Coronavirus Exposure Could Induce Long-Lasting Memory T Cells, Other COVID-19 News

July 24, 2020 | A new collaborative study suggests that infection and exposure to coronaviruses induces long-lasting memory T cells, which could help in the management of the current pandemic and in vaccine development against COVID-19. Elsewhere, two online, free-access COVID-19 Data Dashboards are helping the global scientific community accelerate the discovery of COVID-19 antivirals and vaccines. This, plus more, is included in this week’s COVID-19 news from the biotech and research industries.

Literature Updates

A study by scientists from Duke-NUS Medical School, in collaboration with the National University of Singapore (NUS) Yong Loo Lin School of Medicine, Singapore General Hospital and National Centre for Infectious Diseases suggests that infection and exposure to coronaviruses induces long-lasting memory T cells, which could help in the management of the current pandemic and in vaccine development against COVID-19. The team tested patients recovered from COVID-19 and found the presence of SARS-CoV-2-specific T cells in all of them. They also showed that patients who recovered from SARS 17 years ago, after the 2003 outbreak, still possess virus-specific memory T cells and displayed cross-immunity to SARS-CoV-2. Additionally, more than 50% of uninfected healthy individuals harbored SARS-CoV-2-specific T cells, possibly due to cross-reactive immunity obtained from exposure to other coronaviruses, such as those causing the common cold, or presently unknown animal coronaviruses. Follow-up studies have been initiated on the COVID-19 recovered patients to determine if their immunity as shown in their T cells persists over an extended period. The study published in Nature. DOI: 10.1038/s41586-020-2550-z

Vaccine additives can enhance immune flexibility, according to a study published in Proceedings of the National Academy of Sciences, which could have implications for SARS-CoV-2 as well as influenza. The research focuses on an adjuvant that enhances responses to a vaccine containing the exotic avian flu virus H5N1, strengthening both rookie and veteran elements of the immune response. For a new pathogen like SARS-CoV-2, it would be important for a vaccine to bring out good responses from naïve B cells, whose frequency is low. The adjuvant used in the study is called AS03, which its manufacturer (GlaxoSmithKline) is making available for COVID-19 vaccine trials. DOI: 10.1073/pnas.1906613117

Cannabidiol (CBD) may help reduce the cytokine storm and excessive lung inflammation that is killing many patients with COVID-19, based on a study published online in Cannabis and Cannabinoid Research. The early evidence suggests it could help patients showing signs of respiratory distress avoid extreme interventions like mechanical ventilation as well as death from acute respiratory distress syndrome (ARDS). Findings were enabled by a safe and relatively inexpensive model to duplicate the lung damage caused by ARDS, which was created with the help of a synthetic analog of double-stranded RNA called POLY (I:C). In mice treated with CBD therapy, oxygen levels went up, while temperatures and cytokine levels went down. Days later, levels of IL-6 and infiltrating neutrophils were reduced. DOI: 10.1089/can.2020.0043

Reducing the numbers of senescent cells with senolytic drugs or reducing “inflammageing” with anti-inflammatory drugs may be a beneficial strategy for improving COVID-19 outcomes in older patients, write a pair of University College London researchers in a perspective piece published in Science. They also raise the question of whether vaccines can even be effective within these inflammatory environments. The effective treatment of COVID-19 in older patients may require a combination of anti-inflammatory, anti-viral regimes to complement vaccination against the virus, they say. DOI: 10.1126/science.abb0762

A detailed study of Nsp1, a SARS-Cov-2 protein with a central role in weakening the host anti-viral immune response, shows that it effectively shuts down production of proteins in the host. Targeting this interaction on the pocket of the ribosome that Msp1 binds to may be an important therapeutic strategy, say the researchers who hail from Germany. Their results demonstrate that SARS-CoV-2 Nsp1 almost completely prevents production of various immune molecules that fight viral infection, including interferons, and may provide a starting point for rational structure-based drug design targeting the interaction between Nsp1 and the ribosome. Results published in Science. DOI: 10.1126/science.abc8665

Aspergillus latus, a species of fungus previously found only in soil or plants, has been found for the first time in a hospital environment by an international group of researchers who sequenced its genome to discover it is a hybrid of two relatively distantly related species and up to three times more drug-resistant than the two species from which it derives. Results of that study published in Current Biology. Samples of fungi present in the lungs of COVID-19 patients is now being assembled with the aim of investigating how these organisms can aggravate their condition as a basis for developing strategies to avoid and combat infections. Several COVID-19 patients have died owing to concomitant infection by Aspergillus. Four strains have been isolated, whose genomes will be sequenced to identify the species and see if they're favored by the disease. DOI: 10.1016/j.cub.2020.04.071

T cell memory is potentially more durable than antibody responses in protecting the body against COVID-19, say researchers from Imperial College (London) in a perspective piece appearing in Science Immunology. They summarize key takeaways and emerging points of consensus from nine selected studies, only some of which have published in peer-reviewed journals. The authors say standardized tests to measure T cell immunity to SARS-CoV-2 could be designed using methods in common with established tests for T cell immunity to Mycobacterium tuberculosis. DOI: 10.1126/sciimmunol.abd6160

A new nanoparticle vaccine for SARS-CoV-2 has shown hints of protection and immunity in a preclinical study, safely eliciting the production of antibodies and antiviral T cell responses in mice and pigtail macaques, report a team of U.S. researchers in Science Translational Medicine. The vaccine, named repRNA-CoV2S, generated robust immune responses with a single injection in mice. It is formulated based on repRNAs, molecules that tend to generate stronger immune responses compared with the mRNAs used in more conventional vaccines, based on sequences from the SARS-CoV-2 spike protein alongside an emulsion of nanoparticles that enhance the vaccine's immunogenicity and stability. Adding a booster injection heightened the vaccine's effects in older rodents and generated strong responses from T cells in the spleen and lungs. Both the single-shot and booster approaches were safe and produced similar responses in macaques that lasted for at least 70 days. The authors note they plan to begin clinical development of the vaccine under the name HDT-301. DOI: 10.1126/scitranslmed.abc9396

A study led by Boston Children's Hospital for the first time freeze-frames the COVID-19 spike protein in its "before" and "after" shapes using cryogenic electron microscopy. It also captured some surprise features of the spike protein that may help SARS-CoV-2 hide from the immune system and survive longer in the environment. Researchers propose that there are two routes for the spike protein to assume the rigid hairpin shape seen after fusion of the virus and cell membranes—one is ACE2-dependent, allowing the virus to enter a host cell, and the second is ACE2-independent, possibly explaining how the virus remains viable on various surfaces for hours to days. The authors say current vaccine formulations that use the spike protein to stimulate the immune system may have varying mixes of the pre- and post-fusion forms that may limit their protective efficacy. DOI: 10.1126/science.abd4251

Researchers at Washington University School of Medicine in St. Louis have developed a hybrid virus in the lab that will enable more scientists to enter the fight against the pandemic. So that the virus mimics the one causing COVID-19, they genetically modified a mild virus by swapping one of its genes for one from SARS-CoV-2. The hybrid virus infects cells and is recognized by antibodies just like SARS-CoV-2 but can be handled under ordinary laboratory safety conditions. The study published online in Cell Host & Microbe. Prior to publication, researchers began getting requests for the material, which has been distributed to researchers in Argentina, Brazil, Mexico, Canada and across the U.S. with requests pending from the U.K. and Germany. DOI: 10.1016/j.chom.2020.06.021

Researchers at The Rockefeller University in New York have developed new tools to rapidly test the ability of antibodies to neutralize SARS-CoV-2. The approach, described in the Journal of Experimental Medicine, will help scientists understand whether patients are susceptible to reinfection by SARS-CoV-2 and assess the effectiveness of experimental vaccines, as well as develop antibody-based therapies against the disease. Efforts are underway to treat and prevent COVID-19 using either purified antibodies or whole blood plasma collected from convalescent patients who produce large amounts of neutralizing antibodies. Successful vaccines against SARS-CoV-2 will also have to induce the production of neutralizing antibodies. The researchers developed surrogate viruses—versions of either the human immunodeficiency virus type-1 or vesicular stomatitis virus that produce the SARS-CoV-2 spike protein instead of their own surface proteins—which can be used in place of SARS-CoV-2 to test the neutralizing activity of antibodies targeting the coronavirus spike protein. The surrogate virus-based assays have already been used to determine the neutralizing potencies of hundreds of plasma samples and monoclonal antibodies in a biosafety level 2 laboratory. DOI: 10.1084/jem.20201181

Researchers at Columbia University Irving Medical Center report in Nature that they have isolated antibodies from several COVID-19 patients that are among the most potent in neutralizing the SARS-CoV-2 virus. Produced in large quantities, the antibodies could be used to treat patients early in the course of infection and to prevent infection, particularly in the elderly. They’ve been shown to provide significant protection from SARS-CoV-2 infection in hamsters, and further studies are planned in other animals and people. The Columbia team found a cocktail of new and unique antibodies, whereas previous efforts focused on the receptor binding domain or N-terminal region of the spike protein. DOI: 0.1038/s41586-020-2571-7

In a study in mice that published in the Journal of the American Society of Nephrology, researchers at Northwestern Medicine have found a widely used class of drugs to treat patients with hypertension, cardiovascular disease and diabetic kidney disease does not increase the risk of developing a severe and potentially fatal COVID-19 infection, as previously feared. The concern in the medical community was that the drugs—ACE inhibitors and angiotensin receptor blockers (ARB)—might have caused an increase in ACE2, the main receptor for SARS-CoV-2, possibly increasing the risk for this infection and its severity. The findings revealed a decrease, not an increase, in ACE2 in mice kidney membranes and no change in lung membranes, supporting the safety of these drugs in the face of the COVID-19 pandemic. DOI: /10.1681/ASN.2020050667

A study by researchers at the University of California – Los Angeles Health Sciences shows that in people with mild cases of COVID-19 the antibodies against SARS-CoV-2 drop sharply over the first three months after infection, decreasing by roughly half every 36 days on average. If sustained at that rate, the antibodies would disappear within about a year. An incorrect rate of 73 days was previously reported due to a math miscalculation in the study, published in the New England Journal of Medicine. The researchers studied 20 women and 14 men and antibody tests were conducted at an average of 36 days and 82 days after the initial symptoms of infection. The findings raise concerns about antibody-based "immunity passports," and may have implications for the durability of antibody-based vaccines.

The Infection Biology Unit of the German Primate Center, Leibniz Institute for Primate Research in Göttingen, together with colleagues at the Charité in Berlin, have shown that the malaria drug chloroquine is not able to prevent infection of human lung cells with the novel coronavirus. Chloroquine was previously demonstrated to inhibit the SARS-CoV-2 infection of African green monkey kidney cells, but it was unclear how. The researchers conclude that the antiviral activity of chloroquine is cell type-specific and unlikely to prevent the spread of the virus in the lung. It should therefore not be used for the treatment of COVID-19. Results published in Nature. DOI: 10.1038/s41586-020-2575-3

Scientists at the University of Bath (U.K.) investigating the evolution of SARS-CoV-2 say its mutation seems to be directed by human proteins that degrade it, but that natural selection of the virus enables it to bounce back. The findings, appearing in Molecular Biology and Evolution, could help in the design of vaccines against the virus. The research team examined over 15,000 virus genomes from all the sequencing efforts around the world and identified over 6,000 mutations. They then looked at how much each of the four letters that make up the virus' genetic code (A, C, U and G) were mutating and discovered that the virus had a very high rate of mutations generating U residues. Several research groups are currently trying to make attenuated viruses and this research suggests that a sensible strategy would be to increase U content, as APOBEC (fingerprint of the mutational profile of a human protein) does within our cells. DOI: 10.1093/molbev/msaa188

The challenges facing vaccine developers—from the standpoint of researchers, doctors and business leaders—are the subject of an article appearing in Chemical & Engineering News. As of mid-July, the World Health Organization reported that over 160 vaccine programs were in progress, many using the virus’s spike protein to teach immune cells what to home in on. Gene-based vaccines are very fast for scientists to design and make, but the technology is largely unproven, and it remains to be seen whether they’re effective. Other challenges include less-than-ideal methods for quantifying antibody response in the laboratory and uncertainty about how much neutralization is good enough and for how long the effect would last. Article

Industry Updates

Duality Technologies and the Defense Advanced Research Projects Agency (DARPA) are partnering to develop a privacy-preserving Machine Learning (ML) capability that can train models on encrypted data from multiple sources. The capabilities developed under the contract will be applied to researching genomic susceptibility to severe COVID-19 symptoms in a manner which preserves individual privacy. The development is based on Homomorphic Encryption (HE), a privacy-enhancing technology that allows multiple parties to analyze encrypted data and gain insights without exposing Personally Identifiable Information (PII). Duality is leveraging its capabilities in partnership with Harvard Medical School and Two Six Labs, a research and development company in the field of data science and cybersecurity, to support Genome-Wide Association Studies (GWAS) related to COVID-19 research. Press release.

PerkinElmer has launched two online, free-access COVID-19 Data Dashboards to help the global scientific community accelerate the discovery of COVID-19 antivirals and vaccines. These dashboards are powered by PerkinElmer’s data analytics and data visualization solutions which help researchers more quickly and easily leverage the vast amounts of drug compound and clinical trial data that exist across reliable, yet disparate, sites and sources. The dashboards are supported by PerkinElmer’s Signals Lead Discovery and the TIBCO Spotfire advanced analytics platform. Using the PerkinElmer COVID-19 Drug Compound Dashboard, scientists can narrow down the 1.6 million drug compounds that are publicly available by querying a curated chemical substance dataset and related activity data provided by CAS, a division of the American Chemical Society that specializes in scientific information solutions. Press release.

The deadline just ended for proposals for active substances that have the potential to stop the activity and reproduction of SARS-CoV-2 to be submitted to The Joint European Disruptive Initiative (JEDI), some of which will be ultimately be selected for rapid testing in clinical trials. Among the more than 100 international teams making submissions to the JEDI Grand Challenge was the Biotechnology Center (BIOTEC) of Dresden University of Technology (Germany) with its bioinformatics group and the spinoff PharmAI. They used proprietary algorithms in BIOTEC’s DiscoveryEngine to screen five million substances for candidates against COVID-19 and identified three promising protein targets. In stages two and three of the competition, the collective knowledge of participating international virologists will be used to analyze the promising substances submitted and identify those that can eliminate the virus. Using high-throughput virus testing, new drug combinations with minimal toxicity and virtually no side effects are to proceed to clinical trials. Press release.

Researchers at Dartmouth's and Dartmouth-Hitchcock's Norris Cotton Cancer Center will investigate one of the mechanisms that may be responsible for the body's inability to fight COVID-19. Researchers will investigate the possibility that some patients make antibodies that do not protect against SARS-CoV-2 virus, but rather enhance the ability of the virus to infect cells—a process called "antibody-dependent enhancement" (ADE). ADE occurred previously with Dengue, Zika, the first SARS-CoV, and other coronaviruses. Such nonprotective antibodies could be one reason why some people do much worse than others with COVID-19, which can vary from zero symptoms in some infected people to death in others. The goal is an assay to investigate the correlation of patient outcome with the presence of “good” or “bad” antibodies, and to determine whether a specific vaccine is making more of one or the other type of antibody. Press release.

The Texas A&M Engineering Experiment Station's National Center for Therapeutics Manufacturing (NCTM) will be working on ways to prevent the SARS-CoV-2 virus from binding to cells, protecting people from future infections. The plan is to produce spike proteins to identify antibodies that can attach to the SARS-CoV-2 spike protein receptor-binding domain and prevent the virus from binding to key sites, thus obstructing the virus from entering and infecting human cells. The strategy is derived from the case of an American doctor who donated his plasma after surviving Ebola, from which doctors and scientists identified antibodies that could recognize that virus and prevent it from multiplying further in patients. Similarly, NCTM researchers are making versions of COVID-19 spike proteins that can be used to measure antibody responses to the SARS-CoV-2 virus spike proteins. Once a COVID-19 vaccine is available, NCTM's spike proteins could also be used to determine if protective responses are being generated in response to the vaccination, how long responses persist and if having antibodies to the spike protein provides a person with immunity such that they can safely return to the workplace without fear of reinfection. Press release.

Researchers at the Sanford Burnham Prebys Medical Discovery Institute report that they will use “mini lungs in a dish” (aka lung organoids) to test promising drug candidates against COVID-19. The research team will test two existing drugs, ONO5344 and VBY825, protease inhibitors that emerged as the most promising candidates to hit the Achilles heel of SARS-CoV-2 from a high-throughput screening study of the reFRAME drug repurposing collection. They will also compare drug responses of mini lungs created from Caucasian, African American, and Latino men and women, as well as patients with a reduced capacity to fight infection to make sure that therapies work effectively in all patients. Press release.

Researchers at the University of Colorado Anschutz Medical Campus are studying why many infected with COVID-19 lose their sense of smell. The virus often starts in the nose before making its way to the lungs, and their suspicion is that this sparks an inflammatory response that releases cytokines which in turn silence olfactory sensory neurons in the nose. Their plan is to use human olfactory epithelium cultures to study how the novel coronavirus might alter the cells and circuits that detect stimuli and create perception. The team will investigate whether manipulating a key chemosensory protein (TRPM5) can either inhibit or stimulate a virally induced inflammatory cascade. Then they will test whether the FDA-approved drug flufenamic acid alters inflammation and viral infection of the olfactory epithelium. Press release.

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