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Archive for the ‘Treatment Protocols for COVID-19’ Category


Nir Hacohen and Marcia Goldberg, Researchers at MGH and the Broad Institute identify protein “signature” of severe COVID-19

Curator and Reporter: Aviva Lev-Ari, PhD, RN

Longitudinal proteomic analysis of plasma from patients with severe COVID-19 reveal patient survival-associated signatures, tissue-specific cell death, and cell-cell interactions

Open AccessPublished:April 30, 2021DOI:https://doi.org/10.1016/j.xcrm.2021.100287

Highlights

  • 16% of COVID-19 patients display an atypical low-inflammatory plasma proteome
  • Severe COVID-19 is associated with heterogeneous plasma proteomic responses
  • Death of virus-infected lung epithelial cells is a key feature of severe disease
  • Lung monocyte/macrophages drive T cell activation, together promoting epithelial damage

Summary

Mechanisms underlying severe COVID-19 disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNAseq datasets reveals contributions from circulating immune and tissue cells. Sixteen percent of patients display reduced inflammation yet comparably poor outcomes. Comparison of patients who died to severely ill survivors identifies dynamic immune cell-derived and tissue-associated proteins associated with survival, including exocrine pancreatic proteases. Using derived tissue-specific and cell type-specific intracellular death signatures, cellular ACE2 expression, and our data, we infer whether organ damage resulted from direct or indirect effects of infection. We propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage. These datasets provide important insights and a rich resource for analysis of mechanisms of severe COVID-19 disease.

Graphical Abstract

Figure thumbnail fx1

Image Source: DOI: https://doi.org/10.1016/j.xcrm.2021.100287

https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00115-4

The quest to identify mechanisms that might be contributing to death in COVID-19: Why do some patients die from this disease, while others — who appear to be just as ill do not?

Researchers at Massachusetts General Hospital (MGH) and the Broad Institute of MIT and Harvard have identified the protein “signature” of severe COVID-19

Interest was to develop methods for studying human immune responses to infections, which they had applied to the condition known as bacterial sepsis. The three agreed to tackle this new problem with the goal of understanding how the human immune system responds to SARS-CoV-2, the novel pathogen that causes COVID-19.

How scientists launched a study in days to probe COVID-19’s unpredictability

Collecting these specimens required a large team of collaborators from many departments, which worked overtime for five weeks to amass blood samples from 306 patients who tested positive for COVID-19, as well as from 78 patients with similar symptoms who tested negative for the coronavirus.

Alexandra-Chloé Villani

Credit : Alexandra-Chloé VillaniResearch associates at Mass General who worked countless hours to process blood samples for the COVID Acute Cohort Study (from left to right: Anna Gonye, Irena Gushterova, and Tom Lasalle)By Leah Eisenstadt

https://www.broadinstitute.org/news/how-scientists-launched-study-days-probe-covid-19%E2%80%99s-unpredictability

As the COVID-19 surge began in March, Mass General and Broad researchers worked around the clock to begin learning why some patients fare worse with the disease than others

Protein signatures in the blood

https://www.broadinstitute.org/news/researchers-identify-protein-%E2%80%9Csignature%E2%80%9D-severe-covid-19

The study found that most patients with COVID-19 have a consistent protein signature, regardless of disease severity; as would be expected, their bodies mount an immune response by producing proteins that attack the virus. “But we also found a small subset of patients with the disease who did not demonstrate the pro-inflammatory response that is typical of other COVID-19 patients,” Filbin said, yet these patients were just as likely as others to have severe disease. Filbin, who is also an assistant professor of emergency medicine at Harvard Medical School (HMS), noted that patients in this subset tended to be older people with chronic diseases, who likely had weakened immune systems.

Among other revelations, this showed that the most prevalent severity-associated protein, a pro-inflammatory protein called interleukin-6 (IL-6) rose steadily in patients who died, while it rose and then dropped in those with severe disease who survived. Early attempts by other groups to treat COVID-19 patients experiencing acute respiratory distress with drugs that block IL-6 were disappointing, though more recent studies show promise in combining these medications with the steroid dexamethasone.

Hacohen, who is a professor of medicine at HMS and director of the Broad’s Cell Circuits Program:

“You can ask which of the many thousands of proteins that are circulating in your blood are associated with the actual outcome,” he said, “and whether there is a set of proteins that tell us something.”

Goldberg, who is a professor of emergency medicine at HMS:

They are highly likely to be useful in figuring out some of the underlying mechanisms that lead to severe disease and death in COVID-19,” she said, noting her gratitude to the patients involved in the study. Their samples are already being used to study other aspects of COVID-19, such as identifying the qualities of antibodies that patients form against the virus.

SOURCES

Original Research

Filbin MR, Mehta A, et al. Longitudinal proteomic analysis of plasma from patients with severe COVID-19 reveal patient survival-associated signatures, tissue-specific cell death, and cell-cell interactionsCell Reports Medicine. Online April 30, 2021. DOI: 10.1016/j.xcrm.2021.100287.

Adapted from a press release originally issued by Massachusetts General Hospital.

https://www.broadinstitute.org/news/researchers-identify-protein-%E2%80%9Csignature%E2%80%9D-severe-covid-19

https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00115-4

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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

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

UPDATED on 4/15/2021


Atul Gawande@Atul_Gawande
·

Why wait for more info? A new case of cerebral sinus venus thrombosis was reported in a 25 year old man who became critically ill from a cerebral hemorrhage. And for women age 20-50, CSVT occurred in 1 in 13,000, or 4-15X higher than background.

UPDATED on 4/14/2021

How UK doctor linked rare blood-clotting to AstraZeneca Covid jab

https://www.theguardian.com/society/2021/apr/13/how-uk-doctor-marie-scully-blood-clotting-link-astrazeneca-covid-jab-university-college-london-hospital

From: “Gupta, Ajay” <ajayg1@hs.uci.edu>

Date: Wednesday, April 14, 2021 at 10:33 AM

To: “Aviva Lev-Ari, PhD, RN” <AvivaLev-Ari@alum.berkeley.edu>

Cc: Kate Chiang <kcscience777@gmail.com>

Subject: Mechanism of thrombosis with AstraZeneca and J & J vaccines

https://www.fda.gov/news-events/press-announcements/joint-cdc-and-fda-statement-johnson-johnson-covid-19-vaccine

We have put together the following mechanism for thrombosis including central vein sinus thrombosis as a complication of both J&J and the AstraZeneca vaccines. This unifying mechanism explains the predilection of cerebral veins and higher risk in younger women. Please share your thoughts on the proposed mechanism.

We have submitted the attached manuscript to SSRN.  Sharing this promptly considering the public health significance.

Thanks

Figure 1. AstraZeneca or Janssen COVID-19 vaccine induced thromboinflammation and cerebral venous sinus thrombosis (CVST)-Proposed Mechanisms: Adenovirus carrier delivers SARS-CoV-2 DNA encoding the Spike (S) protein to the lung megakaryocytes via the coxsackie-adenovirus receptor (CAR). Spike protein induces COX-2 expression in megakaryocytes leading to megakaryocyte activation, biogenesis of activated platelets that express COX-2 and generate thromboxane A2 (TxA2). Cerebral vein sinus endothelial cells express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses would be further activated by TxA2 dependent podoplanin-CLEC2 signaling, leading to release of extracellular vesicles, thereby promoting CLEC5A and TLR2 mediated neutrophil activation, thromboinflammation, CVST, and thromboembolism in other vascular beds. Young age and female gender are associated with increased TxA2 generation and platelet activation respectively, and hence increased risk of thromboembolic complications following vaccination.

Best regards,

Ajay

Ajay Gupta, M.B.,B.S., M.D.

Clinical Professor,

Division of Nephrology, Hypertension and Kidney Transplantation

University of California Irvine  

President & CSO, KARE Biosciences (www.karebio.com)

E-mail:     ajayg1@hs.uci.edu

Cell:         1 (562) 412-6259

Office:     1 (562) 419-7029

PERSPECTIVE 

Title: SARS-CoV-2 vaccination induced thrombosis: Is chemoprophylaxis with antiplatelet agents warranted? 

Guest Authors: 

Kate Chander Chiang1 

Ajay Gupta, MBBS, MD1,2 

Affiliations 

(1) KARE Biosciences, Orange, CA 92869 

(2) Department of Medicine, University of California Irvine (UCI) School of Medicine, Orange, CA 92868 

*Corresponding author: 

Ajay Gupta, MBBS, MD 

Clinical Professor of Medicine, 

Division of Nephrology, Hypertension and Kidney Transplantation 

University of California Irvine (UCI) School of Medicine, 

Orange, CA 92868 

Tel: +1 (562) 412-6259 

E-mail: ajayg1@hs.uci.edu 

Word Count 

Abstract: 359 

Main Body: 1,648 

Funding: No funding was required. 

Conflict of Interest: AG and KCC have filed a patent for use of Ramatroban as an anti-thrombotic and immune modulator in SARS-CoV-2 infection. The patents have been licensed to KARE Biosciences. KCC is an employee of KARE Biosciences. 

Author Contributions: AG and KCC conceptualized, created the framework, wrote and reviewed the manuscript. 

Abbreviations: TxA2, thromboxane A2; DIC, disseminated intravascular coagulopathy; COX, cyclooxygenase; TTP, thrombotic thrombocytopenic purpura; CVST, cerebral venous sinus thrombosis; CLEC, C-type lectin-like receptor; TLR, toll-like receptor; CAR, coxsackievirus and adenovirus receptor; COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 2 

ABSTRACT 

The COVID-19 vaccines, Vaxzevria® (AstraZeneca) and the Janssen vaccine (Johnson & Johnson) are highly effective but associated with rare thrombotic complications. These vaccines are comprised of recombinant, replication incompetent, chimpanzee adenoviral vectors encoding the Spike (S) glycoprotein of SARS-CoV-2. The adenovirus vector infects epithelial cells expressing the coxsackievirus and adenovirus receptor (CAR). The S glycoprotein of SARS-CoV-2 is expressed locally stimulating neutralizing antibody and cellular immune responses, which protect against COVID-19. The immune responses are highly effective in preventing symptomatic disease in adults irrespective of age, gender or ethnicity. However, both vaccines have been associated with thromboembolic events including cerebral venous sinus thrombosis (CVST). Megakaryocytes also express CAR, leading us to postulate adenovirus vector uptake and expression of spike glycoprotein by megakaryocytes. Spike glycoprotein induces expression of cyclooxygenase -2 (COX-2), leading to generation of thromboxane A2 (TxA2). TxA2 promotes megakaryocyte activation, biogenesis of activated platelets and thereby increased thrombogenicity. Cerebral vein sinus endothelial cells express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses would be further activated by TxA2 dependent podoplanin-CLEC2 signaling, leading to CVST. The mechanisms proposed are consistent with the following clinical observations. First, a massive increase in TxA2 generation promotes platelet activation and thromboinflammation in COVID-19 patients. Second, TxA2 generation and platelet activation is increased in healthy women compared to men, and in younger mice compared to older mice; and, younger age and female gender appear to be associated with increased risk of thromboembolism as a complication of adenoviral vector based COVID-19 vaccine. The roll out of both AstraZeneca and Janssen vaccines has been halted for adults under 30-60 years of age in many countries. We propose that antiplatelet agents targeting TxA2 receptor signaling should be considered for chemoprophylaxis when administering the adenovirus based COVID-19 vaccines to adults under 30-60 years of age. In many Asian and African countries, only adenovirus-based COVID-19 vaccines are available at present. A short course of an antiplatelet agent such as aspirin could allow millions to avail of the benefits of the AstraZeneca and Janssen COVID-19 vaccines which could be otherwise either denied to them or put them at undue risk of thromboembolic complications. 

Keywords: SARS-CoV-2, COVID-19, Vaxzevria, COVISHIELD, Janssen COVID-19 vaccine, Johnson & Johnson vaccine, AstraZeneca vaccine, AZD1222, thrombosis, cerebral venous sinus thrombosis, thromboembolism, aspirin, antiplatelet agents, thromboxane, COX-2, disseminated intravascular coagulation, thrombocytopenia, thrombotic thrombocytopenia, CLEC2, megakaryocyte 3 

COVID-19 disease is caused by a novel positive-strand RNA coronavirus (SARS-CoV-2), which belongs to the Coronaviridae family, along with the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) coronaviruses.1 The genome of these viruses encodes several non-structural and structural proteins, including spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins.2 The majority of the vaccines for COVID-19 that employ administration of viral antigens or viral gene sequences aim to induce neutralizing antibodies against the viral spike protein (S), preventing uptake through the ACE2 receptor, and thereby blocking infection.3 

The Janssen COVID-19 vaccine (Johnson & Johnson) is comprised of a recombinant, replication- incompetent Ad26 vector, encoding a stabilized variant of the SARS-CoV-2 Spike (S) protein. The ChAdOx1 nCoV-19 vaccine (AZD1222, Vaxzevria®) was developed at Oxford University and consists of a replication-deficient chimpanzee adenoviral vector ChAdOx1, encoding the S protein.4 In US Phase III trials, Vaxzevria has been demonstrated to have 79% efficacy at preventing symptomatic COVID-19, and 100% efficacy against severe or critical disease and hospitalization, with comparable efficacy across ethnicity, gender and age.5 However, Vaxzevria has been associated with thrombotic and embolic events including disseminated intravascular coagulation (DIC) and cerebral venous sinus thrombosis (CVST), occurring within 14 days after vaccination, mostly in people under 55 years of age, the majority of whom have been women.6 Data from Europe suggests that the event rate for thromboembolic events may be about 10 per million vaccinated. Antibodies to platelet factor 4/heparin complexes have been recently reported in a few patients.7 However, the significance of this finding remains to be established. As of April 12, 2021, about 6.8 million doses of the Janssen vaccine have been administered in the U.S.8 CDC and FDA are reviewing data involving six reported U.S. cases of CVST in combination with thrombocytopenia.8 All six cases occurred among women between the ages of 18 and 48, and symptoms occurred 6 to 13 days after vaccination.8 

SARS-CoV-2 is known to cause thromboinflammation leading to thrombotic microangiopathy, pulmonary thrombosis, pedal acro-ischemia (“COVID-toes”), arterial clots, strokes, cardiomyopathy, coronary and systemic vasculitis, deep venous thrombosis, pulmonary embolism, and microvascular thrombosis in renal, cardiac and brain vasculature.9-14 Cerebral venous sinus thrombosis (CVST) has also been reported in COVID-19 patients.15 Amongst 34,331 hospitalized COVID-19 patients, CVST was diagnosed in 28.16 In a multicenter, multinational, cross sectional, retrospective study of 8 patients diagnosed with CVST and COVID-19, seven were women.17 In another series of 41 patients with COVID-19 and CVST, the average age was about 50 years (SD, 16.5 years).17 The pathobiology of thrombotic events associated with the AstraZeneca vaccine should be viewed in the context of mechanisms underlying thromboinflammation that complicates SARS-CoV-2 infection and COVID-19 disease. 

A. Role of COX-2 and thromboxane A2 in thromboinflammation complicating adenovirus based COVID-19 vaccine encoding the Spike protein of SARS-CoV-2 

Thromboinflammation in COVID-19 seems to be primarily caused by endothelial, platelet and neutrophil activation, platelet-neutrophil aggregates and release of neutrophil extracellular traps (NETs).13,18 Platelet activation in COVID-19 is fueled by a lipid storm characterized by massive increases in thromboxane A2 (TxA2) levels in the blood and bronchoalveolar lavage fluid.19,20 Cyclooxygenase (COX) enzymes catalyze the first step in the biosynthesis of TxA2 from arachidonic acid, and COX-2 expression is induced by the spike (S) protein of coronaviruses.21 We postulate that an aberrant increase in TxA2 generation induced by the spike protein expression from the AstraZeneca vaccine leads to thromboinflammation, thromboembolism and CVST. 4 

The support for the above proposed mechanism comes from the following observations. First, when mice of different age groups were infected with SARS-CoV virus, the generation of TxA2 was markedly increased in younger mice compared to middle aged mice.22 Furthermore, in children with asymptomatic or mildly symptomatic SARS-CoV-2 infection, microvascular thrombosis and thrombotic microangiopathy occur early in infection.20 These observations are consistent with the higher risk for thrombosis in adults under 60 years of age, compared with the older age group.6,7 Second, platelets from female mice are much more reactive than from male mice.23 Furthermore, TxA2 generation, TxA2-platelet interaction and activation is increased in women compared to men.24,25 These observations are consistent with disproportionately increased risk of thrombosis in women following AstraZeneca and Janssen COVID-19 vaccines. 

The adenoviral vector ChAdOx1, containing nCoV-19 spike protein gene, infects host cells through the coxsackievirus and adenovirus receptor (CAR).26 CAR-dependent cell entry of the viral vector allows insertion of the SARS-CoV-2 spike protein gene and expression of Spike protein by host cells (Figure 1). CAR is primarily expressed on epithelial tight junctions.27 CAR expression has also been reported in platelets,28 and since platelets are anucleate cells CAR expression by megakaryocytes can be inferred. Therefore, AstraZeneca and Janssen vaccines would be expected to induce expression of Spike protein in megakaryocytes and platelets (Figure 1). 

Spike protein of coronaviruses in known to induce COX-2 gene expression.21,29 COX-2 expression is induced during normal human megakaryopoiesis and characterizes newly formed platelets.30 While in healthy controls <10% of circulating platelets express COX-2, in patients with high platelet generation, up to 60% of platelets express COX-2.30 Generation of TxA2 by platelets is markedly suppressed by COX-2 inhibition in patients with increased megakaryopoiesis versus healthy subjects.30 Therefore, we postulate that expression of Spike protein induces COX-2 expression and generation of thromboxane A2 by megakaryocytes. TxA2 promotes biogenesis of activated platelets expressing COX-2. Platelet TxA2 generation leads to platelet activation and aggregation, and thereby thromboinflammation (Figure 1). 

Extravascular spaces of the lungs comprise populations of mature and immature megakaryocytes that originate from the bone marrow, such that lungs are a major site of platelet biogenesis, accounting for approximately 50% of total platelet production or about 10 million platelets per hour.31 More than 1 million extravascular megakaryocytes have been observed in each lung of transplant mice.31 Following intramuscular injection of the AstraZeneca and Janssen vaccines, the adenovirus vector will traverse the veins and lymphatics to be delivered to the pulmonary circulation thereby exposing lung megakaryocytes in the first pass. Interestingly, under thrombocytopenic conditions, haematopoietic progenitors migrate out of the lung to repopulate the bone marrow and completely reconstitute blood platelet counts.31 

B. Predilection of cerebral venous sinuses for thrombosis following vaccination 

Recent studies have demonstrated that arterial, venous and sinusoidal endothelial cells in the brain uniquely express markers of the lymphatic endothelium including podoplanin.32 Podoplanin serves as a ligand for CLEC2 receptors on platelets.33 Thromboxane A2 dependent CLEC2 signaling leads to platelet activation (Figure 1), while a TxA2 receptor antagonist nearly abolish CLEC2 signaling and platelet activation.33 TxA2 dependent CLEC2 signaling promotes release of exosomes and microvesicles from platelets, leading to activation of CLEC5A and TLR2 receptors respectively on neutrophils, neutrophil activation and release of neutrophil extracellular traps (NETs) (Figure 1).34 Neutrophil activation, more than platelet activation, is associated with thrombotic complications in COVID-19.13,18,35 As proposed above, the expression of podoplanin, a unique molecular signature of cerebral endothelial cells, may be responsible for the predilection of brain vascular bed to thromboinflammation and CVST as a complication of COVID-19 vaccines. 5 

C. Chemoprophylaxis with antiplatelet agents 

In animal models of endotoxin mediated endothelial injury and thromboinflammation, antagonism of TxA2 signaling prevents ARDS, reduces myocardial damage and increases survival.36-38 

Considering the key role played by platelets in thromboinflammation, we propose consideration of antiplatelet agents, either aspirin or TxA2 receptor antagonists, as chemoprophylactic agents when the AstraZeneca vaccine is administered to adults between 18 and 60 years of age.39 High bleeding risk because of another medical condition or medication would be contraindications to use of antiplatelet agents.39 Medical conditions that increase bleeding risk include previous gastrointestinal bleeding, peptic ulcer disease, blood clotting problems, and kidney disease.39 Medications that increase bleeding risk include nonsteroidal anti-inflammatory drugs, steroids, and other anticoagulants or anti-platelet agents.39 Aspirin appears to be safe in COVID-19. In a retrospective observational study in hospitalized patients with COVID-19, low-dose aspirin was found to be effective in reducing morbidity and mortality; and was not associated with any safety issues including major bleeding.40 Therefore, aspirin is likely to be safe as an adjunct to COVID-19 vaccines even in the event of a subsequent infection with SARS-CoV-2 virus. 

Can aspirin influence the host immune response to the COVID-19 vaccines? This issue merits further investigation. When healthy adults > 65 years of age were given influenza vaccine and randomized to receive 300 mg aspirin or placebo on days 1, 2, 3, 5 and 7, the aspirin group showed 4-fold or greater rise in influenza specific antibodies.41 The risk-benefit analysis, based on above information, suggests that a one to three week course of low-dose aspirin merits consideration in order to prevent the thromboembolic events associated with the AstraZeneca vaccine. 

SUMMARY 

Thromboembolic disease including disseminated intravascular coagulation and cerebral venous sinus thrombosis have been reported in association with AstraZeneca and Janssen COVID-19 vaccines. Many countries have halted use of these vaccines either entirely or for adults under 30 to 60 years of age. European and North American countries generally have access to mRNA vaccines. However, in Asian and African countries the choices are limited to adenovirus based COVID-19 vaccines. The governments in such countries are forging ahead with vaccinating all adults, including those under 60 years of age, with Vaxzevria, Covishield (the version of Vaxzevria manufactured by the Serum Institute of India) or the Janssen vaccines. This has led to grave concern and anxiety amongst the citizens and medical professionals. Considering the profound global public health implications of limiting the use of these vaccines, it is critical to understand the pathobiology of vaccination induced thrombotic events in order to guide strategies aimed at prevention. In this regard, studies are urgently needed to examine lipid mediators and thromboxane A2 – platelet axis following vaccination with these vaccines, compared with mRNA vaccines. The risk-benefit analysis based on information presented here suggests that chemoprophylaxis using a short course of low-dose aspirin in adults under 60 years of age may be justified in conjunction with adenovirus based COVID-19 vaccines in order to prevent thromboembolic events and enhance safety. 6 

Figure 1. AstraZeneca or Janssen COVID-19 vaccine induced thromboinflammation and cerebral venous sinus thrombosis (CVST)-Proposed Mechanisms: Adenovirus carrier delivers SARS-CoV-2 DNA encoding the Spike (S) protein to the lung megakaryocytes via the coxsackie-adenovirus receptor (CAR). Spike protein induces COX-2 expression in megakaryocytes leading to megakaryocyte activation, biogenesis of activated platelets that express COX-2 and generate thromboxane A2 (TxA2). Cerebral vein sinus endothelial cells express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses would be further activated by TxA2 dependent podoplanin-CLEC2 signaling, leading to release of extracellular vesicles, thereby promoting CLEC5A and TLR2 mediated neutrophil activation, thromboinflammation, CVST, and thromboembolism in other vascular beds. Young age and female gender are associated with increased TxA2 generation and platelet activation respectively, and hence increased risk of thromboembolic complications following vaccination. 

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16. Baldini T, Asioli GM, Romoli M, et al. Cerebral venous thrombosis and severe acute respiratory syndrome coronavirus-2 infection: A systematic review and meta-analysis. Eur J Neurol. 2021. 

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18. Petito E, Falcinelli E, Paliani U, et al. Association of Neutrophil Activation, More Than Platelet Activation, With Thrombotic Complications in Coronavirus Disease 2019. The Journal of Infectious Diseases. 2020. 8 

19. Archambault A-S, Zaid Y, Rakotoarivelo V, et al. Lipid storm within the lungs of severe COVID-19 patients: Extensive levels of cyclooxygenase and lipoxygenase-derived inflammatory metabolites. medRxiv. 2020:2020.2012.2004.20242115. 

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26. Cohen CJ, Xiang ZQ, Gao G-P, Ertl HCJ, Wilson JM, Bergelson JM. Chimpanzee adenovirus CV-68 adapted as a gene delivery vector interacts with the coxsackievirus and adenovirus receptor. Journal of General Virology. 2002;83(1):151-155. 

27. Cohen CJ, Shieh JT, Pickles RJ, Okegawa T, Hsieh JT, Bergelson JM. The coxsackievirus and adenovirus receptor is a transmembrane component of the tight junction. Proc Natl Acad Sci U S A. 2001;98(26):15191-15196. 

28. Assinger A. Platelets and infection – an emerging role of platelets in viral infection. Front Immunol. 2014;5:649. 

29. Yan X, Hao Q, Mu Y, et al. Nucleocapsid protein of SARS-CoV activates the expression of cyclooxygenase-2 by binding directly to regulatory elements for nuclear factor-kappa B and CCAAT/enhancer binding protein. Int J Biochem Cell Biol. 2006;38(8):1417-1428. 

30. Rocca B, Secchiero P, Ciabattoni G, et al. Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci U S A. 2002;99(11):7634-7639. 

31. Lefrançais E, Ortiz-Muñoz G, Caudrillier A, et al. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature. 2017;544(7648):105-109. 

32. Mezey É, Szalayova I, Hogden CT, et al. An immunohistochemical study of lymphatic elements in the human brain. Proceedings of the National Academy of Sciences. 2021;118(3):e2002574118. 

33. Badolia R, Inamdar V, Manne BK, Dangelmaier C, Eble JA, Kunapuli SP. G(q) pathway regulates proximal C-type lectin-like receptor-2 (CLEC-2) signaling in platelets. J Biol Chem. 2017;292(35):14516-14531. 9 

34. Sung P-S, Huang T-F, Hsieh S-L. Extracellular vesicles from CLEC2-activated platelets enhance dengue virus-induced lethality via CLEC5A/TLR2. Nature Communications. 2019;10(1). 

35. Ng H, Havervall S, Rosell A, et al. Circulating Markers of Neutrophil Extracellular Traps Are of Prognostic Value in Patients With COVID-19. Arteriosclerosis, Thrombosis, and Vascular Biology. 2021;41(2):988-994. 

36. Carey MA, Bradbury JA, Seubert JM, Langenbach R, Zeldin DC, Germolec DR. Contrasting Effects of Cyclooxygenase-1 (COX-1) and COX-2 Deficiency on the Host Response to Influenza A Viral Infection. The Journal of Immunology. 2005;175(10):6878-6884. 

37. Kuhl PG, Bolds JM, Loyd JE, Snapper JR, FitzGerald GA. Thromboxane receptor-mediated bronchial and hemodynamic responses in ovine endotoxemia. Am J Physiol. 1988;254(2 Pt 2):R310-319. 

38. Altavilla D, Canale P, Squadrito F, et al. Protective effects of BAY U 3405, a thromboxane A2 receptor antagonist, in endotoxin shock. Pharmacol Res. 1994;30(2):137-151. 

39. Peters AT, Mutharasan RK. Aspirin for Prevention of Cardiovascular Disease. JAMA. 2020;323(7):676. 

40. Chow JH, Khanna AK, Kethireddy S, et al. Aspirin Use Is Associated With Decreased Mechanical Ventilation, Intensive Care Unit Admission, and In-Hospital Mortality in Hospitalized Patients With Coronavirus Disease 2019. Anesthesia & Analgesia. 2021;132(4). 

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SOURCE

From: “Gupta, Ajay” <ajayg1@hs.uci.edu>

Date: Wednesday, April 14, 2021 at 10:33 AM

To: “Aviva Lev-Ari, PhD, RN” <AvivaLev-Ari@alum.berkeley.edu>

This EXPERT OPINION is in response to:

From: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>
Date: Tuesday, April 13, 2021 at 9:03 AM
To: “Joel Shertok, PhD” <jshertok@yahoo.com>, “Stephen Williams, PhD” <sjwilliamspa@comcast.net>, “Prof. Marcus W Feldman” <mfeldman@stanford.edu>, “Irina Robu, PhD” <irina.stefania@gmail.com>, “Dr. Sudipta Saha” <sudiptasaha1977@gmail.com>, Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>, “Dr. Larry Bernstein” <larry.bernstein@gmail.com>, “Ofer Markman, PhD” <oferm2020@gmail.com>, “Daniel Menzin (gmail)” <dmenzin@gmail.com>, Pnina Abir-Am <pnina.abiram@gmail.com>, Alan <alanalanf@gmail.com>, Justin MDMEPhD <jdpmdphd@gmail.com>, Inbar Ofer <ofer.i@northeastern.edu>, Aviva Lev-Ari <aviva.lev-ari@comcast.net>, Madison Davis <madisond2302@gmail.com>, Danielle Smolyar <dsmolyar@syr.edu>, “Adina Hazan, PhD” <adinathazan@gmail.com>, Gail Thornton <gailsthornton@yahoo.com>, Amandeep kaur <662amandeep@gmail.com>, Premalata Pati <premalata09@gmail.com>, “Ajay Gupta, MD” <charaklabs@outlook.com>, Saul Yedgar <saulye@ekmd.huji.ac.il>, Yigal Blum <yigalblum@gmail.com>, a el <AElRoeiy@gmail.com>, “Dr. Raphael Nir” <rnir@sbhsciences.com>, “George Tetz, MD, PhD” <gtetz@clstherapeutics.com>, “Dr. Martin R Schiller (CEO, Heligenics)” <heligenics@gmail.com>, “Jea Asio (Heligenics)” <JAsio@Heligenics.com>, Yakov Kogan <ykogan@tgv-biomed.com>, Haim Levkowitz <haim@cs.UML.edu>

Subject: APRIL 13. 2021 – J&J Statement – Out of an abundance of caution, the CDC and FDA have recommended a pause in the use of our vaccine. ->> Are there relations between these FINDINGS?

Johnson & Johnson Statement on COVID-19 Vaccine

NEW BRUNSWICK, N.J., April 13, 2021– The safety and well-being of the people who use our products is our number one priority. We are aware of an extremely rare disorder involving people with blood clots in combination with low platelets in a small number of individuals who have received our COVID-19 vaccine. The United States Centers for Disease Control (CDC) and Food and Drug Administration (FDA) are reviewing data involving six reported U.S. cases out of more than 6.8 million doses administered. Out of an abundance of caution, the CDC and FDA have recommended a pause in the use of our vaccine.

In addition, we have been reviewing these cases with European health authorities. We have made the decision to proactively delay the rollout of our vaccine in Europe.

We have been working closely with medical experts and health authorities, and we strongly support the open communication of this information to healthcare professionals and the public.

The CDC and FDA have made information available about proper recognition and management due to the unique treatment required with this type of blood clot. The health authorities advise that people who have received our COVID-19 vaccine and develop severe headache, abdominal pain, leg pain, or shortness of breath within three weeks after vaccination should contact their health care provider.

For more information on the Janssen COVID-19 vaccine, click here.

Please All send me your Expert Opinion on the relations between these FINDINGS?

Linking Thrombotic Thrombocytopenia to ChAdOx1 nCov-19 Vaccination, AstraZeneca | Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/04/12/linking-thrombotic-thrombocytopenia-to-chadox1-ncov-19-vaccination-astrazeneca/

Is SARS-COV2 Hijacking the Complement and Coagulation Systems?

Reporter: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2020/08/04/is-sars-cov2-hijacking-the-complement-and-coagulation-systems/

SAR-Cov-2 is probably a vasculotropic RNA virus affecting the blood vessels: Endothelial cell infection and endotheliitis in COVID-19

Reporter: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2020/06/01/sar-cov-2-is-probably-a-vasculotropic-rna-virus-affecting-the-blood-vessels-endothelial-cell-infection-and-endotheliitis-in-covid-19/

THANK YOU

Best regards,

Aviva

Aviva Lev-Ari, PhD, RN

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

Reporter: Amandeep Kaur, BSc, MSc (Exp. 6/2021)

According to the Global Health Security Index released by Johns Hopkins University in October 2019 in collaboration with Nuclear Threat Initiative (NTI) and The Economist Intelligence Unit (EIU), the United States was announced to be the best developed country in the world to tackle any pandemic or health emergency in future.

The table turned within in one year of outbreak of the novel coronavirus COVID-19. By the end of March 2021, the country with highest COVID-19 cases and deaths in the world was United States. According to the latest numbers provided by World Health Organization (WHO), there were more than 540,000 deaths and more than 30 million confirmed cases in the United States.

Joia Mukherjee, associate professor of global health and social medicine in the Blavatnik Institute at Harvard Medical School said,

“When we think about how to balance control of an epidemic over chaos, we have to double down on care and concern for the people and communities who are hardest hit”.

She also added that U.S. possess all the necessary building blocks required for a health system to work, but it lacks trust, leadership, engagement and care to assemble it into a working system.

Mukherjee mentioned about the issues with the Index that it undervalued the organized and integrated system which is necessary to help public meet their needs for clinical care. Another necessary element for real health safety which was underestimated was conveying clear message and social support to make effective and sustainable efforts for preventive public health measures.

Mukherjee is a chief medical officer at Partners In Health, an organization focused on strengthening community-based health care delivery. She is also a core member of HMS community members who play important role in constructing a more comprehensive response to the pandemic in all over the U.S. With years of experience, they are training global health care workers, analyzing the results and constructing an integrated health system to fight against the widespread health emergency caused by coronavirus all around the world.

Mukherjee encouraged to strengthen the consensus among the community to constrain this infectious disease epidemic. She suggested that validation of the following steps are crucial such as testing of the people with symptoms of infection with coronavirus, isolation of infected individuals by providing them with necessary resources and providing clinical treatment and care to those people who are in need. Mukherjee said, that community engagement and material support are not just idealistic goal rather these are essential components for functioning of health care system during an outburst of coronavirus.

Continued alertness such as social distancing and personal contact with infected individual is important because it is not possible to rapidly replace the old-school public health approaches with new advanced technologies like smart phone applications or biomedical improvements.

Public health specialists emphasized that the infection limitation is the only and most vital strategy for controlling the outbreak in near future, even if the population is getting vaccinated. It is crucial to slowdown the spread of disease for restricting the natural modification of more dangerous variants as that could potentially escape the immune protection mechanism developed by recently generated vaccines as well as natural immune defense systems.

Making Crucial connections

The treatment is more expensive and complicated in areas with less health facilities, said Paul Farmer, the Kolokotrones University Professor at Harvard and chair of the HMS Department of Global Health and Social Medicine. He called this situation as treatment nihilism. Due to shortage of resources, the maximum energy is focused in public health care and prevention efforts. U.S. has resources to cope up with the increasing demand of hospital space and is developing vaccines, but there is a form of containment nihilism- which means prevention and infection containment are unattainable- said by many experts.

Farmer said, integration of necessary elements such as clinical care, therapies, vaccines, preventive measures and social support into a single comprehensive plan is the best approach for a better response to COVID-19 disease. He understands the importance of community trust and integrated health care system for fighting against this pandemic, as being one of the founders of Partners In Health and have years of experience along with his colleagues from HMS and PIH in fighting epidemics of HIV, Ebola, cholera, tuberculosis, other infectious and non-infectious diseases.

PIH launched the Massachusetts Community Tracing Collaborative (CTC), which is an initiative of contact tracing statewide in partnership with several other state bodies, local boards of Health system and PIH. The CTC was setup in April 2020 in U.S. by Governor Charlie Baker, with leadership from HMS faculty, to build a unified response to COVID-19 and create a foundation for a long-term movement towards a more integrated community-based health care system.

The contact tracing involves reaching out to individuals who are COVID-19 positive, then further detect people who came in close contact with infected individuals and screen out people with coronavirus symptoms and encourage them to seek testing and take necessary precautions to break the chain of infection into the community.

In the initial phase of outbreak, the CTC group comprises of contact tracers and health care coordinators who spoke 23 different languages, including social workers, public health practitioners, nurses and staff members from local board health agencies with deep links to the communities they are helping. The CTC worked with 339 out of 351 state municipalities with local public health agencies relied completely on CTC whereas some cities and towns depend occasionally on CTC backup. According to a report, CTC members reached up to 80 percent of contact tracking in hard-hit and resource deprived communities such as New Bedford.

Putting COVID-19 in context

Based on generations of experience helping people surviving some of the deadliest epidemic and endemic outbreaks in places like Haiti, Mexico, Rwanda and Peru, the staff was alert that people with bad social and economic condition have less space to get quarantined and follow other public health safety measures and are most vulnerable people at high risk in the pandemic situation.

Infected individuals or individuals at risk of getting infected by SARS-CoV-2 had many questions regarding when to seek doctor’s help and where to get tested, reported by contact tracers. People were worried about being evicted from work for two weeks and some immigrants worried about basic supplies as they were away from their family and friends.

The CTC team received more than 7,000 requests for social support assistance in the initial three months. The staff members and contact tracers were actively connecting the resourceful individuals with the needy people and filling up the gap when there was shortage in their own resources.

Farmer said, “COVID is a misery-seeking missile that has targeted the most vulnerable.”

The reality that infected individuals concerned about lacking primary household items, food items and access to childcare, emphasizes the urgency of rudimentary social care and community support in fighting against the pandemic. Farmer said, to break the chain of infection and resume society it is mandatory to meet all the elementary needs of people.

“What kinds of help are people asking for?” Farmer said and added “it’s important to listen to what your patients are telling you.”

An outbreak of care

The launch of Massachusetts CTC with the support from PIH, started receiving requests from all around the country to assist initiating contact tracing procedures. In May, 2020 the organization announced the launch of a U.S. public health accompaniment to cope up with the asked need.

The unit has included team members in nearly 24 states and municipal health departments in the country and work in collaboration with local organizations. The technical support on things like choosing and implementing the tools and software for contact tracing was provided by PIH. To create awareness and provide new understanding more rapidly, a learning collaboration was established with more than 200 team members from more than 100 different organizations. The team worked to meet the needs of population at higher risk of infection by advocating them for a stronger and more reliable public health response.

The PIH public health team helped to train contact trackers in the Navajo nation and operate to strengthen the coordination between SARS-CoV-2 testing, efforts for precaution, clinical health care delivery and social support in vulnerable communities around the U.S.

“For us to reopen our schools, our churches, our workplaces,” Mukherjee said, “we have to know where the virus is spreading so that we don’t just continue on this path.”

SOURCE:

https://hms.harvard.edu/news/fighting-chaos-care?utm_source=Silverpop&utm_medium=email&utm_term=field_news_item_1&utm_content=HMNews04052021

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

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/

The WHO team is expected to soon publish a 300-page final report on its investigation, after scrapping plans for an interim report on the origins of SARS-CoV-2 — the new coronavirus responsible for killing 2.7 million people globally

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/03/27/the-who-team-is-expected-to-soon-publish-a-300-page-final-report-on-its-investigation-after-scrapping-plans-for-an-interim-report-on-the-origins-of-sars-cov-2-the-new-coronavirus-responsibl/

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/

Artificial intelligence predicts the immunogenic landscape of SARS-CoV-2

Reporter: Irina Robu, PhD

https://pharmaceuticalintelligence.com/2021/02/04/artificial-intelligence-predicts-the-immunogenic-landscape-of-sars-cov-2/

Read Full Post »


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

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 4/13/2021

Toward Understanding COVID-19 Recovery: National Institutes of Health Workshop on Postacute COVID-19

 

Abstract

Over the past year, the SARS-CoV-2 pandemic has swept the globe, resulting in an enormous worldwide burden of infection and mortality. However, the additional toll resulting from long-term consequences of the pandemic has yet to be tallied. Heterogeneous disease manifestations and syndromes are now recognized among some persons after their initial recovery from SARS-CoV-2 infection, representing in the broadest sense a failure to return to a baseline state of health after acute SARS-CoV-2 infection. On 3 to 4 December 2020, the National Institute of Allergy and Infectious Diseases, in collaboration with other Institutes and Centers of the National Institutes of Health, convened a virtual workshop to summarize existing knowledge on postacute COVID-19 and to identify key knowledge gaps regarding this condition.

Over the past year, the SARS-CoV-2 pandemic has swept the globe, resulting in more than 113 million persons infected and 2.5 million deaths (1). However, the additional toll resulting from long-term consequences of the pandemic has yet to be tallied. Heterogeneous disease manifestations and syndromes are now recognized among some persons after their initial recovery from SARS-CoV-2 infection. Although a standardized case definition does not yet exist for these manifestations, in the broadest sense they represent a failure to return to a baseline state of health after acute SARS-CoV-2 infection. The various terms used to describe this condition have included postacute (or late) sequelae of COVID-19, post-COVID condition or syndrome, long COVID, and long-haul COVID. In this article, we use the general umbrella term of “postacute COVID-19” to refer to multiple disease processes that may have varying degrees of overlap (including but not limited to sequelae of critical illness and hospitalization in persons with COVID-19) and the entity of long COVID, which refers to prolonged health abnormalities in persons previously infected with SARS-CoV-2 who may or may not have required hospitalization. Of note, there is not yet a consensus on terminology, which will likely evolve with a better understanding of this condition.

Reported symptoms are wide-ranging and may involve nearly all organ systems, with fatigue, dyspnea, cognitive dysfunction, anxiety, and depression often described (2–5). Although abnormalities in imaging studies and functional testing have been reported, the long-term clinical significance of some of these findings is not yet clear (367). Postacute manifestations of COVID-19 have been seen in persons of all demographic groups and include reports of multisystem inflammatory syndrome in children (89). Although the epidemiology of the diverse manifestations of postacute COVID-19 is not yet known, the expansive global burden of SARS-CoV-2 infection suggests that the potential public health effects of postacute COVID-19 are significant if even a small proportion of persons with SARS-CoV-2 infection have prolonged recovery or do not return to their baseline health.

On 3 to 4 December 2020, the National Institute of Allergy and Infectious Diseases, in collaboration with other Institutes and Centers of the National Institutes of Health, convened a virtual workshop (available via videocast at https://videocast.nih.gov/watch=38878 and https://videocast.nih.gov/watch=38879) to summarize existing knowledge on postacute COVID-19 and to identify key knowledge gaps. The speakers and participants included epidemiologists, clinicians, clinical and basic scientists, and members of the affected community. The videocast was open to the general public and had more than 1200 registered participants.

SOURCE

UPDATED on 4/7/2021

‘Beyond a Reasonable Doubt’: COVID-19 Brain Health Fallout Is Real, Severe

Sarah Edmonds

April 07, 2021

Editor’s note: Find the latest COVID-19 news and guidance in Medscape’s Coronavirus Resource Center.

START QUOTE

COVID-19 survivors face a sharply elevated risk of developing psychiatric or neurologic disorders in the six months after they contract the virus — a danger that mounts with symptom severity, new research shows.

In what is purported to be the largest study of its kind to-date, results showed that among 236,379 COVID-19 patients, one third were diagnosed with at least one of 14 psychiatric or neurologic disorders within a 6-month span.

The rate of illnesses, which ranged from depression to stroke, rose sharply among those with COVID-19 symptoms acute enough to require hospitalization.  

“If we look at patients who were hospitalized, that rate increased to 39%, and then increased to about just under 1 in 2 patients who needed ICU admission at the time of the COVID-19 diagnosis,” Maxime Taquet, PhD, University of Oxford Department of Psychiatry, Oxford, United Kingdom, told a media briefing.

Incidence jumps to almost two thirds in patients with encephalopathy at the time of COVID-19 diagnosis, he added.

The study, which examined the brain health of 236,379 survivors of COVID-19 via a US database of 81 million electronic health records, was published online April 6 in The Lancet Psychiatry.

High Rate of Neurologic, Psychiatric Disorders

The research team looked at the first-time diagnosis or recurrence of 14 neurologic and psychiatric outcomes in patients with confirmed SARS-CoV-2 infections. They also compared the brain health of this cohort with a control group of those with influenza or with non-COVID respiratory infections over the same period. 

SOURCE

The Effects of Loneliness and Our Brain function: poorer physical and mental health

One review of the science of loneliness found that people with stronger social relationships have a 50 per cent increased likelihood of survival over a set period of time compared with those with weaker social connections. Other studies have linked loneliness to cardiovascular disease, inflammation, and depression.

For loneliness researchers the pandemic has provided an unprecedented natural experiment in the impact that social isolation might have on our brains. As millions of people across the world emerge from months of reduced social contact, a new neuroscience of loneliness is starting to figure out why social relationships are so crucial to our health.

Neural basis of Emotion

Desire for Social Interaction

Are there neurological differences between people who experience short-term isolation and those who have been isolated for long stretches of time? What kinds of social interactions satisfy our social cravings? Is a video call enough to quell our need for social contact, or do some people require an in-person connection to really feel satiated?

START QUOTE

Julianne Holt-Lunstad, a psychology professor at Brigham Young University in the US and the author of two major studies on social isolation and health. “We have a lot of data that very robustly shows that both isolation and loneliness put us at increased risk for premature mortality—and conversely, that being socially connected is protective and reduces our risk,” she says.

START QUOTE

“Trying to investigate isolation or loneliness is not as straightforward in humans. In humans, being lonely is not necessarily correlated with how many people are around you,” says Tomova. She is particularly interested in the impact that the pandemic might have had on young people whose cognitive and social skills are still developing. “I think we will see potentially some differences in how their social behavior developed or things like that,” she says. But as is always the case in the uncertain world of loneliness research, the opposite could be true. “It could also be that most people are fine, because maybe social media does fulfill our social needs really well.”

SOURCE

https://www.wired.co.uk/article/lockdown-loneliness-neuroscience

The Weird Science of Loneliness and Our Brains – Social isolation as been linked to poorer physical and mental health, but scientists are finally starting to understand its neurological impact

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COVID-related financial losses at Mass General Brigham

Reporter: Aviva Lev-Ari, PhD, RN

Based on

Mass General Brigham reports COVID-related financial losses not as bad as expected

By Priyanka Dayal McCluskey Globe Staff,Updated December 11, 2020, 3:02 p.m.

START QUOTE

The state’s largest hospital system on Friday reported the worst financial loss in its history while fighting the COVID-19 pandemic — but still ended the fiscal year in better shape than expected.

Mass General Brigham, formerly known as Partners HealthCare, lost $351 million on operations in the fiscal year that ended Sept. 30. In 2019, the system recorded a gain of $382 million.

The loss, however, is not as great as projected, thanks in part to an infusion of federal aid and patients returning to hospitals in large numbers after the first COVID surge receded.

“2020 is like no other year,” said Peter Markell, chief financial officer at Mass General Brigham, which includes Massachusetts General Hospital, Brigham and Women’s Hospital, and several community hospitals. “At the end of the day, we came out of this better than we thought we might.”

Total revenue for the year remained relatively stable at about $14 billion.

When the pandemic first hit Massachusetts in March, hospitals across the state suddenly experienced sharp drops in revenue because they canceled so much non-COVID care to respond to the crisis at hand. They also faced new costs related to COVID, including the personal protective equipment needed to keep health care workers safe from infection.

Federal aid helped to make up much of the losses, including $546 million in grant money that went to Mass General Brigham. The nonprofit health system also slashed capital expenses in half, by about $550 million, and temporarily froze employee wages and cut their retirement benefits.

Among the unusual new costs for Mass General Brigham this year was the expense of building a field hospital, Boston Hope, at the Boston Convention and Exhibition Center. The project cost $15 million to $20 million, Markell said, and Mass General Brigham is working to recoup those costs from government agencies.

The second surge of COVID, now underway, could hit hospitals’ bottom lines again, though Markell expects a smaller impact this time. One reason is because hospitals are trying to treat most of the patients who need care for conditions other than COVID even while treating growing numbers of COVID patients. In the spring, hospitals canceled vastly more appointments and procedures in anticipation of the first wave of COVID.

Mass General Brigham hospitals were treating more than 300 COVID patients on Friday, among the more than 1,600 hospitalized across the state.

Steve Walsh, president of the Massachusetts Health & Hospital Association, said hospitals across the state will need more federal aid as they continue battling COVID into the new year.

“The financial toll of COVID-19 has been felt by every hospital and health care organization in the Commonwealth,” he said. “Those challenges will continue during 2021.”


Priyanka Dayal McCluskey can be reached at priyanka.mccluskey@globe.com. Follow her on Twitter @priyanka_dayal.

END QUOTE

SOURCE

https://www.bostonglobe.com/2020/12/11/business/mass-general-brigham-reports-covid-related-financial-losses-better-than-expected/?p1=Article_Inline_Related_Box

Integration of Mass General Hospital and Brigham Women’s Hospital was accelerated by the COVID-19 pandemic

Reporter: Aviva Lev-Ari, PhD, RN

BASED on

At Mass General Brigham, a sweeping effort to unify hospitals and shed old rivalries

Executives say greater cooperation is necessary to stay relevant in a dynamic and competitive health care industry. But the aggressive push to integrate is stirring tensions and sowing discontent among doctors and hospital leaders.

By Priyanka Dayal McCluskey and Larry Edelman Globe Staff and Globe Columnist,Updated March 27, 2021, 6:15 p.m.125

https://www.bostonglobe.com/2021/03/27/business/mass-general-brigham-sweeping-effort-unify-hospitals-shed-old-rivalries/?s_campaign=breakingnews:newsletter

START QUOTE

The work of integration was accelerated by the COVID-19 pandemic. As patients flooded hospitals last spring, Mass General Brigham — not each of its individual hospitals — set pandemic policies, from what kind of personal protective equipment health care providers should wear, to which visitors were allowed inside hospitals, to how employees would be paid if they were out sick with the virus.

During the winter surge of COVID, Mass General Brigham officials closely tracked beds across their system and transferred patients daily from one hospital to another to ensure that no one facility became overwhelmed.

And, in the early months of the pandemic, the company dropped the name Partners, which meant little to patients, and unveiled a new brand to reflect the strength of its greatest assets, MGH and the Brigham.

Officials at the nonprofit health system have instructeddepartment heads across their hospitals to coordinate better, so, for example, if a patient needs surgery at the Brigham but is facing a long wait, they can refer that patient to another site within Mass General Brigham.

Some executives want patients, eventually, to be able to go online and book appointments at any Mass General Brigham facility, as easily as they make reservations for dinner or a hotel.

Walls described it like this: “How do we put things together that make things better and easier for patients, and leave alone things that are better where they are?

“We’re not going to push things together that don’t fit together,” he said.

And yet the aggressive pursuit of “systemness,” as executives call it, is taking a toll. Physicians and hospital leaders are struggling with the loss of control over their institutions and worried that the new era of top-down management threatens to homogenize a group of hospitals with different cultures and identities.

Veteran physicians and leaders have been surprised and upset by the power shift that is stripping them of the ability to make key decisions and unhappy with abrupt changes they feel are occurring with little discussion. Most are uncomfortable sharing their concerns publicly.

“If you’re not on the train, you’re getting run over by the train,” said one former Mass General Brigham executive who requested anonymity in orderto speak openly. “It’s not an environment to invite debate.”

Amid the restructuring, senior executives are departing in droves. They include the CEO of the MGH physicians group, Dr. Timothy Ferris; Brigham and Women’s president Dr. Elizabeth Nabel; chief financial officer of the system, Peter Markell; Cooley Dickinson Hospital president Joanne Marqusee; and president of Spaulding Rehabilitation Network, David Storto.

Some also fear the internal discord could hinder Mass General Brigham’s ability to attract talented leaders.

Top executives acknowledge there is angst — “Change is hard,” Klibanski said — but are pushing ahead.

MORE

https://www.bostonglobe.com/2021/03/27/business/mass-general-brigham-sweeping-effort-unify-hospitals-shed-old-rivalries/?s_campaign=breakingnews:newsletter

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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

 

The UK’s COVID-19 vaccine rollout commenced in December, and requires an individual to receive two doses of the same vaccine, either Pfizer/BioNTech’s BNT162b2 or AstraZeneca/Oxford’s ChAdOx1, with a maximum interval of 12 weeks between doses. As of February 3, 10 million first doses have been administered.

Com-COV has been classified as an “Urgent Public Health” study by the National Institutes for Health and Research (NIHR), and it’s hoped that the data produced may offer greater flexibility for vaccine delivery going forward.

“Given the inevitable challenges of immunizing large numbers of the population against COVID-19 and potential global supply constraints, there are definitely advantages to having data that could support a more flexible immunization program, if ever needed and approved by the medicines regulator,” Jonathan Van-Tam, deputy chief medical officer and senior responsible officer for the study, said in a press release.

The study will run for a 13-month period and will recruit over 800 patients across eight sites in the UK, including London – St George’s and UCL, Oxford, Southampton, Birmingham, Bristol, Nottingham and Liverpool.

Com-COV has eight different arms that will test eight different combinations of doses and dose intervals. This is tentative and subject to change should more COVID-19 vaccines be approved for use in the UK. The eight arms include the following dose combinations:

  • Pfizer/BioNTech and Pfizer/BioNTech – 28 days apart
  • Pfizer/BioNTech and Pfizer/BioNTech – 12 weeks apart – (control group)
  • Oxford/AstraZeneca and Oxford/AstraZeneca – 28 days apart
  • Oxford/AstraZeneca and Oxford/AstraZeneca – 12 weeks apart – (control group)
  • Oxford/AstraZeneca and Pfizer/BioNTech – 28 days apart
  • Oxford/AstraZeneca and Pfizer/BioNTech – 12 weeks apart
  • Pfizer/BioNTech and Oxford/AstraZeneca – 28 days apart
  • Pfizer/BioNTech and Oxford/AstraZeneca – 12 weeks apart

Aside from the logistical benefits of using alternative vaccines, there is scientific value to exploring how different vaccines and doses affect the human immune system.

Dr Peter English, consultant in communicable disease control, pointed out that the antigen used across the currently authorized COVID-19 vaccines is the same Spike protein. Therefore, the immune system can be expected to respond just as well if a different product is used for boosting. “It is also the case that many vaccines work better if a different vaccine is used for boosting – an approach described as heterologous boosting,” English said, referencing previously successful trials using Hepatitis B vaccines.

“It is also even possible that by combining vaccines, the immune response could be enhanced giving even higher antibody levels that last longer; unless this is evaluated in a clinical trial we just won’t know,” added Van-Tam.

If warranted by the study data, the Medicines and Healthcare products Regulatory Agency may consider reviewing and authorizing modifications to the UK’s vaccine regimen approach – but only time will tell.

“We need people from all backgrounds to take part in this trial, so that we can ensure we have vaccine options suitable for all. Signing up to volunteer for vaccine studies is quick and easy via the NHS Vaccine Research Registry,” Professor Andrew Ustianowski, national clinical lead for the NIHR COVID Vaccine Research Program, said

SOURCE

First-of-its-Kind Study Will Test Combination of Different COVID-19 Vaccines | Technology Networks

https://www.technologynetworks.com/biopharma/news/first-of-its-kind-study-will-test-combination-of-different-covid-19-vaccines-345245?utm_campaign=NEWSLETTER_TN_Biopharma

WATCH VIDEO

Different Types of COVID-19 Vaccines With Dr Seth Lederman Video | Technology Networks

https://www.technologynetworks.com/biopharma/videos/different-types-of-covid-19-vaccines-with-dr-seth-lederman-345207

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Allocation and Prioritization of Vaccine Dose Administration Schedules: Cover more people or Adhere to Immunization Protocol

Curators:

This curation has four parts:

Part 1:

Waiting on the Covid booster would allow more people to be vaccinated sooner.

  • By Michael Segal, MD, PhD

Part 2:

Expert Opinion by Clinical Authority in Practice of Cardiac Imaging:

  • The Voice of Dr. Justin D. Pearlman, MD, PhD, FACC

Part 3:

Expert Opinion by Scientific Authority in Population Biology

  • The Voice of Prof. Marcus W. Feldman, PhD

Part 4:

Summary

  • The Voices of Prof. Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN

Introduction

Aviva Lev-Ari
@AVIVA1950

We agree the protocol should not be changed

Quote Tweet

Pearl Freier
@PearlF
FDA’s Peter Marks explained why the 2 dose regimen for Pfizer/BioNtech vaccine shouldn’t be changed to 1 dose in attempt to reach more patients while there’s limited supply. Aside from 95% effectiveness w/ 2 dose regimen based on clinical data, he said no one knows how long 1/n

Pearl Freier
@PearlF

Replying to

1 dose would be effective for & no one knows if only given 1 dose if patient would get an immune response that “would just dwindle” “And we know that can happen because we know already that people who get very mild covid-19 tend to lose their immune responses pretty quickly.” 2/n

Pearl Freier
@PearlF

We need to make sure that those who get the vaccine regimen are people who know they’ve gotten that protection [95% effective]. Because that’s something we know, whereas the other [1 dose] is conjecture. And I would hate for people to change their behavior on the basis of 3/n

Pearl Freier
@PearlF

one dose of vaccine where we don’t know what’s really happening.” Peter Marks/FDA said (6 min mark) youtube.com/watch?v=uePet5 (
Research!America Alliance Member Meeting with Dr. Peter Marks
With several COVID-19 vaccine candidates under FDA review, Dr. Peter Marks, Director of FDA’s Center for Biologics Evaluation and Research (CBER), joined us …
youtube.com

 (she/her/hers)

@lisabari

Replying to

It will be really interesting to learn more about the immune response from J&J’s one dose regimen.

Pearl Freier
@PearlF

I think they’re expecting data from J&J in January

Part 1:

Waiting on the Covid booster would allow more people to be vaccinated sooner.

By Michael Segal, MD, PhD

https://www.wsj.com/articles/a-shot-instead-of-two-at-saving-lives-11607643152

A Shot (Instead of Two) at Saving Lives

Waiting on the Covid booster would allow more people to be vaccinated sooner.

By Michael Segal

Dec. 10, 2020 6:32 pm ET

Recent days brought good news and bad news about coronavirus vaccines. The developments could add up to months of delay in getting most Americans inoculated. But there’s a way to make use of the good news to speed up herd immunity.

The bad news is that in July the U.S. passed up an opportunity to secure by June 2021 more than 100 million doses of the Pfizer vaccine, now expected to receive emergency-use authorization in the next few days. Instead, officials followed a balanced-portfolio strategy that reserved as many as 300 million doses of the AstraZeneca vaccine, whose prospects are unclear.

The good news is that the Pfizer and Moderna vaccines performed at the upper end of expectations, with 95% efficacy after two doses. And intriguingly, Pfizer’s submission to the Food and Drug Administration shows that the efficacy of the vaccine in preventing disease had largely kicked in by two weeks after the first dose, and there was no dramatic increase in efficacy after the booster was given three weeks later.

The protocol in Pfizer’s clinical trial was to give all participants two doses. The FDA is likely to approve this protocol, and standard procedure is to prescribe a drug according to protocol. But we are in a pandemic and supplies of vaccine are inadequate. There’s an alternative: vaccinating as many people as possible with a first dose and waiting on the booster until supplies are plentiful.

The Pfizer study wasn’t designed to put a number on first-dose efficacy, but the data in Pfizer’s “cumulative incidence curves” suggest at least 75% efficacy for two weeks after one dose. The question is whether to use the 100 million doses on 50 million people, of whom two doses would protect roughly 47.5 million, or to give one dose each to 100 million people and protect at least 75 million.

States have the authority to allocate vaccines as they choose, but they’re unlikely to deviate from the study protocol unless a federal authority—whether the Centers for Disease Control and Prevention or a coronavirus “czar”—suggests this as an option.

Even under such an approach, some essential personnel—such as doctors and nurses who work directly with coronavirus patients and health aides who work in multiple nursing homes—should get two doses as soon as possible, given their high-risk role in the pandemic response.

The U.S. will have more than these 100 million doses of the Pfizer vaccine. Some will come from Moderna, and the federal government could use the Defense Production Act to snatch some Pfizer doses that the company contracted to sell to other countries. Even so, supply will be constrained at first, and officials need to think clearly and flexibly about how to allocate the limited doses that will be available soon.

Harvard epidemiologist Michael Mina expressed his disappointment with society’s decision making during the pandemic: “I’m just astounded by the dysfunction, the willingness to just stay the course as hundreds of thousands of people die, and the unwillingness to innovate in literally any way.” Here’s a simple innovation that could save many lives.

Dr. Segal is a neurologist and neuroscientist.

Copyright ©2020 Dow Jones & Company, Inc. All Rights Reserved. 87990cbe856818d5eddac44c7b1cdeb8

Appeared in the December 11, 2020, print edition.

Part 2:

Expert Opinion by Clinical Authority in Practice of Cardiac Imaging:

The Voice of Dr. Justin D. Pearlman, MD, PhD, FACC

From: Justin MDMEPhD <jdpmdphd@gmail.com>

Date: Saturday, December 12, 2020 at 10:40 PM

To: “Aviva Lev-Ari, PhD, RN” <AvivaLev-Ari@alum.berkeley.edu>

Subject: Re: I NEED YOUR EXPERT OPINION on Mickey Segal’s WSJ op-ed on vaccine dose allocation

Michael Segal proposes off-label use of the Pfizer 2-injection Covid-19 vaccine, based on data that suggested “75% protection at 2 weeks.” There was no controlled study reported of any sustained benefit from the single injection beyond 2 weeks, because those who received a first injection of vaccine received the designed booster at 2 weeks. Dr. Segal suggests it would be irresponsible to use the medication in the manner designed and tested. Instead, he could have proposed a study to determine the duration and degree of benefit from a single dose injection. However, one might argue that could delay the release of an effective regimen for the possibility that his proposed 1 dose regimen might be adequate for some, and possibly for more than the two weeks observed. Even if his guess is correct on both counts, both in his guess that the partial benefit at two weeks might be adequate and that it might last longer than the observed two weeks, it could still be deemed irresponsible to impose his guess for obvious reasons. His guess might be wrong, and could deprive many of the regimen that was validated as effective. Diverting an effective validated regimen to a guess could put many in harms way who would have been protected by the designed 2 dose regimen. He admits to low confidence in his recommendation when he proposes that essential workers should get the validated 2-dose regimen. Why does his recommendation stop there – why not propose a quarter dose to 4 times as many, or 1/8 dose to 8 times as many? Why apply the argument just to the two-dose regimen? He could also guess that a half dose of the single injection successful vaccines might be adequate. The motivation to second guess supply choices and doses is understandable, but it is not sound, as it is just a guess, not a validated regimen.

In addition, he also argues for 20-20 hindsight in the government distributing funds to mulitiple vaccines, instead of disproportionate purchase from Pfizer. Trials are limited in size, and further data will be collected on those vaccinated. Balanced investment may save more lives, not fewer, depending on those outcomes.

On Sat, Dec 12, 2020, 8:20 PM Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu> wrote:

Dear Dr. Pearlman,

Please send me 1/2 –1 page as a Critic of 

  • Mickey Segal’s WSJ op-ed on vaccine dose allocation, below

Part 3:

Expert Opinion by Scientific Authority in Population Biology

The Voice of Prof. Marcus W. Feldman, PhD

From: Marcus W Feldman <mfeldman@stanford.edu>

Date: Sunday, December 13, 2020 at 6:52 PM

To: “Aviva Lev-Ari, PhD, RN” <AvivaLev-Ari@alum.berkeley.edu>

Subject: Re: Mickey Segal’s WSJ op-ed on vaccine dose allocation

RE Segal’s note:

We need more details on the longer term efficacy of the one-dose regimen. Once we have such data, the question of whether 100 million one-dose treatments will be more protective of the population than 50 million two-dose treatments can be addressed. The question of how many hospitalizations and/or deaths would be avoided by going straight to the one-dose regimen can’t be answered. Both approaches leave unanswered whether the transmission of the virus from a vaccinated person is reduced. I would estimate that we need 300 million 2-dose treatments to vaccinate all under 16 year olds.

On Dec 13, 2020, at 1:56 PM, Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu> wrote:

Dear Prof. Feldman,

Please send me 1/2 –1 page as a Critic of 

  • Mickey Segal’s WSJ op-ed on vaccine dose allocation, below

Part 4:

Summary

The Voices of Prof. Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN

The Voice of Prof. Stephen J. Williams, PhD

In light of just approved Moderna vaccine, AstraZenaca & JNJ forthcoming vaccine and the approved Pfizer BioNTech coverage should be over 200 million in US, making rationing of second booster shot unnecessary.  However, there is still a concern among the developing and underdeveloped nations that access to these vaccines will be restricted.

The following curation are articles related to this matter from the AAAS and CDC.

CDC advisory panel takes first shot at prioritizing who gets the first shots of COVID-19 vaccines
By Jon CohenDec. 1, 2020 , 8:25 PM
Science’s COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

Health care workers and elderly people living in long-term care facilities should receive top priority for COVID-19 vaccines in the United States if, as expected, one or more becomes available next month in limited supply. That’s what a group that advises the U.S. Centers for Disease Control and Prevention (CDC) on such fraught issues decided today in a near-unanimous vote.

After hearing detailed presentations from CDC scientists who explained the rationale for this specific prioritization scheme, the Advisory Committee on Immunization Practices (ACIP) voted 13 to one to support their proposal. Under the scheme, the first phase of vaccination, known as 1a, would begin with about 21 million health care workers and about 3 million adults who live in long-term care facilities. As spelled out in the 4-hour-long virtual meeting, these groups are at highest risk of becoming seriously ill or dying from COVID-19, and protecting them first, in turn, reduces the burden on society.

“I agree strongly with the decision of the committee,” says Stanley Perlman, a veteran coronavirus researcher and clinician at the University of Iowa who advised ACIP but is not part of it. “The discussions were incredibly thoughtful with everyone recognizing that we needed to make difficult choices. Of course, these allocation issues will become irrelevant once there are enough doses of useful vaccines.”

‘Just beautiful’: Another COVID-19 vaccine, from newcomer Moderna, succeeds in large-scale trial
By Jon CohenNov. 16, 2020 , 7:00 AM
Science’s COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

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Now, there are two. Another COVID-19 vaccine using the same previously unproven technology as the vaccine from Pfizer and BioNTech, the U.S. and German companies that reported success on 9 November, appears to work remarkably well. And this time, the maker, U.S. biotech Moderna, is releasing a bit more data to back its claim than the other two companies.

An independent board monitoring Moderna’s 30,000-person vaccine trial met on Sunday and reported to the company and U.S. government health officials that only five people in the vaccinated group developed confirmed cases of COVID-19, whereas 90 people who received placebo shots became ill with the disease. That’s an efficacy of 94.5%, the company reported in a press release this morning. Although the clinical trial measurement may not translate into an equally high level of real-world protection, the success indicates the vaccine is Iikely more than effective enough to stop the pandemic if it can be widely distributed.

“That efficacy is just beautiful, and there’s no question about the veracity of it either,” says Lawrence Corey, a virologist at the Fred Hutchinson Cancer Research Center who co-led the clinical trials network that is testing the vaccine.

Moderna’s COVID-19 vaccine ready to ship pending FDA approval -U.S. health chief

Source: https://www.reuters.com/article/health-coronavirus-usa-azar-idUSKBN28R265?taid=5fdc062c54859c0001437b9b&utm_campaign=trueanthem&utm_medium=trueanthem&utm_source=twitter

WASHINGTON (Reuters) – U.S. Health and Human Services Secretary Alex Azar on Thursday said nearly 6 million doses of Moderna Inc’s experimental COVID-19 vaccine were poised to ship nationwide as soon as it secures Food and Drug Administration approval. Azar, in an interview on CNBC, said federal health officials had allotted 5.9 million doses to send to the nation’s governors, who are managing each state’s distribution. “We’re ready to start shipping this weekend to them for rollout Monday, Tuesday, Wednesday of next week. We’re ready to go,” he said. An FDA panel of outside advisers is weighing the safety and effectiveness of Moderna’s vaccine candidate at a meeting on Thursday. The agency will weigh the committee’s conclusions in making its approval decision.

The strategy seems to have been produce multiple vaccines from multiple sources which reduce the strain on manufacturing of required doses.
However, many underdeveloped nations as well as developing nations are worried about the nationalism of access to these vaccines.  Please read below:

Abstract

The 2030 Agenda for Sustainable Development (AfSD) has the vision to leave no one behind, particularly low-income countries. Yet COVID-19 seems to have brought up new rules and approaches. Through document and critical discourse analysis, it emerges that there has been a surge in COVID-19 vaccines and treatments nationalism. Global solidarity is threatened, with the USA, United Kingdom, European Union and Japan having secured 1.3 billion doses of potential vaccines as of August 2020. Vaccines ran out even before their approval with three candidates from Pfizer-BioNTech, Moderna and AstraZeneca having shown good Phase III results in November 2020. Rich countries have gone years ahead in advance vaccines and treatments purchases. This is a testimony that the 2030 AfSD, especially SDG 3 focusing on health will be difficult to achieve. Low-income countries are left gasping for survival as the COVID-19 pandemic relegates them further into extreme poverty and deeper inequality. The paper recommends the continued mobilisation by the World Health Organisation and other key stakeholders in supporting the GAVI vaccine alliance and the Coalition for Epidemic Preparedness Innovations (COVAX) global vaccines initiative that seeks to make two billion vaccine doses available to 92 low and middle-income countries by December 2021.

Others have voiced their concerns on this matter:

 

Reserving coronavirus disease 2019 vaccines for global access: cross sectional analysis

From: Anthony D So 1 2Joshua Woo 2 BMJ2020 Dec 15;371:m4750. doi: 10.1136/bmj.m4750.

Abstract

Objective: To analyze the premarket purchase commitments for coronavirus disease 2019 (covid-19) vaccines from leading manufacturers to recipient countries.

Design: Cross sectional analysis.

Data sources: World Health Organization’s draft landscape of covid-19 candidate vaccines, along with company disclosures to the US Securities and Exchange Commission, company and foundation press releases, government press releases, and media reports.

Eligibility criteria and data analysis: Premarket purchase commitments for covid-19 vaccines, publicly announced by 15 November 2020.

Main outcome measures: Premarket purchase commitments for covid-19 vaccine candidates and price per course, vaccine platform, and stage of research and development, as well as procurement agent and recipient country.

Results: As of 15 November 2020, several countries have made premarket purchase commitments totaling 7.48 billion doses, or 3.76 billion courses, of covid-19 vaccines from 13 vaccine manufacturers. Just over half (51%) of these doses will go to high income countries, which represent 14% of the world’s population. The US has reserved 800 million doses but accounts for a fifth of all covid-19 cases globally (11.02 million cases), whereas Japan, Australia, and Canada have collectively reserved more than one billion doses but do not account for even 1% of current global covid-19 cases globally (0.45 million cases). If these vaccine candidates were all successfully scaled, the total projected manufacturing capacity would be 5.96 billion courses by the end of 2021. Up to 40% (or 2.34 billion) of vaccine courses from these manufacturers might potentially remain for low and middle income countries-less if high income countries exercise scale-up options and more if high income countries share what they have procured. Prices for these vaccines vary by more than 10-fold, from $6.00 (£4.50; €4.90) per course to as high as $74 per course. With broad country participation apart from the US and Russia, the COVAX Facility-the vaccines pillar of the World Health Organization’s Access to COVID-19 Tools (ACT) Accelerator-has secured at least 500 million doses, or 250 million courses, and financing for half of the targeted two billion doses by the end of 2021 in efforts to support globally coordinated access to covid-19 vaccines.

Conclusions: This study provides an overview of how high income countries have secured future supplies of covid-19 vaccines but that access for the rest of the world is uncertain. Governments and manufacturers might provide much needed assurances for equitable allocation of covid-19 vaccines through greater transparency and accountability over these arrangements.

The Voice of Adina Hazan, PhD

I have a few issues with the proposal and the asserted outcomes:

The author suggests that back in July 2020 “the U.S. passed up an opportunity to secure by June 2021 more than 100 million doses of the Pfizer vaccine…[by] follow[ing] a balanced-portfolio strategy”. By stating that the U.S. “passed up an opportunity” at that time when all available evidence could not indicate which vaccine would prove successful is taking a “hindsight is 2020” approach. Instead, an all-or-nothing portfolio in July 2020 for one vaccine over another would have been at best unwise and at worst could have passed up the “right” vaccine.

In addition, the author’s core suggestion is that every person in America and the world needs the vaccine at the same time, aka as soon as possible. Considering the incredibly striated outcomes of patients that contract COVID-19, this is not the case. We know that males up until 85 years old with have a much worse prognosis than women, for example1. In addition, all data suggests that the lowest risk group is children, with a death rate in the U.S. of 0.1%1. Trying to vaccinate all children with a vaccine whose long-term effects are, at this time, unknown, for a disease with such a low death rate is not urgent and may warrant waiting for more evidence. Instead of trying to inoculate everyone as fast as possible, the two-dose approach that is currently implemented ensures that those most at risk receive the maximum protection, instead of leaving them at higher risks even after vaccination. In this way, the vaccine will do what it was originally intended to do: protect the most vulnerable immediately, and in turn begin to alleviate the strain on the overall population as a result of this disease.

  1. S. CDC website (Deaths by Age Group, 12/18/2020)

The Voice of Aviva Lev-Ari, PhD, RN

  • I recommand to adhere to administration protocol.
  • I agree with Dr. Joel Jertock:

It is very clear that the current COVID vaccination protocols call for two shots, three weeks apart, for maximum protection.

Limiting personnel to a single shot, “to spread the available vaccines further” just means wasting those doses.  It is similar to taking an antibiotic for only 5 days instead of the recommended 10 days, “to make the pills last longer.”

References on Vaccine Development 

Development of Medical Counter-measures for 2019-nCoV, CoVid19, Coronavirus

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The complication of Pfizer’s Vaccine Distribution’s Plan

Reporter : Irina Robu, PhD

Even though Pfizer announcing the development of safe and effective vaccine is cause for celebration, scientists and public experts face  the challenge of how to quickly make millions of doses of the vaccine and getting them to hospitals, clinics and pharmacies. But Pfizer distribution of vaccines rely on a network of companies, federal and state agencies and on the ground health workers in the midst of a pandemic that is spreading at a high rate in United States.

Before Pfizer can begin shipping its vaccine, federal and state governments must inform Pfizer of how many doses are needed along with syringes, needles and other supplies needed to administer the vaccine. In addition, employees at the locations should be trained to store and administer the vaccine and to ensure that after people are vaccinated, they return for a second dose.

The complication of Pfizer’s vaccine is that it has to be stored at minus 70 degree Celsius until before it is injected.  Pfizer is making the vaccine at facilities in Kalamazoo, Mich., and Puurs, Belgium. The doses distributed in the United States will mostly come from Kalamazoo. When they receive emergency authorization from FDA, Pfizer will send limited doses to large hospitals, pharmacies and other vulnerable groups. At the same time, nine other candidates are also in the final stage of testing.

In Kalamazoo, vaccines will go into vials, vi will go into trays (195 vials per tray) and the trays will go into specially designed cooler-type boxes (up to five trays per box).The reusable boxes, each toting between 1,000 and 5,000 doses and stuffed with dry ice, are equipped with GPS-enabled sensors. Pfizer employees will be able to monitor the boxes’ locations and temperatures as FedEx and UPS transport them to hospitals and clinics nationwide.

The minute Pfizer coolers reach their destinations, hospitals or pharmacies will have a few alternatives of  how to store the vaccine. The easiest option is using ultracold freezers, but they can stash the trays in conventional freezers for up to five days. The destinations can keep the vials in the cooler for up to 15 days as long as they replenish the dry ice and don’t open it more than twice a day.

The chief executives at Pfizer and BioNTech suggest that Pfizer is able to produce up to 50 million doses per year and only half of those will go to US. But since two doses are needed for each person, only 12.5 million doses can be vaccinated.

The other challenge is distributing the vaccine in rural areas, where if not administering the doses fast enough it can go bad. Even though Pfizer has developed and tested an effective vaccine, figuring out how to distribute it is the hardest challenge Pfizer will face.

SOURCE

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