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Archive for the ‘Infectious Disease Immunodiagnostics’ Category

The NIH-funded adjuvant improves the efficacy of India’s COVID-19 vaccine.

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

Anthony S. Fauci, Director of the National Institute of Allergy and Infectious Diseases (NIAID), Part of National Institute of Health (NIH) said,

Ending a global pandemic demands a global response. I am thrilled that a novel vaccine adjuvant developed in the United States with NIAID support is now included in an effective COVID-19 vaccine that is available to individuals in India.”

Adjuvants are components that are created as part of a vaccine to improve immune responses and increase the efficiency of the vaccine. COVAXIN was developed and is manufactured in India, which is currently experiencing a terrible health catastrophe as a result of COVID-19. An adjuvant designed with NIH funding has contributed to the success of the extremely effective COVAXIN-COVID-19 vaccine, which has been administered to about 25 million individuals in India and internationally.

Alhydroxiquim-II is the adjuvant utilized in COVAXIN, was discovered and validated in the laboratory by the biotech company ViroVax LLC of Lawrence, Kansas, with funding provided solely by the NIAID Adjuvant Development Program. The adjuvant is formed of a small molecule that is uniquely bonded to Alhydrogel, often known as alum and the most regularly used adjuvant in human vaccines. Alhydroxiquim-II enters lymph nodes, where it detaches from alum and triggers two cellular receptors. TLR7 and TLR8 receptors are essential in the immunological response to viruses. Alhydroxiquim-II is the first adjuvant to activate TLR7 and TLR8 in an approved vaccine against an infectious disease. Additionally, the alum in Alhydroxiquim-II activates the immune system to look for an infiltrating pathogen.

Although molecules that activate TLR receptors strongly stimulate the immune system, the adverse effects of Alhydroxiquim-II are modest. This is due to the fact that after COVAXIN is injected, the adjuvant travels directly to adjacent lymph nodes, which contain white blood cells that are crucial in recognizing pathogens and combating infections. As a result, just a minimal amount of Alhydroxiquim-II is required in each vaccination dosage, and the adjuvant does not circulate throughout the body, avoiding more widespread inflammation and unwanted side effects.

This scanning electron microscope image shows SARS-CoV-2 (round gold particles) emerging from the surface of a cell cultured in the lab. SARS-CoV-2, also known as 2019-nCoV, is the virus that causes COVID-19. Image Source: NIAID

COVAXIN is made up of a crippled version of SARS-CoV-2 that cannot replicate but yet encourages the immune system to produce antibodies against the virus. The NIH stated that COVAXIN is “safe and well tolerated,” citing the results of a phase 2 clinical investigation. COVAXIN safety results from a Phase 3 trial with 25,800 participants in India will be released later this year. Meanwhile, unpublished interim data from the Phase 3 trial show that the vaccine is 78% effective against symptomatic sickness, 100% effective against severe COVID-19, including hospitalization, and 70% effective against asymptomatic infection with SARS-CoV-2, the virus that causes COVID-19. Two tests of blood serum from persons who had received COVAXIN suggest that the vaccine creates antibodies that efficiently neutralize the SARS-CoV-2 B.1.1.7 (Alpha) and B.1.617 (Delta) variants (1) and (2), which were originally identified in the United Kingdom and India, respectively.

Since 2009, the NIAID Adjuvant Program has supported the research of ViroVax’s founder and CEO, Sunil David, M.D., Ph.D. His research has focused on the emergence of new compounds that activate innate immune receptors and their application as vaccination adjuvants.

Dr. David’s engagement with Bharat Biotech International Ltd. of Hyderabad, which manufactures COVAXIN, began during a 2019 meeting in India organized by the NIAID Office of Global Research under the auspices of the NIAID’s Indo-US Vaccine Action Program. Five NIAID-funded adjuvant investigators, including Dr. David, two representatives of the NIAID Division of Allergy, Immunology, and Transplantation, and the NIAID India representative, visited 4 top biotechnology companies to learn about their work and discuss future collaborations. The delegation also attended a consultation in New Delhi, which was co-organized by the NIAID and India’s Department of Biotechnology and hosted by the National Institute of Immunology.

Among the scientific collaborations spawned by these endeavors was a licensing deal between Bharat Biotech and Dr. David to use Alhydroxiquim-II in their candidate vaccines. During the COVID-19 outbreak, this license was expanded to cover COVAXIN, which has Emergency Use Authorization in India and more than a dozen additional countries. COVAXIN was developed by Bharat Biotech in partnership with the Indian Council of Medical Research’s National Institute of Virology. The company conducted thorough safety research on Alhydroxiquim-II and undertook the arduous process of scaling up production of the adjuvant in accordance with Good Manufacturing Practice standards. Bharat Biotech aims to generate 700 million doses of COVAXIN by the end of 2021.

NIAID conducts and supports research at the National Institutes of Health, across the United States, and across the world to better understand the causes of infectious and immune-mediated diseases and to develop better methods of preventing, detecting, and treating these illnesses. The NIAID website contains news releases, info sheets, and other NIAID-related materials.

Main Source:

https://www.miragenews.com/adjuvant-developed-with-nih-funding-enhances-587090/

References

  1. https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciab411/6271524?redirectedFrom=fulltext
  2. https://academic.oup.com/jtm/article/28/4/taab051/6193609

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

Comparing COVID-19 Vaccine Schedule Combinations, or “Com-COV” – First-of-its-Kind Study will explore the Impact of using eight different Combinations of Doses and Dosing Intervals for Different COVID-19 Vaccines

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/02/08/comparing-covid-19-vaccine-schedule-combinations-or-com-cov-first-of-its-kind-study-will-explore-the-impact-of-using-eight-different-combinations-of-doses-and-dosing-intervals-for-diffe/

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/

National Public Radio interview with Dr. Anthony Fauci on his optimism on a COVID-19 vaccine by early 2021

Reporter: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2020/07/19/national-public-radio-interview-with-dr-anthony-fauci-on-his-optimism-on-a-covid-19-vaccine-by-early-2021/

Cryo-EM disclosed how the D614G mutation changes SARS-CoV-2 spike protein structure

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

https://pharmaceuticalintelligence.com/2021/04/10/cryo-em-disclosed-how-the-d614g-mutation-changes-sars-cov-2-spike-protein-structure/

Updates on the Oxford, AstraZeneca COVID-19 Vaccine

Reporter: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2020/06/16/updates-on-the-oxford-astrazeneca-covid-19-vaccine/

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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

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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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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/

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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

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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/

Read Full Post »

Cryo-EM disclosed how the D614G mutation changes SARS-CoV-2 spike protein structure.

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

SARS-CoV-2, the virus that causes COVID-19, has had a major impact on human health globally; infecting a massive quantity of people around 136,046,262 (John Hopkins University); causing severe disease and associated long-term health sequelae; resulting in death and excess mortality, especially among older and prone populations; altering routine healthcare services; disruptions to travel, trade, education, and many other societal functions; and more broadly having a negative impact on peoples physical and mental health.

It’s need of the hour to answer the questions like what allows the variants of SARS-CoV-2 first detected in the UK, South Africa, and Brazil to spread so quickly? How can current COVID-19 vaccines better protect against them?

Scientists from the Harvard Medical School and the Boston Children’s Hospital help answer these urgent questions. The team reports its findings in the journal “Science a paper entitled Structural impact on SARS-CoV-2 spike protein by D614G substitution. The mutation rate of the SARS-CoV-2 virus has rapidly evolved over the past few months, especially at the Spike (S) protein region of the virus, where the maximum number of mutations have been observed by the virologists.

Bing Chen, HMS professor of pediatrics at Boston Children’s, and colleagues analyzed the changes in the structure of the spike proteins with the genetic change by D614G mutation by all three variants. Hence they assessed the structure of the coronavirus spike protein down to the atomic level and revealed the reason for the quick spreading of these variants.


This model shows the structure of the spike protein in its closed configuration, in its original D614 form (left) and its mutant form (G614). In the mutant spike protein, the 630 loop (in red) stabilizes the spike, preventing it from flipping open prematurely and rendering SARS-CoV-2 more infectious.

Fig. 1. Cryo-EM structures of the full-length SARS-CoV-2 S protein carrying G614.

(A) Three structures of the G614 S trimer, representing a closed, three RBD-down conformation, an RBD-intermediate conformation and a one RBD-up conformation, were modeled based on corresponding cryo-EM density maps at 3.1-3.5Å resolution. Three protomers (a, b, c) are colored in red, blue and green, respectively. RBD locations are indicated. (B) Top views of superposition of three structures of the G614 S in (A) in ribbon representation with the structure of the prefusion trimer of the D614 S (PDB ID: 6XR8), shown in yellow. NTD and RBD of each protomer are indicated. Side views of the superposition are shown in fig. S8.

IMAGE SOURCE: Bing Chen, Ph.D., Boston Children’s Hospital, https://science.sciencemag.org/content/early/2021/03/16/science.abf2303

The work

The mutant spikes were imaged by Cryo-Electron microscopy (cryo-EM), which has resolution down to the atomic level. They found that the D614G mutation (substitution of in a single amino acid “letter” in the genetic code for the spike protein) makes the spike more stable as compared with the original SARS-CoV-2 virus. As a result, more functional spikes are available to bind to our cells’ ACE2 receptors, making the virus more contagious.


Fig. 2. Cryo-EM revealed how the D614G mutation changes SARS-CoV-2 spike protein structure.

IMAGE SOURCE:  Zhang J, et al., Science

Say the original virus has 100 spikes,” Chen explained. “Because of the shape instability, you may have just 50 percent of them functional. In the G614 variants, you may have 90 percent that is functional. So even though they don’t bind as well, the chances are greater and you will have an infection

Forthcoming directions by Bing Chen and Team

The findings suggest the current approved COVID-19 vaccines and any vaccines in the works should include the genetic code for this mutation. Chen has quoted:

Since most of the vaccines so far—including the Moderna, Pfizer–BioNTech, Johnson & Johnson, and AstraZeneca vaccines are based on the original spike protein, adding the D614G mutation could make the vaccines better able to elicit protective neutralizing antibodies against the viral variants

Chen proposes that redesigned vaccines incorporate the code for this mutant spike protein. He believes the more stable spike shape should make any vaccine based on the spike more likely to elicit protective antibodies. Chen also has his sights set on therapeutics. He and his colleagues are further applying structural biology to better understand how SARS-CoV-2 binds to the ACE2 receptor. That could point the way to drugs that would block the virus from gaining entry to our cells.

In January, the team showed that a structurally engineered “decoy” ACE2 protein binds to SARS-CoV-2 200 times more strongly than the body’s own ACE2. The decoy potently inhibited the virus in cell culture, suggesting it could be an anti-COVID-19 treatment. Chen is now working to advance this research into animal models.

Main Source:

Abstract

Substitution for aspartic acid by glycine at position 614 in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 appears to facilitate rapid viral spread. The G614 strain and its recent variants are now the dominant circulating forms. We report here cryo-EM structures of a full-length G614 S trimer, which adopts three distinct prefusion conformations differing primarily by the position of one receptor-binding domain. A loop disordered in the D614 S trimer wedges between domains within a protomer in the G614 spike. This added interaction appears to prevent premature dissociation of the G614 trimer, effectively increasing the number of functional spikes and enhancing infectivity, and to modulate structural rearrangements for membrane fusion. These findings extend our understanding of viral entry and suggest an improved immunogen for vaccine development.

https://science.sciencemag.org/content/early/2021/03/16/science.abf2303?rss=1

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

COVID-19-vaccine rollout risks and challenges

Reporter : Irina Robu, PhD

https://pharmaceuticalintelligence.com/2021/02/17/covid-19-vaccine-rollout-risks-and-challenges/

COVID-19 Sequel: Neurological Impact of Social isolation been linked to poorer physical and mental health

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/03/30/covid-19-sequel-neurological-impact-of-social-isolation-been-linked-to-poorer-physical-and-mental-health/

Comparing COVID-19 Vaccine Schedule Combinations, or “Com-COV” – First-of-its-Kind Study will explore the Impact of using eight different Combinations of Doses and Dosing Intervals for Different COVID-19 Vaccines

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/02/08/comparing-covid-19-vaccine-schedule-combinations-or-com-cov-first-of-its-kind-study-will-explore-the-impact-of-using-eight-different-combinations-of-doses-and-dosing-intervals-for-diffe/

COVID-19 T-cell immune response map, immunoSEQ T-MAP COVID for research of T-cell response to SARS-CoV-2 infection

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/11/20/covid-19-t-cell-immune-response-map-immunoseq-t-map-covid-for-research-of-t-cell-response-to-sars-cov-2-infection/

Tiny biologic drug to fight COVID-19 show promise in animal models

Reporter : Irina Robu, PhD

https://pharmaceuticalintelligence.com/2020/10/11/tiny-biologic-drug-to-fight-covid-19-show-promise-in-animal-models/

Miniproteins against the COVID-19 Spike protein may be therapeutic

Reporter: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2020/09/30/miniproteins-against-the-covid-19-spike-protein-may-be-therapeutic/

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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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Placenta lacks molecules required for COVID-19 infection

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

The pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected more than 10 million people, including pregnant women. To date, no consistent evidence for the vertical transmission of SARS-CoV-2 has been found. The placenta serves as the lungs, gut, kidneys, and liver of the fetus. This fetal organ also has major endocrine actions that modulate maternal physiology and, importantly, together with the extraplacental chorioamniotic membranes shield the fetus against microbes from hematogenous dissemination and from invading the amniotic cavity.

 

Most pathogens that cause hematogenous infections in the mother are not able to reach the fetus, which is largely due to the potent protective mechanisms provided by placental cells (i.e. trophoblast cells: syncytiotrophoblasts and cytotrophoblasts). Yet, some of these pathogens such as Toxoplasma gondii, Rubella virus, herpesvirus (HSV), cytomegalovirus (CMV), and Zika virus (ZIKV), among others, are capable of crossing the placenta and infecting the fetus, causing congenital disease.

 

The placental membranes that contain the fetus and amniotic fluid lack the messenger RNA (mRNA) molecule required to manufacture the ACE2 receptor, the main cell surface receptor used by the SARS-CoV-2 virus to cause infection. These placental tissues also lack mRNA needed to make an enzyme, called TMPRSS2, that SARS-CoV-2 uses to enter a cell. Both the receptor and enzyme are present in only miniscule amounts in the placenta, suggesting a possible explanation for why SARS-CoV-2 has only rarely been found in fetuses or newborns of women infected with the virus, according to the study authors.

 

The single-cell transcriptomic analysis presented by the researchers provides evidence that SARS-CoV-2 is unlikely to infect the placenta and fetus since its canonical receptor and protease, ACE2 and TRMPSS2, are only minimally expressed by the human placenta throughout pregnancy. In addition, it was shown that the SARS-CoV-2 receptors are not expressed by the chorioamniotic membranes in the third trimester. However, viral receptors utilized by CMV, ZIKV, and others are highly expressed by the human placental tissues.

 

Transcript levels do not always correlate with protein expression, but the data of the present study indicates a low likelihood of placental infection and vertical transmission of SARS-CoV-2. However, it is still possible that the expression of these proteins is much higher in individuals with pregnancy complications related with the renin-angiotensin-aldosterone system, which can alter the expression of ACE2. The cellular receptors and mechanisms that could be exploited by SARS-CoV-2 are still under investigation.

 

References:

 

https://www.nih.gov/news-events/news-releases/placenta-lacks-major-molecules-used-sars-cov-2-virus-cause-infection

 

https://pubmed.ncbi.nlm.nih.gov/32662421/

 

https://pubmed.ncbi.nlm.nih.gov/32217113/

 

https://pubmed.ncbi.nlm.nih.gov/32161408/

 

https://pubmed.ncbi.nlm.nih.gov/32335053/

 

https://pubmed.ncbi.nlm.nih.gov/32298273/

 

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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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