Nanotechnology-Based Vaccine Candidate, Blood Type A Raises Risk, Neanderthal-Derived Protein Offers Protection: COVID-19 Updates
March 5, 2021 I Variant that emerged in the UK could be more transmissible, SARS-CoV-2 may be particularly attracted to blood group A respiratory cells, a balanced T cell response is key to clearing virus without symptoms, and out-of-place large bone marrow cells responsible for brain fog. Plus: Heart muscle cells a target and could lead to cell death, interfere with heart muscle contraction and MIS-C patients have highly activated immune systems that are similar to adult COVID-19 patients.
Research News
The SARS-CoV-2 variant that emerged in southeast England in November 2020, VOC 202012/01, may be more transmissible than other current variants, a new modeling study published in Science has found. Researchers analyzed 150,000 sequenced samples from across the United Kingdom and found that the relative population growth rate of the VOC 202012/01 variant in the first 31 days following its initial observation was higher than that of all 307 other virus variant lineages. Authors of the study then structured a mathematical model of SARS-CoV-2 transmission to test several assumptions, including that the variant has a higher viral load or longer shedding period. Based on this analysis, they identified increased transmissibility as the model that best explains the variant’s rapid speed and estimate that the variant has a 43-90% higher reproduction number than preexisting variants of SARS-CoV-2 in England. The researchers suggest a substantially increased vaccine roll-out and school closures for 2021 to prevent COVID-19 deaths and hospitalizations from exceeding those in 2020. DOI:10.1126/science.abg3055
University of Bonn pharmacists have discovered two families of active substances that can block the replication of SARS-CoV-2, and they have published these findings in Angewandte Chemie. Authors of the study report that the drug candidates are able to switch off the key enzyme of the virus, the main protease. They developed a new test system for high-throughput screening and offered the main protease a substrate to which a reporter molecule was coupled. When the protease catalytically cleaved this coupling, the fluorescence of the product was measurable. However, if a simultaneously administered inhibitor successfully blocked the activity of the protease, there was no fluorescence. The team says that for most of the test compounds, no enzyme inhibition was observed, except for two exceptions. They identified two classes of drugs that appeared to be particularly promising but note that extensive clinical trials are still required. DOI:10.1002/anie.202016961
SARS-CoV-2 may be particularly attracted to the blood group A antigen found on respiratory cells, according to a new study published in Blood Advances. Researched assessed the behavior of the SARS-CoV-2 receptor-binding domain (RBD) while testing synthetic blood group antigens on respiratory and red blood cells found in blood group A, B, and O individuals. They discovered that the RBD had a strong preference for binding to blood group A found on respiratory cells, but it did not display a preference for blood group A red blood cells, or for other blood groups found on respiratory or red blood cells. Interestingly, the research group also found that the SARS-CoV (SARS) RBD exhibited the same preference to bind to the group A antigens on respiratory cells. Authors of the study conclude that the capacity for the RBD to preferentially recognize and attach to the blood type A antigen found in the lungs of blood type A individuals may provide insight into the potential link between blood group A and COVID-19 infection. DOI:10.1182/bloodadvances.2020003259
Researchers from Cleveland Clinic’s Global Center for Pathogen Research & Human Health have developed a new COVID-19 vaccine candidate that utilizes nanotechnology and has shown promise in preclinical studies. These results, published in mBio, show that the vaccine candidate produced potent neutralizing antibodies in preclinical models, and it also prevented infection and disease symptoms with SARS-CoV-2 exposure. Researchers report that the vaccine may be thermostable and other benefits of the protein nanoparticles include minimizing cellular damage and providing stronger immunity at lower doses than traditional protein subunit vaccines against other viruses, like influenza. The vaccine uses ferritin nanoparticles to deliver tiny, weakened fragments from the region of the SAR-CoV-2 spike protein that selectively binds to the RBD. The researchers tested this vaccine candidate on a ferret model of COVID-19 and aim to confirm their findings in human clinical trials soon. DOI:10.1128/mBio.00230-21
SARS-CoV-2 can invade and replicate inside heart muscle cells, which may lead to cell death and interfere with heart muscle contraction, according to a new study published in the JACC: Basic to Translational Science. Washington University School of Medicine researchers used stem cells to engineer heart tissue that models the human infection to determine these findings. The research team also discovered that this cell death and loss of heart muscle fibers can occur in the absence of inflammation. They validated these findings by studying tissue from four COVID-19 patients who had heart injury associated with the infection. The team is now planning further research through development of a mouse model of the heart injury. Authors of the study emphasize the urgency of this work, as even young COVID-19 patients with mild symptoms could go on to develop heart injury that may limit their exercise capacity. DOI:10.1016/j.jacbts.2021.01.002
Children’s Hospital of Philadelphia (CHOP) researchers have found that children with Multisystem Inflammatory Syndrome in Children (MIS-C) have highly activated immune systems that are similar to those of adults with severe COVID-19. The study, published in Science Immunology, analyzed blood samples that were collected from patients admitted to CHOP with COVID-19 or MIS-C between April and June 2020. Over 200 immune parameters were measured, including serologic and plasma cytokine data, and were compared with samples from adult COVID-19 patients, recovered adult COVID-19 individuals, and healthy adults. The researchers found that children with MIS-C had highly elevated T cells, particularly CD8 T cells and a highly activated vascular patrolling CD8 T cell subset. These MIS-C patients also required vasoactive support, had elevated D-dimer, and had decreased platelets. The researchers also found that patients with MIS-C were almost universally seropositive for SARS-CoV-2. The team concludes that these insights gained by studying MIS-C patients may reveal new therapeutic opportunities for pediatric and adult COVID-19 patients. DOI:10.1126/sciimmunol.abf7570
A balanced T cell response could be the key to clearing the SARS-CoV-2 virus without developing symptoms, finds a new study published in the Journal of Experimental Medicine. Researchers studied a group of migrant workers who were exposed to the virus in their shared living space in April 2020. Over the course of six weeks, the team of researchers took regular blood samples from 85 workers who were infected but remained asymptomatic and compared their T cells to those of 75 patients who were hospitalized with mild to moderate COVID-19 infection. They found that the overall magnitude of T cell responses against the virus was similar in both groups, however, the T cells of asymptomatic individuals produced greater amounts of two proteins called IFN-y and IL-2. These signaling cytokines help coordinate the immune system’s response. The team then challenged some of the blood samples with fragments of viral proteins and found that the immune cells of asymptomatic individuals produced a balanced, well-proportioned mix of pro- and anti-inflammatory molecules. The symptomatic COVID-19 patients produced a disproportionate amount of proinflammatory molecules. DOI:10.1084/jem.20202617
Assessing a drug compound by its activity, not simply its structure, could be a new approach to accelerate drug discovery for COVID-19. This new action-based focus, called biological activity-based modeling (BABM), forms the core of this new approach developed by the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH). To test the BABM approach, the researchers utilized the large pool of data generated by hundreds of quantitative high-throughput screening (qHTS) analyses run on NCATS’ collection of over 500,000 compounds and drugs. They were able to verify BABM’s ability to identify compounds already shown effective against Zika and Ebola viruses. They then applied BABM, a structure-based model and a combined approach to analyze the NCATS library’s compounds to identify 311 compounds that indicated promise against SARS-CoV-2. After laboratory testing, nearly one-third of the BABM-backed compounds (99) showed antivirus activity. This research is published in Nature Biotechnology. DOI:10.1038/s41587-021-00839-1
Scientists from the Earlham Institute (EI) and the Quadram Institute have mapped out how the immune system responds to SARS-CoV-2 infection to identify unique features in severely ill COVID-19 patients. The researchers collected and analyzed thousands of COVID-19 research papers to identify similarities and differences in cytokine storm and looked for patterns in cytokine changes in patients who had been infected by respiratory viruses that cause cytokine release syndrome. After a systematic analysis of over 5,000 studies, the researchers showed that SARS-CoV-2 has a unique tendency of blocking the rise of specific cytokines in certain patients when compared to other similar viruses. The researchers explain that SARS-CoV-2 is similar to other respiratory viruses but, by targeting specific regulators of the cytokine response, with just small-scale differences, it could lead to more severe disease. This is caused not from the virus itself, but from the patient’s immune system response. These findings are published in Frontiers in Immunology. DOI:10.3389/fimmu.2021.629193
OAS1, a Neanderthal-derived protein, may reduce the risk of mortality and severe disease with COVID-19 infection, according to a new study published in Nature Medicine. Researchers from the Lady Davis Institute (LDI) explored 931 proteins detectable in peripheral blood through the use of proteomic technology combined with genetic analyses using Mendelian randomization (MR). They determined that an increased in OAS1 levels was associated with reduced COVID-19 death or ventilation, hospitalization, and susceptibility in up to 14,134 COVID-19 cases and 1.2 million controls. These results were consistent in multiple sensitivity analyses. The researchers then measured OAS1 levels in 504 patients with varying COVID-19 outcomes and found that increased OAS1 levels in post-infection patients were associated with protection against severe COVID-19, hospitalization, and susceptibility. Authors of the study report that this protective effect was quite substantial, as they observed a 50% decrease in the odds of very severe COVID-19 per standard deviation increase in OAS1 circulating levels. They explain that this form of OAS1 likely emerged in people of European ancestry through inbreeding with Neanderthals thousands of years ago and is now detectable in more than 30 percent of people of European descent. DOI:10.1038/s41591-021-01281-1
University of Bern scientists, along with an international team, have demonstrated in laboratory and animal models the reason why the D614G variant of SARS-CoV-2 has rapidly spread to become the most abundant variant worldwide. The researchers first demonstrated in human cell cultures from the upper respiratory tract and nose that the D614G variant binds more strongly and replicated faster than the original strain of the virus. The increased replication of the variant was then confirmed in a mouse model described in this study, published in Nature. To examine further, the researchers mixed equal parts of the original version of the SARS-CoV-2 virus and the D614G variant and infected hamsters and ferrets and then housed them with a non-infected sentinel animal of the same species. In virtually all sentinel animals, the proportion of transmitted SARS-CoV-2 virus was dominated by the D614G variant early on. The team believes that this approach could also be applied to test any single mutation or a specific combination of mutations that are now present. DOI:10.1038/s41586-021-03361-1
The Southern California COVID-19 strain, CAL.20C, now accounts for nearly half of current COVID-19 cases in that region of the state and has been detected in 26 other U.S. states and six foreign countries. This is according to Cedar-Sinai Medical Center researchers, who have published their findings in JAMA. The researchers report that Southern California travelers are likely carrying CAL.20C to other states and parts of the world, as Los Angeles International Airport (LAX) is one of the busiest travel hubs in the United States and a key gateway for a number of foreign destinations. Cedars-Sinai investigators add that it is still unclear whether CAL.20C might be more deadly than other current variants of the coronavirus or whether it might resist current vaccines. They are tracking the rise and spread of this strain using next-generation sequencing and are interested in this particular strain because three of its five variants involve the spike protein of the SARS-CoV-2 virus. DOI:10.1001/jama.2021.1612
University of California San Diego researchers have shown how the lungs and brain respond differently to SARS-CoV-2 infection using stem cell-derived organoids and have published this work in Stem Cell Reports. The research team infected the organoids, which both produced the ACE2 and TMPRSS2 molecules, with a SARS-CoV-2 pseudovirus. They observed approximately 10-fold more ACE2 and TMPRSS2 receptors and correspondingly much higher viral infection in lung organoids when compared to the brain organoids. The organoids also differed in their responses. Infected brain organoids showed an increase in TLR3 molecules, which activate innate immunity but also can aid in programmed cell death. The researchers believe that this finding may explain some of the neurological effects reported by COVID-19 patients. DOI:10.1016/j.stemcr.2021.02.005
John Hopkins Medicine pathologists with collaborators have found evidence that large bone marrow cells, or megakaryocytes, could be responsible for brain fog in COVID-19 patients. The researchers analyzed brain tissue from autopsies of 15 COVID-19 patients who had died and in five of the samples, they discovered large cell nuclei resembling those of megakaryocyte immigrants from bone marrow. Further immunohistochemical testing confirmed these observations. They believe that these out-of-place cells may reduce or completely block the flow of nourishing blood through individual capillaries in the cerebral cortex, where most information processing occurs in the brain. According to the researchers, such capillary occlusions could lead to neurological impairment. The research team has published these findings in JAMA Neurology. DOI:10.1001/jamaneurol.2021.0225
Industry News
CPI has received a £5 million investment to support the development of an mRNA vaccine ‘library’ as part of the UK Government’s vaccine support package. The vaccine library will form the basis of a rapid response facility, which will enable mRNA vaccines to be developed to help protect against new variants of COVID-19 as they emerge. When new variants of COVID-19 are identified, their DNA can be used to develop mRNA vaccines in a matter of days. The vaccines will be banked in a ‘vaccine library’, ready for future manufacturing and to scale-up when needed. Press Release
New forecasts on the impact of vaccines and variants on the U.S. COVID-19 trajectory over the next few weeks have been published in a report summary released by Lehigh University researchers. A consensus of 91 forecasters predicts that the B.1.1.7 variant will be found in 42% of all genetic sequences with an S-gene mutation in the first two weeks of March and in 72% in all sequences between March 29 and April 4, 2021. The consensus among experts in the modeling of infectious disease and trained forecasters from Metaculus, is that by the end of February, 55,420,000 people will have received at least one dose of a COVID-19 vaccine. Preliminary data from the Centers for Disease Control (CDC) shows that 49,772,180 people have received an initial dose on February 28, 2021. Consensus forecasts from both Metaculus and Good Judgement Open predicted a decrease in the rate of cases, deaths, and hospitalizations for the last week of February. The researchers say the goal of the report is to support public health officials and the general public. Report
New research presented at the 65th Annual Meeting of the Biophysical Society revealed how glycans, the sugars coating SARS-CoV-2, activate the virus. Using advanced High Performance Computing algorithms that run many simulations in parallel, the researchers examined how the position of each atom changes as the SARS-CoV-2 spike becomes activated. The team identified the glycans and molecules that are responsible for activating the spike protein, and they also pinpointed one glycan that appeared to be responsible for initiating the entire opening. Other glycans were involved in subsequent steps. The researchers are now validating these findings with further lab testing, and they hope these developed simulations can be utilized to identify treatments that will block or prevent SARS-CoV-2 activation. Press Release
Using molecular simulations, researchers from the University of Arkansas have discovered one explanation as to why SARS-CoV-2 is much more infectious than SARS-CoV-1. They determined that SARS-CoV-1 moves faster through activation and deactivation, which gives it less time to infect human cells. In contrast, SARS-CoV-2 remains stable due to an important region at the tail end of its spike protein. The researchers explain that this piece, which has not been given much recognition, is critical to the stability of the protein. They believe that mutations in that region could affect the transmissibility and further research is warranted. These findings were presented at the 65th Annual Meeting of the Biophysical Society. Press Release
In more research presented at the 65th Annual Meeting of the Biophysical Society, researchers from the University of Illinois revealed new molecular models that show which parts of SARS-CoV-2 are vital for the virus to insert itself into the membrane of human cells. Using computer simulations, the team merged what is known about the SARS-CoV-2 fusion peptide with the established three-dimensional structures and behaviors of other coronavirus fusion peptides and simulated its interaction with a model human cell membrane. Their simulations revealed how the SARS-CoV-2 fusion peptide interacts with and penetrates the cell membrane. The researchers explain that, since this model is theoretical, the next step is to repeat their computer experiments in the lab with pieces of SARS-CoV-2 and cell membranes. They believe those experiments will likely be completed quickly and efficiently, having already discovered parts of the fusion peptide that are likely critical to its function, and it may be possible to start testing drugs that disrupt the interaction and could block SARS-CoV-2 from entering human cells. Press Release
New England Biolabs (NEB), in collaboration with the ARTIC Network, has developed three new NEBNext ARTIC SAR-CoV-2 kits based on ARTIC Network’s validated protocols on epidemiological changes to the virus and optimized them for accurate and reliable sequencing of the SARS-CoV-2 virus on Illumina and Oxford Nanopore Technologies (ONT) platforms. The kits are specifically designed with balanced primers for uniform genome coverage and accept a wide range of SARS-CoV-2 genome copies with the same RT conditions. The kits, developed with the homebrew scientist in mind, were built upon a well-established ARTIC workflow and provide accurate, reliable sequencing results of the virus, making it ideal for core labs and research institutions. Press Release
