Tag Archives: #COVID-19

A Protein-based COVID-19 Vaccine That Mimics the Shape of the Virus (Medicine)

Even as several safe and effective COVID-19 vaccines are being administered to people worldwide, scientists are still hard at work developing different vaccine strategies that could provide even stronger or longer-lasting immunity against SARS-CoV-2 and its variants. Now, researchers reporting in ACS Central Science have immunized mice with nanoparticles that mimic SARS-CoV-2 by displaying multiple copies of the receptor binding domain (RBD) antigen, showing that the vaccine triggers robust antibody and T cell responses.

Although the first vaccines to receive Emergency Use Authorization by the U.S. Food and Drug Administration were based on mRNA, more conventional protein-based vaccines have also shown promise in clinical trials. Most train the immune system to recognize the RBD, a peptide that is the portion of the SARS-CoV-2 spike protein that binds to the ACE-2 receptor on host cell surfaces. However, not all of these vaccines elicit both antibody and T cell responses, both of which are thought to be important for longer-lasting immunity. Melody Swartz, Jeffrey Hubbell and colleagues had previously developed a vaccine delivery tool called polymersomes –– self-assembling, spherical nanoparticles that can encapsulate antigens and adjuvants (helper molecules that boost the immune response) and then release them inside immune cells. Polymersomes trigger robust T cell immunity, and the researchers wondered if they could further improve the antibody response by engineering the nanoparticles to mimic viruses by displaying multiple copies of the RBD on their surfaces.

So the team made polymersomes that were similar in size to SARS-CoV-2 and decorated them with many RBDs. After characterizing the nanoparticles in vitro, they injected them into mice, along with separate polymersomes containing an adjuvant, in two doses that were three weeks apart. For comparison, they immunized another group of mice with polymersomes that encapsulated the RBD, along with the nanoparticles containing the adjuvant. Although both groups of mice produced high levels of RBD-specific antibodies, only the surface-decorated polymersomes generated neutralizing antibodies that prevented SARS-CoV-2 infection in cells. Both the surface-decorated and encapsulated RBDs triggered robust T cell responses. Although the new vaccine still needs to be tested for safety and efficacy in humans, it could have advantages over mRNA vaccines with regard to widespread distribution in resource-limited areas, the researchers say. That’s because the surface-decorated polymersomes are stable and active for at least 6 months with refrigeration, in contrast to mRNA vaccines that require subzero temperature storage.

The authors acknowledge funding from the Chicago Immunoengineering Innovation Center of the University of Chicago, the Chicago Biomedical Consortium COVID-19 Response Award, the National Institutes of Health, the Canadian Institutes of Health Research and the University of Chicago Comprehensive Cancer Center.

“Polymersomes Decorated with the SARS-CoV-2 Spike Protein Receptor-Binding Domain Elicit Robust Humoral and Cellular Immunity”
ACS Central Science

Featured image: Researchers have developed a protein-based COVID-19 vaccine that mimics the shape of the virus and has shown promise in animal testing. Credit: Andy Dean Photography/Shutterstock.com

Provided by ACS

Will COVID-19 Become A Mostly Childhood Disease? (Medicine)

Within the next few years, as the SARS-CoV-2 virus becomes endemic in the global population, COVID-19 may behave like other common-cold coronaviruses, affecting mostly young children who have not yet been vaccinated or exposed to the virus, according to new modeling results. Because COVID-19 severity is generally lower among children, the overall burden from this disease is expected to decline.

“Following infection by SARS-CoV-2, there has been a clear signature of increasingly severe outcomes and fatality with age,” said Ottar Bjornstad. “Yet, our modeling results suggest that the risk of infection will likely shift to younger children as the adult community becomes immune either through vaccination or exposure to the virus.”

Bjornstad explained that such shifts have been observed in other coronaviruses and influenza viruses as they have emerged and then become endemic.

“Historical records of respiratory diseases indicate that age-incidence patterns during virgin epidemics can be very different from endemic circulation,” he said. “For example, ongoing genomic work suggests that the 1889-1890 pandemic, sometimes known as the Asiatic or Russian flu—which killed one million people, primarily adults over age 70—may have been caused by the emergence of HCoV-OC43 virus, which is now an endemic, mild, repeat-infecting cold virus affecting mostly children ages 7-12 months old.”

Bjornstad cautioned, however, that if immunity to reinfection by SARS-CoV-2 wanes among adults, disease burden could remain high in that group, although previous exposure to the virus would lessen the severity of disease.

“Empirical evidence from seasonal coronaviruses indicates that prior exposure may only confer short-term immunity to reinfection, allowing recurrent outbreaks, this prior exposure may prime the immune system to provide some protection against severe disease,” said Bjornstad. “However, research on COVID-19 shows that vaccination provides stronger protection than exposure to the SARS-CoV-2 virus, so we encourage everyone to get vaccinated as soon as possible.”

The U.S.-Norwegian team developed what is known as a “realistic age-structured (RAS) mathematical model” that integrates demography, degree of social mixing, and duration of infection-blocking and disease-reducing immunity to examine potential future scenarios for age-incidence and burden of mortality for COVID-19.

Specifically, the researchers examined disease burden over immediate, medium and long terms—1, 10 and 20 years, respectively. They also examined disease burden for 11 different countries—including China, Japan, South Korea, Europe, Spain, United Kingdom, France, Germany, Italy, United States, Brazil and South Africa—that differed widely in their demographics. They used data from the United Nations for each of these countries to parameterize the model.

“Regardless of immunity and mixing, the population-level burden of mortality may differ among countries because of varying demographics,” said Ruiyun Li, postdoctoral fellow, University of Oslo. “Our general model framework allows for robust predictions of age-dependent risk in the face of either short or long-term protective immunity, reduction of severity of disease given previous exposure, and consideration of the range of countries with their different demographics and social mixing patterns.”

According to Li, social distancing is well documented to affect transmissibility, and many countries implemented interventions, such as “shelter in place,” during the build-up of the virgin COVID-19 epidemic. Therefore, the team’s model assumes that the reproduction number (R0)—or the level of transmissibility—on any given day is linked to the amount of mobility on that day. The model also incorporates a variety of scenarios for immunity, including both independence and dependence of disease severity on prior exposure, as well as short- (either three months or one year) and long-term (either 10 years or permanent) immunity.

The team’s results appear today (August 11) in the journal Science Advances.

“For many infectious respiratory diseases, prevalence in the population surges during a virgin epidemic but then recedes in a diminishing wave pattern as the spread of the infection unfolds over time toward an endemic equilibrium,” said Li. “Depending on immunity and demography, our RAS model supports this observed trajectory; it predicts a strikingly different age-structure at the start of the COVID-19 epidemic compared to the eventual endemic situation. In a scenario of long-lasting immunity, either permanent or at least 10 years, the young are predicted to have the highest rates of infection as older individuals are protected from new infections by prior infection.”

Jessica Metcalf, associate professor of ecology, evolutionary biology and public affairs, Princeton University, noted that this prediction is likely to hold only if reinfections produce only mild disease. However, she said, the burden of mortality over time may remain unchanged if primary infections do not prevent reinfections or mitigate severe disease among the elderly.

“In this bleakest scenario, excess deaths due to continual severe reinfections that result from waning immunity will continue until more effective pharmaceutical tools are available,” she said.

Interestingly, due to variations in demographics, the model predicts different outcomes for different countries.

“Given the marked increase of the infection-fatality ratio with age, countries with older population structures would be expected to have a larger fraction of deaths than those with relatively younger population structures,” said Nils Chr. Stenseth, professor of ecology and evolution, University of Oslo. “Consistent with this, for example, South Africa—likely due, in part, to its younger population structure—has a lower number of deaths compared to older populations such as Italy. We found that such ‘death disparities’ are heavily influenced by demographics. However, regardless of demographics, we predict a consistent shift of the risk to the young.”

The researchers said that they designed their model so that health authorities will have a powerful and flexible tool to examine future age-circulation of COVID-19 for use in strengthening preparedness and deployment of interventions.

Bjornstad said, “The mathematical framework we built is flexible and can help in tailoring mitigation strategies for countries worldwide with varying demographics and social mixing patterns, thus providing a critical tool for policy decision making.”

Reference: Ruiyun Li et al. A general model for the demographic signatures of the transition from pandemic emergence to endemicity, Science Advances (2021). Vol. 7, no. 33, eabf9040  DOI: 10.1126/sciadv.abf9040

Provided by Pennsylvania State University

A COVID-19 Vaccine Strategy To Give the Body ‘Border Protection’ (Medicine)

Study in animals shows a way to promote immune response in nose, mouth and blood

A simple addition to injected COVID-19 vaccines could enhance their effectiveness and provide “border protection” immunity in areas like the nose and mouth to supplement antibodies in the bloodstream, new research suggests.

The strategy involves dampening the activity of an enzyme produced by some white blood cells when they’re responding to the vaccine challenge. When highly active, this enzyme breaks down not just the pathogen – its job – but also degrades pieces of cells that participate in the immune response.

Prosper Boyaka © OSU

Research in mice showed that an experimental COVID-19 vaccine containing a compound to inhibit the enzyme stimulated a robust antibody response that included immunity in the nose and mouth, ultimately providing extra protection for airways and the gastrointestinal tract.

“Our approach is to improve ‘border control.’ The benefits are broad because in addition to providing protection in the bloodstream like most vaccines do, we also have excellent protection in the doors and windows of the body that communicate with the outside,” said senior study author Prosper Boyaka, professor and chair of the Department of Veterinary Biosciences at The Ohio State University.

“If we protect the mucosal area where the pathogen enters, then even if you don’t reach total immunity there, you limit the amount of pathogen that enters the body so the antibodies inside are more efficient at clearing the infection.”

The experimental vaccine was produced by packaging a segment of the SARS-CoV-2 (the virus that causes COVID-19) spike protein as an antigen with the common vaccine ingredient aluminum salts and an enzyme inhibitor. The findings suggest this affordable design could be particularly helpful in developing countries, where cold storage needed for existing vaccines is a challenge, said Boyaka, also an investigator and program director in Ohio State’s Infectious Diseases Institute.

The study was published online Aug. 5 in Proceedings of the National Academy of Sciences.

There is an irony to the use of aluminum salts (also known as alum) in about 70% of the world’s vaccines: While alum’s presence actually enhances the immune response, it also recruits the white blood cells that secrete the enzyme, called elastase.

Alum is inexpensive to obtain or produce and can be stored at room temperature, and is effective at promoting development of a bloodstream-based antibody response to vaccination. But it doesn’t do much for cell-mediated immunity that improves protection against viruses and bacteria that use cells to reproduce, and can’t generate a useful number of antibodies in the body’s portals of entry for most pathogens: the nose, mouth and genitourinary tract.

The researchers found that suppressing elastase in a vaccine containing alum had the dual benefits of broadening and speeding up the antibody response in the bloodstream and triggering the specific types of antibodies needed for immune protection of mucous membranes.

“We found a way to have the cells come and help the immune response to develop and the enzyme to break down the pathogen, but we don’t want that response to be so high that it goes out of control. So we’re just putting a brake on the activity those enzymes would have,” Boyaka said. “And we found if you apply that strategy, you can induce a response in the airways even if the vaccine is not given through the airway.”

The experimental vaccine enhanced the magnitude of mouse antibodies, which reacted to the same section of the spike protein in the vaccine that antibodies in plasma from COVID-19 patients attach to, as well as generating antibodies in mucosal areas. Immunized mice lacking the gene for the enzyme developed high-affinity antibodies as well.

To further test the concept, the researchers found the enzyme-suppressing compound used in the study triggered production of specialized inflammation-regulating cells in cultures of human immune cells and pig spleen cells, showing that this strategy could improve vaccine immune responses in other species – including people.

Boyaka’s team envisions that a future injected vaccine containing an elastase inhibitor could expand SARS-CoV-2 vaccination availability across the world and even be used to boost existing vaccines.

“COVID will stay with us for some time, unfortunately, with the new variants,” he said. “What we need to do is have a portfolio of options that we could use depending on the health environment.

“Reprogramming the immune response induced by an injected vaccine containing alum is a way to make the vaccine more efficient for what we need. This could be a cheap and simple approach that can benefit people in developing countries.”

This work was supported by grants from the National Institutes of Health and an Ohio State Office of Research COVID-19 seed grant. A patent application has been filed spanning this research; the overall patent portfolio includes an additional U.S. issued patent.

Co-authors, all from Ohio State, include Eunsoo Kim, Zayed Attia, Rachel Woodfint, Cong Zeng, Sun Hee Kim, Haley Steiner, Rajni Kant Shukla, Namal Liyanage, Shristi Ghimire, Jianrong Li, Gourapura Renukaradhya, Abhay Satoskar, Amal Amer, Shan-Lu Liu and Estelle Cormet-Boyaka.

Featured image: Researchers envision that a future injected vaccine containing an elastase inhibitor could expand SARS-CoV-2 vaccination availability across the world and even be used to boost existing vaccines. Photo: Shutterstock.com

Reference: Eunsoo Kim et al, Inhibition of elastase enhances the adjuvanticity of alum and promotes anti–SARS-CoV-2 systemic and mucosal immunity, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2102435118

Provided by Ohio State news

Researchers Find Important Clue to Rare Inflammatory Disease in Children Following COVID-19 Infection (Medicine)

Mount Sinai researchers have found an important clue to a rare but serious aftereffect of COVID-19 in children, known as multisystem inflammatory syndrome in children or MIS-C.

The researchers reported that RNA sequencing of blood samples from the Mount Sinai COVID-19 Biobank led to the discovery that specific infection-fighting cells of the immune system are downregulated in children with MIS-C, and that this is associated with a sustained inflammatory response, a hallmark of infection with SARS-CoV-2, the virus that causes COVID-19. The study was published in Nature Communications on August 11.

MIS-C is characterized by fever, pain, and inflammation of multiple organs including the heart, lungs, kidneys, skin, eyes, or gastrointestinal tract. More than 2,600 cases of MIS-C have been reported in the United States since the COVID-19 pandemic began. While an autoimmune condition has been suggested as an underlying cause, specific genes, pathways, and cell types remain unknown. Through Mount Sinai’s extensive gene-expression study, the researchers have taken a significant step in providing the field with new exploratory pathways involving complex networks and subnetworks of genes they constructed from pediatric cases of MIS-C and COVID-19 from the Mount Sinai COVID-19 Biobank.

One of the more significant of these gene networks implicated the suppression of two types of immune cells: natural killer (NK) cells and CD8+ T cells. Previous research has shown that when CD8+ T cells are persistently exposed to pathogens, they enter a state of “exhaustion,” resulting in a loss of their effectiveness and ability to proliferate. The researchers in the new study specifically pointed to the CD8+ T cells being in this exhausted state, thus potentially weakening the inflammatory immune response. An increase in NK cells is also associated with exhausted CD8+ T cells.

“Our study implicated T cell exhaustion in MIS-C patients as one of the potential drivers of this disease, suggesting that an increase in both NK cells and circulating exhausted CD8+ T cells may improve inflammatory disease symptoms,” says lead co-author Noam Beckmann, PhD, Assistant Professor of Genetics and Genomic Sciences, and member of the Mount Sinai Clinical Intelligence Center (MSCIC), at the Icahn School of Medicine at Mount Sinai. “Additionally, we found nine key regulators of this network known to have associations with NK cell and exhausted CD8+ T cell functionality.”

Dr. Beckmann adds that one of those regulators, TBX21, is a promising therapeutic target because it serves as a master coordinator of the transition of CD8+ T cells from effective to exhausted.

Mount Sinai’s work on MIS-C represents the first gene-expression study from the hospital’s COVID-19 Biobank. Created through the work of a volunteer team of more than 100 nurses, doctors, and researchers, the repository serves as the backbone of Mount Sinai’s rapidly expanding COVID-19 research. The team has collected blood samples from several hundred COVID-19 patients (including “longitudinal” or multiple samples from the same person) admitted to Mount Sinai hospitals which, in turn, have generated a diverse set of molecular data yielding invaluable insights into better understanding and new therapeutic approaches to the disease.

Reference: Beckmann, N.D., Comella, P.H., Cheng, E. et al. Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children. Nat Commun 12, 4854 (2021). https://doi.org/10.1038/s41467-021-24981-1

Provided by Mount Sinai Health System

Shared Antibodies May Push COVID-19 Variants (Biology)

Researchers at Vanderbilt University Medical Center have found that people recovering from COVID-19 and those vaccinated against the causative virus, SARS-CoV-2, produce identical clones, or groups, of antibody-producing white blood cells.

Their discovery, reported this week in the journal Cell Reports, sheds light on the selection pressures driving the emergence of SARS-CoV-2 variants that have the potential to escape from naturally occurring antibodies and those induced by vaccination.

Current vaccines, including those that use genetic material, mRNA, encoding a viral protein to elicit an immune response, are largely protective against the delta variant now sweeping through unvaccinated populations around the world. Yet scientists worry other variants may emerge that are more virulent and transmissible—even among those already vaccinated.

The findings reported this week could help scientists design more effective vaccines and antibody therapies against a broader range of variants, the researchers concluded.

“We were surprised to discover that there are so many shared antibodies between individuals after SARS-CoV-2 infection, but that is a good sign,” said the paper’s corresponding author, James Crowe, Jr., MD, director of the Vanderbilt Vaccine Center.

James Crowe, Jr., MD, director of the Vanderbilt Vaccine Center © Vanderbilt University Medical Center

“It was encouraging to find that an mRNA vaccine also induces those clones, which in part explains why these antibodies work so well in so many people,” said Crowe, who holds the Ann Scott Carell Chair and is Professor of Pediatrics and Pathology, Microbiology & Immunology at VUMC.

Antibodies are proteins produced by specialized white blood cells called B lymphocytes, or B cells. When a virus binds to the surface of a B cell, it stimulates the cell to divide and mature into a clone of identical cells.

The mature B cells, called plasma cells, secrete millions of antibodies into the bloodstream and lymphatic system, some of which attach to the virus and prevent it from infecting its target cell.

The researchers identified 27 public clonotypes, genetically similar clones of antibodies, which were shared by COVID-19 survivors and by uninfected people who had been vaccinated against SARS-CoV-2.

Most of the public clonotypes were formed against part of the viral surface “spike” or S protein that attaches to a specific receptor on the surface of cells in the lungs and other tissues.

This part of the S protein is variable, meaning that it can change, or mutate, in ways that can make the virus virtually invisible to circulating antibodies.

If many people independently make the same antibody against the variable part of the S protein, this may exert selective pressure on it to mutate.

Scientists believe this is what led to the delta variant of SARS-CoV-2, which is more infectious than the original strain of the virus, and much more transmissible from person to person.

In this study, researchers for the first time found two public clonotypes recognizing another, more conserved part of the S protein that fuses with the cell membrane. Once fusion occurs, SARS-CoV-2 enters its target cell, where it hijacks the cell’s genetic machinery to copy itself.

Neutralizing antibodies that bind the conserved part of the S protein are of interest because this part of the protein is less likely to mutate. Variants of SARS-CoV-2 may be less likely to evade vaccines and antibody therapies when its less mutable “Achilles heel” is targeted.

The research was conducted in collaboration with colleagues at Washington University School of Medicine in St. Louis, Missouri, the University of Arizona College of Medicine in Tucson, and Integral Molecular Inc. in Philadelphia, Pennsylvania.

Elaine Chen, a graduate student in the Crowe lab, was the paper’s first author. Other VUMC coauthors were Pavlo Gilchuk, PhD, Seth Zost, PhD, Naveen Suryadevara, PhD, Elad Binshtein, PhD, Rachel Sutton, Jessica Rodriguez, Sam Day, Luke Myers, Andrew Trivette, MS, and Robert Carnahan, PhD.

The research was supported by the Defense Advanced Research Projects Agency of the U.S. Department of Defense, the National Institutes of Health, the Dolly Parton COVID-19 Research Fund at Vanderbilt, grants from the University of Arizona, the Mercatus Center of George Mason University and Merck KGaA, and funding from AstraZeneca.

The research, “Convergent antibody responses to the SARS-CoV-2 spike protein in convalescent and vaccinated individuals”, published in the Journal Cell Reports on dated 9 Aug 2021. DOI: https://doi.org/10.1016/j.celrep.2021.109604

Provided by Vanderbilt University Medical Center

Researchers Pinpoint Promising Inhibitors That Could Lead To New Antiviral Drugs To Treat COVID-19 (Medicine)

The rapid development of safe and effective COVID-19 vaccines has been a major step forward in helping bring the pandemic under control. But with the rise of variants and an uneven global distribution of vaccines, COVID-19 is a disease that will have to be managed for some time.

Antiviral drugs that target the way the virus replicates may be the best option for treating outbreaks of COVID-19 in unvaccinated and undervaccinated populations.

Using the Canadian Light Source (CLS), a national research facility at the University of Saskatchewan, researchers from the University of Alberta isolated promising inhibitors that could be used to treat COVID-19 infections. The scientists used the synchrotron at CLS remotely during the facility’s special COVID-19 call for proposals, an initiative created to support research to help fight the pandemic.

“With the help of the CLS and the multiple teams here at the U of A, including our lab and the Young lab in the Department of Biochemistry, the Vederas lab in the Department of Chemistry and the Tyrrell team in the Department of Medical Microbiology and Immunology, we’ve been very efficient at developing a group of inhibitors that is very promising,” said Joanne Lemieux, a professor in the U of A’s Faculty of Medicine & Dentistry.

The synchrotron creates light millions of times brighter than the sun that helps researchers to find very detailed information about their samples. Lemieux and colleagues used the CMCF beamline at the CLS to search for molecules that could stop SARS-CoV-2—the virus that causes COVID-19—from replicating inside human cells.

The team found inhibitors that target a special kind of protein called a protease, which is used by the virus to make more copies of itself. Proteases act like an ax and help the virus chop up large proteins. Without this protein, the virus would be unable to multiply and harm human health.

“One of the inhibitors that we used as our benchmark starting point was one that was developed to treat a feline coronavirus,” Lemieux said. “This was not an optimal inhibitor given the dosage for humans, which is why new derivatives needed to be made in order to provide patients with a lower dosage.”

While COVID-19 and its cousins SARS and MERS cause serious respiratory diseases, coronaviruses are also responsible for a wide range of illnesses in humans and animals. Lemieux said the proteases are very similar among the different coronaviruses.

“It’s likely that any antiviral that is developed for one coronavirus would also be a broad specificity inhibitor that could treat a variety of coronavirus infections, including those found in animals,” Lemieux said.

Over the past decade, oral antiviral medication has become more accessible to patients in need. There are oral protease inhibitors that treat and manage symptoms for diseases like HIV and hepatitis C. The research team wants to help make SARS-CoV-2 inhibitors available in a pill form, which would make it easier to treat COVID-19.

Lemieux’s team is not alone in their quest for antivirals that will help treat diseases like COVID-19. Pfizer, the pharmaceutical company behind the successful mRNA vaccine, is moving its antivirals to Phase 1 clinical trials. Lemieux sees this as a sign that her group has been headed in the right direction.

“With many people working around the world developing antivirals targeting proteases, there is very likely to be one or more antivirals on the market,” Lemieux said. “This would enable ease of accessibility for people around the world, especially in regions or populations where vaccines are not an option.”

The team’s findings were recently published in the European Journal of Medicinal Chemistry.

Reference: Wayne Vuong et al, Improved SARS-CoV-2 Mpro inhibitors based on feline antiviral drug GC376: Structural enhancements, increased solubility, and micellar studies, European Journal of Medicinal Chemistry (2021). DOI: 10.1016/j.ejmech.2021.113584

Provided by University of Alberta

Fight-or-flight Response Is Altered in Healthy Young People Who Had COVID-19 (Physiology)

New research published in the Journal of Physiology found that otherwise healthy young people diagnosed with COVID-19, regardless of their symptom severity, have problems with their nervous system when compared with healthy control subjects.

Specifically, the system that oversees the fight-or-flight response, the sympathetic nervous system, seems to be abnormal (overactive in some instances and underactive in others) in those recently diagnosed with COVID-19.

These results are especially important given the emerging evidence of symptoms like racing hearts being reported in conjunction with “long-COVID.”

The impact of this alteration in fight-or-flight response, especially if prolonged, means that many processes within the body could be disrupted or affected. This research team has specifically been looking at the impact on the cardiovascular system—including blood pressure and blood flow—but the sympathetic nervous system is also important in exercise responses, the digestive system, the immune function, and more.

Understanding what happens in the body shortly following diagnosis of COVID-19 is an important first step towards understanding the potential long-term consequences of contracting the disease.

Importantly, if similar disruption of the flight-or-fight response, like that found here in young individuals, is present in older adults following COVID-19 infection, there may be substantial adverse implications for cardiovascular health.

The researchers studied lung function, exercise capacity, vascular function, and neural cardiovascular control (the control of heartbeat by the brain).

They used a technique called microneurography, wherein the researchers inserted a tiny needle with an electrode into a nerve behind the knee, which records the electrical impulses of that nerve and measures how many bursts of electrical activity are happening and how big the bursts are.

From this nerve activity, they can assess the function of the sympathetic nervous system through a series of tests. For all the tests, the subject was lying on their back on a bed. First, the researchers looked at the baseline resting activity of the nerves, heart rate, and blood pressure. Resting sympathetic nerve activity was higher in the COVID-19 participants than healthy people used as controls in the experiment.

Then, the subject did a “cold pressor test,” where they stick their hand in an ice-water mixture (~0° C) for two minutes. In healthy individuals, this causes a profound increase in that sympathetic nerve (fight-or-flight) activity and blood pressure. The COVID-19 subjects rated their pain substantially lower than healthy subjects typically do.

Finally, the participant was moved to an upright position (the bed they’re lying on can tilt up and down) to see how well their body can respond to a change in position. The COVID-19 subjects had a pretty large increase in heart rate during this test; they also had higher sympathetic nerve activity throughout the tilt test compared with other healthy young adults.

As with all research on humans, there are limitations to this study. However, the biggest limitation in the present study is its cross-sectional nature—in other words, we do not know what the COVID-19 subjects’ nervous system activity “looked like” before they were diagnosed with COVID-19.

These findings are consistent with the increasing reports of long-COVID symptoms pertaining to problems with the fight-or-flight response.

Abigail Stickford, senior author on this study said, “Through our collaborative project, we have been following this cohort of COVID-19 subjects for six months following their positive test results. This work was representative of short-term data, so the next steps for us are to wrap up data collection and interpret how the subjects have changed over this time.”

Reference: Nina L. Stute et al, COVID‐19 is getting on our nerves: Sympathetic neural activity and hemodynamics in young adults recovering from SARS‐CoV‐2, The Journal of Physiology (2021). DOI: 10.1113/JP281888

Provided by The Journal of Physiology

New Light Shed On Treatment of Rare Cases Of Blood Clotting in Brain Following Covid-19 Vaccination (Medicine)

A new UCL and UCLH-led study of patients with cerebral venous thrombosis (CVT) following Covid-19 vaccination, provides a clearer guide for clinicians trying to diagnose and treat patients.

The research, published in The Lancet, is the most detailed account of the characteristics of CVT, when it is caused by the novel condition vaccine-induced immune thrombotic thrombocytopenia (VITT).

VITT is a condition characterised by a blockage of the veins and a marked reduction of platelets, blood components which are an important part of the blood clotting system. The commonest and severest manifestation of VITT is CVT, in which veins draining blood from the brain become blocked.

This new study looks in detail at 70 patients with VITT-associated CVT following vaccination are compared to 25 with CVT without evidence of VITT.

The authors suggest that some treatments such as intravenous immunoglobulin seem to be associated with better outcomes but caution against reading too much into the findings of the observational study, saying that reliable evidence about treatments can only be obtained in a randomised clinical trial.

The NHS’s success with the vaccination programme makes the UK a very good place to study rare side-effects of COVID-19 vaccination. The authors started collecting their cases within a few weeks of the discovery of this new condition and submitted their report within two months of it being reported in the medical literature.

VITT-associated CVT has a very high mortality rate. Even without VITT, CVT is a very serious medical condition, with around 4% of patients dying during their hospital admission. In patients with VITT-associated CVT observed in this study, though, the mortality rate during admission was around seven times higher than that, at 29%.

This poorer outcome is explained at least in part because the abnormal blockage of veins is much more extensive in this condition, with more veins blocked both in the head and elsewhere in the body.

Lead author, Dr Richard Perry, consultant neurologist at the National Hospital for Neurology and Neurosurgery and Module Convenor for the Stroke Medicine MSc at UCL Queen Square Institute of Neurology, said: “With an illness of such severity, often in young patients who were previously fit and well, doctors have been desperate for evidence regarding treatments that might prevent some of the death and disability that arises from this condition.

“While an observational study is not the ideal platform to provide evidence for which medications work, it may be a long time before we have evidence from randomised clinical trials, the gold standard for testing new treatments. For the moment we are dependent on observational studies like CAIAC for our evidence.”

The study provides support for the three principles of treatment established so far by the Expert Haematology Panel, based on early work at UCLH and two other European sites:

  1. The use of non-heparin-based anticoagulation
  2. Give treatments to try to reduce the level of the abnormal antibody that is implicated in this condition, and
  3. Avoid the strategy of trying to bring the platelet count back up to normal levels by giving platelet transfusions.

Co-author, Professor David Werring (UCL Queen Square Institute of Neurology) said: “Although this syndrome has previously been reported, this multicentre UK-wide study is the most detailed description to date of the clinical and radiological features, which should help clinicians to recognise and treat it promptly.” 

Co-author Marie Scully, a Professor of Haemostasis and Thrombosis at UCL Institute of Cardiovascular Science and UCLH consultant haematologist, said: “Tempting though it might be to replace the platelets that are missing in this condition by infusing new platelets from blood donors, we do not advise this approach. However, it is difficult in cases requiring neurosurgical interventions and in such situations they are required to prevent bleeding.  Presumably, the reason why the numbers of platelets in the bloodstream is so low in VITT is because they are quickly used up by the abnormal clotting. Infusing more platelets may simply add more fuel to the fire.”

Co-author, Christine Roffe, Professor of Stroke Medicine at Keele University, said “Although there are sound theoretical reasons supporting the adoption of these treatment strategies, until now there has been no clinical evidence for their use. In our study, non-heparin blood thinners and intravenous immunoglobulin were both associated with better patient outcomes, providing the first clinical evidence from a large case series in support of these treatments.”

Dr Alastair Webb, consultant neurologist at the John Radcliffe Hospital in Oxford said: “We found that those patients who were given intravenous immunoglobulin – the treatment in which the body is flooded with normal antibodies to try to reduce the effects of the abnormal one – were more likely to leave hospital alive and able to live an independent life rather than depending on carers or family to look after them.

“Use of non-heparin blood thinners was similarly associated with a more favourable outcome. Our data does not prove that these treatments work, as the most severely affected patients may have been too unwell to receive them in time, but the results support their use whilst we seek better evidence,” he said.

On the other hand, platelet transfusions were associated with a worse outcome in patients with VITT-associated CVT. Although observational data cannot prove harm from this treatment approach, the study provides support for the concern that has already been raised about the potential harm of platelet transfusions.

Although VITT-associated CVT is a severe condition, it appears to be extremely rare and the authors stress that, for most individuals, the risk to their health of not getting vaccinated against COVID-19 is likely to be much higher.



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Potential Drug Against COVID-19 Found Among Tapeworm Medications (Medicine)

Re-engineered compound fights both cytokine storm and viral replication, experiments show.

A group of medications long prescribed to treat tapeworm has inspired a compound that shows two-pronged effectiveness against COVID-19 in laboratory studies, according to a new publication appearing online in the journal ACS Infectious Disease.

The compound, part of a class of molecules called salicylanilides, was designed in the laboratory of Professor Kim Janda, PhD, the Ely R. Callaway, Jr. Professor of Chemistry and director of the Worm Institute for Research and Medicine at Scripps Research, in La Jolla, CA.

“It has been known for 10 or 15 years that salicylanilides work against certain viruses,” Janda says. “However, they tend to be gut-restricted and can have toxicity issues.”

Janda’s compound overcomes both issues, in mouse and cell-based tests, acting as both an antiviral and an anti-inflammatory drug-like compound, with properties that auger well for its use in pill form.

Salicylanilides were first discovered in Germany in the 1950s and used to address worm infections in cattle. Versions including the drug niclosamide are used in animals and humans today to treat tapeworm. They have also been studied for anti-cancer and antimicrobial properties.

The modified salicylanilide compound that Janda created was one of about 60 that he built years ago for another project. When the SARS-CoV-2 virus became a global pandemic in early 2020, knowing that they may have antiviral properties, he started screening his old collection, first in cells with collaborators from Sorrento Therapeutics and The University of Texas Medical Branch, and later, after seeing promising results, working with Scripps Research immunologist John Teijaro, PhD, who conducted rodent studies.

One compound stood out. Dubbed simply “No. 11,” it differs from the commercial tapeworm medicines in key ways, including its ability to pass beyond the gut and be absorbed into the bloodstream—and without the worrisome toxicity.

“Niclosamide is basically digestive-track restricted, and that makes sense, because that’s where parasites reside,” Janda says. “For that reason, simple drug repurposing for a COVID treatment would be counterintuitive, as you want something that is readily bioavailable, yet does not possess the systemic toxicity that niclosamide has.”

About 80 percent of salicylanilide 11 passed into the bloodstream, compared to about 10 percent of the antiparasitic drug niclosamide, which has recently entered clinical trials as a COVID-19 treatment, Janda says.  

The experiments showed that of the many modified salicylanilides he had built in his laboratory, No. 11 affected pandemic coronavirus infections in two ways. First, it interfered with how the virus deposited its genetic material into infected cells, a process called endocytosis. Endocytosis requires the virus to form a lipid-based packet around viral genes. The packet enters the infected cell and dissolves, so the infected cell’s protein-building machinery can read it and churn out new viral copies. No. 11 appears to prevent the packet’s dissolution.

“The compound’s antiviral mechanism is the key,” Janda says. “It blocks the viral material from getting out of the endosome, and it just gets degraded. This process does not allow new viral particles to be made as readily.”

Importantly, because it acts inside cells rather than on viral spikes, questions about whether it would work in new variants like Delta and Lambda aren’t a concern, he adds.

“This mechanism is not dependent on the virus spike protein, so these new variants coming up aren’t going to relegate us to finding new molecules as is the case with vaccines or antibodies,” Janda says.

In addition, No. 11 helped quiet potentially toxic inflammation in the research animals, Janda says, which could be important for treating acute respiratory distress associated with life-threatening COVID infections. It reduced levels of interleukin 6, a signaling protein which is a key contributor of inflammation typically found in advanced stages of COVID-19.

Better medications against COVID-19 are urgently needed, as highly infectious new variants drive renewed surges of illness and death globally. But Janda says salicylanilide No. 11 was created long before the pandemic.

After fighting an unpleasant bacterial infection called Clostridioides difficile about 10 years ago, he saw a clear need for better treatment options. Multi-drug-resistant strains of C. difficile have become a major cause of drug-resistant diarrheal disease outbreaks in health care institutions globally, and among people using antibiotics. As director of the Worm Institute, which focused on parasitic infections, Janda was very familiar with salicylanilides, and knew of their antimicrobial properties. His laboratory created a “library” of modified salicylanilides several of which showed strong efficacy against C. difficile, and the collection was subsequently licensed by pharmaceutical firm Sorrento Therapeutics. Among them was salicylanilide 11.  

“Salicylanilide 11 actually was placed on the back burner in my laboratory against C. difficile because it’s not as gut-restricted as we would like it to be,” Janda says. “But salicylanilide 11 has got a lot of really positive things going for it as a potential therapeutic for COVID.”

In addition to Janda and Teijaro, authors of the study, “Salicylanilides reduce SARS-CoV-2 replication and suppress induction of inflammatory cytokines in a rodent model,” are Steven Blake, Namir Shaabarani, Lisa Eubanks and Nathan Beutler of Scripps Research, Junki Maruyama, John Manning,and Slobodan Paessler of the University of Texas Medical Branch Department of Pathology, and Henry Ji of Sorrento Therapeutics, Inc.

Paessler received funding from Sorrento Therapeutics for the part of the work.

Featured image: Colorized scanning electron micrograph of an apoptotic cell (pink) heavily infected with SARS-COV-2 virus particles (green), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. (Photo credit: National Institute of Allergy and Infectious Diseases/NIH.)

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