COVID-19’s Achilles’ Heel, Other News From the Bio-IT Community

June 12, 2020 | The Bio-IT community is continuing to adapt to their newfound role in the fight against the COVID-19 virus. Recent updates include recent collaborations between organizations and universities, as well as innovative modeling tools. Here, we round up the week’s research and industry news for COVID-19.

Literature Updates

A study coming out of Queen Mary University (London) and Cardiff University (Wales) has demonstrated the effectiveness of the GloBody platform to detect anti-drug antibodies in the blood of patients with multiple sclerosis. Researchers say the platform, which uses a light-producing enzyme called nanoluciferase, has also been applied to COVID-19 for potential use in antibody testing to determine whether someone has previously been infected with the virus. Their study, published in Neurology: Neuroimmunology & Neuroinflammation, focused on the detection of antibodies predicting which MS patients were subsequently likely to fail treatment with Alemtuzumab. But the GloBody platform could be applied to any therapeutic antibody in any clinical condition as well as pre-clinical animal models to save time and effort before moving to clinical trials in humans. In a matter of days, researchers were able to produce enough of the COVID-19 GloBody reagent to potentially test 1.6 million people for COVID-19. If the virus mutates, a new test could be made just as quickly. DOI: 10.1212/NXI.0000000000000767

The COVID-19 virus has an Achilles' heel—its main protease, which is structurally very similar to the SARS coronavirus—making it an excellent target for inhibitors or new drugs, according to a mathematician and expert in complex systems at the ARAID Foundation at the University of Zaragoza (Spain). He and his colleagues transformed those structures into protein residue networks, whereby every amino acid was represented as a node and the interaction between two amino acids was represented by a link between the two. Researchers then applied a sophisticated mathematical measure allowing them to detect how far away a perturbation within a network can be propagated. It revealed that the protease of SARS-CoV-2 is 1,900% more sensitive to the long-range transmission of perturbations than the protease of SARS-CoV-1. Perturbation of a single amino acid within the protease of SARS-CoV-2 gets transmitted to almost the whole network, including very distant amino acids. The group's approach, described in Chaos, could be used for massive screening protocols to identify potent inhibitors of the main protease of the COVID-19 virus and, consequently, development of new drugs to kill it. DOI: 10.1063/5.0013029

The most innovative modeling tools—including 3D supports for cell cultures, microfluidic chambers for the culture of organoids and intravital microscopy in animals—were identified as the most suitable for accelerating the discovery and preclinical development of antiviral drugs and vaccines for COVID-19 in an article that published in Theranostics. Researchers in Spain specifically called out devices developed over the last decade at the Polytechnic University of Milan: artificial niches for stem cell culture, microfluidic bioreactors for tissue culture, and miniaturized imaging windows for intravital microscopy. Some of these devices are already being used for research on neurodegenerative diseases. The same team has also developed a lymph node model engineered inside a miniaturized bioreactor called MOAB, allowing for the study of immunization mechanisms such as those produced by vaccines. The authors say these tools are much more realistic than conventional ones and could even replace much of the preclinical research currently conducted on animals. DOI: 10.7150/thno.47406

It was recently announced that scientists from Stanford University are collaborating with researchers at the Molecular Foundry (a nanoscience user facility located at the Department of Energy's Berkeley Lab) to develop a gene-targeting, antiviral agent against COVID-19. They’ll be applying the Stanford-developed “PAC-MAN" technique originally developed to fight influenza that uses the gene-editing tool CRISPR as well as a lipitoid delivery system developed at the Molecular Foundry. The two groups have been working on a system that delivers PAC-MAN into the cells of a patient since late March. PAC-MAN is composed of the virus-killing enzyme Cas13 and a strand of guide RNA that commands it to destroy specific nucleotide sequences in the coronavirus's genome. By scrambling the virus's genetic code, PAC-MAN could neutralize the coronavirus and stop it from replicating inside cells. In late April, researchers overcame one of the key challenges after testing a type of lipitoid that self-assembles with DNA and RNA into PAC-MAN carriers in a sample of human epithelial lung cells. When packaged with coronavirus-targeting PAC-MAN, the system reduced the amount of synthetic SARS-CoV-2 in solution by more than 90%. The PAC-MAN strategy is described in an article in Cell. DOI: 10.1016/j.cell.2020.04.020

Cancer researchers at Children's Hospital of Philadelphia have adapted computational tools for the development of cancer immunotherapies to identify the right regions of the SARS-CoV-2 virus to target with a vaccine, a strategy they describe in Cell Reports Medicine. They believe a resulting vaccine would provide protection across the human population and drive a long-term immune response. The team looked for regions that would stimulate a memory T-cell response which, when paired with the right B cells, would drive memory B cell formation and provide lasting immunity and do so across most human genomes. They made sure the targeted regions were present across multiple related coronaviruses, as well as new mutations that increase infectivity, and were as dissimilar as possible from sequences naturally occurring in humans to maximize safety. The result was a proposed list of 65 peptide sequences, a dozen or so of which are now being tested in various combinations in mouse models to assess their safety and effectiveness. DOI: 10.1016/j.xcrm.2020.100036

A group of researchers with the FDA’s Center for Biologics Evaluation and Research has determined how different proteins associated with SARS-CoV-2 generate immune responses when given to rabbits as immunizations. The results, published in Science Translational Medicine, offer a better understanding of the quantitative and qualitative aspects of immune response generated by different vaccine antigens, which could benefit the development and evaluation of therapeutics and vaccine for COVID-19. Rabbits were immunized with one of four SARS-CoV-2 spike protein antigens like those being used in clinical trials, and the authors observed that antibodies from animals immunized with the receptor-binding domain (RBD), the S1 domain, or the S1+S2 ectodomain neutralized as many as 98% of SARS-CoV-2 virions after two vaccinations. Importantly, the RBD immunization was the most effective option, as it generated more high-affinity antibodies. The researchers did not directly test their vaccine's protective capabilities in the rabbits but say that the ability to elicit high-affinity antibodies may enhance the protective properties of vaccines for COVID-19. DOI: 10.1126/scitranslmed.abc3539

Virologists in the Institute for Biomedical Sciences at Georgia State University have identified detailed methods on how to perform research on SARS-CoV-2, including procedures that effectively inactivate the virus to enable safe study of infected cells. The peer-reviewed paper, published in Viruses, is a resource for newcomers in the field. Because the new pathogen causes serious disease for which there are no definitive treatments, biosafety level 3 (BSL3) facilities are required. At Georgia State, biosafety experts that oversee the high-containment core created a plan that identified the optimal BSL3 facility on the university's Atlanta Campus for the work, developed rigorous training for researchers already experienced with high-containment work, and implemented procedures to enable safe and efficient work on SARS-CoV-2. DOI: 10.3390/v12060622

University of Michigan researchers have found that a long-ignored white blood cell may be central to the immune system overreaction that is the most common cause of death for COVID-19 patients—and that the rod-shaped particles can be taken out of circulation. Neutrophils lead the charge in acute respiratory distress syndrome, a complication seen in severe cases of COVID-19, and it’s their lack of lack of specialization that sometimes makes them not know when to quit. The researchers previously showed that plastic microparticles injected into the blood of mice could distract neutrophils, diverting them away from areas of severe inflammation in their lungs. Thye also discovered that neutrophils, unlike other phagocytes, prefer eating rod-shaped particles. This opens the possibility of a sphere-based therapy where other white blood cells are left to do their job. The team is currently exploring whether neutrophil-distracting particles can be made from medications rather than plastic, and the new delivery system is moving toward clinical trials. U-M has also applied for patent protection and launched a start-up company, Asalyxa. The study published in Science Advances. DOI: 10.1126/sciadv.aba1474

Researchers at Washington University School of Medicine (St. Louis) report in Cell journal pre-proof that they have developed a mouse model of COVID-19 that replicates the illness in people—and say the same approach could be adopted easily by other scientists to dramatically accelerate the testing of experimental COVID-19 treatments and preventives. Additionally, the model could be used with mice bred to develop health conditions such as obesity, diabetes or chronic lung disease to investigate why some people develop life-threatening cases of COVID-19 while others recover on their own. The emergence of COVID-19 earlier this year triggered a frantic rush to begin breeding genetically modified mice with the human ACE2 protein, but there are still not nearly enough mice for all the researchers who want to study the disease and test potential vaccines and therapeutics. DOI: 10.1016/j.cell.2020.06.011

Comparing the frequencies of human leukocyte antigen (HLA) variants in different human populations, an international team of researchers has determined that we're not all equal in the face of COVID-19. Their study provides an essential reference inventory for identifying the genetic resistance or susceptibility of individuals to the virus. One surprising finding was that indigenous populations in America had both the highest frequencies of HLA variants that bind the most strongly to peptides of SARS-CoV-2 and the lowest frequencies of those that bind the least strongly. But, as the authors point out, HLA molecules are only one element of immune response that is predictive of effective or ineffective resistance to a virus—verified by the fact that America's Indigenous populations are apparently no less affected than others by COVID-19. The same study showed that many HLA variants (“generalists”) are capable of binding strongly to the peptides of six other viruses with pandemic potential (two other coronaviruses, three influenza viruses and the HIV-1 virus of AIDS). Others do the same for all respiratory-type viruses (coronavirus and influenza). Findings were peer-reviewed and published in HLA. DOI: 10.1111/tan.13956

Using an immunoinformatic-based computational approach, researchers from Bar-Ilan University (Israel) identified a set of potential immunodominant epitopes from the SARS-CoV-2 proteome. The epitopes can generate both antibody- and cell-mediated immune responses. The team pinpointed 15 immunogenic regions from three proteins of SARS-CoV-2 and mapped 25 immunodominant epitopes on other SARS-CoV-2 proteins. Seven epitopes, verified as being non-allergenic and non-toxic, were deemed to be present in more than 87% of the worldwide virus-affected population—making them potentially effective vaccine candidates. Complete lists of major histocompatibility complex (MHC) proteins that recognize each epitope have been generated and are presented in both the submitted manuscript and a provisional U.S. patent application. The study published in Vaccines. DOI: 10.3390/vaccines8020290

Updates from Industry

Adaptive Biotechnologies has launched ImmuneCODE with Microsoft to begin sharing one of the largest, most detailed views of the immune response to COVID-19 in real time based on de-identified data generated from thousands of COVID-19 blood samples from patients around the globe. The open database contains detailed information on the extraordinarily diverse set of T cells shown to specifically recognize unique features of the COVID-19 virus, called antigens, with unprecedented speed and scale. T cells contain a treasure trove of information that could provide one consistent and trackable measure of the immune response. This could help diagnose and manage COVID-19 from exposure through clearance of the virus, and potentially offer an accurate assessment of immunity. Data from ImmuneCODE will accelerate ongoing global efforts to develop better diagnostics, vaccines and therapeutics and answer important questions about the virus to support initiatives to safely reopen society. Press release.

Janssen Pharmaceutical Companies has accelerated the initiation of the Phase 1/2a first-in-human clinical trial of its investigational SARS-CoV-2 vaccine, Ad26.COV2-S, recombinant. Initially scheduled to begin in September, the trial is now expected to commence in the second half of July. The randomized, double-blind, placebo-controlled Phase 1/2a study will evaluate the safety, reactogenicity (response to vaccination), and immunogenicity (immune response) of the investigational SARS-CoV-2 vaccine, Ad26.COV2-S, recombinant in 1045 healthy adults aged 18 to 55 years, as well as adults aged 65 years and older. The study will take place in the U.S. and Belgium. Press release.

Illumina has been issued an Emergency Use Authorization by FDA for the COVIDSeq Test, a high-throughput, sequencing-based, in vitro diagnostic workflow enabling the detection of SARS-CoV-2. COVIDSeq uses upper respiratory specimens, including a nasopharyngeal or oropharyngeal swab, and delivers sample receipt to result in 24 hours using the NovaSeq 6000 Sequencing System. The differentiated diagnostic design includes 98 amplicons that target the full SARS-CoV-2 genome, creating accurate detection and high sensitivity. The workflow accommodates up to 3,072 samples per NovaSeq run leveraging the S4 flow cell, and includes steps for viral RNA extraction, RNA-to-CDNA conversion, PCR, library preparation, sequencing and report generation. The key components leveraged include the NovaSeq 6000, coupled with Illumina Tagmentation library preparation technology, and the DRAGEN COVIDSeq Test Pipeline for rapid reporting. COVIDSeq is currently available to a limited number of early access sites and is expected to be more broadly available this summer. Press release.

The Milken Institute published an interactive COVID-19 Community Explorer, allowing users to determine what community-wide risk factors can make certain areas more vulnerable to the virus. At this time, COVID-19 fatalities are disproportionately higher among Black and Latino populations, older adults, and individuals with hypertension and diabetes. In developing this multimedia platform, the Milken Institute Research Department set out to understand what commonalities exist in communities more likely to see a potential resurgence with the virus. The new tool features: an interactive map allowing users to toggle between community characteristics in relation to COVID-19 cases and deaths in more than 2,800 counties; an interactive map highlighting the 100 most affected communities across the country; and a table summarizing the key health and social characteristics of the most and least affected counties nationwide. More information.

Researchers from the Spanish National Research Council (CSIC) are leading a project that aims to use the CRISPR genetic editing tool to destroy the RNA genome of SARS-CoV-2. The functionality and non-toxicity of CRISPR reagents will initially be tested in zebrafish embryos, followed by testing against RNA viruses and finally cells infected with the current coronavirus. If successful, the next step would be to test the therapeutic strategy on mice. Collaborators are National Center for Biotechnology-CSIC, the Andalusian Center for Development Biology and the CIBER-ISCIII. The project’s goal is to “program” a Cas13d protein so that it cuts the coronavirus genome, promoting its destruction by the cell. Press release.

A National Science Foundation COVID-19 Rapid Response Research grant has been awarded to a pair of Texas Tech University evolutionary biologists to investigate how bats adapted to the SARS-CoV-2 virus and if they might offer a solution to the pandemic. Bats are known to tolerate viruses well, but it is uncertain how. One possibility is that they dampen their immune response. By finding out how the immune system responds differently in bats than humans, researchers hope they can inform clinicians on how to replicate that in people. Their approach will be to examine bat genome assemblies from 10 species to identify patterns of gene duplication, gain and loss and relate those patterns to differences in how bats respond to viral infection. Texas Tech is well positioned for such research as the home of the Natural Science Research Laboratory, a repository of hundreds of thousands of preserved animal tissue specimens that researchers can use for projects just like this one. Press release.

Twist Bioscience and Serimmune are collaborating to identify and evaluate SARS-CoV-2 therapeutic antibody candidates from Twist libraries. The collaboration will evaluate existing Twist antibody candidates that bind with high affinity to either SARS-CoV-2 S1 spike protein or the human ACE2 cellular receptor, using Serimmune’s Serum Epitope Repertoire Analysis (SERA) platform, which maps the antigenic targets of antibody repertoires. Epitopes identified in the first phase will then be used to re-screen Twist’s proprietary synthetic antibody discovery libraries to identify and evaluate new candidates while at the same time further increasing the specificity of antibody candidates. Twist will be responsible for advancing all antibodies resulting from the collaboration. Press release.