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Archive for the ‘Viral diseases’ Category


Non-toxic antiviral nanoparticles with a broad spectrum of virus inhibition

Curator and Reporter: Dr. Premalata Pati, Ph.D., Postdoc

Infectious diseases account for 20% of global deaths, with viruses accounting for over a third of these deaths (1). Lower respiratory effects and human immunodeficiency viruses (HIV) are among the top ten causes of death worldwide, both of which contribute significantly to health-care costs (2). Every year, new viruses (such as Ebola) increase the mortality toll. Vaccinations are the most effective method of avoiding viral infections, but there are only a few of them, and they are not available in all parts of the world (3). After infection, antiviral medications are the only option; unfortunately, only a limited number of antiviral medications are approved in this condition. Antiviral drugs on a big scale that can influence a wide spectrum of existing and emerging viruses are critical.

The three types of treatments currently available are small molecules (such as nucleoside analogues and peptidomimetics), proteins that stimulate the immune system (such as interferon), and oligonucleotides (for example, fomivirsen). The primary priorities include HIV, hepatitis B and C viruses, Herpes Simplex Virus (HSV), human cytomegalovirus (HCMV), and influenza virus. They work mainly on viral enzymes, which are necessary for viral replication but which differ from other host enzymes to ensure selective function. The specificity of antivirals is far from perfect because viruses rely on the biosynthesis machinery for reproduction of infected cells, which results in a widespread and inherent toxicity associated with such therapy. However, most viruses mutate rapidly due to their improper replicating mechanisms and so often develop resistance (4). Finally, since antiviral substances are targeted at viral proteins, it is challenging to build broad-based antivirals that can act with a wide range of phylogenetic and structurally different virus.

Over the last decade breakthroughs in nanotechnology have led to scientists developing incredibly specialized nanoparticles capable of traveling in specific cells through a human body. A broad spectrum of destructive viruses is being targeted and not only bind to, but also destroy, by modern computer modeling technology.

An international team of researchers led by the University of Illinois at Chicago chemistry professor Petr Kral developed novel anti-viral nanoparticles that bind to a variety of viruses, including herpes simplex virus, human papillomavirus, respiratory syncytial virus, Dengue, and lentiviruses. In contrast to conventional broad-spectrum antivirals, which just prevent viruses from invading cells, the new nanoparticles eradicate viruses. The team’s findings have been published in the journal “Nature Materials.”

A molecular dynamics model showing a nanoparticle binding to the outer envelope of the human papillomavirus. (Credit: Petr Kral) https://today.uic.edu/files/2017/09/viralbindingcropped.png

The goal of this new study was to create a new anti-viral nanoparticle that could exploit the HSPG binding process to not only tightly attach with virus particles but also to destroy them. The work was done by a group of researchers ranging from biochemists to computer modeling experts until the team came up with a successful nanoparticle design that could, in principle, accurately target and kill individual virus particles.

The first step to combat many viruses consists in the attachment of heparin sulfate proteoglycan on cell surfaces to a protein (HSPG). Some of the antiviral medications already in place prevent an infection by imitating HSPG’s connection to the virus. An important constraint of these antivirals is that not only is this antiviral interaction weak, it does not kill the virus.

Kral said

We knew how the nanoparticles should bind on the overall composition of HSPG binding viral domains and the structures of the nanoparticles, but we did not realize why the various nanoparticles act so differently in terms of their both bond strength and viral entry in cells

Kral and colleagues assisted in resolving these challenges and guiding the experimentalists in fine-tuning the nanoparticle design so that it performed better.

The researchers have employed advanced computer modeling techniques to build exact structures of several target viruses and nanoparticles up to the atom’s position. A profound grasp of the interactions between individual atom groupings in viruses and nanoparticles allows the scientists to evaluate the strength and duration of prospective links between these two entities and to forecast how the bond could change over time and eventually kill the virus.


Atomistic MD simulations of an L1 pentamer of HPV capsid protein with the small NP (2.4 nm core, 100 MUP ligands). The NP and the protein are shown by van der Waals (vdW) and ribbon representations respectively. In the protein, the HSPG binding amino acids are displayed by vdW representation.

Kral added

We were capable of providing the design team with the data needed to construct a prototype of an antiviral of high efficiency and security, which may be utilized to save lives

The team has conducted several in vitro experiments following the development of a prototype nanoparticle design which have demonstrated success in binding and eventually destroying a wide spectrum of viruses, including herpes simplex, human papillomaviruses, respiratory syncytial viruses and dengue and lentiviruses.

The research is still in its early phases, and further in vivo animal testing is needed to confirm the nanoparticles’ safety, but this is a promising new road toward efficient antiviral therapies that could save millions of people from devastating virus infections each year.

The National Centers of Competence in Research on Bio-Inspired Materials, the University of Turin, the Ministry of Education, Youth and Sports of the Czech Republic, the Leenards Foundation, National Science Foundation award DMR-1506886, and funding from the University of Texas at El Paso all contributed to this study.

Main Source

Cagno, V., Andreozzi, P., D’Alicarnasso, M., Silva, P. J., Mueller, M., Galloux, M., … & Stellacci, F. (2018). Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism. Nature materials17(2), 195-203. https://www.nature.com/articles/nmat5053

Other Related Articles published in this Open Access Online Scientific Journal include the following:

Rare earth-doped nanoparticles applications in biological imaging and tumor treatment

Reporter: Irina Robu, PhD

https://pharmaceuticalintelligence.com/2020/10/04/rare-earth-doped-nanoparticles-applications-in-biological-imaging-and-tumor-treatment/

Nanoparticles Could Boost Effectiveness of Allergy Shots

Reporter: Irina Robu, PhD

https://pharmaceuticalintelligence.com/2019/05/25/nanoparticles-could-boost-effectiveness-of-allergy-shots/

Immunoreactivity of Nanoparticles

Author: Tilda Barliya PhD

https://pharmaceuticalintelligence.com/2012/10/27/immunoreactivity-of-nanoparticles/

Nanotechnology and HIV/AIDS Treatment

Author: Tilda Barliya, PhD

https://pharmaceuticalintelligence.com/2012/12/25/nanotechnology-and-hivaids-treatment/

Nanosensors for Protein Recognition, and gene-proteome interaction

Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/01/30/nanosensors-for-protein-recognition-and-gene-proteome-interaction/

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C.D.C. Reviewing Cases of Heart Problem in Youngsters After Getting Vaccinated and AHA Reassures that Benefits Overwhelm the Risks of Vaccination

Reporter: Amandeep Kaur, B.Sc. , M.Sc.

The latest article in New York times reported by Apoorva Mandavilli outlines the statement of officials that C.D.C. agency is investigating few cases of young adults and teenagers who might have developed myocarditis after getting vaccinated. It is not confirmed by the agency that whether this condition is caused by vaccine or not.

According to the vaccine safety group of the Centers for Disease Control and Prevention, the reports of heart problems experienced by youngsters is relatively very small in number. The group stated that these cases could be unlinked to vaccination. The condition of inflammation of heart muscle which can occur due to certain infections is known as myocarditis.

Moreover, the agency still has to determine any evidence related to vaccines causing the heart issues. The C.D.C. has posted on its website the updated guidance for doctors and clinicians, urging them to be alert to uncommon symptoms related to heart cases among teenagers who are vaccine recipients.

In New York, Dr. Celine Gounder, an infectious disease specialist at Bellevue Hospital Center stated that “It may simply be a coincidence that some people are developing myocarditis after vaccination. It’s more likely for something like that to happen by chance, because so many people are getting vaccinated right now.”

The article reported that the cases appeared mainly in young adults after about four days of their second shot of mRNA vaccines, made by Moderna and Pfizer-BioNTech. Such cases are more prevalent in males as compared to females.

The vaccine safety group stated “Most cases appear to be mild, and follow-up of cases is ongoing.” It is strongly recommended by C.D.C. that American young adults from the age of 12 and above should get vaccinated against COVID-19.

Dr. Yvonne Maldonado, chair of the American Academy of Pediatrics’s Committee on Infectious Diseases stated “We look forward to seeing more data about these cases, so we can better understand if they are related to the vaccine or if they are coincidental. Meanwhile, it’s important for pediatricians and other clinicians to report any health concerns that arise after vaccination.”

Experts affirmed that the potentially uncommon side effects of myocarditis get insignificant compared to the potential risks of SARS-CoV-2 infection, including the continuous syndrome known as “long Covid.” It is reported in the article that acute Covid can lead to myocarditis.

According to the data collected by A.A.P, about 16 thousand children were hospitalized and more than 3.9 million children were infected by coronavirus till the second week of May. In the United States, about 300 children died of SARS-CoV-2 infection, which makes it among the top 10 death causes in children since the start of pandemic.

Dr. Jeremy Faust, an emergency medicine physician at Brigham and Women’s Hospital in Boston stated that “And that’s in the context of all the mitigation measures taken.”

According to researchers, about 10 to 20 of every 1 lakh people each year develop myocarditis in the general population, facing symptoms from fatigue and chest pain to arrhythmias and cardiac arrest, whereas some have mild symptoms which remain undiagnosed.

Currently, the number of reports of myocarditis after vaccination is less than that reported normally in young adults, confirmed by C.D.C. The article reported that the members of vaccine safety group felt to communicate the information about upcoming cases of myocarditis to the providers.

The C.D.C. has not yet specified the ages of the patients involved in reporting. Since December 2020, the Pfizer-BioNTech vaccine was authorized for young people of age 16 and above. The Food and Drug Administration extended the authorization to children of age 12 to 15 years, by the starting of this month.

On 14th May, the clinicians have been alerted by C.D.C. regarding the probable link between myocarditis and vaccination. Within three days, the team started reviewing data on myocarditis, reports filed with the Vaccine Adverse Event Reporting System and others from the Department of Defense.

A report on seven cases has been submitted to the journal Pediatrics for review and State health departments in Washington, Oregon and California have notified emergency providers and cardiologists about the potential problem.

In an interview, Dr. Liam Yore, past president of the Washington State chapter of the American College of Emergency Physicians detailed a case of teenager with myocarditis after vaccination. The patient was provided treatment for mild inflammation of the inner lining of the heart and was discharged afterwards. Later, the young adult returned for care due to decrease in the heart’s output. Dr. Yore reported that still he had come across worse cases in youngsters with Covid, including in a 9-year-old child who arrived at the hospital after a cardiac arrest last winter.

He stated that “The relative risk is a lot in favor of getting the vaccine, especially considering how coronavirus vaccine have been administered.”

In the United States, more than 161 million people have received their first shot of vaccine in which about 4.5 million people were between the age 12 to 18 years.

Benefits Overwhelm Risks of COVID Vaccination, AHA Reassures

The latest statement of American Heart Association (AHA)/ American Stroke Association (ASA) on May 23rd states that the benefits of COVID-19 vaccination enormously outweigh the rare risk for myocarditis cases, which followed the C.D.C. report that the agency is tracking the Vaccine Adverse Events Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) for myocarditis cases linked with mRNA vaccines against coronavirus.

The myocarditis cases in young adults are more often observed after the second dose of vaccine rather than the first one, and have more cases of males than females. The CDC’s COVID-19 Vaccine Safety Technical Work Group (VaST) observed such heart complications after 4 days of vaccination.

CDC reported that “Within CDC safety monitoring systems, rates of myocarditis reports in the window following COVID-19 vaccination have not differed from expected baseline rates.”

The CDC team stated that “The evidence continues to indicate that the COVID-19 vaccines are nearly 100% effective at preventing death and hospitalization due to COVID-19 infection, and Strongly urged all young adults and children 12 years and above to get vaccinated as soon as possible.”

Even though the analysis of myocarditis reports related to coronavirus vaccine is in progress, the AHA/ASA stated that “myocarditis is typically the result of an actual viral infection, and it is yet to be determined if these cases have any correlation to receiving a COVID-19 vaccine.”

Richard Besser, MD, president and CEO of the Robert Wood Johnson Foundation (RWJF) and former acting director of the CDC stated on ABC’s Good Morning America “We’ve lost hundreds of children and there have been thousands who have been hospitalized, thousands who developed an inflammatory syndrome, and one of the pieces of that can be myocarditis.” He added “still, from my perspective, the risk of COVID is so much greater than any theoretical risk from the vaccine.”

After COVID-19 vaccination the symptoms that occur include tiredness, muscle pain, headaches, chills, nausea and fever. The AHA/ASA stated that “typically appear within 24 to 48 hours and usually pass within 36-48 hours after receiving the vaccine.”

All healthcare providers are suggested to be aware of the rare adverse symptoms such as myocarditis, low platelets, blood clots, and severe inflammation. The agency stated that “Healthcare professionals should strongly consider inquiring about the timing of any recent COVID vaccination among patients presenting with these conditions, as needed, in order to provide appropriate treatment quickly.”

President Mitchell S.V. Elkind, M.D., M.S., FAHA, FAAN, Immediate Past President Robert A. Harrington, M.D., FAHA, President-Elect Donald M. Lloyd-Jones, M.D., Sc.M., FAHA, Chief Science and Medical Officer Mariell Jessup, M.D., FAHA, and Chief Medical Officer for Prevention Eduardo Sanchez, M.D, M.P.H., FAAFP are science leaders of AHA/ASA and reflected their views in the following statements:

We strongly urge all adults and children ages 12 and older in the U.S. to receive a COVID vaccine as soon as they can receive it, as recently approved by the U.S. Food and Drug Administration and the CDC. The evidence continues to indicate that the COVID-19 vaccines are nearly 100% effective at preventing death and hospitalization due to COVID-19 infection. According to the CDC as of May 22, 2021, over 283 million doses of COVID-19 vaccines have been administered in the U.S. since December 14, 2020, and more than 129 million Americans are fully vaccinated (i.e., they have received either two doses of the Pfizer-BioNTech or Moderna COVID-19 vaccine, or the single-dose Johnson & Johnson/Janssen COVID-19 vaccine).

We remain confident that the benefits of vaccination far exceed the very small, rare risks. The risks of vaccination are also far smaller than the risks of COVID-19 infection itself, including its potentially fatal consequences and the potential long-term health effects that are still revealing themselves, including myocarditis. The recommendation for vaccination specifically includes people with cardiovascular risk factors such as high blood pressure, obesity and type 2 diabetes, those with heart disease, and heart attack and stroke survivors, because they are at much greater risk of an adverse outcome from the COVID-19 virus than they are from the vaccine.

We commend the CDC’s continual monitoring for adverse events related to the COVID-19 vaccines through VAERS and VSD, and the consistent meetings of ACIP’s VaST Work Group, demonstrating transparent and robust attention to any and all health events possibly related to a COVID-19 vaccine. The few cases of myocarditis that have been reported after COVID-19 vaccination are being investigated. However, myocarditis is usually the result of a viral infection, and it is yet to be determined if these cases have any correlation to receiving a COVID-19 vaccine, especially since the COVID-19 vaccines authorized in the U.S. do not contain any live virus.

We also encourage everyone to keep in touch with their primary care professionals and seek care immediately if they have any of these symptoms in the weeks after receiving the COVID-19 vaccine: chest pain including sudden, sharp, stabbing pains; difficulty breathing/shortness of breath; abnormal heartbeat; severe headache; blurry vision; fainting or loss of consciousness; weakness or sensory changes; confusion or trouble speaking; seizures; unexplained abdominal pain; or new leg pain or swelling.

We will stay up to date with the CDC’s recommendations regarding all potential complications related to COVID-19 vaccines, including myocarditis, pericarditis, central venous sinus thrombosis (CVST) and other blood clotting events, thrombosis thrombocytopenia syndrome (TTS), and vaccine-induced immune thrombosis thrombocytopenia (VITT).

The American Heart Associationrecommends all health care professionals be aware of these very rare adverse events that may be related to a COVID-19 vaccine, including myocarditis, blood clots, low platelets, or symptoms of severe inflammation. Health care professionals should strongly consider inquiring about the timing of any recent COVID vaccination among patients presenting with these conditions, as needed, in order to provide appropriate treatment quickly. As detailed in last month’s AHA/ASA statement, all suspected CVST or blood clots associated with the COVID-19 vaccine should be treated initially using non-heparin anticoagulants. Heparin products should not be administered in any dose if TTS/VITT is suspected, until appropriate testing can be done to exclude heparin-induced antibodies. In addition, health care professionals are required to report suspected vaccine-related adverse events to the Vaccine Adverse Event Reporting System, in accordance with federal regulations.

Individuals should refer to their local and state health departments for specific information about when and where they can get vaccinated. We implore everyone ages 12 and older to get vaccinated so we can return to being together, in person – enjoying life with little to no risk of severe COVID-19 infection, hospitalization or death.

We also support the CDC recommendations last week that loosen restrictions on mask wearing and social distancing for people who are fully vaccinated. For those who are unable to be vaccinated, we reiterate the importance of handwashing, social distancing and wearing masks, particularly for people at high risk of infection and/or severe COVID-19. These simple precautions remain crucial to protecting people who are not vaccinated from the virus that causes COVID-19.

Source:

Other related articles were published in this Open Access Online Scientific Journal, including the following:

Thriving Vaccines and Research: Weizmann Institute Coronavirus Research Development

Reporter: Amandeep Kaur, B.Sc., M.Sc.

https://pharmaceuticalintelligence.com/2021/05/04/thriving-vaccines-and-research-weizmann-coronavirus-research-development/

Identification of Novel genes in human that fight COVID-19 infection

Reporter: Amandeep Kaur, B.Sc., M.Sc.

https://pharmaceuticalintelligence.com/2021/04/19/identification-of-novel-genes-in-human-that-fight-covid-19-infection/

Fighting Chaos with Care, community trust, engagement must be cornerstones of pandemic response

Reporter: Amandeep Kaur, B.Sc., M.Sc. 

https://pharmaceuticalintelligence.com/2021/04/13/fighting-chaos-with-care/

T cells recognize recent SARS-CoV-2 variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/03/30/t-cells-recognize-recent-sars-cov-2-variants/

Need for Global Response to SARS-CoV-2 Viral Variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/02/12/need-for-global-response-to-sars-cov-2-viral-variants/

Read Full Post »


Thriving Vaccines and Research: Weizmann Institute Coronavirus Research Development

Reporter: Amandeep Kaur, B.Sc., M.Sc.

In early February, Prof. Eran Segal updated in one of his tweets and mentioned that “We say with caution, the magic has started.”

The article reported that this statement by Prof. Segal was due to decreasing cases of COVID-19, severe infection cases and hospitalization of patients by rapid vaccination process throughout Israel. Prof. Segal emphasizes in another tweet to remain cautious over the country and informed that there is a long way to cover and searching for scientific solutions.

A daylong webinar entitled “COVID-19: The epidemic that rattles the world” was a great initiative by Weizmann Institute to share their scientific knowledge about the infection among the Israeli institutions and scientists. Prof. Gideon Schreiber and Dr. Ron Diskin organized the event with the support of the Weizmann Coronavirus Response Fund and Israel Society for Biochemistry and Molecular Biology. The speakers were invited from the Hebrew University of Jerusalem, Tel-Aviv University, the Israel Institute for Biological Research (IIBR), and Kaplan Medical Center who addressed the molecular structure and infection biology of the virus, treatments and medications for COVID-19, and the positive and negative effect of the pandemic.

The article reported that with the emergence of pandemic, the scientists at Weizmann started more than 60 projects to explore the virus from different range of perspectives. With the help of funds raised by communities worldwide for the Weizmann Coronavirus Response Fund supported scientists and investigators to elucidate the chemistry, physics and biology behind SARS-CoV-2 infection.

Prof. Avi Levy, the coordinator of the Weizmann Institute’s coronavirus research efforts, mentioned “The vaccines are here, and they will drastically reduce infection rates. But the coronavirus can mutate, and there are many similar infectious diseases out there to be dealt with. All of this research is critical to understanding all sorts of viruses and to preempting any future pandemics.”

The following are few important projects with recent updates reported in the article.

Mapping a hijacker’s methods

Dr. Noam Stern-Ginossar studied the virus invading strategies into the healthy cells and hijack the cell’s systems to divide and reproduce. The article reported that viruses take over the genetic translation system and mainly the ribosomes to produce viral proteins. Dr. Noam used a novel approach known as ‘ribosome profiling’ as her research objective and create a map to locate the translational events taking place inside the viral genome, which further maps the full repertoire of viral proteins produced inside the host.

She and her team members grouped together with the Weizmann’s de Botton Institute and researchers at IIBR for Protein Profiling and understanding the hijacking instructions of coronavirus and developing tools for treatment and therapies. Scientists generated a high-resolution map of the coding regions in the SARS-CoV-2 genome using ribosome-profiling techniques, which allowed researchers to quantify the expression of vital zones along the virus genome that regulates the translation of viral proteins. The study published in Nature in January, explains the hijacking process and reported that virus produces more instruction in the form of viral mRNA than the host and thus dominates the translation process of the host cell. Researchers also clarified that it is the misconception that virus forced the host cell to translate its viral mRNA more efficiently than the host’s own translation, rather high level of viral translation instructions causes hijacking. This study provides valuable insights for the development of effective vaccines and drugs against the COVID-19 infection.

Like chutzpah, some things don’t translate

Prof. Igor Ulitsky and his team worked on untranslated region of viral genome. The article reported that “Not all the parts of viral transcript is translated into protein- rather play some important role in protein production and infection which is unknown.” This region may affect the molecular environment of the translated zones. The Ulitsky group researched to characterize that how the genetic sequence of regions that do not translate into proteins directly or indirectly affect the stability and efficiency of the translating sequences.

Initially, scientists created the library of about 6,000 regions of untranslated sequences to further study their functions. In collaboration with Dr. Noam Stern-Ginossar’s lab, the researchers of Ulitsky’s team worked on Nsp1 protein and focused on the mechanism that how such regions affect the Nsp1 protein production which in turn enhances the virulence. The researchers generated a new alternative and more authentic protocol after solving some technical difficulties which included infecting cells with variants from initial library. Within few months, the researchers are expecting to obtain a more detailed map of how the stability of Nsp1 protein production is getting affected by specific sequences of the untranslated regions.

The landscape of elimination

The article reported that the body’s immune system consists of two main factors- HLA (Human Leukocyte antigen) molecules and T cells for identifying and fighting infections. HLA molecules are protein molecules present on the cell surface and bring fragments of peptide to the surface from inside the infected cell. These peptide fragments are recognized and destroyed by the T cells of the immune system. Samuels’ group tried to find out the answer to the question that how does the body’s surveillance system recognizes the appropriate peptide derived from virus and destroy it. They isolated and analyzed the ‘HLA peptidome’- the complete set of peptides bound to the HLA proteins from inside the SARS-CoV-2 infected cells.

After the analysis of infected cells, they found 26 class-I and 36 class-II HLA peptides, which are present in 99% of the population around the world. Two peptides from HLA class-I were commonly present on the cell surface and two other peptides were derived from coronavirus rare proteins- which mean that these specific coronavirus peptides were marked for easy detection. Among the identified peptides, two peptides were novel discoveries and seven others were shown to induce an immune response earlier. These results from the study will help to develop new vaccines against new coronavirus mutation variants.

Gearing up ‘chain terminators’ to battle the coronavirus

Prof. Rotem Sorek and his lab discovered a family of enzymes within bacteria that produce novel antiviral molecules. These small molecules manufactured by bacteria act as ‘chain terminators’ to fight against the virus invading the bacteria. The study published in Nature in January which reported that these molecules cause a chemical reaction that halts the virus’s replication ability. These new molecules are modified derivates of nucleotide which integrates at the molecular level in the virus and obstruct the works.

Prof. Sorek and his group hypothesize that these new particles could serve as a potential antiviral drug based on the mechanism of chain termination utilized in antiviral drugs used recently in the clinical treatments. Yeda Research and Development has certified these small novel molecules to a company for testing its antiviral mechanism against SARS-CoV-2 infection. Such novel discoveries provide evidences that bacterial immune system is a potential repository of many natural antiviral particles.

Resolving borderline diagnoses

Currently, Real-time Polymerase chain reaction (RT-PCR) is the only choice and extensively used for diagnosis of COVID-19 patients around the globe. Beside its benefits, there are problems associated with RT-PCR, false negative and false positive results and its limitation in detecting new mutations in the virus and emerging variants in the population worldwide. Prof. Eran Elinavs’ lab and Prof. Ido Amits’ lab are working collaboratively to develop a massively parallel, next-generation sequencing technique that tests more effectively and precisely as compared to RT-PCR. This technique can characterize the emerging mutations in SARS-CoV-2, co-occurring viral, bacterial and fungal infections and response patterns in human.

The scientists identified viral variants and distinctive host signatures that help to differentiate infected individuals from non-infected individuals and patients with mild symptoms and severe symptoms.

In Hadassah-Hebrew University Medical Center, Profs. Elinav and Amit are performing trails of the pipeline to test the accuracy in borderline cases, where RT-PCR shows ambiguous or incorrect results. For proper diagnosis and patient stratification, researchers calibrated their severity-prediction matrix. Collectively, scientists are putting efforts to develop a reliable system that resolves borderline cases of RT-PCR and identify new virus variants with known and new mutations, and uses data from human host to classify patients who are needed of close observation and extensive treatment from those who have mild complications and can be managed conservatively.

Moon shot consortium refining drug options

The ‘Moon shot’ consortium was launched almost a year ago with an initiative to develop a novel antiviral drug against SARS-CoV-2 and was led by Dr. Nir London of the Department of Chemical and Structural Biology at Weizmann, Prof. Frank von Delft of Oxford University and the UK’s Diamond Light Source synchroton facility.

To advance the series of novel molecules from conception to evidence of antiviral activity, the scientists have gathered support, guidance, expertise and resources from researchers around the world within a year. The article reported that researchers have built an alternative template for drug-discovery, full transparency process, which avoids the hindrance of intellectual property and red tape.

The new molecules discovered by scientists inhibit a protease, a SARS-CoV-2 protein playing important role in virus replication. The team collaborated with the Israel Institute of Biological Research and other several labs across the globe to demonstrate the efficacy of molecules not only in-vitro as well as in analysis against live virus.

Further research is performed including assaying of safety and efficacy of these potential drugs in living models. The first trial on mice has been started in March. Beside this, additional drugs are optimized and nominated for preclinical testing as candidate drug.

Source: https://www.weizmann.ac.il/WeizmannCompass/sections/features/the-vaccines-are-here-and-research-abounds

Other related articles were published in this Open Access Online Scientific Journal, including the following:

Identification of Novel genes in human that fight COVID-19 infection

Reporter: Amandeep Kaur, B.Sc., M.Sc. (ept. 5/2021)

https://pharmaceuticalintelligence.com/2021/04/19/identification-of-novel-genes-in-human-that-fight-covid-19-infection/

Fighting Chaos with Care, community trust, engagement must be cornerstones of pandemic response

Reporter: Amandeep Kaur, B.Sc., M.Sc. (ept. 5/2021)

https://pharmaceuticalintelligence.com/2021/04/13/fighting-chaos-with-care/

T cells recognize recent SARS-CoV-2 variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/03/30/t-cells-recognize-recent-sars-cov-2-variants/

Need for Global Response to SARS-CoV-2 Viral Variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/02/12/need-for-global-response-to-sars-cov-2-viral-variants/

Mechanistic link between SARS-CoV-2 infection and increased risk of stroke using 3D printed models and human endothelial cells

Reporter: Adina Hazan, PhD

https://pharmaceuticalintelligence.com/2020/12/28/mechanistic-link-between-sars-cov-2-infection-and-increased-risk-of-stroke-using-3d-printed-models-and-human-endothelial-cells/

Read Full Post »


Identification of Novel genes in human that fight COVID-19 infection

Reporter: Amandeep Kaur, B.Sc., M.Sc. (ept. 5/2021)

Scientists have recognized human genes that fight against the SARS-CoV-2 viral infection. The information about genes and their function can help to control infection and aids the understanding of crucial factors that causes severe infection. These novel genes are related to interferons, the frontline fighter in our body’s defense system and provide options for therapeutic strategies.

The research was published in the journal Molecular Cell.

Sumit K. Chanda, Ph.D., professor and director of the Immunity and Pathogenesis Program at Sanford Burnham Prebys reported in the article that they focused on better understanding of the cellular response and downstream mechanism in cells to SARS-CoV-2, including the factors which causes strong or weak response to viral infection. He is the lead author of the study and explained that in this study they have gained new insights into how the human cells are exploited by invading virus and are still working towards finding any weak point of virus to develop new antivirals against SARS-CoV-2.

With the surge of pandemic, researchers and scientists found that in severe cases of COVID-19, the response of interferons to SARS-CoV-2 viral infection is low. This information led Chanda and other collaborators to search for interferon-stimulated genes (ISGs), are genes in human which are triggered by interferons and play important role in confining COVID-19 infection by controlling their viral replication in host.

The investigators have developed laboratory experiments to identify ISGs based on the previous knowledge gathered by the outbreak of SARS-CoV-1 from 2002-2004 which was similar to COVID-19 pandemic caused by SARS-CoV-2 virus.

The article reports that Chanda mentioned “we found that 65 ISGs controlled SAR-CoV-2 infection, including some that inhibited the virus’ ability to enter cells, some that suppressed manufacture of the RNA that is the virus’s lifeblood, and a cluster of genes that inhibited assembly of the virus.” They also found an interesting fact about ISGs that some of these genes revealed control over unrelated viruses, such as HIV, West Nile and seasonal flu.

Laura Martin-Sancho, Ph.D., a senior postdoctoral associate in the Chanda lab and first author of the study reported in the article that they identified 8 different ISGs that blocked the replication of both SARS-CoV-1 and CoV-2 in the subcellular compartments responsible for packaging of proteins, which provide option to exploit these vulnerable sites to restrict infection. They are further investigating whether the genetic variability within the ISGs is associated with COVID-19 severity.

The next step for researchers will be investigating and observing the biology of variants of SARS-CoV-2 that are evolving and affecting vaccine efficacy. Martin-Sancho mentioned that their lab has already started gathering all the possible variants for further investigation.

“It’s vitally important that we don’t take our foot off the pedal of basic research efforts now that vaccines are helping control the pandemic,” reported in the article by Chanda.

“We’ve come so far so fast because of investment in fundamental research at Sanford Burnham Prebys and elsewhere, and our continued efforts will be especially important when, not if, another viral outbreak occurs,” concluded Chanda.

Source: https://medicalxpress.com/news/2021-04-covid-scientists-human-genes-infection.html

Reference: Laura Martin-Sancho et al. Functional Landscape of SARS-CoV-2 Cellular Restriction, Molecular Cell (2021). DOI: 10.1016/j.molcel.2021.04.008

Other related articles were published in this Open Access Online Scientific Journal, including the following:

Fighting Chaos with Care, community trust, engagement must be cornerstones of pandemic response

Reporter: Amandeep Kaur

https://pharmaceuticalintelligence.com/2021/04/13/fighting-chaos-with-care/

Mechanism of Thrombosis with AstraZeneca and J & J Vaccines: Expert Opinion by Kate Chander Chiang & Ajay Gupta, MD

Reporter & Curator: Dr. Ajay Gupta, MD

https://pharmaceuticalintelligence.com/2021/04/14/mechanism-of-thrombosis-with-astrazeneca-and-j-j-vaccines-expert-opinion-by-kate-chander-chiang-ajay-gupta-md/

T cells recognize recent SARS-CoV-2 variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/03/30/t-cells-recognize-recent-sars-cov-2-variants/

Need for Global Response to SARS-CoV-2 Viral Variants

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/02/12/need-for-global-response-to-sars-cov-2-viral-variants/

Mechanistic link between SARS-CoV-2 infection and increased risk of stroke using 3D printed models and human endothelial cells

Reporter: Adina Hazan, PhD

https://pharmaceuticalintelligence.com/2020/12/28/mechanistic-link-between-sars-cov-2-infection-and-increased-risk-of-stroke-using-3d-printed-models-and-human-endothelial-cells/

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Did FDA Reverse Course on Convalescent Plasma Therapy for COVID-19?

Reporter: Stephen J. Williams, PhD

 

Starting with a timeline of recent announcements by the FDA on convalescent plasma therapy

April 16, 2020

FDA STATEMENT

Coronavirus (COVID-19) Update: FDA Encourages Recovered Patients to Donate Plasma for Development of Blood-Related Therapies

 

As part of the all-of-America approach to fighting the COVID-19 pandemic, the U.S. Food and Drug Administration has been working with partners across the U.S. government, academia and industry to expedite the development and availability of critical medical products to treat this novel virus. Today, we are providing an update on one potential treatment called convalescent plasma and encouraging those who have recovered from COVID-19 to donate plasma to help others fight this disease.

Convalescent plasma is an antibody-rich product made from blood donated by people who have recovered from the disease caused by the virus. Prior experience with respiratory viruses and limited data that have emerged from China suggest that convalescent plasma has the potential to lessen the severity or shorten the length of illness caused by COVID-19. It is important that we evaluate this potential therapy in the context of clinical trials, through expanded access, as well as facilitate emergency access for individual patients, as appropriate.

The response to the agency’s recently announced national efforts to facilitate the development of and access to convalescent plasma has been tremendous. More than 1,040 sites and 950 physician investigators nationwide have signed on to participate in the Mayo Clinic-led expanded access protocol. A number of clinical trials are also taking place to evaluate the safety and efficacy of convalescent plasma and the FDA has granted numerous single patient emergency investigational new drug (eIND) applications as well.

Source: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-encourages-recovered-patients-donate-plasma-development-blood

August 23, 2020

 

Recommendations for Investigational COVID-19 Convalescent Plasma

 

  • FDA issues guidelines on clinical trials and obtaining emergency enrollment concerning convalescent plasma

FDA has issued guidance to provide recommendations to health care providers and investigators on the administration and study of investigational convalescent plasma collected from individuals who have recovered from COVID-19 (COVID-19 convalescent plasma) during the public health emergency.

The guidance provides recommendations on the following:

Because COVID-19 convalescent plasma has not yet been approved for use by FDA, it is regulated as an investigational product.  A health care provider must participate in one of the pathways described below.  FDA does not collect COVID-19 convalescent plasma or provide COVID-19 convalescent plasma.  Health care providers or acute care facilities should instead obtain COVID-19 convalescent plasma from an FDA-registered blood establishment.

Excerpts from the guidance document are provided below.

Background

The Food and Drug Administration (FDA or Agency) plays a critical role in protecting the United States (U.S.) from threats including emerging infectious diseases, such as the Coronavirus Disease 2019 (COVID-19) pandemic.  FDA is committed to providing timely guidance to support response efforts to this pandemic.

One investigational treatment being explored for COVID-19 is the use of convalescent plasma collected from individuals who have recovered from COVID-19.  Convalescent plasma that contains antibodies to severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 (the virus that causes COVID-19) is being studied for administration to patients with COVID-19. Use of convalescent plasma has been studied in outbreaks of other respiratory infections, including the 2003 SARS-CoV-1 epidemic, the 2009-2010 H1N1 influenza virus pandemic, and the 2012 MERS-CoV epidemic.

Although promising, convalescent plasma has not yet been shown to be safe and effective as a treatment for COVID-19. Therefore, it is important to study the safety and efficacy of COVID-19 convalescent plasma in clinical trials.

Pathways for Use of Investigational COVID-19 Convalescent Plasma

The following pathways are available for administering or studying the use of COVID-19 convalescent plasma:

  1. Clinical Trials

Investigators wishing to study the use of convalescent plasma in a clinical trial should submit requests to FDA for investigational use under the traditional IND regulatory pathway (21 CFR Part 312). CBER’s Office of Blood Research and Review is committed to engaging with sponsors and reviewing such requests expeditiously. During the COVID-19 pandemic, INDs may be submitted via email to CBERDCC_eMailSub@fda.hhs.gov.

  1. Expanded Access

An IND application for expanded access is an alternative for use of COVID-19 convalescent plasma for patients with serious or immediately life-threatening COVID-19 disease who are not eligible or who are unable to participate in randomized clinical trials (21 CFR 312.305). FDA has worked with multiple federal partners and academia to open an expanded access protocol to facilitate access to COVID-19 convalescent plasma across the nation. Access to this investigational product may be available through participation of acute care facilities in an investigational expanded access protocol under an IND that is already in place.

Currently, the following protocol is in place: National Expanded Access Treatment Protocol

  1. Single Patient Emergency IND

Although participation in clinical trials or an expanded access program are ways for patients to obtain access to convalescent plasma, for various reasons these may not be readily available to all patients in potential need. Therefore, given the public health emergency that the COVID-19 pandemic presents, and while clinical trials are being conducted and a national expanded access protocol is available, FDA also is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections through the process of the patient’s physician requesting a single patient emergency IND (eIND) for the individual patient under 21 CFR 312.310. This process allows the use of an investigational drug for the treatment of an individual patient by a licensed physician upon FDA authorization, if the applicable regulatory criteria are met.  Note, in such case, a licensed physician seeking to administer COVID-19 convalescent plasma to an individual patient must request the eIND (see 21 CFR 312.310(b)).

To Obtain a Single Patient Emergency IND  

The requesting physician may contact FDA by completing Form FDA 3926 (https://www.fda.gov/media/98616/download) and submitting the form by email to CBER_eIND_Covid-19@FDA.HHS.gov.

FACT SHEET FOR PATIENTS AND PARENTS/CAREGIVERS EMERGENCY USE AUTHORIZATION (EUA) OF COVID-19 CONVALESCENT PLASMA FOR TREATMENT OF COVID-19 IN HOSPITALIZED PATIENTS

  • FDA issues fact sheet for patients on donating plasma

August 23, 2020

 

FDA Issues Emergency Use Authorization for Convalescent Plasma as Potential Promising COVID–19 Treatment, Another Achievement in Administration’s Fight Against Pandemic

 

Today, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for investigational convalescent plasma for the treatment of COVID-19 in hospitalized patients as part of the agency’s ongoing efforts to fight COVID-19. Based on scientific evidence available, the FDA concluded, as outlined in its decision memorandum, this product may be effective in treating COVID-19 and that the known and potential benefits of the product outweigh the known and potential risks of the product.

Today’s action follows the FDA’s extensive review of the science and data generated over the past several months stemming from efforts to facilitate emergency access to convalescent plasma for patients as clinical trials to definitively demonstrate safety and efficacy remain ongoing.

The EUA authorizes the distribution of COVID-19 convalescent plasma in the U.S. and its administration by health care providers, as appropriate, to treat suspected or laboratory-confirmed COVID-19 in hospitalized patients with COVID-19.

Alex Azar, Health and Human Services Secretary:
“The FDA’s emergency authorization for convalescent plasma is a milestone achievement in President Trump’s efforts to save lives from COVID-19,” said Secretary Azar. “The Trump Administration recognized the potential of convalescent plasma early on. Months ago, the FDA, BARDA, and private partners began work on making this product available across the country while continuing to evaluate data through clinical trials. Our work on convalescent plasma has delivered broader access to the product than is available in any other country and reached more than 70,000 American patients so far. We are deeply grateful to Americans who have already donated and encourage individuals who have recovered from COVID-19 to consider donating convalescent plasma.”

Stephen M. Hahn, M.D., FDA Commissioner:
“I am committed to releasing safe and potentially helpful treatments for COVID-19 as quickly as possible in order to save lives. We’re encouraged by the early promising data that we’ve seen about convalescent plasma. The data from studies conducted this year shows that plasma from patients who’ve recovered from COVID-19 has the potential to help treat those who are suffering from the effects of getting this terrible virus,” said Dr. Hahn. “At the same time, we will continue to work with researchers to continue randomized clinical trials to study the safety and effectiveness of convalescent plasma in treating patients infected with the novel coronavirus.”

Scientific Evidence on Convalescent Plasma

Based on an evaluation of the EUA criteria and the totality of the available scientific evidence, the FDA’s Center for Biologics Evaluation and Research determined that the statutory criteria for issuing an EUA criteria were met.

The FDA determined that it is reasonable to believe that COVID-19 convalescent plasma may be effective in lessening the severity or shortening the length of COVID-19 illness in some hospitalized patients. The agency also determined that the known and potential benefits of the product, when used to treat COVID-19, outweigh the known and potential risks of the product and that that there are no adequate, approved, and available alternative treatments.

 

August 24, 2020

Donate COVID-19 Plasma

 

  • FDA posts video and blog about how to donate plasms if you had been infected with COVID

 

https://youtu.be/PlX15rWdBbY

 

 

Please go to https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/donate-covid-19-plasma

to read more from FDA

 

 

August 25, 2020

 

CLINICAL MEMORANDUM From: , OBRR/DBCD/CRS To: , OBRR Through: , OBRR/DBCD , OBRR/DBCD , OBRR/DBCD/CRS Re: EUA 26382: Emergency Use Authorization (EUA) Request (original request 8/12/20; amended request 8/23/20) Product: COVID-19 Convalescent Plasma Items reviewed: EUA request Fact Sheet for Health Care Providers Fact Sheet for Recipients Sponsor: Robert Kadlec, M.D. Assistant Secretary for Preparedness and Response (ASPR) Office of Assistant Secretary for Preparedness and Response (ASPR) U.S. Department of Health and Human Services (HHS) EXECUTIVE SUMMARY COVID-19 Convalescent Plasma (CCP), an unapproved biological product, is proposed for use under an Emergency Use Authorization (EUA) under section 564 of the Federal Food, Drug, and Cosmetic Act (the Act),(21 USC 360bbb-3) as a passive immune therapy for the treatment of hospitalized patients with COVID-19, a serious or life-threatening disease. There currently is no adequate, approved, and available alternative to CCP for treating COVID-19. The sponsor has pointed to four lines of evidence to support that CCP may be effective in the treatment of hospitalized patients with COVID-19: 1) History of convalescent plasma for respiratory coronaviruses; 2) Evidence of preclinical safety and efficacy in animal models; 3) Published studies of the safety and efficacy of CCP; and 4) Data on safety and efficacy from the National Expanded Access Treatment Protocol (EAP) sponsored by the Mayo Clinic. Considering the totality of the scientific evidence presented in the EUA, I conclude that current data for the use of CCP in adult hospitalized patients with COVID-19 supports the conclusion that CCP meets the “may be effective” criterion for issuance of an EUA from section 564(c)(2)(A) of the Act. It is reasonable to conclude that the known and potential benefits of CCP outweigh the known and potential risks of CCP for the proposed EUA. Current data suggest the largest clinical benefit is associated with high-titer units of CCP administered early course of the disease.

Source: https://www.fda.gov/media/141480/download

 

And Today August 26, 2020

  • A letter, from Senator Warren, to Commissioner Hahn from Senate Committee asking for documentation for any communication between FDA and White House

August 25, 2020 Dr. Stephen M. Hahn, M.D. Commissioner of Food and Drugs U.S. Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993 Dear Commissioner Hahn: We write regarding the U.S. Food and Drug Administration’s (FDA) troubling decision earlier this week to issue an Emergency Use Authorization (EUA) for convalescent plasma as a treatment for coronavirus disease 2019 (COVID-19).1 Reports suggests that the FDA granted the EUA amid intense political pressure from President Trump and other Administration officials, despite limited evidence of convalescent plasma’s effectiveness as a COVID-19 treatment.2 To help us better understand whether the issuance of the blood plasma EUA was motivated by politics, we request copies of any and all communications between FDA and White House officials regarding the blood plasma EUA.

Source: https://www.warren.senate.gov/imo/media/doc/2020.08.25%20Letter%20to%20FDA%20re%20Blood%20Plasma%20EUA.pdf

…….. which may have been a response to this article

FDA chief walks back comments on effectiveness of coronavirus plasma treatment

 

From CNBC: https://www.cnbc.com/2020/08/25/fda-chief-walks-back-comments-on-effectiveness-of-coronavirus-plasma-treatment.html

PUBLISHED TUE, AUG 25 202010:45 AM EDTUPDATED TUE, AUG 25 20204:12 PM EDT

Berkeley Lovelace Jr.@BERKELEYJR

Will Feuer@WILLFOIA

KEY POINTS

  • The authorization will allow health-care providers in the U.S. to use the plasma to treat hospitalized patients with Covid-19.
  • The FDA’s emergency use authorization came a day after President Trump accused the agency of delaying enrollment in clinical trials for vaccines or therapeutics.
  • The criticism from Trump and action from the FDA led some scientists to believe the authorization, which came on the eve of the GOP national convention, was politically motivated.

FDA Commissioner Dr. Stephen Hahn is walking back comments on the benefits of convalescent plasma, saying he could have done a better job of explaining the data on its effectiveness against the coronavirus after authorizing it for emergency use over the weekend.

Commisioners responses over Twitter

https://twitter.com/SteveFDA/status/1298071603675373569?s=20

https://twitter.com/SteveFDA/status/1298071619236245504?s=20

August 26, 2020

In an interview with Bloomberg’s , FDA Commissioner Hahn reiterates that his decision was based on hard evidence and scientific fact, not political pressure.  The whole interview is at the link below:

https://www.bloomberg.com/news/articles/2020-08-25/fda-s-hahn-vows-to-stick-to-the-science-amid-vaccine-pressure?sref=yLCixKPR

Some key points:

  • Dr. Hahn corrected his initial statement about 35% of people would be cured by convalescent plasma. In the interview he stated:

I was trying to do what I do with patients, because patients often understand things in absolute terms versus relative terms. And I should’ve been more careful, there’s no question about it. What I was trying to get to is that if you look at a hundred patients who receive high titre, and a hundred patients who received low titre, the difference between those two particular subset of patients who had these specific criteria was a 35% reduction in mortality. So I frankly did not do a good job of explaining that.

  • FDA colleagues had frank discussion after the statement was made.  He is not asking for other people in HHS to retract their statements, only is concerned that FDA has correct information for physicians and patients
  • Hahn is worried that people will not enroll due to chance they may be given placebo
  • He gave no opinion when asked if FDA should be an independent agency

 

For more articles on COVID19 please go to our Coronavirus Portal at

https://pharmaceuticalintelligence.com/coronavirus-portal/

 

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Recent Grim COVID-19 Statistics in U.S. and Explanation from Dr. John Campbell: Why We Need to be More Proactive

Reporter: Stephen J. Williams, Ph.D.

In case you have not been following the excellent daily YouTube sessions on COVID-19 by Dr. John Campbell I am posting his latest video on how grim the statistics have become and the importance of using proactive measures (like consistent use of facial masks, proper social distancing) instead of relying on reactive measures (e.g. lockdowns after infection spikes).  In addition, below the video are some notes from his presentation and some links to sites discussed within the video.

 

Notes from the video:

  • approaching 5 million confirmed cases in US however is probably an underestimation
  • 160,00 deaths as of 8/08/2020

From the University of Washington Institute for Health Metrics and Evaluation in Seattle WA

  • 295,000 US COVID-19 related deaths estimated by December 1, 2020
  • however if 95% of people in US consistently and properly wear masks could save 66,000 lives
  • however this will mean a remaining 228,271 deaths which is a depressing statistic
  • Dr. John Campbell agrees with Dr. Christopher Murray, director of the Institute for Health Metrics that “people’s inconsistent use of these measures (face masks, social distancing) is a serious problem”
  • States with increasing transmission like Colorado, Idaho, Kansas, Kentucky, Mississippi, Missouri, Ohio, Oklahoma, Oregon, and Virginia are suggested to have a lockdown when death rate reaches 8 deaths per million population however it seems we should be also focusing on population densities rather than geographic states
  • Dr. Campbell and Dr. Murray stress more proactive measures than reactive ones like lockdowns
  • if mask usage were to increase to 95% usage reimposition to shutdown could be delayed 6 to 8 weeks

 

New IHME COVID-19 Forecasts See Nearly 300,000 Deaths by December 1

SEATTLE (August 6, 2020) – America’s COVID-19 death toll is expected to reach nearly 300,000 by December 1; however, consistent mask-wearing beginning today could save about 70,000 lives, according to new data from the Institute for Health Metrics and Evaluation (IHME) at the University of Washington’s School of Medicine.The US forecast totals 295,011 deaths by December. As of today, when, thus far, 158,000 have died, IHME is projecting approximately 137,000 more deaths. However, starting today, if 95% of the people in the US were to wear masks when leaving their homes, that total number would decrease to 228,271 deaths, a drop of 49%. And more than 66,000 lives would be saved.Masks and other protective measures against transmission of the virus are essential to staying COVID-free, but people’s inconsistent use of those measures is a serious problem, said IHME Director Dr. Christopher Murray.

“We’re seeing a rollercoaster in the United States,” Murray said. “It appears that people are wearing masks and socially distancing more frequently as infections increase, then after a while as infections drop, people let their guard down and stop taking these measures to protect themselves and others – which, of course, leads to more infections. And the potentially deadly cycle starts over again.”

Murray noted that there appear to be fewer transmissions of the virus in Arizona, California, Florida, and Texas, but deaths are rising and will continue to rise for the next week or two. The drop in infections appears to be driven by the combination of local mandates for mask use, bar and restaurant closures, and more responsible behavior by the public.

“The public’s behavior had a direct correlation to the transmission of the virus and, in turn, the numbers of deaths,” Murray said. “Such efforts to act more cautiously and responsibly will be an important aspect of COVID-19 forecasting and the up-and-down patterns in individual states throughout the coming months and into next year.”

Murray said that based on cases, hospitalizations, and deaths, several states are seeing increases in the transmission of COVID-19, including Colorado, Idaho, Kansas, Kentucky, Mississippi, Missouri, Ohio, Oklahoma, Oregon, and Virginia.

“These states may experience increasing cases for several weeks and then may see a response toward more responsible behavior,” Murray said.

In addition, since July 15, several states have added mask mandates. IHME’s statistical analysis suggests that mandates with no penalties increase mask wearing by 8 percentage points. But mandates with penalties increase mask wearing by 15 percentage points.

“These efforts, along with media coverage and public information efforts by state and local health agencies and others, have led to an increase in the US rate of mask wearing by about 5 percentage points since mid-July,” Murray said. Mask-wearing increases have been larger in states with larger epidemics, he said.

IHME’s model assumes that states will reimpose a series of mandates, including non-essential business closures and stay-at-home orders, when the daily death rate reaches 8 per million. This threshold is based on data regarding when states and/or communities imposed mandates in March and April, and implies that many states will have to reimpose mandates.

As a result, the model suggests which states will need to reimpose mandates and when:

  • August – Arizona, Florida, Mississippi, and South Carolina
  • September – Georgia and Texas
  • October – Colorado, Kansas, Louisiana, Missouri, Nevada, North Carolina, and Oregon.
  • November – Alabama, Arkansas, California, Iowa, New Mexico, Oklahoma, Utah, Washington, and Wisconsin.

However, if mask use is increased to 95%, the re-imposition of stricter mandates could be delayed 6 to 8 weeks on average.

Source: http://www.healthdata.org/news-release/new-ihme-covid-19-forecasts-see-nearly-300000-deaths-december-1

 

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The Inequality and Health Disparity seen with the COVID-19 Pandemic Is Similar to Past Pandemics

Curator: Stephen J. Williams, PhD

2019-nCoV-CDC-23311

It has become very evident, at least in during this pandemic within the United States, that African Americans and poorer communities have been disproportionately affected by the SARS-CoV2 outbreak . However, there are many other diseases such as diabetes, heart disease, and cancer in which these specific health disparities are evident as well :

Diversity and Health Disparity Issues Need to be Addressed for GWAS and Precision Medicine Studies

Personalized Medicine, Omics, and Health Disparities in Cancer:  Can Personalized Medicine Help Reduce the Disparity Problem?

Disease like cancer have been shown to have wide disparities based on socioeconomic status, with higher incidence rates seen in poorer and less educated sub-populations, not just here but underdeveloped countries as well (see Opinion Articles from the Lancet: COVID-19 and Cancer Care in China and Africa) and graphics below)

 

 

 

 

 

 

 

 

 

 

In an article in Science by Lizzie Wade, these disparities separated on socioeconomic status, have occurred in many other pandemics throughout history, and is not unique to the current COVID19 outbreak.  The article, entitled “An Unequal Blow”, reveal how

in past pandemics, people on the margins suffered the most.

Source: https://science.sciencemag.org/content/368/6492/700.summary

Health Disparities during the Black Death Bubonic Plague Pandemic in the 14th Century (1347-1351)

During the mid 14th century, all of Europe was affected by a plague induced by the bacterium Yersinia pestis, and killed anywhere between 30 – 60% of the European population.  According to reports by the time the Black Death had reached London by January 1349 there had already been horrendous reports coming out of Florence Italy where the deadly disease ravished the population there in the summer of 1348 (more than half of the city’s population died). And by mid 1349 the Black Death had killed more than half of Londoners.  It appeared that no one was safe from the deadly pandemic, affecting the rich, the poor, the young, the old.

However, after careful and meticulous archaeological and historical analysis in England and other sites, revealed a distinct social and economic inequalities that predominated and most likely guided the pandemics course throughout Europe.   According to Dr. Gwen Robbins Schug, a bio-archaeologist at Appalachian State University,

Bio-archaeology and other social sciences have repeatedly demonstrated that these kinds of crises play out along the preexisting fault lines of each society.  The people at greatest risk were often those already marginalized- the poor and minorities who faced discrimination in ways that damaged their health or limited their access to medical care even in pandemic times.

At the start of the Black Death, Europe had already gone under a climactic change with erratic weather.  As a result, a Great Famine struck Europe between 1315-17.  Wages fell and more people fell into poverty while the wealthiest expanded their riches, leading to an increased gap in wealth and social disparity.  In fact according to recordkeeping most of Englanders were living below the poverty line.

Author Lizzie Wade also interviewed Dr. Sharon, DeWitte, a biological anthropologist at University of South Carolina, who looks at skeletal remains of Black Death victims to get evidence on their health status, like evidence of malnutrition, osteoporosis, etc.   And it appears that most of the victims may have had preexisting health conditions indicative of poorer status.  And other evidence show that wealthy landowners had a lower mortality rate than poorer inner city dwellers.

1918 Spanish Flu

Socioeconomic and demographic studies have shown that both Native American Indians and African Americans on the lower end of the socioeconomic status were disproportionately affected by the 1918 Spanish flu pandemic.  According to census records, the poorest had a 50% higher mortality rate than wealthy areas in the city of Oslo.  In the US, minors and factory workers died at the highest rates.  In the US African Americans had already had bouts with preexisting issues like tuberculosis and may have contributed to the higher mortality.  In addition Jim Crow laws in the South, responsible for widespread discrimination, also impacted the ability of African Americans to seek proper medical care.

From the Atlantic

Source: https://www.theatlantic.com/politics/archive/2016/05/americas-health-segregation-problem/483219/

America’s Health Segregation Problem

Has the country done enough to overcome its Jim Crow health care history?

VANN R. NEWKIRK II

MAY 18, 2016

Like other forms of segregation, health-care segregation was originally a function of explicitly racist black codes and Jim Crow laws. Many hospitals, clinics, and doctor’s offices were totally segregated by race, and many more maintained separate wings or staff that could never intermingle under threat of law. The deficit of trained black medical professionals (itself caused by a number of factors including education segregation) meant that no matter where black people received health-care services, they would find their care to be subpar compared to that of whites. While there were some deaths that were directly attributable to being denied emergency service, most of the damage was done in establishing the same cumulative health disparities that plague black people today as a societal fate. The descendants of enslaved people lived much more dangerous and unhealthy lives than white counterparts, on disease-ridden and degraded environments. Within the confines of a segregated health-care system, these factors became poor health outcomes that shaped black America as if they were its genetic material.

 

https://twitter.com/time4equity/status/1175080469425266688?s=20

 

R.A.HahnaB.I.TrumanbD.R.Williamsc.Civil rights as determinants of public health and racial and ethnic health equity: Health care, education, employment, and housing in the United States.

SSM – Population Health: Volume 4, April 2018, Pages 17-24

Highlights

  • Civil rights are characterized as social determinants of health.
  • Four domains in civil rights history since 1950 are explored in—health care, education, employment, and housing.
  • Health care, education, employment show substantial benefits when civil rights are enforced.
  • Housing shows an overall failure to enforce existing civil rights and persistent discrimination.
  • Civil rights and their enforcement may be considered a powerful arena for public health theorizing, research, policy, and action.

 

For more articles on COVID-19 Please go to our Coronovirus Portal

https://pharmaceuticalintelligence.com/coronavirus-portal/

 

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From Cell Press:  New Insights on the D614G Strain of COVID: Will a New Mutated Strain Delay Vaccine Development?

Reporter: Stephen J. Williams, PhD

Two recent articles in Cell Press, both peer reviewed, discuss the emergence and potential dominance of a new mutated strain of COVID-19, in which the spike protein harbors a D614G mutation.

In the first article “Making Sense of Mutation: What D614G means for the COVID-19 pandemic Remains Unclear”[1] , authors Drs. Nathan Grubaugh, William Hanage, and Angela Rasmussen discuss the recent findings by Korber et al. 2020 [2] which describe the potential increases in infectivity and mortality of this new mutant compared to the parent strain of SARS-CoV2.  For completeness sake I will post this article as to not defer from their interpretations of this important paper by Korber and to offer some counter opinion to some articles which have surfaced this morning in the news.

Making sense of mutation: what D614G means for the COVID-19 pandemic remains unclear

 

Nathan D. Grubaugh1 *, William P. Hanage2 *, Angela L. Rasmussen3 * 1Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT 06510, USA 2Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA 3Center for Infection and Immunity, Columbia Mailman School of Public Health, New York, NY 10032, USA Correspondence: grubaughlab@gmail.com

 

Abstract: Korber et al. (2020) found that a SARS-CoV-2 variant in the spike protein, D614G, rapidly became dominant around the world. While clinical and in vitro data suggest that D614G changes the virus phenotype, the impact of the mutation on transmission, disease, and vaccine and therapeutic development are largely unknown.

Introduction: Following the emergence of SARS-CoV-2 in China in late 2019, and the rapid expansion of the COVID19 pandemic in 2020, questions about viral evolution have come tumbling after. Did SARS-CoV-2 evolve to become better adapted to humans? More infectious or transmissible? More deadly? Virus mutations can rise in frequency due to natural selection, random genetic drift, or features of recent epidemiology. As these forces can work in tandem, it’s often hard to differentiate when a virus mutation becomes common through fitness or by chance. It is even harder to determine if a single mutation will change the outcome of an infection, or a pandemic. The new study by Korber et al. (2020) sits at the heart of this debate. They present compelling data that an amino acid change in the virus’ spike protein, D614G, emerged early during the pandemic, and viruses containing G614 are now dominant in many places around the world. The crucial questions are whether this is the result of natural selection, and what it means for the COVID-19 pandemic. For viruses like SARS-CoV-2 transmission really is everything – if they don’t get into another host their lineage ends. Korber et al. (2020) hypothesized that the rapid spread of G614 was because it is more infectious than D614. In support of their hypothesis, the authors provided evidence that clinical samples from G614 infections have a higher levels of viral RNA, and produced higher titers in pseudoviruses from in vitro experiments; results that now seem to be corroborated by others [e.g. (Hu et al., 2020; Wagner et al., 2020)]. Still, these data do not prove that G614 is more infectious or transmissible than viruses containing D614. And because of that, many questions remain on the potential impacts, if any, that D614G has on the COVID-19 pandemic.

The authors note that this new G614 variant has become the predominant form over the whole world however in China the predominant form is still the D614 form.  As they state

“over the period that G614 became the global majority variant, the number of introductions from China where D614 was still dominant were declining, while those from Europe climbed. This alone might explain the apparent success of G614.”

Grubaugh et al. feel there is not enough evidence that infection with this new variant will lead to higher mortality.  Both Korber et al. and the Seattle study (Wagner et al) did not find that the higher viral load of this variant led to a difference in hospitalizations so apparently each variant might be equally as morbid.

In addition, Grubaugh et al. believe this variant would not have much affect on vaccine development as, even though the mutation lies within the spike protein, D614G is not in the receptor binding domain of the spike protein.  Korber suggest that there may be changes in glycosylation however these experiments will need to be performed.  In addition, antibodies from either D614 or G614 variant infected patients could cross neutralize.

 

Conclusions: While there has already been much breathless commentary on what this mutation means for the COVID19 pandemic, the global expansion of G614 whether through natural selection or chance means that this variant now is the pandemic. As a result its properties matter. It is clear from the in vitro and clinical data that G614 has a distinct phenotype, but whether this is the result of bonafide adaptation to human ACE2, whether it increases transmissibility, or will have a notable effect, is not clear. The work by Korber et al. (2020) provides an early base for more extensive epidemiological, in vivo experimental, and diverse clinical investigations to fill in the many critical gaps in how D614G impacts the pandemic.

The link to the Korber Cell paper is here: https://www.cell.com/cell/fulltext/S0092-8674(20)30820-5

Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases infectivity of the COVID-19 virus

DOI: https://doi.org/10.1016/j.cell.2020.06.043

Keypoints

  • The consistent increase of G614 at regional levels may indicate a fitness advantage

 

  • G614 is associated with lower RT PCR Ct’s, suggestive of higher viral loads in patients

 

  • The G614 variant grows to higher titers as pseudotyped virions

Summary

A SARS-CoV-2 variant carrying the Spike protein amino acid change D614G has become the most prevalent form in the global pandemic. Dynamic tracking of variant frequencies revealed a recurrent pattern of G614 increase at multiple geographic levels: national, regional and municipal. The shift occurred even in local epidemics where the original D614 form was well established prior to the introduction of the G614 variant. The consistency of this pattern was highly statistically significant, suggesting that the G614 variant may have a fitness advantage. We found that the G614 variant grows to higher titer as pseudotyped virions. In infected individuals G614 is associated with lower RT-PCR cycle thresholds, suggestive of higher upper respiratory tract viral loads, although not with increased disease severity. These findings illuminate changes important for a mechanistic understanding of the virus, and support continuing surveillance of Spike mutations to aid in the development of immunological interventions.

 

References

  1. Grubaugh, N.D., Hanage, W.P., Rasmussen, A.L., Making sense of mutation: what D614G means for the COVID-19 pandemic remains unclear, Cell (2020), doi: https:// doi.org/10.1016/j.cell.2020.06.040.
  2. Korber, B., Fischer, W.M., Gnanakaran, S., Yoon, H., Theiler, J., Abfalterer, W., Hengartner, N., Giorgi, E.E., Bhattacharya, T., Foley, B., et al. (2020). Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases infectivity of the COVID-19 virus. Cell 182.
  3. Endo, A., Centre for the Mathematical Modelling of Infectious Diseases COVID-19 Working Group, Abbott, S., Kucharski, A.J., and Funk, S. (2020). Estimating the overdispersion in COVID-19 transmission using outbreak sizes outside China. Wellcome Open Res 5, 67.
  4. Hu, J., He, C.-L., Gao, Q.-Z., Zhang, G.-J., Cao, X.-X., Long, Q.-X., Deng, H.-J., Huang, L.-Y., Chen, J., Wang, K., et al. (2020). The D614G mutation of SARS-CoV-2 spike protein enhances viral infectivity and decreases neutralization sensitivity to individual convalescent sera. bioRxiv 2020.06.20.161323.
  5. Wagner, C., Roychoudhury, P., Hadfield, J., Hodcroft, E.B., Lee, J., Moncla, L.H., Müller, N.F., Behrens, C., Huang, M.-L., Mathias, P., et al. (2020). Comparing viral load and clinical outcomes in Washington State across D614G mutation in spike protein of SARS-CoV-2. Https://github.com/blab/ncov-D614G.

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RNA from the SARS-CoV-2 virus taking over the cells it infects: Virulence – Pathogen’s ability to infect a Resistant Host: The Imbalance between Controlling Virus Replication versus Activation of the Adaptive Immune Response

Curator: Aviva Lev-Ari, PhD, RN – I added colors and bold face

 

UPDATED on 9/8/2020

What bats can teach us about developing immunity to Covid-19 | Free to read

Clive Cookson, Anna Gross and Ian Bott, London

https://www.ft.com/content/743ce7a0-60eb-482d-b1f4-d4de11182fa9?utm_source=Nature+Briefing&utm_campaign=af64422080-briefing-dy-20200908&utm_medium=email&utm_term=0_c9dfd39373-af64422080-43323101

 

UPDATED on 6/29/2020

Another duality and paradox in the Treatment of COVID-19 Patients in ICUs was expressed by Mike Yoffe, MD, PhD, David H. Koch Professor of Biology and Biological Engineering, Massachusetts Institute of Technology. Dr. Yaffe has a joint appointment in Acute Care Surgery, Trauma, and Surgical Critical Care, and in Surgical Oncology @BIDMC

on 6/29 at SOLUTIONS with/in/sight at Koch Institute @MIT

How Are Cancer Researchers Fighting COVID-19? (Part II)” Jun 29, 2020 11:30 AM EST

Mike Yoffe, MD, PhD 

In COVID-19 patients: two life threatening conditions are seen in ICUs:

  • Blood Clotting – Hypercoagulability or Thrombophilia
  • Cytokine Storm – immuno-inflammatory response
  • The coexistence of 1 and 2 – HINDERS the ability to use effectively tPA as an anti-clotting agent while the cytokine storm is present.

Mike Yoffe’s related domain of expertise:

Signaling pathways and networks that control cytokine responses and inflammation

Misregulation of cytokine feedback loops, along with inappropriate activation of the blood clotting cascade causes dysregulation of cell signaling pathways in innate immune cells (neutrophils and macrophages), resulting in tissue damage and multiple organ failure following trauma or sepsis. Our research is focused on understanding the role of the p38-MK2 pathway in cytokine control and innate immune function, and on cross-talk between cytokines, clotting factors, and neutrophil NADPH oxidase-derived ROS in tissue damage, coagulopathy, and inflammation, using biochemistry, cell biology, and mouse knock-out/knock-in models.  We recently discovered a particularly important link between abnormal blood clotting and the complement pathway cytokine C5a which causes excessive production of extracellular ROS and organ damage by neutrophils after traumatic injury.

SOURCE

https://www.bidmc.org/research/research-by-department/surgery/acute-care-surgery-trauma-and-surgical-critical-care/michael-b-yaffe

 

See

The Genome Structure of CORONAVIRUS, SARS-CoV-2

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/05/04/the-genome-structure-of-coronavirus-sars-cov-2-i-awaited-for-this-article-for-60-days/

 

Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

Open Access Published:May 15, 2020DOI:https://doi.org/10.1016/j.cell.2020.04.026

Highlights

  • SARS-CoV-2 infection induces low IFN-I and -III levels with a moderate ISG response
  • Strong chemokine expression is consistent across in vitroex vivo, and in vivo models
  • Low innate antiviral defenses and high pro-inflammatory cues contribute to COVID-19

Summary

Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.

Graphical Abstract

Keywords

Results

Defining the Transcriptional Response to SARS-CoV-2 Relative to Other Respiratory Viruses

To compare the transcriptional response of SARS-CoV-2 with other respiratory viruses, including MERS-CoV, SARS-CoV-1, human parainfluenza virus 3 (HPIV3), respiratory syncytial virus (RSV), and IAV, we first chose to focus on infection in a variety of respiratory cell lines (Figure 1). To this end, we collected poly(A) RNA from infected cells and performed RNA sequencing (RNA-seq) to estimate viral load. These data show that virus infection levels ranged from 0.1% to more than 50% of total RNA reads (Figure 1A).

Discussion

In the present study, we focus on defining the host response to SARS-CoV-2 and other human respiratory viruses in cell lines, primary cell cultures, ferrets, and COVID-19 patients. In general, our data show that the overall transcriptional footprint of SARS-CoV-2 infection was distinct in comparison with other highly pathogenic coronaviruses and common respiratory viruses such as IAV, HPIV3, and RSV. It is noteworthy that, despite a reduced IFN-I and -III response to SARS-CoV-2, we observed a consistent chemokine signature. One exception to this observation is the response to high-MOI infection in A549-ACE2 and Calu-3 cells, where replication was robust and an IFN-I and -III signature could be observed. In both of these examples, cells were infected at a rate to theoretically deliver two functional virions per cell in addition to any defective interfering particles within the virus stock that were not accounted for by plaque assays. Under these conditions, the threshold for PAMP may be achieved prior to the ability of the virus to evade detection through production of a viral antagonist. Alternatively, addition of multiple genomes to a single cell may disrupt the stoichiometry of viral components, which, in turn, may itself generate PAMPs that would not form otherwise. These ideas are supported by the fact that, at a low-MOI infection in A549-ACE2 cells, high levels of replication could also be achieved, but in the absence of IFN-I and -III induction. Taken together, these data suggest that, at low MOIs, the virus is not a strong inducer of the IFN-I and -III system, as opposed to conditions where the MOI is high.
Taken together, the data presented here suggest that the response to SARS-CoV-2 is imbalanced with regard to controlling virus replication versus activation of the adaptive immune response. Given this dynamic, treatments for COVID-19 have less to do with the IFN response and more to do with controlling inflammation. Because our data suggest that numerous chemokines and ILs are elevated in COVID-19 patients, future efforts should focus on U.S. Food and Drug Administration (FDA)-approved drugs that can be rapidly deployed and have immunomodulating properties.

SOURCE

https://www.cell.com/cell/fulltext/S0092-8674(20)30489-X

SARS-CoV-2 ORF3b is a potent interferon antagonist whose activity is further increased by a naturally occurring elongation variant

Yoriyuki KonnoIzumi KimuraKeiya UriuMasaya FukushiTakashi IrieYoshio KoyanagiSo NakagawaKei Sato

Abstract

One of the features distinguishing SARS-CoV-2 from its more pathogenic counterpart SARS-CoV is the presence of premature stop codons in its ORF3b gene. Here, we show that SARS-CoV-2 ORF3b is a potent interferon antagonist, suppressing the induction of type I interferon more efficiently than its SARS-CoV ortholog. Phylogenetic analyses and functional assays revealed that SARS-CoV-2-related viruses from bats and pangolins also encode truncated ORF3b gene products with strong anti-interferon activity. Furthermore, analyses of more than 15,000 SARS-CoV-2 sequences identified a natural variant, in which a longer ORF3b reading frame was reconstituted. This variant was isolated from two patients with severe disease and further increased the ability of ORF3b to suppress interferon induction. Thus, our findings not only help to explain the poor interferon response in COVID-19 patients, but also describe a possibility of the emergence of natural SARS-CoV-2 quasi-species with extended ORF3b that may exacerbate COVID-19 symptoms.

Highlights

  • ORF3b of SARS-CoV-2 and related bat and pangolin viruses is a potent IFN antagonist

  • SARS-CoV-2 ORF3b suppresses IFN induction more efficiently than SARS-CoV ortholog

  • The anti-IFN activity of ORF3b depends on the length of its C-terminus

  • An ORF3b with increased IFN antagonism was isolated from two severe COVID-19 cases

Competing Interest Statement

The authors have declared no competing interest.

Paper in collection COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv

 

SOURCE

https://www.biorxiv.org/content/10.1101/2020.05.11.088179v1

 

 

A deep dive into how the new coronavirus infects cells has found that it orchestrates a hostile takeover of their genes unlike any other known viruses do, producing what one leading scientist calls “unique” and “aberrant” changes.Recent studies show that in seizing control of genes in the human cells it invades, the virus changes how segments of DNA are read, doing so in a way that might explain why the elderly are more likely to die of Covid-19 and why antiviral drugs might not only save sick patients’ lives but also prevent severe disease if taken before infection.“It’s something I have never seen in my 20 years of” studying viruses, said virologist Benjamin tenOever of the Icahn School of Medicine at Mount Sinai, referring to how SARS-CoV-2, the virus that causes Covid-19, hijacks cells’ genomes.The “something” he and his colleagues saw is how SARS-CoV-2 blocks one virus-fighting set of genes but allows another set to launch, a pattern never seen with other viruses. Influenza and the original SARS virus (in the early 2000s), for instance, interfere with both arms of the body’s immune response — what tenOever dubs “call to arms” genes and “call for reinforcement” genes.The first group of genes produces interferons. These proteins, which infected cells release, are biological semaphores, signaling to neighboring cells to activate some 500 of their own genes that will slow down the virus’ ability to make millions of copies of itself if it invades them. This lasts seven to 10 days, tenOever said, controlling virus replication and thereby buying time for the second group of genes to act.This second set of genes produce their own secreted proteins, called chemokines, that emit a biochemical “come here!” alarm. When far-flung antibody-making B cells and virus-killing T cells sense the alarm, they race to its source. If all goes well, the first set of genes holds the virus at bay long enough for the lethal professional killers to arrive and start eradicating viruses.

“Most other viruses interfere with some aspect of both the call to arms and the call for reinforcements,” tenOever said. “If they didn’t, no one would ever get a viral illness”: The one-two punch would pummel any incipient infection into submission.

SARS-CoV-2, however, uniquely blocks one cellular defense but activates the other, he and his colleagues reported in a study published last week in Cell. They studied healthy human lung cells growing in lab dishes, ferrets (which the virus infects easily), and lung cells from Covid-19 patients. In all three, they found that within three days of infection, the virus induces cells’ call-for-reinforcement genes to produce cytokines. But it blocks their call-to-arms genes — the interferons that dampen the virus’ replication.

The result is essentially no brakes on the virus’s replication, but a storm of inflammatory molecules in the lungs, which is what tenOever calls an “unique” and “aberrant” consequence of how SARS-CoV-2 manipulates the genome of its target.

In another new study, scientists in Japan last week identified how SARS-CoV-2 accomplishes that genetic manipulation. Its ORF3b gene produces a protein called a transcription factor that has “strong anti-interferon activity,” Kei Sato of the University of Tokyo and colleagues found — stronger than the original SARS virus or influenza viruses. The protein basically blocks the cell from recognizing that a virus is present, in a way that prevents interferon genes from being expressed.

In fact, the Icahn School team found no interferons in the lung cells of Covid-19 patients. Without interferons, tenOever said, “there is nothing to stop the virus from replicating and festering in the lungs forever.”

That causes lung cells to emit even more “call-for-reinforcement” genes, summoning more and more immune cells. Now the lungs have macrophages and neutrophils and other immune cells “everywhere,” tenOever said, causing such runaway inflammation “that you start having inflammation that induces more inflammation.”

At the same time, unchecked viral replication kills lung cells involved in oxygen exchange. “And suddenly you’re in the hospital in severe respiratory distress,” he said.

In elderly people, as well as those with diabetes, heart disease, and other underlying conditions, the call-to-arms part of the immune system is weaker than in younger, healthier people, even before the coronavirus arrives. That reduces even further the cells’ ability to knock down virus replication with interferons, and imbalances the immune system toward the dangerous inflammatory response.

The discovery that SARS-CoV-2 strongly suppresses infected cells’ production of interferons has raised an intriguing possibility: that taking interferons might prevent severe Covid-19 or even prevent it in the first place, said Vineet Menachery of the University of Texas Medical Branch.

In a study of human cells growing in lab dishes, described in a preprint (not peer-reviewed or published in a journal yet), he and his colleagues also found that SARS-CoV-2 “prevents the vast amount” of interferon genes from turning on. But when cells growing in lab dishes received the interferon IFN-1 before exposure to the coronavirus, “the virus has a difficult time replicating.”

After a few days, the amount of virus in infected but interferon-treated cells was 1,000- to 10,000-fold lower than in infected cells not pre-treated with interferon. (The original SARS virus, in contrast, is insensitive to interferon.)

Ending the pandemic and preventing its return is assumed to require an effective vaccine to prevent infectionand antiviral drugs such as remdesivir to treat the very sick, but the genetic studies suggest a third strategy: preventive drugs.

It’s possible that treatment with so-called type-1 interferon “could stop the virus before it could get established,” Menachery said.

Giving drugs to healthy people is always a dicey proposition, since all drugs have side effects — something considered less acceptable than when a drug is used to treat an illness. “Interferon treatment is rife with complications,” Menachery warned. The various interferons, which are prescribed for hepatitis, cancers, and many other diseases, can cause flu-like symptoms.

But the risk-benefit equation might shift, both for individuals and for society, if interferons or antivirals or other medications are shown to reduce the risk of developing serious Covid-19 or even make any infection nearly asymptomatic.

Interferon “would be warning the cells the virus is coming,” Menachery said, so such pretreatment might “allow treated cells to fend off the virus better and limit its spread.” Determining that will of course require clinical trials, which are underway.

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A Series of Recently Published Papers Report the Development of SARS-CoV2 Neutralizing Antibodies and Passive Immunity toward COVID19

Curator: Stephen J. Williams, Ph.D.

 

Passive Immunity and Treatment of Infectious Diseases

The ability of one person to pass on immunity to another person (passive immunity) is one of the chief methods we develop immunity to many antigens.  For instance, maternal antibodies are passed to the offspring in the neonatal setting as well as in a mother’s milk during breast feeding.  In the clinical setting this is achieved by transferring antibodies from one patient who has been exposed to an antigen (like a virus) to the another individual.   However, the process of purifying the most efficacious antibody as well as its mass production is limiting due to its complexity and cost and can be prohibitively long delay during a pandemic outbreak, when therapies are few and needed immediately.  Regardless, the benefits of developing neutralizing antibodies to confer passive immunity versus development of a vaccine are evident, as the former takes considerable less time than development of a safe and effective vaccine.  For a good review on the development and use of neutralizing antibodies and the use of passive immunity to treat infectious diseases please read the following review:

Margaret A. Keller1,* and E. Richard Stiehm. Passive Immunity in Prevention and Treatment of Infectious Diseases. Clin Microbiol Rev. 2000 Oct; 13(4): 602–614. doi: 10.1128/cmr.13.4.602-614.2000

ABSTRACT

Antibodies have been used for over a century in the prevention and treatment of infectious disease. They are used most commonly for the prevention of measles, hepatitis A, hepatitis B, tetanus, varicella, rabies, and vaccinia. Although their use in the treatment of bacterial infection has largely been supplanted by antibiotics, antibodies remain a critical component of the treatment of diptheria, tetanus, and botulism. High-dose intravenous immunoglobulin can be used to treat certain viral infections in immunocompromised patients (e.g., cytomegalovirus, parvovirus B19, and enterovirus infections). Antibodies may also be of value in toxic shock syndrome, Ebola virus, and refractory staphylococcal infections. Palivizumab, the first monoclonal antibody licensed (in 1998) for an infectious disease, can prevent respiratory syncytial virus infection in high-risk infants. The development and use of additional monoclonal antibodies to key epitopes of microbial pathogens may further define protective humoral responses and lead to new approaches for the prevention and treatment of infectious diseases.

TABLE 1

Summary of the efficacy of antibody in the prevention and treatment of infectious diseases

Infection
Bacterial infections
 Respiratory infections (streptococcus, Streptococcus pneumoniaeNeisseria meningitisHaemophilus influenzae)
 Diphtheria
 Pertussis
 Tetanus
 Other clostridial infections
  C. botulinum
  C. difficile
 Staphylococcal infections
  Toxic shock syndrome
  Antibiotic resistance
  S. epidermidis in newborns
 Invasive streptococcal disease (toxic shock syndrome)
 High-risk newborns
 Shock, intensive care, and trauma
Pseudomonas infection
  Cystic Fibrosis
  Burns
Viral diseases
 Hepatitis A
 Hepatitis B
 Hepatitis C
 HIV infection
 RSV infection
 Herpesvirus infections
  CMV
  EBV
  HSV
  VZV
 Parvovirus infection
 Enterovirus infection
  In newborns
 Ebola
 Rabies
 Measles
 Rubella
 Mumps
 Tick-borne encephalitis
 Vaccinia

Go to:

A Great Explanation of Active versus Passive Immunity by Dr. John Campbell, one of the pioneers in the field of immunology:Antibodies have been used for over a century in the prevention and treatment of infectious disease. They are used most commonly for the prevention of measles, hepatitis A, hepatitis B, tetanus, varicella, rabies, and vaccinia. Although their use in the treatment of bacterial infection has largely been supplanted by antibiotics, antibodies remain a critical component of the treatment of diptheria, tetanus, and botulism. High-dose intravenous immunoglobulin can be used to treat certain viral infections in immunocompromised patients (e.g., cytomegalovirus, parvovirus B19, and enterovirus infections). Antibodies may also be of value in toxic shock syndrome, Ebola virus, and refractory staphylococcal infections. Palivizumab, the first monoclonal antibody licensed (in 1998) for an infectious disease, can prevent respiratory syncytial virus infection in high-risk infants. The development and use of additional monoclonal antibodies to key epitopes of microbial pathogens may further define protective humoral responses and lead to new approaches for the prevention and treatment of infectious diseases.

 

However, developing successful neutralizing antibodies can still be difficult but with the latest monoclonal antibody technology, as highlighted by the following papers, this process has made much more efficient.  In addition, it is not feasable to isolate antibodies from the plasma of covalescent patients in a scale that is needed for a worldwide outbreak.

A good explanation of the need can be found is Dr. Irina Robu’s post Race to develop antibody drugs for COVID-19 where:

When fighting off foreign invaders, our bodies make antibodies precisely produced for the task. The reason vaccines offer such long-lasting protection is they train the immune system to identify a pathogen, so immune cells remember and are ready to attack the virus when it appears. Monoclonal antibodies for coronavirus would take the place of the ones our bodies might produce to fight the disease. The manufactured antibodies would be infused into the body to either tamp down an existing infection, or to protect someone who has been exposed to the virus. However, these drugs are synthetic versions of the convalescent plasma treatments that rely on antibodies from people who have recovered from infection. But the engineered versions are easier to scale because they’re manufactured in rats, rather than from plasma donors.

The following papers represent the latest published work on development of therapeutic and prophylactic neutralizing antibodies to the coronavirus SARS-CoV2

1.  Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody.

Pinto, D., Park, Y., Beltramello, M. et al. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature (2020).                                                                            https://doi.org/10.1038/s41586-020-2349-y

Abstract

SARS-CoV-2 is a newly emerged coronavirus responsible for the current COVID-19 pandemic that has resulted in more than 3.7 million infections and 260,000 deaths as of 6 May 20201,2. Vaccine and therapeutic discovery efforts are paramount to curb the pandemic spread of this zoonotic virus. The SARS-CoV-2 spike (S) glycoprotein promotes entry into host cells and is the main target of neutralizing antibodies. Here we describe multiple monoclonal antibodies targeting SARS-CoV-2 S identified from memory B cells of an individual who was infected with SARS-CoV in 2003. One antibody, named S309, potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 by engaging the S receptor-binding domain. Using cryo-electron microscopy and binding assays, we show that S309 recognizes a glycan-containing epitope that is conserved within the sarbecovirus subgenus, without competing with receptor attachment. Antibody cocktails including S309 along with other antibodies identified here further enhanced SARS-CoV-2 neutralization and may limit the emergence of neutralization-escape mutants. These results pave the way for using S309- and S309-containing antibody cocktails for prophylaxis in individuals at high risk of exposure or as a post-exposure therapy to limit or treat severe disease.

 

2.  Potent neutralizing antibodies against SARS-CoV-2 identified by high-throughput single-cell sequencing of convalescent patients’ B cells

Yunlong Cao et al.  Potent neutralizing antibodies against SARS-CoV-2 identified by high-throughput single-cell sequencing of convalescent patients’ B cells. Cell (2020).

https://doi.org/10.1016/j.cell.2020.05.025

Summary

The COVID-19 pandemic urgently needs therapeutic and prophylactic interventions. Here we report the rapid identification of SARS-CoV-2 neutralizing antibodies by high-throughput single-cell RNA and VDJ sequencing of antigen-enriched B cells from 60 convalescent patients. From 8,558 antigen-binding IgG1+ clonotypes, 14 potent neutralizing antibodies were identified with the most potent one, BD-368-2, exhibiting an IC50 of 1.2 ng/mL and 15 ng/mL against pseudotyped and authentic SARS-CoV-2, respectively. BD-368-2 also displayed strong therapeutic and prophylactic efficacy in SARS-CoV-2-infected hACE2-transgenic mice. Additionally, the 3.8Å Cryo-EM structure of a neutralizing antibody in complex with the spike-ectodomain trimer revealed the antibody’s epitope overlaps with the ACE2 binding site. Moreover, we demonstrated that SARS-CoV-2 neutralizing antibodies could be directly selected based on similarities of their predicted CDR3H structures to those of SARS-CoV neutralizing antibodies. Altogether, we showed that human neutralizing antibodies could be efficiently discovered by high-throughput single B-cell sequencing in response to pandemic infectious diseases.

3. A human monoclonal antibody blocking SARS-CoV-2 infection

Wang, C., Li, W., Drabek, D. et al. A human monoclonal antibody blocking SARS-CoV-2 infection. Nat Commun 11, 2251 (2020). https://doi.org/10.1038/s41467-020-16256-y

Abstract

The emergence of the novel human coronavirus SARS-CoV-2 in Wuhan, China has caused a worldwide epidemic of respiratory disease (COVID-19). Vaccines and targeted therapeutics for treatment of this disease are currently lacking. Here we report a human monoclonal antibody that neutralizes SARS-CoV-2 (and SARS-CoV) in cell culture. This cross-neutralizing antibody targets a communal epitope on these viruses and may offer potential for prevention and treatment of COVID-19.

Extra References on Development of Neutralizing antibodies for COVID19 {Sars-CoV2} published this year (2020)  [1-4]

  1. Fan P, Chi X, Liu G, Zhang G, Chen Z, Liu Y, Fang T, Li J, Banadyga L, He S et al: Potent neutralizing monoclonal antibodies against Ebola virus isolated from vaccinated donors. mAbs 2020, 12(1):1742457.
  2. Dussupt V, Sankhala RS, Gromowski GD, Donofrio G, De La Barrera RA, Larocca RA, Zaky W, Mendez-Rivera L, Choe M, Davidson E et al: Potent Zika and dengue cross-neutralizing antibodies induced by Zika vaccination in a dengue-experienced donor. Nature medicine 2020, 26(2):228-235.
  3. Young CL, Lyons AC, Hsu WW, Vanlandingham DL, Park SL, Bilyeu AN, Ayers VB, Hettenbach SM, Zelenka AM, Cool KR et al: Protection of swine by potent neutralizing anti-Japanese encephalitis virus monoclonal antibodies derived from vaccination. Antiviral research 2020, 174:104675.
  4. Sautto GA, Kirchenbaum GA, Abreu RB, Ecker JW, Pierce SR, Kleanthous H, Ross TM: A Computationally Optimized Broadly Reactive Antigen Subtype-Specific Influenza Vaccine Strategy Elicits Unique Potent Broadly Neutralizing Antibodies against Hemagglutinin. J Immunol 2020, 204(2):375-385.

 

For More Articles on COVID-19 Please see Our Coronavirus Portal on this Open Access Scientific Journal at:

https://pharmaceuticalintelligence.com/coronavirus-portal/

and the following Articles on  Immunity at

Race to develop antibody drugs for COVID-19
Bispecific and Trispecific Engagers: NK-T Cells and Cancer Therapy
Issues Need to be Resolved With ImmunoModulatory Therapies: NK cells, mAbs, and adoptive T cells
Antibody-bound Viral Antigens

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