibodies increased in the convalescent plasma, so did the number of memory CD8+ T cells that recognized SARS-CoV-2 epitopes. They believe this means lasting protection against reinfection, and this knowledge will guide COVID-19 vaccine design to produce a strong immune response that could provide years of protection. DOI:10.1172/JCI145476

Severe COVID-19 patients have significantly elevated levels of a certain type of immune cell in their blood, call monocytic myeloid-derived suppressor cells (M-MDSC), according to a new study published in the Journal of Clinical Investigation. Karolinska Institutet researchers studied 147 patients with mild to fatal COVID-19 who were sampled repeatedly from blood and respiratory tract. These samples were then compared with patients who had influenza and healthy individuals. They found that the patients with severe COVID-19 had significantly higher levels of M-MDSCs in their blood when compared to milder cases and healthy participants. COVID-19 patients also had fewer T cells in their blood than healthy individuals that showed signs of impaired function. Additionally, their analysis revealed that the levels of M-MDSCs early in the course of infection seemed to reflect subsequent disease severity. DOI:10.1172/JCI44734

Researchers have engineered an antibody that effectively neutralizes SARS-CoV-2 and that also acts against multiple SARS-like viruses. Their antibody, ADG-2, was studied in mice. To engineer this broadly neutralizing antibody (bnAb), the researchers started with antibodies from the memory B cells of a 2003 SARS survivor that cross-neutralized multiple SARS-related viruses with modest potency. They then selectively engineered the binding affinities of several of these bnAbs, creating improvements in their abilities to bind the virus. The researchers then studied the engineered antibodies for SARS-CoV-2 neutralizing activity in mouse cell lines. ADG-2 was particularly effective. It showed broad binding activity to more than a dozen SARS-related coronaviruses. This research is published in Science. DOI:10.1126/science.abf4830

Plitidepsin has shown a potent efficacy against SARS-CoV-2 in preclinical trials, outperforming the antiviral remdesivir. These results, published in Science, show that in studies in human cells, plitidepsin demonstrated potent anti-SARS-CoV-2 activity: 27.5-fold more so than remdesivir as tested in the same cell line. In a model of human lung cells, plitidepsin greatly reduced viral replication. In further experiments involving both plitidepsin and remdesivir in vitro, the researchers suggest that plitidepsin has an additive effect with the approved drug and would be a potential candidate for a combined therapy. Authors of the research article believe that this promising treatment, which has limited clinical approval for the treatment of multiple myeloma, should be strongly considered for expanded clinical trials for the treatment of COVID-19. DOI:10.1126/science.abf4058

Oregon Health & Science University (OHSU) researchers have demonstrated that antibodies generated by the SARS-CoV-2 virus react to other strains of coronavirus and vice-versa. They determined, however, that antibodies generated by the 2003 SARS outbreak had only limited effectiveness in neutralizing SARS-CoV-2. The researchers believe that these findings have implications on both vaccine effectiveness and diagnosis of COVID-19. They believe that more work needs to be done to determine the lasting effectiveness of COVID-19 vaccine, given the speed of mutations. The team believes their study also suggests that efforts to accurately discern a previous COVID-19 infection, by analyzing antibodies in the blood, may be complicated by the presence of antibodies reacting to other strains of coronavirus including the common cold. This study is published in Cell Reports. DOI:10.1016/j.celrep.2021.108737

A new method to mapping viral mutations that escape leading clinical antibodies against COVID-19 has revealed mutations in the SARS-CoV-2 virus that allow it to evade treatments, including a single amino-acid mutation that fully escapes Regeneron’s antibody cocktail. University of Washington researchers and colleagues developed this scanning method to map how mutations to the receptor-binding domain (RBD) affect its recognition by antibodies. Their maps identified mutations that escape antibody binding, including a single mutation that escapes both antibodies in the Regeneron antibody cocktail. To further investigate, the team examined deep sequencing data from a persistently infected patient who was treated with the antibody cocktail at day 145 after diagnosis with COVID-19, and their analysis identified resistance mutations that arose in the patient. Furthermore, after they examined all human-derived SARS-CoV-2 sequences available as of mid-January 2021, the researchers report a substantial number of RBD mutations that escaped one or more of the antibodies that are in circulation. This paper is published in Science. DOI:10.1126/science.abf9302

Monash University researchers have discovered two new molecules that provide profound protection in experimental models of asthma, as well as protection from acute respiratory distress syndrome (ARDS) that is seen in some patients with severe COVID-19. In their study, originally designed to investigate how the immune system impacts gut bacteria, the researchers found that p-cresol sulfate (PCS), a gut bacteria by-product, led to a striking protection against asthma. They then determined that PCS was produced by enhanced bacterial metabolism of L-tyrosine, a well-known amino acid found in dietary supplements. The researchers saw significant protection against lung inflammation in mice given either L-tyrosine or PCS, as well as protection from ARDS. The researchers now aim to test one of the molecules in a clinical trial in asthmatics this year. These new findings are published in Nature Immunology. DOI:10.1038/s41590-020-00856-3

Non-steroidal anti-inflammatory drugs (NSAIDs) reduced both antibody and inflammatory responses to SARS-CoV-2 infection in mice, a new study finds that is published in the Journal of Virology. The authors of the study highlight that the timing of NSAID use during COVID-19 is important. They explain that NSAID’s anti-inflammatory activity could be detrimental early in SARS-CoV-2 infection because inflammation is usually helpful during this stage. This changes at later stages of COVID-19, particularly if the patient experiences intense inflammation known as cytokine storm. The researchers also note that a reduction in neutralizing antibodies caused by NSAIDs could be benign, or it might hinder the immune system’s ability to fight the infection in its early stages. It could also reduce the magnitude or duration of protection from either natural infection or vaccination. DOI:10.1128/JVI.00014-21

Rhesus macaque monkeys infected with SARS-CoV-2 developed protective immune responses that could be reproduced with a vaccine, according to University of California, Davis (UC Davis) researchers. The team infected eight rhesus macaques at the California National Primate Research Center (CNPRC) with SARS-CoV-2 virus isolated from the first human patient treated at UC Davis, and they followed the immune responses in the monkeys over two weeks. The animals showed signs of lasting immunity and, most importantly, structures called germinal centers developed in the lymph nodes near the lungs. These germinal centers contained cells call T follicular helper (Tfh) cells. Germinal centers and Tfh cells are associated with generating plasma cells that remain in the body for many years to produce antibodies against pathogens the immune system has seen before, the researchers explain. They believe these results suggest that vaccines that induce this response will support immunity against COVID-19. This study is published in Nature Communications. DOI:10.1038/s41467-020-20642-x

Patients who have recovered from severe COVID-19 infection could be left with more protective T cells needed to fight reinfection, finds a team of researchers led at La Jolla Institute for Immunology (LJI). For their study, published in Science Immunology, the team analyzed CD8+ T cells from 39 COVID-19 patients and 10 individuals who had never been exposed to the virus. Of the COVID-19 patients, 17 had a mild case that did not require hospitalization, 13 had been hospitalized, and nine needed intensive care support.  Surprisingly, the researchers saw weaker CD8+ T cell responses in patients with milder COVID-19 cases and saw the strongest CD8+ T cell responses in the patients who required hospitalization or intensive care. The team now hopes to study how T cells in tissues hit hardest by SARS-CoV-2, such as the lungs, react to the virus. They explain the importance of this as the memory T cells that provide long-term immunity need to live in the tissues. DOI:10.11260/sciimmunol.abe4782

In a new study published in Science Signaling, scientists discovered that SARS-CoV-2 may enter and replicate in human cells by exploiting newly identified sequences within cell receptors. They also suggest that these sequences could potentially serve as targets for new therapies against COVID-19. After analyzing the Eukaryotic Linear Motif database, the team of scientists discovered that ACE2 and various receptors contained several short linear motifs (SLiMs), or small amino acid sequences, that they predict plays a role in endocytosis and autophagy, or the entering of human cells and cellular housekeeping. The team determined that two SLiMs in ACE2 bound to endocytosis-related proteins, and one SLiM in the integrin beta-3 (β3) bound to two proteins involved in autophagy. They believe that their prediction models could help identify similar SLiMs that assist with the replication of not only SARS-CoV-2, but other viruses that cause disease. DOI:10.1126/scisignal.abd0334

Ohio University researchers have published the first structural biology analysis of a section of the COVID-19 viral RNA called the stem-loop II motif, which they believe could be a potential target for anti-viral drugs to combat the virus. The research team identified this non-coding section of the RNA that is likely key to SARS-CoV-2 replication. Interestingly, they determined that the structural flexibility of this noncoding RNA motif differs by only a single nucleotide when compared to that in the early 2000s SARS-CoV outbreak, and the team also identified FDA-approved drugs that bind to the RNA motif and alter its flexibility. Since the structure and flexibility of noncoding RNA affects its function, the researchers suggest that it may be possible to develop antiviral drugs that specifically target this RNA motif to battle the virus. This research is published in Biochemical and Biophysical Research Communications. DOI:10.1016/j.bbrc.2021.01.013

Innate immunity may play a larger role in controlling SARS-CoV-2 viral load than adaptive immunity, according to a new study published in ACS Pharmacology & Translational Science. Researchers of the study developed a mathematical model that predicts viral load over time in organs that express the ACE2 receptor, which allows SARS-CoV-2 entry into human cells. They then used this model to simulate different conditions to determine this key role for innate immunity in controlling viral load. The researchers suggest the importance of starting antiviral or interferon therapy as soon as possible after the onset of COVID-19 symptoms. DOI:10.1021/acsptsci.0c00183


Industry News

Allarity Therapeutics in Denmark plans to further test the antiviral activity of stenoparib, its Poly ADP-Ribose Polymerase (PARP) inhibitor, against the B.1.1.7 variant of SARS-CoV-2. Stenoparib is a small molecule, targeting inhibitor of PARP, a key DNA damage repair enzyme active in tumors, which was originally developed by the pharmaceutical company Eisai. Results of previous pre-clinical studies for SARS-CoV-2 demonstrated that stenoparib inhibits SARS-CoV-2 as a single agent, and stenoparib in combination with remdesivir was active in inhibiting coronavirus in vitro. Allarity will now work with scientists at Northern Arizona University’s Pathogen and Microbiome Institute (PMI) to test the similar ability of stenoparib to block the infection and replication of Coronavirus Variant B117. Press Release

Clear Labs announced the availability of the Clear Dx Whole Genome Sequencing (WGS), the first automated WGS solution that determines the complete RNA sequence of the SARS-CoV-2 genome in less than 24-hours with only minutes of hands-on time. The Clear Dx™ platform is powered by next generation sequencing (NGS), robotics and cloud-based analytics, and as a result, their WGS can more easily determine the nature of virus transmission by differentiating virus strains and monitoring mutations that lead to variants. In addition to WGS, the platform also features the Clear Dx SARS-CoV-2 Diagnostic Assay, which has received EUA, that allows labs to perform diagnostic screening and genomic surveillance simultaneously. Press Release