Tag Archives: #covid19

Binding Affinities Of These Recently Recognized Receptors To Spike Protein Are Higher Than ACE2 (Biology)

Dongjie Guo and colleagues identified CAT, AGTR2, L-SIGN and DC-SIGN as potential receptors for the entry of SARS-CoV-2 into human cells

A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) recently emerged and is rapidly spreading in humans, causing COVID-19. A key to tackling this pandemic is to understand the receptor recognition mechanism of the virus, which regulates its infectivity, pathogenesis and host range. SARS-CoV-2 and SARS-CoV recognize the same receptor—angiotensin-converting enzyme 2 (ACE2)—in humans. However, the relatively low expression level of this known receptor in the lungs, which is the predominantly infected organ in COVID-19, indicates that there may be some other co-receptors or alternative receptors of SARS-CoV-2 to work in coordination with ACE2. Now, Dongjie Guo and colleagues identified twenty-one candidate receptors of SARS-CoV-2, including ACE2-interactor proteins and SARS-CoV receptors.

They investigated the protein expression levels of these twenty-one candidate receptors in different human tissues such as lungs, gastrointestinal tract, kidney, testis, epididymis. Gallbladder etc. and found that five of which CAT, MME, L-SIGN, DC-SIGN, and AGTR2 were specifically expressed in SARS-CoV-2 affected tissues.

Next, they performed molecular simulations of the above five candidate receptors with SARS-CoV-2 spike (S) protein, and found that the binding affinities of CAT, AGTR2, L-SIGN and DC-SIGN to spike protein were even higher than ACE2.

Interestingly, they also observed that CAT and AGTR2 bound to spike protein in different regions with ACE2 conformationally, suggesting that these two proteins are likely capable of the co-receptors of ACE2.

Conclusively, they considered that CAT, AGTR2, L-SIGN and DC-SIGN were the potential receptors of SARS-CoV-2.

Moreover, AGTR2 and DC-SIGN tend to be highly expressed in the lungs of smokers, which is consistent with clinical phenomena of COVID-19, and further confirmed their conclusion.

(article continues below image)

Figure 1: The binding hot spots in RBD-ACE2 and potential receptors-S1 complexes. (A) Residues on RBD that interact with ACE2 are marked. (B&C) In the complexes of CAT, and AGTR2 with S1, binding hot spots on CAT, AGTR2 are indicated in red fonts, and on S1 are indicated in black fonts. © Dongjie Guo et al.

Besides, based on the modeled potential receptors-S protein complex, they also predicted the binding hot spots, which would be helpful to repurpose or design drugs targeting these potential receptors. Currently, some inhibitors targeting these potential receptors can be found in DrugBank, such as CAT inhibitor Fomepizole, AGTR2 antagonist Tasosartan. In addition, L-SIGN inhibitor Dextran and DC-SIGN inhibitors quinoxalinones were also identified as potential drugs.

Finally, their findings suggested that CAT, AGTR2, L-SIGN and DC-SIGN could be novel potential receptors for the entry of SARS-CoV-2 into human cells and the identified agents should be carefully considered in anti-SARS-CoV-2 usage.

Featured image: Protein interaction networks of ACE2 from STRING © Dongjie Guo et al.


Reference: Dongjie Guo, Ruifang Guo, Zhaoyang Li, Yuyang Zhang, Wei Zheng, Xiaoqiang Huang, Tursunjan Aziz, Yang Zhang, Lijun Liu, “CAT, AGTR2, L-SIGN and DC-SIGN are potential receptors for the entry of SARS-CoV-2 into human cells”, bioRxiv 2021.07.07.451411; doi: https://doi.org/10.1101/2021.07.07.451411


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New Treatment Demonstrated For People With Vaccine Clots (Medicine)

A new lifesaving treatment for people suffering from vaccine-related blood clots has been demonstrated by scientists of the Faculty of Health Sciences.

Researchers at the McMaster Platelet Immunology Laboratory (MPIL) are recommending two treatments, a combination of anti-clotting drugs with high doses of intravenous immunoglobulin, to combat vaccine-induced immune thrombotic thrombocytopenia (VITT).

The treatment’s effectiveness was described in a report describing three Canadian patients who received the AstraZeneca vaccine, and who subsequently developed VITT. Two suffered clotting in their legs and the third had clots blocking arteries and veins inside their brain.

“If you were a patient with VITT, I’d be telling you we know of a treatment approach. We can diagnose it accurately with our tests, treat it and we know exactly how the treatment works,” said Ishac Nazy, scientific director of the lab and associate professor of medicine.

“Our job is to understand this disease mechanism so we can improve diagnosis and patient management. This study brings together successful lab diagnostics and patient care. It’s a true translational medicine approach, which is really our forte, bench-side to bedside.”

VITT occurs when antibodies attack a blood protein, called platelet factor 4 (PF4), which results in activation of platelets in the blood, causing them to clump together and form clots. Blood samples taken from the patients after treatment showed reduced antibody-mediated platelet activation in all cases.

While the study patients were older, many VITT cases have affected younger people. However, Nazy and his MPIL colleagues said VITT is a rare disorder, regardless of people’s age.

The lab’s scientists include professors of medicine Donald Arnold and John Kelton and professor of pathology and molecular medicine Ted Warkentin. Together they devised an effective VITT test and treatment by building on their previous investigations of heparin-induced thrombocytopaenia (HIT).

While the two conditions are similar, using a standard HIT antibody test to detect VITT can yield false negative results.

This led the scientists to modify the HIT test to detect VITT-specific antibodies that are found, albeit rarely, in patients who had a COVID-19 vaccine.

Subsequent lab tests on patient blood samples showed how high doses of immunoglobulin coupled with blood-thinner medications shut down platelet activation and stopped clot formation.

“We now understand the mechanism that leads to platelet activation and clotting,” said Nazy.

The study was published by the The New England Journal of Medicine. External funding for the study was provided by the Canadian Institutes for Health Research.

Featured image: Ishac Nazy is scientific director of the McMaster Platelet Immunology Laboratory (MPIL) and associate professor of medicine © McMaster University


Provided by McMaster University

Researchers Show How the COVID-19 Virus Triggers Immune Signaling ‘Storm’ (Medicine)

Researchers have discovered new ways in which the coronavirus disease (COVID-19) virus causes human immune cells to overreact, a deadly part of the disease.

Led by researchers from NYU Grossman School of Medicine and Perlmutter Cancer Center at NYU Langone, the new study found that SARS-CoV-2, the pandemic virus, interacts with specific proteins on immune cells, causing these cells to release abnormally high levels of immune signaling proteins called cytokines (a “cytokine storm”). These cytokines, in turn, cause fluid buildup in the lungs and make it hard to breathe.

Before the current study, SARS-CoV-2 was thought to interact mostly with a protein called angiotensin converting enzyme 2 (ACE2), which is present on the outer surfaces of lung cells. The virus evolved to have a protein spike that snags ACE2 as the first step in invading human lung cells, where the virus multiplies. Accordingly, all approved COVID-19 antiviral drugs and vaccines work by interfering with, or protecting against, this viral spike/ACE2 interaction.

Mounting evidence, however, suggests that the virus also interacts directly with human immune cells, which have little ACE2 on their surfaces. Published online May 9 in the journal Immunity, the new study identified six surface proteins on immune cells that attach to the viral spike protein, but in different places than ACE2.

The virus does not appear to replicate in immune cells, as it does when it binds with ACE2 on lung cells, but instead, the newfound interactions cause damaging immune responses, say the study authors. Based on their new understanding, the team generated nanobodies, a type of protein-based therapeutic, to block viral attachment to both ACE2 and the newfound immune cell surface proteins (receptors).

“Our results suggest that we can simultaneously keep SARS-CoV-2 from invading lung cells while also blocking the dangerous hyperactivation that the viral spike protein causes in immune cells,” says corresponding study author Jun Wang, PhD, assistant professor in the Department of Pathology at NYU Langone. “Such dual action, if confirmed in human studies, could more fully address a disease that has taken more than 3.3 million lives globally.”

In the study, the authors used a technique called single-cell RNA-sequencing to examine which genes were expressed, and consequently, which proteins were built, in cells present in lung fluid taken from patients with COVID-19, including cells lining the lungs (epithelial cells) and immune cells.

Their high-speed receptor screening approach identified and described the six human immune cell membrane proteins that bound to SARS-CoV-2 spike protein. Five were C-type lectins, carbohydrate-binding protein units with many biological functions, including in immune defenses. The authors also found that SARS-CoV-2 spike attaches to Tweety family member 2, a protein that controls the entry of charged particles (chloride) into cells, and possibly a switch that activates immune cells. Importantly, the team found the virus spike interacts with these activating surface proteins mostly on myeloid cells, a group of vital immune cells that arise in bone marrow and circulate in the blood.

In addition, the study authors generated nanobodies that blocked SARS-CoV-2 spike/ACE2 and myeloid cell interactions. Nanobodies are smaller derivatives of antibodies, immune proteins that form a surveillance system by recognizing invading microbes. Industry designs synthetic antibodies that specifically glom onto targets of their choice, which can change the action of disease-causing proteins. More recently, researchers began fine-tuning just pieces of antibodies, called nanobodies, which are easier to make.

“Our study will change how the field thinks about mechanisms behind COVID-19, demonstrating that viruses can directly reprogram immune cells with potentially deadly consequences,” says co-first study author Qiao Lu, PhD, a postdoctoral scholar in Dr. Wang’s lab.

As a next step, he says, the research team plans to explore their nanobody’s potential in preclinical and clinical studies in patients with severe cases of COVID-19, as well as in those with emerging virus mutants that cause more severe symptoms.

Along with Dr. Wang, co-corresponding authors for the study were Siyuan Ding in the Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, and Qi Xie of the Institute of Basics Medical Sciences, Westlake Institute for Advanced Study in Hangzhou, China. Along with Dr. Lu, co-first authors were Jia Liu of the Department of Pathology at NYU Langone; and Shuai Zhao of Westlake University. Study authors from the Department of Pathology at NYU Langone were Triantafyllia Karakousi, Ze Zhang, Xufeng Chen, Marianna Teplova, Tenny Mudianto, Jasper Du, Alberto Herrera, Sergei Koralov, Iannis Aifantis; and Leopoldo Segal in the Department of Medicine; as well as Payal Damani-Yokota, Maria Kaczmarek, Stephen Yeung, Kamal Khanna, and Kenneth Stapleford in the Department of Microbiology.

Additional study authors were Xiaojuan Ran, Hongzhen Tang, Haijing Deng, Zhilin Long, Shumin Jin, Peng Lin, and Ming Zhou of the Institute of Basics Medical Sciences, Westlake Institute for Advanced Study; Maria Florencia, Gomez Castro, Juhee Son, Ruochen Zang, Broc McCune, Rita Chen, and Michael Diamond of the Washington University School of Medicine, St. Louis; Maudry Laurent-Rolle, Jack Hsu, Tina Tianjiao Su, and Peter Cresswell of the Department of Immunobiology at Yale University School of Medicine; Jianbo Dong, Betty Huang, and Yue Liu of Ab Studio Inc.; Fei Tang, Xianwen Ren, and Zemin Zhang of the Beijing Advanced Innovation Center for Genomics at Peking University; Renhong Yan and Qiang Zhou of the Joint Research Center of Hangzhou First Hospital Group and Westlake University; Jia Cui of Kactus Biosystems in Shanghai; James Zhu and Tao Wang of the Quantitative Biomedical Research Center at University of Texas Southwestern Medical Center; and Jianzhu Ma of the Department of Computer Science at Purdue University.

This work is supported by internal funds provided by the Office of Science and Research at NYU Langone, Westlake Education Foundation, Tencent Foundation grant XHTX202001008, Hangzhou Science and Technology Development Foundation grant 20202013A05, a Cancer Research Institute Irvington Postdoctoral Fellowship, and National Institutes of Health grants P30 DK052574, R00 AI135031, R01 AI150796, R01 AI157155, R01 AI143861, AI143861S1, and R01-AI059167. Dr. Wang, Dr. Lu, and Dr. Liu from NYU Langone; and Dr. Huang, Dr. Dong, and Dr. Yue Liu from Ab Studio Inc., are named as inventors on patent applications that describe the anti-SARS-CoV-2 blocking nanobodies. Dr. Wang is also a paid consultant for Lilly Asia Ventures and Rootpath Genomics (work not related to the current study).

Featured image: GETTY/FOTOGRAZIA


Reference: Qiao Lu, Jia Liu, Shuai Zhao et al., “SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2”, Immunity, 2021. DOI: https://doi.org/10.1016/j.immuni.2021.05.006


Provided by NYU Langone

New Vaccine Blocks COVID-19 and Variants, Plus Other Coronaviruses (Medicine)

Study in animals identifies a potential way to build vaccines to fight future pandemics

A potential new vaccine developed by members of the Duke Human Vaccine Institute has proven effective in protecting monkeys and mice from a variety of coronavirus infections — including SARS-CoV-2 as well as the original SARS-CoV-1 and related bat coronaviruses that could potentially cause the next pandemic.

The new vaccine, called a pan-coronavirus vaccine, triggers neutralizing antibodies via a nanoparticle. The nanoparticle is composed of the coronavirus part that allows it to bind to the body’s cell receptors, and is formulated with a chemical booster called an adjuvant. Success in primates is highly relevant to humans.

The findings appear Monday, May 10 in the journal Nature.

“We began this work last spring with the understanding that, like all viruses, mutations would occur in the SARS-CoV-2 virus, which causes COVID-19,” said senior author Barton F. Haynes, M.D., director of the Duke Human Vaccine Institute (DHVI). “The mRNA vaccines were already under development, so we were looking for ways to sustain their efficacy once those variants appeared.

“This approach not only provided protection against SARS-CoV-2, but the antibodies induced by the vaccine also neutralized variants of concern that originated in the United Kingdom, South Africa and Brazil,” Haynes said. “And the induced antibodies reacted with quite a large panel of coronaviruses.”

Haynes and colleagues, including lead author Kevin Saunders, Ph.D., director of research at DHVI, built on earlier studies involving SARS, the respiratory illness caused by a coronavirus called SARS-CoV-1. They found a person who had been infected with SARS developed antibodies capable of neutralizing multiple coronaviruses, suggesting that a pan-coronavirus might be possible.

The Achilles heel for the coronaviruses is their receptor-binding domain, located on the spike that links the viruses to receptors in human cells. While this binding site enables it to enter the body and cause infection, it can also be targeted by antibodies.

The research team identified one particular receptor-binding domain site that is present on SARS-CoV-2, its circulating variants and SARS-related bat viruses that makes them highly vulnerable to cross-neutralizing antibodies.

The team then designed a nanoparticle displaying this vulnerable spot. The nanoparticle is combined with a small molecule adjuvant — specifically, the toll-like receptor 7 and 8 agonist called 3M-052, formulated with Alum, which was developed by 3M and the Infectious Disease Research Institute. The adjuvant boosts the body’s immune response. 

In tests of its effect on monkeys, the nanoparticle vaccine blocked COVID-19 infection by 100%. The new vaccine also elicited significantly higher neutralizing levels in the animals than current vaccine platforms or natural infection in humans. 

“Basically what we’ve done is take multiple copies of a small part of the coronavirus to make the body’s immune system respond to it in a heightened way,” Saunders said. “We found that not only did that increase the body’s ability to inhibit the virus from causing infection, but it also targets this cross-reactive site of vulnerability on the spike protein more frequently. We think that’s why this vaccine is effective against SARS-CoV-1, SARS-CoV-2 and at least four of its common variants, plus additional animal coronaviruses.”

“There have been three coronavirus epidemics in the past 20 years, so there is a need to develop effective vaccines that can target these pathogens prior to the next pandemic,” Haynes said. “This work represents a platform that could prevent, rapidly temper, or extinguish a pandemic.”

In addition to Haynes and Saunders, study authors include Esther Lee, Robert Parks1,5, David R. Martinez, Dapeng, Haiyan Chen, Robert J. Edwards, Sophie Gobeil, Maggie Barr, Katayoun Mansour, S. Munir Alam, Laura L. Sutherland, Fangping Cai, Aja M. Sanzone, Madison Berry, Kartik Manne, Kevin W. Bock, Mahnaz Minai, Bianca M. Nagata, Anyway B. Kapingidza, Mihai Azoitei, Longping V. Tse, Trevor D. Scobey, Rachel L. Spreng, R. Wes Rountree, C. Todd DeMarco, Thomas N. Denny, Christopher W. Woods, Elizabeth W. Petzold, Thomas H. Oguin III, Gregory D. Sempowski, Matthew Gagne, Daniel C. Douek, Mark A. Tomai, Christopher B. Fox, Robert Seder, Kevin Wiehe, Drew Weissman, Norbert Pardi, Hana Golding, Surender Khurana, Priyamvada Acharya, Hanne Andersen, Mark G. Lewis, Ian N. Moore, David C. Montefiori and Ralph S. Baric.

The study received funding from the State of North Carolina with funds from the federal CARES Act; the National Institutes of Health (AI142596, R01AI157155 U54 CA260543, F32 AI152296, T32 AI007151); the North Carolina Policy Collaboratory at the University of North Carolina at Chapel Hill with funding from the North Carolina Coronavirus Relief Fund; and a Burroughs Wellcome Fund Postdoctoral Enrichment Program Award. COVID sample processing was performed in the Duke Regional Biocontainment Laboratory, which received partial support for construction from the NIH/NIAD (UC6AI058607) with support from a cooperative agreement with DOD/DARPA (HR0011-17-2-0069).


Provided by Duke Health

University of Miami Researchers Report COVID-19 Found in Penile Tissue Could Contribute to ED (Medicine)

First to demonstrate COVID-19 present in penis tissue long after COVID-19 recovery

University of Miami Miller School of Medicine researchers are the first to demonstrate that COVID-19 can be present in the penis tissue long after men recover from the virus.

The widespread blood vessel dysfunction, or endothelial dysfunction, that results from the COVID-19 infection could then contribute to erectile dysfunction, or ED, according to the study recently published in the World Journal of Men’s Health. Endothelial dysfunction is a condition in which the lining of the small blood vessels fails to perform all of its functions normally. As a result, the tissues supplied by those vessels could undergo damage.

“Our research shows that COVID-19 can cause widespread endothelial dysfunction in organ systems beyond the lungs and kidneys. The underlying endothelial dysfunction that happens because of COVID-19 can enter the endothelial cells and affect many organs, including the penis,” said study author Ranjith Ramasamy, M.D., associate professor and director of the Miller School’s Reproductive Urology Program. “In our pilot study, we found that men who previously did not complain of erectile dysfunction developed pretty severe erectile dysfunction after the onset of COVID-19 infection.”

Dr. Ramasamy and colleagues collected penile tissue from two men with a history of COVID-19 infection who underwent penile prosthesis surgery for ED. One of the men was hospitalized for COVID-19, while the other patient only had mild symptoms when he contracted the virus.

The researchers also collected tissue from two additional men with no history of COVID-19 infection undergoing the same surgery for ED. The investigators analyzed all the tissue samples for not only evidence of the virus but also endothelial dysfunction.

They found COVID-19 was present in the penile tissue of both men who had been infected, but not in the men with no history of the virus. The men had been infected six and eight months prior, respectively. These men had evidence of endothelial dysfunction, while the men who had been free of the virus did not.

“This suggests that men who develop COVID-19 infection should be aware that erectile dysfunction could be an adverse effect of the virus, and they should go to a physician if they develop ED symptoms,” Dr. Ramasamy said.

Ranjith Ramasamy, M.D., associate professor and director of the University of Miami Miller School’s Reproductive Urology Program © University of Miami Health System

The authors hypothesize that similar to other COVID-19 related complications, widespread infection and subsequent endothelial dysfunction could result in ED, and that worsening of ED could be due to the virus’s presence in the penile tissue, itself.

In a previously published study, Dr. Ramasamy and Miller School colleagues found that COVID-19 can also invade testis tissue in some men who are infected with the virus, which might be the first step in understanding the virus’s potential impact on male fertility and whether COVID-19 can be sexually transmitted.

“These latest findings are yet another reason that we should all do our best to avoid COVID-19,” said first author Eliyahu Kresch, a medical student working with Dr. Ramasamy.

“We recommend vaccination and to try to stay safe in general,” Kresch said.

Miller School coauthors are medical student Justin K. Achua, M.S.; clinical research coordinator Russell Saltzman; clinical research associate Kajal Khodamoradi, Ph.D.; Research Assistant Professor of Urology Himanshu Arora, Ph.D.; Assistant Professor of Urology and Neurological Surgery Emad Ibrahim, M.D., HCLD; Associate Professor of Pathology Oleksandr N. Kryvenko, M.D.; Transmission Electron Microscopy Core Vania Wolff Almeida; Fakiha Firdaus; and Founding Director of the Interdisciplinary Stem Cell Institute Joshua M. Hare, M.D.

Featured image: Ultrastructure features of penile tissue from live seroconverted COVID-19 patients. (A) Coronavirus-like spiked viral particles (arrows) visualized via TEM in the peri-vascular erectile tissue of a live patient who had previously contracted the COVID-19 virus and subsequently seroconverted. Particle diameter measurement indicated on image. (B) Coronavirus-like spiked viral particles (arrows) visualized via TEM in the peri-vascular erectile tissue of a live patient who had previously contracted the Covid-19 virus and subsequently seroconverted. Particle diameter measurement indicated on image. © Dr. Ranjith Ramasamy/University of Miami Health System


Reference: Kresch E, Achua J, Saltzman R, Khodamoradi K, Arora H, Ibrahim E, Kryvenko O, Almeida VW, Firdaus F, Hare JM, Ramasamy R.   COVID-19 Endothelial Dysfunction Can Cause Erectile Dysfunction: Histopathological, Immunohistochemical, and Ultrastructural Study of the Human Penis.   World J Mens Health. 2021;39:e22.   https://doi.org/10.5534/wjmh.210055


Provided by University of Miami School of Medicine

How To Predict Severe Influenza in Hospitalised Patients? (Medicine)

Melbourne researchers have identified predictors of both severe disease and recovery in hospitalised influenza patients, finding that the immune system works in concert to fight influenza.

Published today in Nature Communications, the team from the Peter Doherty Institute for Infection and Immunity (Doherty Institute), Alfred Health and Monash University sought to understand which patients would recover quickly from influenza and which would become severely ill.

The four-year project took samples from patients hospitalised with influenza at up to five time points during their hospital stay, and 30 days after discharge. They analysed the breadth of the immune response, enabling them to describe the specific roles of several different types of immune cells, including killer and helper T cells, B cells and innate cells.

University of Melbourne Dr Oanh Nguyen, Research Fellow at the Doherty Institute, said two significant findings of the research include understanding the biomarkers that drive recovery and identifying four specific cytokines that cause serious inflammation during influenza virus infection.

“Cytokines are key molecules needed for a robust immune response. However, too much of these cytokines can result in inflammation and in the case of influenza, much more serious infection,” Dr Nguyen said.

“We found four specific types of cytokines that would cause severe inflammation, and this provides clinicians the ability to predict whether a patient will become really sick with influenza.”

The team also consistently saw large populations of immune cells called T-follicular helper cells, working in parallel with antibody-secreting cells, in patients at around three days prior to their recovery.

“These findings are the first to report the importance of T-follicular helper cells during acute influenza virus infection, following previous discoveries from our work and others on the key role of these immune cells after influenza vaccination. Signs of these cells could be used as a biomarker for recovery from influenza,” Dr Nguyen said.

Professor Allen Cheng, Director of Infection Prevention and Healthcare Epidemiology at Alfred Health and Professor of Infectious Diseases Epidemiology at Monash University, said this had been a great collaboration between clinicians and world-renowned immunologists, and a good example of ‘bedside to bench’ science.

“The COVID-19 pandemic, and before this, the swine flu pandemic, has highlighted the importance of improving our understanding of respiratory viral infections to improve the identification of patients at risk of severe outcomes and potentially future treatments,” Professor Cheng said.

University of Melbourne Professor Katherine Kedzierska, Laboratory Head at the Doherty Institute and world-leading influenza immunologist, said this research laid the groundwork for her team’s understanding of how the immune system responds to COVID-19.

“Because of our years of experience, experimental set up, knowledge and collaborations with Alfred Health for this and other influenza studies, we had the speed and agility to apply our work to immune studies of COVID-19,” Professor Kedzierska said.

“This influenza study was the blueprint for our COVID-19 research.”


Reference: Nguyen, T.H.O., Koutsakos, M., van de Sandt, C.E. et al. Immune cellular networks underlying recovery from influenza virus infection in acute hospitalized patients. Nat Commun 12, 2691 (2021). https://doi.org/10.1038/s41467-021-23018-x


Provided by Doherty Institute

New Vaccine Blocks COVID-19 and Variants, Plus Other Coronaviruses (Medicine)

Study in animals identifies a potential way to build vaccines to fight future pandemics

A potential new vaccine developed by members of the Duke Human Vaccine Institute has proven effective in protecting monkeys and mice from a variety of coronavirus infections — including SARS-CoV-2 as well as the original SARS-CoV-1 and related bat coronaviruses that could potentially cause the next pandemic.

The new vaccine, called a pan-coronavirus vaccine, triggers neutralizing antibodies via a nanoparticle. The nanoparticle is composed of the coronavirus part that allows it to bind to the body’s cell receptors, and is formulated with a chemical booster called an adjuvant. Success in primates is highly relevant to humans.

The findings appear Monday, May 10 in the journal Nature.

“We began this work last spring with the understanding that, like all viruses, mutations would occur in the SARS-CoV-2 virus, which causes COVID-19,” said senior author Barton F. Haynes, M.D., director of the Duke Human Vaccine Institute (DHVI). “The mRNA vaccines were already under development, so we were looking for ways to sustain their efficacy once those variants appeared.

“This approach not only provided protection against SARS-CoV-2, but the antibodies induced by the vaccine also neutralized variants of concern that originated in the United Kingdom, South Africa and Brazil,” Haynes said. “And the induced antibodies reacted with quite a large panel of coronaviruses.”

Haynes and colleagues, including lead author Kevin Saunders, Ph.D., director of research at DHVI, built on earlier studies involving SARS, the respiratory illness caused by a coronavirus called SARS-CoV-1. They found a person who had been infected with SARS developed antibodies capable of neutralizing multiple coronaviruses, suggesting that a pan-coronavirus might be possible.

The Achilles heel for the coronaviruses is their receptor-binding domain, located on the spike that links the viruses to receptors in human cells. While this binding site enables it to enter the body and cause infection, it can also be targeted by antibodies.

The research team identified one particular receptor-binding domain site that is present on SARS-CoV-2, its circulating variants and SARS-related bat viruses that makes them highly vulnerable to cross-neutralizing antibodies.

The team then designed a nanoparticle displaying this vulnerable spot. The nanoparticle is combined with a small molecule adjuvant — specifically, the toll-like receptor 7 and 8 agonist called 3M-052, formulated with Alum, which was developed by 3M and the Infectious Disease Research Institute. The adjuvant boosts the body’s immune response. 

In tests of its effect on monkeys, the nanoparticle vaccine blocked COVID-19 infection by 100%. The new vaccine also elicited significantly higher neutralizing levels in the animals than current vaccine platforms or natural infection in humans. 

“Basically what we’ve done is take multiple copies of a small part of the coronavirus to make the body’s immune system respond to it in a heightened way,” Saunders said. “We found that not only did that increase the body’s ability to inhibit the virus from causing infection, but it also targets this cross-reactive site of vulnerability on the spike protein more frequently. We think that’s why this vaccine is effective against SARS-CoV-1, SARS-CoV-2 and at least four of its common variants, plus additional animal coronaviruses.”

“There have been three coronavirus epidemics in the past 20 years, so there is a need to develop effective vaccines that can target these pathogens prior to the next pandemic,” Haynes said. “This work represents a platform that could prevent, rapidly temper, or extinguish a pandemic.”

In addition to Haynes and Saunders, study authors include Esther Lee, Robert Parks1,5, David R. Martinez, Dapeng, Haiyan Chen, Robert J. Edwards, Sophie Gobeil, Maggie Barr, Katayoun Mansour, S. Munir Alam, Laura L. Sutherland, Fangping Cai, Aja M. Sanzone, Madison Berry, Kartik Manne, Kevin W. Bock, Mahnaz Minai, Bianca M. Nagata, Anyway B. Kapingidza, Mihai Azoitei, Longping V. Tse, Trevor D. Scobey, Rachel L. Spreng, R. Wes Rountree, C. Todd DeMarco, Thomas N. Denny, Christopher W. Woods, Elizabeth W. Petzold, Thomas H. Oguin III, Gregory D. Sempowski, Matthew Gagne, Daniel C. Douek, Mark A. Tomai, Christopher B. Fox, Robert Seder, Kevin Wiehe, Drew Weissman, Norbert Pardi, Hana Golding, Surender Khurana, Priyamvada Acharya, Hanne Andersen, Mark G. Lewis, Ian N. Moore, David C. Montefiori and Ralph S. Baric.

The study received funding from the State of North Carolina with funds from the federal CARES Act; the National Institutes of Health (AI142596, R01AI157155 U54 CA260543, F32 AI152296, T32 AI007151); the North Carolina Policy Collaboratory at the University of North Carolina at Chapel Hill with funding from the North Carolina Coronavirus Relief Fund; and a Burroughs Wellcome Fund Postdoctoral Enrichment Program Award.


Reference: Saunders, K.O., Lee, E., Parks, R. et al. Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses. Nature (2021). https://doi.org/10.1038/s41586-021-03594-0


Provided by Duke Health

COVID-19 Vaccine is Associated With Fewer Asymptomatic SARS-CoV-2 Infections (Medicine)

St. Jude Children’s Research Hospital COVID-19 screening and vaccination program for employees offers early evidence that vaccine protects against asymptomatic infection, which has fueled the pandemic.

Vaccination dramatically reduced COVID-19 symptomatic and asymptomatic infections in St. Jude Children’s Research Hospital employees compared with their unvaccinated peers, according to a research letter that appears today in the Journal of the American Medical Association.

The study is among the first to show an association between COVID-19 vaccination and fewer asymptomatic infections. When the Pfizer-BioNTech BNT162b2 vaccine was authorized for use in the U.S., the vaccine was reported to be highly effective at preventing laboratory-confirmed COVID-19. Clinical trial data suggested that the two-dose regimen reduced symptomatic disease, including hospitalization and death. But an association with reduced asymptomatic infection was unclear.

“While further research is needed, by preventing infections, including in people who have no symptoms, there is a high possibility that vaccination will decrease transmission of SARS-CoV-2,” said Diego Hijano, M.D., of the St. Jude Department of Infectious Diseases. He and Li Tang, Ph.D., of St. Jude Biostatistics, are the first authors of the report. Tang is also the corresponding author.

The study involved 5,217 St. Jude employees who were eligible under Tennessee state guidelines for vaccination between Dec. 17, 2020, and March 20, 2021. More than 58% of employees were vaccinated during that period. Most workers received both doses.

Overall, vaccination reduced the risk of asymptomatic and symptomatic SARS-CoV-2 infection by 79% in vaccinated employees compared with their unvaccinated colleagues. An analysis of asymptomatic infections alone found vaccination reduced the risk by 72%.   

Protection was even greater for employees who completed two doses. A week or more after receiving the second dose, vaccinated employees were 96% less likely than unvaccinated workers to become infected with SARS-CoV-2. When researchers looked just at asymptomatic infections, vaccination reduced the risk by 90%.

Finding SARS-CoV-2 infections

First author Li Tang, Ph.D., of St. Jude Biostatistics, contributed to the study that is published in the Journal of the American Medical Association. © St. Jude

The research stems from a program that St. Jude leaders began in March 2020 to protect patients and employees from the pandemic virus.

The effort included targeted testing for employees with COVID-19 symptoms or known exposure to the pandemic virus. The plan also involved routine, laboratory testing of asymptomatic employees. Nasal swabs were collected at least weekly from self-reported asymptomatic on-campus workers to perform polymerase chain reaction to detect asymptomatic SARS-CoV-2 infection.

“This study was possible because St. Jude invested in resources to determine how best to control the disease and protect our patients and employees,” Tang said. “Few places then or now provide such broad asymptomatic testing.”

Hijano said, “Testing has been invaluable to the institutional COVID-19 mitigation plan. In the end, the testing also serves as a unique tool that helps to fill in critical knowledge gaps.”

Results by the numbers

During the study, 236 of the 5,217 employees included in the analysis tested positive for SARS-CoV-2. They included 185 unvaccinated employees and 51 of the 3,052 workers who had received at least one dose of the vaccine.

Almost half of the positive cases, 108, reported no symptoms upon testing. The asymptomatic cases included 20 employees who had received one vaccine dose and three who tested positive within seven days of the second dose. “The results are a reminder of the many hidden cases in the population, which makes containing the virus a big challenge,” Tang said.

The study group included a cross-section of employees in regard to race and gender. More than 80% of employees were younger than 65 years old. The vaccinated group included a higher percentage of health care staff, 47%, than the unvaccinated employees, 25.7%.

Authors and funding

The senior authors are James Hoffman, Pharm.D., and Randall Hayden, M.D., of St. Jude. The other authors are Aditya Gaur, Terrence Geiger and Ellis Neufeld, all of St. Jude.

The research was funded in part by ALSAC, the St. Jude fundraising and awareness organization.

Featured image: First author Diego Hijano, M.D., of the St. Jude Department of Infectious Diseases, studied how the COVID-19 vaccine reduced symptomatic and asymptomatic infections in employees. © St. Jude

Read the full text of the article:

Asymptomatic and Symptomatic SARS-CoV-2 Infections after BNT162b2 Vaccination in a Routinely Screened Workforce. Journal of the American Medical Association, Published May 6, 2021.


Provided by St. Jude Children’s Research Hospital

Urine of COVID-19 Patients Could Predict Who Will Develop Severe Disease (Medicine)

Inflammatory markers were higher in people with high blood pressure and diabetes

Urine analysis of COVID-19 patients revealed elevated levels of specific biomarkers of the immune system compared to those who were not infected with the coronavirus. In addition, levels of these inflammatory markers were higher in patients with comorbidities such as high blood pressure and diabetes, according to researchers from Wayne State University in Detroit. The findings will be presented virtually at the American Physiological Society’s (APS) annual meeting at Experimental Biology 2021.

Researchers said they undertook this study in hopes of determining whether biomarkers of COVID-19 could predict which individuals will develop “overly exuberant immune responses,” also called a cytokine storm. They chose to screen the urine of COVID-19 patients because of its non-invasive nature that doesn’t require the use of needles or blood samples.

Scientists said they hope the results of this study will translate to a regular screening process for COVID-19 patients to predict who is more likely to develop severe disease and to aid in a successful treatment strategy.

NOTE TO JOURNALISTS: To schedule an interview with a member of the research team, and/or request the abstract, “Urine cytokines as biomarkers in COVID-19 patients,” please contact the APS Communications Office or call 301.634.7314. Find more research highlights in the APS Newsroom.

Featured image: Dragana Komnenov, PhD, Wayne State University, Detroit © Dragana Komnenov


Provided by American Physiological Society


About Experimental Biology 2021

Experimental Biology is the annual meeting of five societies that explores the latest research in physiology, anatomy, biochemistry and molecular biology, investigative pathology and pharmacology. With a mission to share the newest scientific concepts and research findings shaping clinical advances, the meeting offers an unparalleled opportunity for global exchange among scientists who represent dozens of scientific areas, from laboratory to translational to clinical research.

About the American Physiological Society

Physiology is a broad area of scientific inquiry that focuses on how molecules, cells, tissues and organs function in health and disease. The American Physiological Society connects a global, multidisciplinary community of more than 10,000 biomedical scientists and educators as part of its mission to advance scientific discovery, understand life and improve health. The Society drives collaboration and spotlights scientific discoveries through its 16 scholarly journals and programming that support researchers and educators in their work.