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Archive for the ‘Vaccinology’ Category


COVID-19’s seasonal cycle to be estimated at Lawrence Berkeley National Laboratory (Berkeley Lab) by Artificial Intelligence and Machine Learning Algorithms: Will A Fall and Winter resurgence be Likely??

Reporter: Aviva Lev-Ari, PhD, RN

Using machine learning to estimate COVID-19’s seasonal cycle

Woman walks down empty city street wearing a mask

Credit: Ivan Marc/Shutterstock

Berkeley Lab researchers have launched a project to determine if the novel coronavirus might be seasonal, waning in summer months and resurging in fall and winter.

One of the many unanswered scientific questions about COVID-19 is whether it is seasonal like the flu — waning in warm summer months then resurging in the fall and winter.

Now scientists at Lawrence Berkeley National Laboratory (Berkeley Lab) are launching a project to apply machine-learning methods to a plethora of health and environmental datasets, combined with high-resolution climate models and seasonal forecasts, to tease out the answer.

“Environmental variables, such as temperature, humidity, and UV [ultraviolet radiation] exposure, can have an effect on the virus directly, in terms of its viability. They can also affect the transmission of the virus and the formation of aerosols,” said Berkeley Lab scientist Eoin Brodie, the project lead. “We will use state-of-the-art machine-learning methods to separate the contributions of social factors from the environmental factors to attempt to identify those environmental variables to which disease dynamics are most sensitive.

The research team will take advantage of an abundance of health data available at the county level — such as the severity, distribution and duration of the COVID-19 outbreak, as well as what public health interventions were implemented when — along with demographics, climate and weather factors, and, thanks to smartphone data, population mobility dynamics. The initial goal of the research is to predict — for each county in the United States — how environmental factors influence the transmission of the SARS-CoV-2 virus, which causes COVID-19.

Multidisciplinary team for a complex problem

Untangling environmental factors from social and health factors is a knotty problem with a large number of variables, all interacting in different ways. On top of that, climate and weather affect not only the virus but also human physiology and behavior. For example, people may spend more or less time indoors, depending on the weather; and their immune systems may also change with the seasons.

It’s a complex data problem similar to others tackled by Berkeley Lab’s researchers studying systems like watersheds and agriculture; the challenge involves integrating data across scales to make predictions at the local level. “Downscaling of climate information is something that we routinely do to understand how climate impacts ecosystem processes,” Brodie said. “It involves the same types of variables — temperature, humidity, solar radiation.”

Brodie, deputy director of Berkeley Lab’s Climate and Ecosystem Sciences Division, is leading a cross-disciplinary team of Lab scientists with expertise in climate modeling, data analytics, machine learning, and geospatial analytics. Ben Brown, a computational biologist in Berkeley Lab’s Biosciences Area, is leading the machine-learning analysis. One of their main aims is to understand how climate and weather interact with societal factors.

“We don’t necessarily expect climate to be a massive or dominant effect in and of itself. It’s not going to trump which city shut down when,” Brown said. “But there may be some really important interactions [between the variables]. Looking at New York and California for example, even accounting for the differences between the timing of state-instituted interventions, the death rate in New York may be four times higher than in California — though additional testing on random samples of the population is needed to know for sure. Understanding the environmental interactions may help explain why these patterns appear to be emerging. This is a quintessential problem for machine learning and AI [artificial intelligence].”

The computing work will be conducted at the National Energy Research Scientific Computing Center (NERSC), a DOE Office of Science user facility located at Berkeley Lab.

Signs of climatic influences

map of the worldwide incidence rate of COVID-19
The worldwide incidence rate of COVID-19.
Credit: Center for Systems Science and Engineering at Johns Hopkins University

Already, geographical differences in how the disease behaves have been reported, the researchers point out. Temperature, humidity, and the UV Index have all been statistically associated with rates of COVID-19 transmission — although contact rates are still the dominant influence on the spread of disease. In the southern hemisphere, for example, where it’s currently fall, disease spread has been slower than in the northern hemisphere. “There’s potentially other factors associated with that,” Brodie said. “The question is, when the southern hemisphere moves into winter, will there be an increase in transmission rate, or will fall and winter 2020 lead to a resurgence across the U.S. in the absence of interventions?”

India is another place where COVID-19 does not yet appear to be as virulent. “There are cities where it behaves as if it’s the most infectious disease in recorded history. Then there are cities where it behaves more like influenza,” Brown said. “It is really critical to understand why we see those massive differences.”

Brown notes other experiments suggesting the SARS-CoV-2 virus could be seasonal. In particular, the National Biodefense Analysis and Countermeasures Center (NBACC) assessed the longevity of the virus on various surfaces. “Under sunlight and humidity, they found that the virus loses viability in under 60 minutes,” Brown said. “But in darkness and low temperatures it’s stable for eight days. There’s some really serious differences that need investigating.”

The Berkeley Lab team believes that enough data may now be available to determine what environmental factors may influence the virulence of the virus. “Now we should have enough data from around the world to really make an assessment,” Brown said.

The team hopes to have the first phase of their analysis available by late summer or early fall. The next phase will be to make projections under different scenarios, which could aid in public health decisions.

“We would use models to project forward, with different weather scenarios, different health intervention scenarios — such as continued social distancing or whether there are vaccines or some level of herd immunity — in different parts of the country. For example, we hope to be able to say, if you have kids going back to school under this type of environment, the climate and weather in this zone will influence the potential transmission by this amount,” Brodie explained. “That will be a longer-term task for us to accomplish.”

This research is supported by Berkeley Lab’s Laboratory Directed Research and Development (LDRD) program. Other team members include Dan Feldman, Zhao Hao, Chaincy Kuo, Haruko Wainwright, and Nicola Falco. Berkeley Lab mobilized quickly to provide LDRD funding for several research projects to address the COVID-19 pandemic, including one on text mining scientific literature and another on indoor transmission of the virus.

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COVID-19: Novel Treatment Protocols using Approved drugs vs Standard of Care vs Vaccine and Antiviral new drug discovery and development – An LPBI Group Response and An LPBI Group & Affiliates Response

Curator: Aviva Lev-Ari, PhD, RN

 

On 5/26/2020 LPBI organized a Symposium on New Therapeutics for COVID-19

AGENDA included presentations by:

  • Dr. Raphael Nir, PhD, CSO, SBH, Sciences, Inc. – Drug Concept to mitigate Cytokine Storm in COVID-19 – ATTACHMENT
  • Dr. Ajay Gupta, MD, Professor & Entrepreneur – Rhinitis drug approved in Japan – REPURPOSED for COVID-19 and Application for FDA Approval
  • Dr. Yigal Blum, PhD, ex-SRI Int’l VP and Entrepreneur –  AMORPHOUS CALCIUM CARBONATE (ACC) TREATMENT FOR COVID-19
  • Dr. Orna Harel, PhD, Managing Partner, Agbiopro – Representation for – Prof. Saul Yedgar on the concept and state of preclinical efforts for COVID-19 drug development 
  • Aviva Lev-Ari, PhD, RN – The Potential of REVIVAL of Drug Discovery Initiative and Explorations of Joint Ventures with Biotech companies – An Interim Phase toward POST Coronavirus Pandemic Exit

DISCUSSION – Where and What is the INTERFACE between what our External Relations attempt to accomplish and the Capabilities of LPBI Group’s Team

In the concluding remarks, Dr. Lev-Ari discussed the importance of TREATMENT PROTOCOLS vs. one Therapeutics at a time vs. Combination Drug therapies.

Dr. Lev-Ari pointed the Symposium attendees to the following two points:

1.  The State of Science been endorsed by LPBI Group

RNA from the SARS-CoV-2 virus taking over the cells it infects: Virulence – Pathogen’s ability to infect a Resistant Host: The Imbalance between Controlling Virus Replication versus Activation of the Adaptive Immune Response
Curator: Aviva Lev-Ari, PhD, RN – I added colors and bold face
https://pharmaceuticalintelligence.com/2020/05/23/rna-from-the-sars-cov-2-virus-taking-over-the-cells-it-infects-virulence-pathogens-ability-to-infect-a-resistant-host-the-imbalance-between-controlling-virus-replication-versus-activation-of-the/

2.  LPBI Group’s Position for Treatment Protocol(s)

In continuation to 5/26/2020 Symposium on New Therapeutics for COVID-19, we will follow up with an AGENDA for 6/16/2020 

Part I: Therapeutics for COVID-19

  • Prof. Saul Yedgar – Holder of US Patents on Rhinitis, anti-inflatation and other indications – 40 minutes
  • Dr. Ajay Gupta, MD – Rhinitis drug approved in Japan – FDA Application for Approval of Repurpusing to COVID-19 in the US – 40 minutes
  • Discussion – 20 minutes

 

On 5/29/2020 Dr. Lev-Ari read the article, COVID-19 Critical Care

Analysis by Dr. Joseph Mercola

STORY AT-A-GLANCE

  • Despite the fact that many critical care specialists are using treatment protocols that differ from standard of care, information about natural therapeutics in particular are still being suppressed by the media and is not received by critical care physicians
  • Five critical care physicians have formed the Front Line COVID-19 Critical Care Working Group (FLCCC). The group has developed a highly effective treatment protocol known as MATH+
  • Of the more than 100 hospitalized COVID-19 patients treated with the MATH+ protocol as of mid-April, only two died. Both were in their 80s and had advanced chronic medical conditions
  • The protocols call for the use of intravenous methylprednisolone, vitamin C and subcutaneous heparin within six hours of admission into the hospital, along with high-flow nasal oxygen. Optional additions include thiamine, zinc and vitamin D
  • COVID-19 kills by triggering hyperinflammation, hypercoagulation and hypoxia. The MATH+ protocol addresses these three core pathological processes

COVID-19 Early Intervention Protocol

According to Kory, the FLCCCs MATH+ protocol has been delivered to the White House on four occasions, yet no interest has been shown. Worse, he says they continue to be stonewalled by the U.S. Centers for Disease Control and the National Institute for Health. Why?

Isn’t saving lives, right now, and by any means possible, more important than pushing for a vaccine? If the MATH+ protocol works with near-100% effectiveness, a vaccine may not even be necessary. The MATH+ protocol gets its name from:

Intravenous Methylprednisolone

High-dose intravenous Ascorbic acid

Plus optional treatments Thiamine, zinc and vitamin D

Full dose low molecular weight Heparin

Kory’s testimony transcript reviews and summarizes the MATH+ protocol, and explains why the timing of the treatment is so important. As explained by Kory, there are two distinct yet overlapping phases of COVID-19 infection.

  1. Phase 1 is the viral replication phase. Typically, patients will only experience mild symptoms, if any, during this phase. At this time, it’s important to focus on antiviral therapies.
  2. In Phase 2, the hyperinflammatory immune response sets in, which can result in organ failures (lungs, brain, heart and kidneys). The MATH+ protocol is designed to treat this active phase, but it needs to be administered early enough.

The MATH+ Protocol

The MATH+ protocol7 calls for the use of three medicines, all of which need to be started within six hours of hospital admission:

  • Intravenous methylprednisolone, to suppress the immune system and prevent organ damage from cytokine storms — For mild hypoxia, 40 milligrams (mg) daily until off oxygen; moderate to severe illness, 80 mg bolus followed by 20 mg per day for seven days. On Day 8, switch to oral prednisone and taper down over the next six days.
  • Intravenous ascorbic acid (vitamin C), to control inflammation and prevent the development of leaky blood vessels in the lungs — 3 grams/100 ml every six hours for up to seven days.
  • Subcutaneous heparin (enoxaparin), to thin the blood and prevent blood clots — For mild to moderate illness, 40 mg to 60 mg daily until discharged.

Optional additions include thiamine, zinc and vitamin D. In addition to these medications, the protocol calls for high-flow nasal oxygen to avoid mechanical ventilation, “which itself damages the lungs and is associated with a mortality rate approaching nearly 90% in some centers,” Kory notes.8

Together, this approach addresses the three core pathological processes seen in COVID-19, namely hyperinflammation, hypercoagulability of the blood, and hypoxia (shortness of breath due to low oxygenation).

COVID-19 Should Not Be Treated as ARDS

In the video, Dr. Paul Marik points out that it’s crucial for doctors to treat each patient as an individual case, as COVID-19 is not conventional acute respiratory distress syndrome (ARDS).

If the patient is assumed to have ARDS and placed on a ventilator, you’re likely going to damage their lungs. Indeed, research has now shown that patients placed on mechanical ventilation have far higher mortality rates than patients who are not ventilated. While not discussed here, some doctors are also incorporating hyperbaric oxygen treatment in lieu of ventilation, with great success.

The reason for this is because the primary problem is inflammation, not fluid in the lungs. So, Marik says, they need anti-inflammatory drugs. “It’s not the virus that is hurting the host, it’s the acute inflammatory dysregulated response,” he says. “That’s why you need to use vitamin C and steroids.” He points out that steroids play a crucial role, as it creates synergy with vitamin C.

COVID-19 patients also have a hypercoagulation problem, so they need anticoagulants. In addition to using the proper medication, they must also be treated early. “You have to intervene early and aggressively to prevent them from deteriorating,” Marik says.

Methylprednisolone May Be a Crucial Component

Kory expresses concerns over the fact that health organizations around the world are warning doctors against the use of corticosteroids, calling this a “tragic error”9 as “COVID-19 is a steroid-responsive disease.”10 In his testimony, he points out:11

“Sorin Draghici, CEO of Advaita Bioinformatics, just reported12 that their incredibly sophisticated Artificial Intelligence platform called iPathwayGuide, using cultured human cell lines infected with COVID-19, is able to map all the human genes which are activated by this virus …

Note almost all the activated genes are those that express triggers of inflammation. With this knowledge of the specific COVID inflammatory gene activation combined with knowledge of the gene suppression activity of all known medicines they were able to match the most effective drug for COVID-19 human gene suppression, and that drug is methylprednisolone.

This must be recognized, as the ability of other corticosteroids to control inflammation in COVID-19 was much less impactful. This is, we believe, an absolutely critical and historic finding. Many centers are using similar but less effective agents such as dexamethasone or prednisone.”

As noted by Kory in his senate testimony, Marik, chief of pulmonary and critical care medicine at the Eastern Virginia Medical School in Norfolk, Virginia, is a member of the FLCCC.13 You may recall that Marik was the one who in 2017 announced he had developed an extraordinarily effective treatment against sepsis.

Marik’s sepsis protocol also calls for intravenous vitamin C and a steroid, in this case hydrocortisone, along with thiamine. I for one am not surprised that the two protocols are so similar, seeing how sepsis is also a major cause of death in severe COVID-19 cases.

Safe and Effective Treatments Must Not Be Ignored

As noted by Marik in the video, COVID-19 is not regular ARDS and should not be treated as such. What kills people with COVID-19 is the inflammation, and steroids in combination with vitamin C work synergistically together to control and regulate that inflammation. The heparin, meanwhile, addresses the hypercoagulation that causes blood clots, which is a unique feature of COVID-19. As for the “lack of studies” supporting their protocol, FLCCC notes:14

“A number of official guidelines, such as those of the WHO and several other U.S. agencies, recommend limiting treatment for … critically ill patients to ‘supportive care only’ — and to allow the therapies described here to be studied in randomized controlled trials where half of the patients would receive placebo and where the results would come in months or years.

Our physicians agree that while a randomized controlled trial (RCT), under normal circumstances, might be considered, the early provisions of MATH+, which must be given within hours of critical illness, would inevitably be delayed by such a study design, rendering the validity of the RCT questionable.

Furthermore, while the results of an RCT would not be available for months or more, well-designed observational studies of the protocol could yield timely feedback during this pandemic, to improve the treatment process much more quickly.”

I believe this information needs to be shared far and wide, if we are to prevent more people from dying unnecessarily. More and more, as doctors are starting to speak openly about their clinical findings, we’re seeing that there are quite a few different ways to tackle this illness without novel antivirals or vaccines, using older, inexpensive and readily available medications that are already known to be safe.

References

SOURCE

https://blogs.mercola.com/sites/vitalvotes/archive/2020/05/28/lab-escape-theory-of-sarscov2-origin-gaining-scientific-support.aspx

 

A Response by LPBI Group and a Potential Response by LPBI Group and its Affiliates

 

LPBI Group’s Components in Novel Treatment Protocol Definition

 

  • Forthcoming by Stephen J. Williams, PhD – Immuno-theraphy boosting Protocol

based on

T cells found in COVID-19 patients ‘bode well’ for long-term immunity | Science | AAAS
https://www.sciencemag.org/news/2020/05/t-cells-found-covid-19-patients-bode-well-long-term-immunity

 

  • Forthcoming by Aviva Lev-Ari, PhD, RN and Stephen J. Williams, PhD – Nitric Oxide Inhaler OR Bystolic® (nebivolol) www.bystolicpro.com
  • Two alternatives per stage of COVID-19 infections: Severe or Moderate

based on

 

  • LPBI Group’s Affiliates:

If you wish your Therapeutic solution to be included in the NEW DEFINITION of Treatment Protocol(s), then propose your component for inclusion in the Novel Treatment Protocol to be discussed on June 16, 2020

LPBI Group’s Affiliates Components in the Novel Treatment Protocol(s) Definition

  • Prof. Saul Yedgar – Holder of US Patents on Rhinitis, anti-inflammation and other indications – 40 minutes
  • Dr. Ajay Gupta, MD – Rhinitis drug approved in Japan – FDA Application for Approval of Repurposing to COVID-19 in the US – 40 minutes
  • Dr. Raphael Nir, PhD, CSO, SBH, Sciences, Inc. – Drug Concept to mitigate Cytokine Storm in COVID-19 
  • Dr. Yigal Blum, PhD, ex-SRI Int’l VP and Entrepreneur –  AMORPHOUS CALCIUM CARBONATE (ACC) TREATMENT FOR COVID-19

References on Nitric Oxide on PharmaceuticalIntellige.com – Open Access Online Scientific Journal include 299 articles

https://pharmaceuticalintelligence.com/?s=Nitric+Oxide

Of note

 

Included in the 299 articles

  • Transposon-mediated Gene Therapy improves Pulmonary Hemodynamics and attenuates Right Ventricular Hypertrophy: eNOS gene therapy reduces Pulmonary vascular remodeling and Arterial wall hyperplasia

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/31/transposon-mediated-gene-therapy-improves-pulmonary-hemodynamics-and-attenuates-right-ventricular-hypertrophy-enos-gene-therapy-reduces-pulmonary-vascular-remodeling-and-arterial-wall-hyperplasia/

 

Author and Curator of an Investigator Initiated Study: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/04/endothelin-receptors-in-cardiovascular-diseases-the-role-of-enos-stimulation/

 

  • Inhibition of ET-1, ETA and ETA-ETB, Induction of NO production,  stimulation of eNOS and Treatment Regime with PPAR-gamma agonists (TZD): cEPCs Endogenous Augmentation for Cardiovascular Risk Reduction – A Bibliography

Curator of an Investigator Initiated Study: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/04/inhibition-of-et-1-eta-and-eta-etb-induction-of-no-production-and-stimulation-of-enos-and-treatment-regime-with-ppar-gamma-agonists-tzd-cepcs-endogenous-augmentation-for-cardiovascular-risk-reduc/

 

  • Cardiovascular Disease (CVD) and the Role of Agent Alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production

Curator and Investigator Initiated Study: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/07/19/cardiovascular-disease-cvd-and-the-role-of-agent-alternatives-in-endothelial-nitric-oxide-synthase-enos-activation-and-nitric-oxide-production/

 

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

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

 

See

The Genome Structure of CORONAVIRUS, SARS-CoV-2

Reporter: Aviva Lev-Ari, PhD, RN

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

 

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

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

Highlights

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

Summary

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

Graphical Abstract

Keywords

Results

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

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

Discussion

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

SOURCE

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

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

Yoriyuki KonnoIzumi KimuraKeiya UriuMasaya FukushiTakashi IrieYoshio KoyanagiSo NakagawaKei Sato

Abstract

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

Highlights

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

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

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

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

Competing Interest Statement

The authors have declared no competing interest.

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

 

SOURCE

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

 

 

A deep dive into how the new coronavirus infects cells has found that it orchestrates a hostile takeover of their genes unlike any other known viruses do, producing what one leading scientist calls “unique” and “aberrant” changes.Recent studies show that in seizing control of genes in the human cells it invades, the virus changes how segments of DNA are read, doing so in a way that might explain why the elderly are more likely to die of Covid-19 and why antiviral drugs might not only save sick patients’ lives but also prevent severe disease if taken before infection.“It’s something I have never seen in my 20 years of” studying viruses, said virologist Benjamin tenOever of the Icahn School of Medicine at Mount Sinai, referring to how SARS-CoV-2, the virus that causes Covid-19, hijacks cells’ genomes.

The “something” he and his colleagues saw is how SARS-CoV-2 blocks one virus-fighting set of genes but allows another set to launch, a pattern never seen with other viruses. Influenza and the original SARS virus (in the early 2000s), for instance, interfere with both arms of the body’s immune response — what tenOever dubs “call to arms” genes and “call for reinforcement” genes.

The first group of genes produces interferons. These proteins, which infected cells release, are biological semaphores, signaling to neighboring cells to activate some 500 of their own genes that will slow down the virus’ ability to make millions of copies of itself if it invades them. This lasts seven to 10 days, tenOever said, controlling virus replication and thereby buying time for the second group of genes to act.

This second set of genes produce their own secreted proteins, called chemokines, that emit a biochemical “come here!” alarm. When far-flung antibody-making B cells and virus-killing T cells sense the alarm, they race to its source. If all goes well, the first set of genes holds the virus at bay long enough for the lethal professional killers to arrive and start eradicating viruses.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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The Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) Partnership on May 18, 2020: Leadership of AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Eisai, Eli Lilly, Evotec, Gilead, GlaxoSmithKline, Johnson & Johnson, KSQ Therapeutics, Merck, Novartis, Pfizer, Roche, Sanofi, Takeda, and Vir. We also thank multiple NIH institutes (especially NIAID), the FDA, BARDA, CDC, the European Medicines Agency, the Department of Defense, the VA, and the Foundation for NIH

Reporter: Aviva Lev-Ari, PhD, RN

May 18, 2020

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) An Unprecedented Partnership for Unprecedented Times

JAMA. Published online May 18, 2020. doi:10.1001/jama.2020.8920

First reported in Wuhan, China, in December 2019, COVID-19 is caused by a highly transmissible novel coronavirus, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). By March 2020, as COVID-19 moved rapidly throughout Europe and the US, most researchers and regulators from around the world agreed that it would be necessary to go beyond “business as usual” to contain this formidable infectious agent. The biomedical research enterprise was more than willing to respond to the challenge of COVID-19, but it soon became apparent that much-needed coordination among important constituencies was lacking.

Clinical trials of investigational vaccines began as early as January, but with the earliest possible distribution predicted to be 12 to 18 months away. Clinical trials of experimental therapies had also been initiated, but most, except for a trial testing the antiviral drug remdesivir,2 were small and not randomized. In the US, there was no true overarching national process in either the public or private sector to prioritize candidate therapeutic agents or vaccines, and no efforts were underway to develop a clear inventory of clinical trial capacity that could be brought to bear on this public health emergency. Many key factors had to change if COVID-19 was to be addressed effectively in a relatively short time frame.

On April 3, leaders of the National Institutes of Health (NIH), with coordination by the Foundation for the National Institutes of Health (FNIH), met with multiple leaders of research and development from biopharmaceutical firms, along with leaders of the US Food and Drug Administration (FDA), the Biomedical Advanced Research and Development Authority (BARDA), the European Medicines Agency (EMA), and academic experts. Participants sought urgently to identify research gaps and to discuss opportunities to collaborate in an accelerated fashion to address the complex challenges of COVID-19.

These critical discussions culminated in a decision to form a public-private partnership to focus on speeding the development and deployment of therapeutics and vaccines for COVID-19. The group assembled 4 working groups to focus on preclinical therapeutics, clinical therapeutics, clinical trial capacity, and vaccines (Figure). In addition to the founding members, the working groups’ membership consisted of senior scientists from each company or agency, the Centers for Disease Control and Prevention (CDC), the Department of Veterans Affairs (VA), and the Department of Defense.

Figure.

Accelerating COVID-19 Therapeutic Interventions and Vaccines

ACTIV’s 4 working groups, each with one cochair from NIH and one from industry, have made rapid progress in establishing goals, setting timetables, and forming subgroups focused on specific issues (Figure). The goals of the working group, along with a few examples of their accomplishments to date, include the following.

 

The Preclinical Working Group was charged to standardize and share preclinical evaluation resources and methods and accelerate testing of candidate therapies and vaccines to support entry into clinical trials. The aim is to increase access to validated animal models and to enhance comparison of approaches to identify informative assays. For example, through the ACTIV partnership, this group aims to extend preclinical researchers’ access to high-throughput screening systems, especially those located in the Biosafety Level 3 (BSL3) facilities currently required for many SARS-CoV-2 studies. This group also is defining a prioritization approach for animal use, assay selection and staging of testing, as well as completing an inventory of animal models, assays, and BSL 3/4 facilities.

 

The Therapeutics Clinical Working Group has been charged to prioritize and accelerate clinical evaluation of a long list of therapeutic candidates for COVID-19 with near-term potential. The goals have been to prioritize and test potential therapeutic agents for COVID-19 that have already been in human clinical trials. These may include agents with either direct-acting or host-directed antiviral activity, including immunomodulators, severe symptom modulators, neutralizing antibodies, or vaccines. To help achieve these goals, the group has established a steering committee with relevant expertise and objectivity to set criteria for evaluating and ranking potential candidate therapies submitted by industry partners. Following a rigorous scientific review, the prioritization subgroup has developed a complete inventory of approximately 170 already identified therapeutic candidates that have acceptable safety profiles and different mechanisms of action. On May 6, the group presented its first list of repurposed agents recommended for inclusion in ACTIV’s master protocol for adaptive clinical trials. Of the 39 agents that underwent final prioritization review, the group identified 6 agents—including immunomodulators and supportive therapies—that it proposes to move forward into the master protocol clinical trial(s) expected to begin later in May.

 

The Clinical Trial Capacity Working Group is charged with assembling and coordinating existing networks of clinical trials to increase efficiency and build capacity. This will include developing an inventory of clinical trial networks supported by NIH and other funders in the public and private sectors, including contract research organizations. For each network, the working group seeks to identify their specialization in different populations and disease stages to leverage infrastructure and expertise from across multiple networks, and establish a coordination mechanism across networks to expedite trials, track incidence across sites, and project future capacity. The clinical trials inventory subgroup has already identified 44 networks, with access to adult populations and within domestic reach, for potential inclusion in COVID-19 trials. Meanwhile, the survey subgroup has developed 2 survey instruments to assess the capabilities and capacities of those networks, and its innovation subgroup has developed a matrix to guide deployment of innovative solutions throughout the trial life cycle.

 

The Vaccines Working Group has been charged to accelerate evaluation of vaccine candidates to enable rapid authorization or approval.4 This includes development of a harmonized master protocol for adaptive trials of multiple vaccines, as well as development of a trial network that could enroll as many as 100 000 volunteers in areas where COVID-19 is actively circulating. The group also aims to identify biomarkers to speed authorization or approval and to provide evidence to address cross-cutting safety concerns, such as immune enhancement. Multiple vaccine candidates will be evaluated, and the most promising will move to a phase 2/3 adaptive trial platform utilizing large geographic networks in the US and globally.5 Because time is of the essence, ACTIV will aim to have the next vaccine candidates ready to enter clinical trials by July 1, 2020.

References

1.

Desai  A .  Twentieth-century lessons for a modern coronavirus pandemic.   JAMA. Published online April 27, 2020. doi:10.1001/jama.2020.4165
ArticlePubMedGoogle Scholar

2.

NIH clinical trial shows remdesivir accelerates recovery from advanced COVID-19. National Institutes of Health. Published April 29, 2020. Accessed May 7, 2020. https://www.nih.gov/news-events/news-releases/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19

3.

NIH to launch public-private partnership to speed COVID-19 vaccine and treatment options. National Institutes of Health. Published April 17, 2020. Accessed May 7, 2020. https://www.nih.gov/news-events/news-releases/nih-launch-public-private-partnership-speed-covid-19-vaccine-treatment-options

4.

Corey  L , Mascola  JR , Fauci  AS , Collins  FS .  A strategic approach to COVID-19 vaccine R&D.   Science. Published online May 11, 2020. doi:10.1126/science.abc5312PubMedGoogle Scholar

5.

Angus  DC .  Optimizing the trade-off between learning and doing in a pandemic.   JAMA. Published online March 30, 2020. doi:10.1001/jama.2020.4984
ArticlePubMedGoogle Scholar

6.

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) portal. National Institutes of Health. Accessed May 15, 2020. https://www.nih.gov/ACTIV

7.

Accelerating Medicines Partnership (AMP). National Institutes of Health. Published February 4, 2014. Accessed May 7, 2020. https://www.nih.gov/research-training/accelerating-medicines-partnership-amp
SOURCE

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Vaccinology in the Age of Pandemics:
Strategies Against COVID-19 & Other Global Threats

June 15–16, 2020 | 11:00AM–3:30PM ET | 3:00–7:30PM UTC | 5:00–9:30PM CEST*
*Program is subject to change


As the world faces the greatest global pandemic of our lifetimes, the critical importance of vaccine development has come to the forefront of scientific and public audiences alike. Over the course of history, vaccination has enabled us to conquer devastating diseases from measles to smallpox, but new challenges arise when addressing an emerging pandemic in real time. This virtual meeting will assemble the world’s leading vaccinology and global health experts to present the latest advances in vaccine design and development. Finally, this virtual conference will discuss how to best apply these strategies in the context of the current pandemic.

The field of vaccinology has made great leaps in recent years, providing novel technologies and approaches that can be leveraged to our advantage against the novel coronavirus, COVID-19. Incredible advances in science and technology now make it technically possible to develop vaccines against many new targets. Meanwhile, innovative approaches to vaccine development are tackling challenges of emerging infections and implementation in low-income countries. These advances, among many others, will guide the way towards a safe and effective COVID-19 vaccine. Additionally, these new scientific advances will set the stage for success against this pandemic, as vaccinologists race against the ever-rising global death toll.

This virtual meeting program will cover many important facets of vaccine science, technology and strategy, including:

  • transformative new technologies, including structure-based design, adjuvants, nucleic acid vaccines (especially RNA), viral vectors, systems biology, and controlled human infections
  • scientific underpinnings of new vaccinology strategies, including advances in the fields of human immunology, genomics, synthetic biology, molecular structure of antigens and antigen-antibody complexes, germinal centers, and microbiome
  • multidisciplinary technologies and strategies, including efforts of Coalition for Epidemic Preparedness Innovations (CEPI), Bill & Melinda Gates Foundation and Wellcome Trust, which will change the way vaccines are developed

Program is intended for scientific researchers and clinical audiences.

Join us for this landmark virtual event, brought to you by Keystone Symposia.

Regular Registration Rate: $50 USD

#VKSvaxcovid19

SPEAKERS

Program Details

Keynote Speaker


Anthony S. Fauci, MD
Anthony S. Fauci, MD
NIAID, National Institutes of Health
Transforming Vaccinology: Considerations for the Next Decade

Speaking at this eSymposia


Galit Alter

MIT and Harvard University

Yasmine Belkaid

NIAID, National Institutes of Health

Anthony S. Fauci, MD

Anthony S. Fauci

NIAID, National Institutes of Health

Barney S. Graham

NIAID, National Institutes of Health

Richard Hatchett

Coalition for Epidemic Preparedness Innovations, CEPI

Neil P. King

University of Washington

Antonio Lanzavecchia

Institute for Research in Biomedicine

Ulrike Protzer

Technische Universität München

Bali Pulendran

Stanford University School of Medicine

Rino Rappuoli

GlaxoSmithKline Vaccines

Federica Sallusto

Università della Svizzera Italiana & ETH Zurich

Robert A. Seder

NIAID, National Institutes of Health

Christine Shaw

Moderna

Gabriel D. Victora

Gabriel D. Victora

Rockefeller University

Hedda Wardemann

German Cancer Research Center

Catherine J. Wu

Dana-Farber Cancer Institute

SOURCE

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