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Archive for the ‘Virus Infective Acute Respiratory Syndrome: SARS-CoV’ Category


Rise of a trio of mutated viruses hints at an increase in transmissibility, speeding the virus’ leaps from one host to the next

Reporter: Aviva Lev-Ari, PhD, RN

“We have uncontrolled viral spread in much of the world,” says Adam Lauring, an infectious disease physician and virologist at the University of Michigan. “So the virus has a lot of opportunity to evolve.”

“The variants may be more transmissible, but physics has not changed,” says Müge Çevik, an infectious disease physician at the University of St. Andrews in Scotland.

Many changes don’t affect the virus’ function, and some even harm SARS-CoV-2’s ability to multiply, but they keep happening. “Viruses mutate; that’s what they do,” says Akiko Iwasaki, an immunologist at Yale School of Medicine in Connecticut.

U.K., Brazil, and South Africa. In the United Kingdom, variant B.1.1.7 likely drove the region’s record-setting spike of COVID-19 cases in January. The variant is now circulating in more than 60 countries, including the United States—and projections suggest it will become the most common virus variety in the U.S. by mid-March.

An independently arising lineage called P.1 might also be driving a wave of cases in Manaus, Brazil, where it accounted for nearly half of new COVID-19 infections in December. On January 26, Minnesotan officials reported the first U.S. case of P.1 in a resident who previously traveled to Brazil. And a third lineage raising alarms, known as B.1.351, was first spotted amid a December wave of infections in South Africa. On January 28, the first known U.S. cases of the variant were reported in South Carolina.

One specific mutation, known as N501Y, popped up independently in all three variants, suggesting it could provide an advantage to the virus. “That’s a sign that there is natural selection going on,” Lauring says. The N501Y mutation affects the virus’ spike protein, which is the key it uses to unlock entry into its host’s cells.

Another possibility is that new variants cause people who are infected to harbor more copies of the virus. This results in greater viral “shedding” in airborne droplets spewed when people talk, sing, cough, and breath.

mutations in 501Y.V2 could diminish the effectiveness of antibodies in the blood of people previously infected with the virus. But understanding whether that could lead to more re-infections, or if it could affect vaccine efficacy.

Dramatically scale up production of high-filtration masks for the general public.

Based on:

Why some coronavirus variants are more contagious‹and how we can stop them

https://www.nationalgeographic.com/science/2021/01/why-some-coronavirus-variants-are-more-contagious/?cmpid=org=ngp::mc=crm-email::src=ngp::cmp=editorial::add=SpecialEdition_20210129

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A Platform called VirtualFlow: Discovery of Pan-coronavirus Drugs help prepare the US for the Next Coronavirus Pandemic

Reporter: Aviva Lev-Ari, PhD, RN

 

ARTICLE|ONLINE NOW, 102021

A multi-pronged approach targeting SARS-CoV-2 proteins using ultra-large virtual screening

Open AccessPublished:January 04, 2021DOI:https://doi.org/10.1016/j.isci.2020.102021

 

The work was made possible in large part by about $1 million in cloud computing hours awarded by Google through a COVID-19 research grant program.

The work reported, below was sponsored by

  • a Google Cloud COVID-19 research grant. Funding was also provided by the
  • Fondation Aclon,
  • National Institutes of Health (GM136859),
  • Claudia Adams Barr Program for Innovative Basic Cancer Research,
  • Math+ Berlin Mathematics Research Center,
  • Templeton Religion Trust (TRT 0159),
  • U.S. Army Research Office (W911NF1910302), and
  • Chleck Family Foundation

 

Harvard University, AbbVie form research alliance to address emergent viral diseases

This article is part of Harvard Medical School’s continuing coverage of medicine, biomedical research, medical education and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.

Harvard University and AbbVie today announced a $30 million collaborative research alliance, launching a multi-pronged effort at Harvard Medical School to study and develop therapies against emergent viral infections, with a focus on those caused by coronaviruses and by viruses that lead to hemorrhagic fever.

The collaboration aims to rapidly integrate fundamental biology into the preclinical and clinical development of new therapies for viral diseases that address a variety of therapeutic modalities. HMS has led several large-scale, coordinated research efforts launched at the beginning of the COVID-19 pandemic.

“A key element of having a strong R&D organization is collaboration with top academic institutions, like Harvard Medical School, to develop therapies for patients who need them most,” said Michael Severino, vice chairman and president of AbbVie. “There is much to learn about viral diseases and the best way to treat them. By harnessing the power of collaboration, we can develop new therapeutics sooner to ensure the world is better prepared for future potential outbreaks.”

“The cataclysmic nature of the COVID-19 pandemic reminds us how vital it is to be prepared for the next public health crisis and how critical collaboration is on every level—across disciplines, across institutions and across national boundaries,” said George Q. Daley, dean of Harvard Medical School. “Harvard Medical School, as the nucleus of an ecosystem of fundamental discovery and therapeutic translation, is uniquely positioned to propel this transformative research alongside allies like AbbVie.”

AbbVie will provide $30 million over three years and additional in-kind support leveraging AbbVie’s scientists, expertise and facilities to advance collaborative research and early-stage development efforts across five program areas that address a variety of therapeutic modalities:

  • Immunity and immunopathology—Study of the fundamental processes that impact the body’s critical immune responses to viruses and identification of opportunities for therapeutic intervention.

Led by Ulirich Von Andrian, the Edward Mallinckrodt Jr. Professor of Immunopathology in the Blavatnik Institute at HMS and program leader of basic immunology at the Ragon Institute of MGH, MIT and Harvard, and Jochen Salfeld, vice president of immunology and virology discovery at AbbVie.

  • Host targeting for antiviral therapies—Development of approaches that modulate host proteins in an effort to disrupt the life cycle of emergent viral pathogens.

Led by Pamela Silver, the Elliot T. and Onie H. Adams Professor of Biochemistry and Systems Biology in the Blavatnik Institute at HMS, and Steve Elmore, vice president of drug discovery science and technology at AbbVie.

  • Antibody therapeutics—Rapid development of therapeutic antibodies or biologics against emergent pathogens, including SARS-CoV-2, to a preclinical or early clinical stage.

Led by Jonathan Abraham, assistant professor of microbiology in the Blavatnik Institute at HMS, and by Jochen Salfeld, vice president of immunology and virology discovery at AbbVie.

  • Small molecules—Discovery and early-stage development of small-molecule drugs that would act to prevent replication of known coronaviruses and emergent pathogens.

Led by Mark Namchuk, executive director of therapeutics translation at HMS and senior lecturer on biological chemistry and molecular pharmacology in the Blavatnik Institute at HMS, and Steve Elmore, vice president of drug discovery science and technology at AbbVie.

  • Translational development—Preclinical validation, pharmacological testing, and optimization of leading approaches, in collaboration with Harvard-affiliated hospitals, with program leads to be determined.

SOURCE

https://hms.harvard.edu/news/joining-forces

 

 

A Screen Door Opens

Virtual screen finds compounds that could combat SARS-CoV-2

This article is part of Harvard Medical School’s continuing coverage of medicine, biomedical research, medical education, and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.

Less than a year ago, Harvard Medical School researchers and international colleagues unveiled a platform called VirtualFlow that could swiftly sift through more than 1 billion chemical compounds and identify those with the greatest promise to become disease-specific treatments, providing researchers with invaluable guidance before they embark on expensive and time-consuming lab experiments and clinical trials.

Propelled by the urgent needs of the pandemic, the team has now pushed VirtualFlow even further, conducting 45 screens of more than 1 billion compounds each and ranking the compounds with the greatest potential for fighting COVID-19—including some that are already approved by the FDA for other diseases.

“This was the largest virtual screening effort ever done,” said VirtualFlow co-developer Christoph Gorgulla, research fellow in biological chemistry and molecular pharmacology in the labs of Haribabu Arthanari and Gerhard Wagner in the Blavatnik Institute at HMS.

The results were published in January in the open-access journal iScience.

The team searched for compounds that bind to any of 15 proteins on SARS-CoV-2 or two human proteins, ACE2 and TMPRSS2, known to interact with the virus and enable infection.

Researchers can now explore on an interactive website the 1,000 most promising compounds from each screen and start testing in the lab any ones they choose.

The urgency of the pandemic and the sheer number of candidate compounds inspired the team to release the early results to the scientific community.

“No one group can validate all the compounds as quickly as the pandemic demands,” said Gorgulla, who is also an associate of the Department of Physics at Harvard University. “We hope that our colleagues can collectively use our results to identify potent inhibitors of SARS-CoV-2.

In most cases, it will take years to find out whether a compound is safe and effective in humans. For some of the compounds, however, researchers have a head start.

Hundreds of the most promising compounds that VirtualFlow flagged are already FDA approved or being studied in clinical or preclinical trials for other diseases. If researchers find that one of those compounds proves effective against SARS-CoV-2 in lab experiments, the data their colleagues have already collected could save time establishing safety in humans.

Other compounds among VirtualFlow’s top hits are currently being assessed in clinical trials for COVID-19, including several drugs in the steroid family. In those cases, researchers could build on the software findings to investigate how those drug candidates work at the molecular level—something that’s not always clear even when a drug works well.

It shows what we’re capable of computationally during a pandemic.

Hari Arthanari

SOURCE

https://hms.harvard.edu/news/screen-door-opens?utm_source=Silverpop&utm_medium=email&utm_term=field_news_item_1&utm_content=HMNews02012021

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Inflammation and potential links with the microbiome: Mechanisms of infection by SARS-CoV-2

Reporter: Aviva Lev-Ari, PhD, RN

Mechanisms of infection by SARS-CoV-2, inflammation and potential links with the microbiome

Published Online:https://doi.org/10.2217/fvl-2020-0310

Human coronaviruses (HCoVs) were first isolated from patients with the common cold in the 1960s [1–3]. Seven HCoVs known to cause disease in humans have since been identified: HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, the SARS coronavirus (SARS-CoV), the Middle East respiratory syndrome coronavirus and the novel SARS-CoV-2 [4]. The latter was identified after a spike in cases of pneumonia of unknown etiology in Wuhan, Hubei Province, China during December 2019 and was initially named novel coronavirus (2019-nCoV) [5,6]. The virus was renamed SARS-CoV-2 according to the International Committee on Taxonomy of Viruses classification criteria due to its genomic closeness to SARS-CoV; the disease caused by this virus was named coronavirus disease (COVID-19) according to the WHO criteria for naming emerging diseases [7]. SARS-CoV-2 belongs to the genera Betacoronavirus and shares a different degree of genomic similarity with the other two epidemic coronaviruses: SARS-CoV (∼79%) and Middle East respiratory syndrome coronavirus (∼50%) [8].

COVID-19 has caused considerable morbidity and mortality worldwide and has become the central phenomenon that is shaping our current societies. Human-to-human transmission is the main route of spread of the virus, mainly through direct contact, respiratory droplets and aerosols [9–12]. Management of COVID-19 has been extremely challenging due to its high infectivity, lack of effective therapeutics and potentially small groups of individuals (i.e., asymptomatic or mild disease) rapidly spreading the disease [13–17]. Although research describing COVID-19 and the mechanisms of infection by SARS-CoV-2 and its pathogenesis has expanded rapidly, there is still much to be learnt. Important gaps in knowledge which remain to be elucidated are the dynamic and complex interactions between the virus and the host’s immune system, as well as the potential interspecies communications occurring between ecological niches encompassing distinct microorganisms in both healthy individuals and persons living with chronic diseases, and how these interactions could determine or modulate disease progression and outcomes.

In this review, we describe recent insights into these topics, as well as remaining questions whose answers will allow us to understand how interactions between the virus, the immune system and microbial components could possibly be related to disease states in patients with COVID-19, as well as existing studies of the microbiome in patients with COVID-19.

SOURCE

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Mysteries of COVID Smell Loss

Reported : Irina  Robu, PhD

When Covid-19 patients have smell loss it tends to be sudden and severe. They are usually don’t have a blocked, stuffy or runny nose – most people with coronavirus can still breathe freely.  Since the epidemy started in march, an estimated of 80 percent of people with COVID-19 have experience smell disturbances in addition to loss of taste and the ability to smell chemical irritants. Research has shown that smell loss is common in people with COVID-19 disease, the reason why researchers and doctors have recommended to use a diagnostic test to determine if a patient has COVID-19.

Yet, the mystery is how the new coronavirus robs patients of their senses. During the early days of the epidemic, physicians and researchers thought that COVID related loss of smell might signal that the virus makes its way into the brain through the nose, where it can do the most severe damage. According to Sandeep Robert Data, a neuroscientist at Harvard Medical School, the research data showed that the primary source is the in the nose, but more specifically in the nasal epithelium. It looks like the virus attacks the cells responsible for registering odors rather than attacking neurons directly.  

It is well known that  olfactory neurons do not have angiotensin-converting enzyme 2 (ACE2) receptors, which permit the virus entry to cells, on their surface. But sustentacular cells, which provide support for  olfactory neurons are scattered with the receptors. These cells preserve the important  balance of salt ions in the mucus that neurons rest on on to send signals to the brain. If that balance is disturbed, it could lead to a closure of neuronal signaling and loss of smell.

The sustentacular cells correspondingly deliver the metabolic and physical support necessary to keep the fingerlike cilia on the olfactory neurons wherever receptors that detect odors are disturbed. Nicolas Meunier, a neuroscientist at the Paris-Saclay University in France determined that disruption of the olfactory epithelium might explain the loss of smell. Yet, it remains unclear if the damage done by the virus or because it invades immune cells.

Since COVID-19 doesn’t cause nasal congestion, researchers have found a few clues about the loss of smell. Taste receptor cells, which detect chemicals in the saliva and sends signals to the brain do not have ACE receptors. They don’t necessarily  get infected by COVID-19, but other support cells in the tongue carry the receptor.

Researchers determined that more clues on  to how the virus obliterates smell. However, some patients have seen that after five months the ability to smell has returned but not as great as expected. That news is welcomed for patients that have suffered loss of smell due to the COVID-19 virus, yet apprehensions about long term loss of smell is a large cause of concern.

SOURCE

https://www.scientificamerican.com/article/mysteries-of-covid-smell-loss-finally-yield-some-answers1/

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

Reporter: Aviva Lev-Ari, PhD, RN

 

Read our latest blog | T cells: Understanding Exposure and Immunity to COVID-19 by Adaptive Co-Founder and CSO, Harlan Robins. Read here

Watch the video

T cells are the adaptive immune system’s first responders to any virus, circulating in the blood to detect and quickly multiply to attack the virus, often before symptoms appear. Adaptive Biotechnologies’ unique MIRA Technology and immunoSEQ Technology has enabled us to create a comprehensive view of the T-cell response to SARS-CoV-2 infection. This data has been made public as part of the ImmuneCODE Initiative in order to help propel drug, vaccine, and clinical trial research. We are launching immunoSEQ T-MAP COVID with the tools to study and analyze the COVID-19 T-cell immune response map.

SARS-CoV-2-specific Antigen-TCR sequence-level data
Quantitative sequence level data for TCR repertoires for SARS-CoV-2 specific antigens
Monitor immunologic response to SARS-CoV-2 infection or vaccine
Track COVID-19 specific TCR sequences longitudinally
Dive into Patient, Population, or Cohort-level data
Determine TCR clones shared between cohorts & those that are Public vs Private clones

 

Learn more about the science behind the ImmuneCODE database in our first publication (Nolan et al.) and to discover initial COVID-19 data insights, read our recently updated pre-print publication (Snyder et al.)

A large-scale database of T-cell receptor beta (TCRβ) sequences and binding associations from natural and synthetic exposure to SARS-CoV-2

Magnitude and Dynamics of the T-Cell Response to SARS-CoV-2 Infection at Both Individual and Population Levels

End-to-end solution; from experimental design to publication ready data

SARS-CoV-2-specific TCR repertoire sequences & antigen data

✔  Validated TCR-antigen data from over 70 MIRA experiments

✔  In vivo identified SARS-CoV-2-specific TCR sequences

✔  TCR-Antigen sequence level data with the PCR, bias-controlled, reproducible immunoSEQ Assay

Data analysis through the immunoSEQ Analyzer or Computational Biology Services

✔  Explore SARS-CoV-2-specific TCR-Antigen sequence data in the immunoSEQ Analyzer

✔  Compare your COVID-19 samples against our COVID-19 samples to identify public vs private clones

✔  Computational Biology Services for COVID-19 data and Metadata analysis

Comprehensive COVID-19 TCR-Antigen sequence database

✔  Providing you a comprehensive view of SARS-CoV-2-specific antigen and TCR level data

✔  Database will constantly be updated with new findings and TCR-Antigen sequence data

 

Check out the publications below to learn how researchers are propelling their COVID-19 research by leveraging immunoSEQ T-MAP COVID and the ImmuneCODE COVID-19 database

Analysis of SARS-CoV-2 specific T-cell receptors in ImmuneCode reveals cross-reactivity to immunodominant Influenza M1 epitope

 

Watch our video, about how the immunoSEQ Technology and immunoSEQ T-MAP COVID can be used to better understand the immune response to SARS-CoV-2 infection.

 

Ready to learn more about how our immunoSEQ T-MAP COVID service can help you propel your research forward? Contact us below to speak with one of our experts.

SOURCE

https://ww2.adaptivebiotech.com/immunoseq-TMAP-COVID?utm_source=genomeweb&utm_medium=email&utm_campaign=dailynews

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Why Do Some COVID-19 Patients Infect Many Others, Whereas Most Don’t Spread the Virus At All?

Guest Reporter: Jason S Zielonka, MD

One of the key parameters in COVID-19 pandemic epidemiology has been to define the spread metrics, basically identifying how a host spreads the virus to uninfected individuals. The pattern of spread can impact how and which preventative measures such as social distancing and hand washing can impact spread patterns. In particular, two metrics, the average number of new patients infected by each host (the reproduction number, R) and a factor representing the tendency to cluster (the dispersion factor, k) can be used to describe and model the spread of a virus quite well. Higher values of R mean more people are infected by a single host, i.e, the disease is more contagious; lower values of k mean that a host infects a larger number of new patients, i.e., the disease is more clustered.

The reproduction number, R, for SARS-CoV-2, without social distancing, is about 3. But this is an average, taken over an aggregate of patients. For most individuals, R is zero, i.e., most patients do not transmit the virus to others. For comparison, SARS and MERS, both coronaviruses, had R > 3 and the 1918 influenza pandemic had R >> 3. So what determines viral spread and how can we use that information to treat and eradicate SARS-CoV-2?

In 2005, by modeling the Chinese SARS outbreak and comparing the model to the real-world data, Lloyd-Smith and co-authors were able to determine that SARS had a k of about 0.16. MERS, in 2012, was estimated to have k around 0.25; the 1918 pandemic, by contrast, had a k of 1, meaning it had very little cluster effect. The current modeling indicates that k for SARS-CoV-2 is not conclusive, but it appears higher than k for either SARS or MERS.

This work has provided insights into some of the factors influencing cluster spread, which can be controlled in a more specific way than quarantining an entire population. There will be individual variance, but we know that people are particularly infectious over a certain time period; that certain activities are more conducive to droplet formation and wider spread, and that being outdoors rather than in confined and noisy indoor locations leads to less spread. This can all lead to better, faster and more tolerable approaches to either future pandemics or to a recurrence of SARS-CoV-2.

SOURCE

https://www.sciencemag.org/news/2020/05/why-do-some-covid-19-patients-infect-many-others-whereas-most-don-t-spread-virus-all

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From AAAS Science News on COVID19: New CRISPR based diagnostic may shorten testing time to 5 minutes

Reporter: Stephen J. Williams, Ph.D.

 

 

 

 

 

 

 

 

 

A new CRISPR-based diagnostic could shorten wait times for coronavirus tests.

 

 

New test detects coronavirus in just 5 minutes

By Robert F. ServiceOct. 8, 2020 , 3:45 PM

Science’s COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

 

Researchers have used CRISPR gene-editing technology to come up with a test that detects the pandemic coronavirus in just 5 minutes. The diagnostic doesn’t require expensive lab equipment to run and could potentially be deployed at doctor’s offices, schools, and office buildings.

“It looks like they have a really rock-solid test,” says Max Wilson, a molecular biologist at the University of California (UC), Santa Barbara. “It’s really quite elegant.”

CRISPR diagnostics are just one way researchers are trying to speed coronavirus testing. The new test is the fastest CRISPR-based diagnostic yet. In May, for example, two teams reported creating CRISPR-based coronavirus tests that could detect the virus in about an hour, much faster than the 24 hours needed for conventional coronavirus diagnostic tests.CRISPR tests work by identifying a sequence of RNA—about 20 RNA bases long—that is unique to SARS-CoV-2. They do so by creating a “guide” RNA that is complementary to the target RNA sequence and, thus, will bind to it in solution. When the guide binds to its target, the CRISPR tool’s Cas13 “scissors” enzyme turns on and cuts apart any nearby single-stranded RNA. These cuts release a separately introduced fluorescent particle in the test solution. When the sample is then hit with a burst of laser light, the released fluorescent particles light up, signaling the presence of the virus. These initial CRISPR tests, however, required researchers to first amplify any potential viral RNA before running it through the diagnostic to increase their odds of spotting a signal. That added complexity, cost, and time, and put a strain on scarce chemical reagents. Now, researchers led by Jennifer Doudna, who won a share of this year’s Nobel Prize in Chemistry yesterday for her co-discovery of CRISPR, report creating a novel CRISPR diagnostic that doesn’t amplify coronavirus RNA. Instead, Doudna and her colleagues spent months testing hundreds of guide RNAs to find multiple guides that work in tandem to increase the sensitivity of the test.

In a new preprint, the researchers report that with a single guide RNA, they could detect as few as 100,000 viruses per microliter of solution. And if they add a second guide RNA, they can detect as few as 100 viruses per microliter.

That’s still not as good as the conventional coronavirus diagnostic setup, which uses expensive lab-based machines to track the virus down to one virus per microliter, says Melanie Ott, a virologist at UC San Francisco who helped lead the project with Doudna. However, she says, the new setup was able to accurately identify a batch of five positive clinical samples with perfect accuracy in just 5 minutes per test, whereas the standard test can take 1 day or more to return results.

The new test has another key advantage, Wilson says: quantifying a sample’s amount of virus. When standard coronavirus tests amplify the virus’ genetic material in order to detect it, this changes the amount of genetic material present—and thus wipes out any chance of precisely quantifying just how much virus is in the sample.

By contrast, Ott’s and Doudna’s team found that the strength of the fluorescent signal was proportional to the amount of virus in their sample. That revealed not just whether a sample was positive, but also how much virus a patient had. That information can help doctors tailor treatment decisions to each patient’s condition, Wilson says.

Doudna and Ott say they and their colleagues are now working to validate their test setup and are looking into how to commercialize it.

Posted in:

doi:10.1126/science.abf1752

Robert F. Service

Bob is a news reporter for Science in Portland, Oregon, covering chemistry, materials science, and energy stories.

 

Source: https://www.sciencemag.org/news/2020/10/new-test-detects-coronavirus-just-5-minutes

Other articles on CRISPR and COVID19 can be found on our Coronavirus Portal and the following articles:

The Nobel Prize in Chemistry 2020: Emmanuelle Charpentier & Jennifer A. Doudna
The University of California has a proud legacy of winning Nobel Prizes, 68 faculty and staff have been awarded 69 Nobel Prizes.
Toaster Sized Machine Detects COVID-19
Study with important implications when considering widespread serological testing, Ab protection against re-infection with SARS-CoV-2 and the durability of vaccine protection

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Miniproteins against the COVID-19 Spike protein may be therapeutic

Reporter: Stephen J. Williams, PhD

Computer-designed proteins may protect against coronavirus

At a Glance

  • Researchers designed “miniproteins” that bound tightly to the SARS-CoV-2 spike protein and prevented the virus from infecting human cells in the lab.
  • More research is underway to test the most promising of the antiviral proteins.

 

 

 

 

 

 

 

An artist’s conception of computer-designed miniproteins (white) binding coronavirus spikes. UW Institute for Protein Design

The surface of SARS-CoV-2, the virus that causes COVID-19, is covered with spike proteins. These proteins latch onto human cells, allowing the virus to enter and infect them. The spike binds to ACE2 receptors on the cell surface. It then undergoes a structural change that allows it to fuse with the cell. Once inside, the virus can copy itself and produce more viruses.

Blocking entry of SARS-CoV-2 into human cells can prevent infection. Researchers are testing monoclonal antibody therapies that bind to the spike protein and neutralize the virus. But these antibodies, which are derived from immune system molecules, are large and not ideal for delivery through the nose. They’re also often not stable for long periods and usually require refrigeration.

Researchers led by Dr. David Baker of the University of Washington set out to design synthetic “miniproteins” that bind tightly to the coronavirus spike protein. Their study was funded in part by NIH’s National Institute of General Medical Sciences (NIGMS) and National Institute of Allergy and Infectious Diseases (NIAID). Findings appeared in Science on September 9, 2020.

The team used two strategies to create the antiviral miniproteins. First, they incorporated a segment of the ACE2 receptor into the small proteins. The researchers used a protein design tool they developed called Rosetta blueprint builder. This technology allowed them to custom build proteins and predict how they would bind to the receptor.

The second approach was to design miniproteins from scratch, which allowed for a greater range of possibilities. Using a large library of miniproteins, they identified designs that could potentially bind within a key part of the coronavirus spike called the receptor binding domain (RBD). In total, the team produced more than 100,000 miniproteins.

Next, the researchers tested how well the miniproteins bound to the RBD. The most promising candidates then underwent further testing and tweaking to improve binding.

Using cryo-electron microscopy, the team was able to build detailed pictures of how two of the miniproteins bound to the spike protein. The binding closely matched the predictions of the computational models.

Finally, the researchers tested whether three of the miniproteins could neutralize SARS-CoV-2. All protected lab-grown human cells from infection. Candidates LCB1 and LCB3 showed potent neutralizing ability. These were among the designs created from the miniprotein library. Tests suggested that these miniproteins may be more potent than the most effective antibody treatments reported to date.

“Although extensive clinical testing is still needed, we believe the best of these computer-generated antivirals are quite promising,” says Dr. Longxing Cao, the study’s first author. “They appear to block SARS-CoV-2 infection at least as well as monoclonal antibodies but are much easier to produce and far more stable, potentially eliminating the need for refrigeration.”

Notably, this study demonstrates the potential of computational models to quickly respond to future viral threats. With further development, researchers may be able to generate neutralizing designs within weeks of obtaining the genome of a new virus.

—by Erin Bryant

Source: https://www.nih.gov/news-events/nih-research-matters/computer-designed-proteins-may-protect-against-coronavirus

Original article in Science

De novo design of picomolar SARS-CoV-2 miniprotein inhibitors

 

  1. View ORCID ProfileLongxing Cao1,2
  2. Inna Goreshnik1,2
  3. View ORCID ProfileBrian Coventry1,2,3
  4. View ORCID ProfileJames Brett Case4
  5. View ORCID ProfileLauren Miller1,2
  6. Lisa Kozodoy1,2
  7. Rita E. Chen4,5
  8. View ORCID ProfileLauren Carter1,2
  9. View ORCID ProfileAlexandra C. Walls1
  10. Young-Jun Park1
  11. View ORCID ProfileEva-Maria Strauch6
  12. View ORCID ProfileLance Stewart1,2
  13. View ORCID ProfileMichael S. Diamond4,7
  14. View ORCID ProfileDavid Veesler1
  15. View ORCID ProfileDavid Baker1,2,8,*

See all authors and affiliations

Science  09 Sep 2020:
eabd9909
DOI: 10.1126/science.abd9909

Abstract

Targeting the interaction between the SARS-CoV-2 Spike protein and the human ACE2 receptor is a promising therapeutic strategy. We designed inhibitors using two de novo design approaches. Computer generated scaffolds were either built around an ACE2 helix that interacts with the Spike receptor binding domain (RBD), or docked against the RBD to identify new binding modes, and their amino acid sequences designed to optimize target binding, folding and stability. Ten designs bound the RBD with affinities ranging from 100pM to 10nM, and blocked ARS-CoV-2 infection of Vero E6 cells with IC 50 values between 24 pM and 35 nM; The most potent, with new binding modes, are 56 and 64 residue proteins (IC 50 ~ 0.16 ng/ml). Cryo-electron microscopy structures of these minibinders in complex with the SARS-CoV-2 spike ectodomain trimer with all three RBDs bound are nearly identical to the computational models. These hyperstable minibinders provide starting points for SARS-CoV-2 therapeutics.

 

RESEARCH ARTICLE

De novo design of picomolar SARS-CoV-2 miniprotein inhibitors

  1. View ORCID ProfileLongxing Cao1,2
  2. Inna Goreshnik1,2
  3. View ORCID ProfileBrian Coventry1,2,3
  4. View ORCID ProfileJames Brett Case4
  5. View ORCID ProfileLauren Miller1,2
  6. Lisa Kozodoy1,2
  7. Rita E. Chen4,5
  8. View ORCID ProfileLauren Carter1,2
  9. View ORCID ProfileAlexandra C. Walls1
  10. Young-Jun Park1
  11. View ORCID ProfileEva-Maria Strauch6
  12. View ORCID ProfileLance Stewart1,2
  13. View ORCID ProfileMichael S. Diamond4,7
  14. View ORCID ProfileDavid Veesler1
  15. View ORCID ProfileDavid Baker1,2,8,*

See all authors and affiliations

Science  09 Sep 2020:
eabd9909
DOI: 10.1126/science.abd9909

Abstract

Targeting the interaction between the SARS-CoV-2 Spike protein and the human ACE2 receptor is a promising therapeutic strategy. We designed inhibitors using two de novo design approaches. Computer generated scaffolds were either built around an ACE2 helix that interacts with the Spike receptor binding domain (RBD), or docked against the RBD to identify new binding modes, and their amino acid sequences designed to optimize target binding, folding and stability. Ten designs bound the RBD with affinities ranging from 100pM to 10nM, and blocked ARS-CoV-2 infection of Vero E6 cells with IC 50 values between 24 pM and 35 nM; The most potent, with new binding modes, are 56 and 64 residue proteins (IC 50 ~ 0.16 ng/ml). Cryo-electron microscopy structures of these minibinders in complex with the SARS-CoV-2 spike ectodomain trimer with all three RBDs bound are nearly identical to the computational models. These hyperstable minibinders provide starting points for SARS-CoV-2 therapeutics.

 

SARS-CoV-2 infection generally begins in the nasal cavity, with virus replicating there for several days before spreading to the lower respiratory tract (1). Delivery of a high concentration of a viral inhibitor into the nose and into the respiratory system generally might therefore provide prophylactic protection and/or therapeutic benefit for treatment of early infection, and could be particularly useful for healthcare workers and others coming into frequent contact with infected individuals. A number of monoclonal antibodies are in development as systemic treatments for COVID-19 (26), but these proteins are not ideal for intranasal delivery as antibodies are large and often not extremely stable molecules and the density of binding sites is low (two per 150 KDa. antibody); antibody-dependent disease enhancement (79) is also a potential issue. High-affinity Spike protein binders that block the interaction with the human cellular receptor angiotensin-converting enzyme 2 (ACE2) (10) with enhanced stability and smaller sizes to maximize the density of inhibitory domains could have advantages over antibodies for direct delivery into the respiratory system through intranasal administration, nebulization or dry powder aerosol. We found previously that intranasal delivery of small proteins designed to bind tightly to the influenza hemagglutinin can provide both prophylactic and therapeutic protection in rodent models of lethal influenza infection (11).

Design strategy

We set out to design high-affinity protein minibinders to the SARS-CoV-2 Spike RBD that compete with ACE2 binding. We explored two strategies: first we incorporated the alpha-helix from ACE2 which makes the majority of the interactions with the RBD into small designed proteins that make additional interactions with the RBD to attain higher affinity (Fig. 1A). Second, we designed binders completely from scratch without relying on known RBD-binding interactions (Fig. 1B). An advantage of the second approach is that the range of possibilities for design is much larger, and so potentially a greater diversity of high-affinity binding modes can be identified. For the first approach, we used the Rosetta blueprint builder to generate miniproteins which incorporate the ACE2 helix (human ACE2 residues 23 to 46). For the second approach, we used RIF docking (12) and design using large miniprotein libraries (11) to generate binders to distinct regions of the RBD surface surrounding the ACE2 binding site (Fig. 1 and fig. S1).

 

 

 

 

 

 

 

 

 

 

 

Download high-res image

Fig. 1 Overview of the computational design approaches.

(A) Design of helical proteins incorporating ACE2 helix. (B) Large scale de novo design of small helical scaffolds (top) followed by rotamer interaction field (RIF) docking to identify shape and chemically complementary binding modes.

For full article please  go to Science at https://science.sciencemag.org/content/early/2020/09/08/science.abd9909

 

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The Impact of COVID-19 on the Human Heart

Reporters: Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

The Voice of Dr. Pearlman:

 

 

Editorial

September 22/29, 2020

The COVID-19 Pandemic and the JAMA Network

In 13 Viewpoints in this issue,214 JAMA Network editors reflect on the clinical, public health, operational, and workforce issues related to COVID-19 in each of their specialties. Questions and concerns they identify in their clinical communities include the following:

  • Benefits and harms of treatments and identifying mortality risk markers beyond age and comorbidities

  • Cardiovascular consequences of COVID-19 infection, including risks to those with comorbid hypertension and risks for myocardial injury

  • Risk for direct central nervous system invasion and COVID-19 encephalitis and for long-term neuropsychiatric manifestations in a post–COVID-19 syndrome

  • Risks related to SARS-CoV-2 infection for patients with compromised immunity, such as those receiving treatment for cancer

  • Challenges unique to patients with acute kidney injury and chronic kidney disease

  • Risks of viral transmission from aerosol-generating procedures, including most minimally invasive surgeries, and the need for eye protection as well as personal protective equipment as part of universal precautions

  • The prevalence and pathophysiology of skin findings in patients with COVID-19, determining if they are primary or secondary cutaneous manifestations of infection, and how best to manage them

  • The prevalence and significance of eye findings in patients with COVID-19 and the risk of transmission and infection through ocular surfaces

  • The role of anticoagulation for managing the endotheliopathy and coagulopathy characteristic of the infection in some patients

  • Developmental effects on children of the loss of family routines, finances, older loved ones, school and education, and social-based activities and milestone events

  • Effects of the pandemic, mitigation efforts, and economic downturn on the mental health of patients and frontline clinicians

  • Seasonality of transmission as the pandemic enters its third season

  • How to implement reliable seroprevalence surveys to document progression of the pandemic and effects of public health measures

  • Effects of the pandemic on access to care and the rise of telehealth

  • Consequences of COVID-19 for clinical capabilities, such as workforce availability in several specialties, delays in performing procedures and operations, and implications for medical education and resident recruitment.

Additional important questions that require careful observation and research include

  • Randomized evaluations of treatment: what is effective and safe, and what timing of which drug will reduce morbidity and mortality? Will a combination of therapies be more effective than any single drug?
  • Randomized evaluations of preventive interventions, including convalescent plasma, monoclonal antibodies, and vaccines. Which are effective and safe enough to prevent COVID-19 at a population level?
  • How can COVID-19 vaccines and therapeutics be distributed and paid for in ways that are fair and equitable?
  • Is immunity complete or partial, permanent or temporary, what is its mechanism, and how best is it measured? Can the virus mutate around host defenses?
  • How important are preadolescent children to the spread of infection to older family members and adult communities, and what are the implications for parent, caregiver, and teacher personal risk and disease transmission?
  • Is SARS-CoV-2 like influenza (continually circulating without or with seasonality), measles (transmissible but containable beneath threshold limits), or smallpox and polio (eradicable, or nearly so)?
  • Has the pandemic fundamentally altered the way health care is financed and delivered? By shining a spotlight on health inequities, can the pandemic motivate changes in health care finance, organization, and delivery to reduce those inequities?
  • Cardiology and COVID-19

Cardiology and COVID-19 – Original Article

Bonow  RO, O’Gara  PT, Yancy  CW.  Cardiology and COVID-19.   JAMA. Published online September 22, 2020. doi:10.1001/jama.2020.15088
Article Google Scholar

The initial reports on the epidemiology of coronavirus disease 2019 (COVID-19) emanating from Wuhan, China, offered an ominous forewarning of the risks of severe complications in elderly patients and those with underlying cardiovascular disease, including the development of acute respiratory distress syndrome, cardiogenic shock, thromboembolic events, and death. These observations have been confirmed subsequently in numerous reports from around the globe, including studies from Europe and the US. The mechanisms responsible for this vulnerability have not been fully elucidated, but there are several possibilities. Some of these adverse consequences could reflect the basic fragility of older individuals with chronic conditions subjected to the stress of severe pneumonia similar to influenza infections. In addition, development of type 2 myocardial infarction related to increased myocardial oxygen demand in the setting of hypoxia may be a predominant concern, and among patients with chronic coronary artery disease, an episode of acute systemic inflammation might also contribute to plaque instability, thus precipitating acute coronary syndromes, as has also been reported during influenza outbreaks.

However, in the brief timeline of the current pandemic, numerous publications highlighting the constellation of observed cardiovascular consequences have emphasized certain distinctions that appear unique to COVID-19.1 Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gains entry via the upper respiratory tract, its affinity and selective binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which is abundant in the endothelium of arteries and veins as well as in the respiratory tract epithelium, create a scenario in which COVID-19 is as much a vascular infection as it is a respiratory infection with the potential for serious vascular-related complications. This may explain why hypertension is one of the cardiovascular conditions associated with adverse outcomes. In the early stages of the pandemic, the involvement of the ACE2 receptor as the target for viral entry into cells created concerns regarding the initiation or continuation of treatment with ACE inhibitors and angiotensin receptor antagonists in patients with hypertension, left ventricular dysfunction, or other cardiac conditions. Subsequently, many studies have shown that these drugs do not increase susceptibility to infection or increase disease severity in those who contract the disease,2 thus supporting recommendations from academic societies that these drugs should not be discontinued in patients who develop COVID-19 infections.

Thrombosis, arterial or venous, is a hallmark of severe COVID-19 infections, related both to vascular injury and the prothrombotic cytokines released during the intense systemic inflammatory and immune responses.3 This sets the stage for serious thrombotic complications including acute coronary syndromes, ischemic strokes, pulmonary embolism, and ischemic damage to multiple other organ systems. Such events can complicate the course of any patient with COVID-19 but would be particularly devasting to individuals with preexisting cardiovascular disease.

Another unique aspect of COVID-19 infections that is not encountered by patients with influenza is myocardial injury, manifested by elevated levels of circulating troponin, creatinine kinase-MB, and myoglobin. Hospitalized patients with severe COVID-19 infections and consequent evidence of myocardial injury have a high risk of in-hospital mortality.4 Troponin elevations are most concerning, and when accompanied by elevations of brain natriuretic peptide, the risk is further accentuated. Although myocardial injury could reflect a COVID-19–related acute coronary event, most patients with troponin elevations who undergo angiography do not have epicardial coronary artery obstruction. Rather, those with myocardial injury have a high incidence of acute respiratory distress syndrome, elevation of D-dimer levels, and markedly elevated inflammatory biomarkers such as C-reactive protein and procalcitonin, suggesting that the combination of hypoxia, microvascular thrombosis, and systemic inflammation contributes to myocardial injury. Myocarditis is a candidate explanation for myocardial injury but has been difficult to confirm consistently. However, features of myocarditis have been reported in case reports5 based on clinical presentation and results of noninvasive imaging, but thus far confirmation of myocarditis based on myocardial biopsy or autopsy examinations has been a rare finding.6 Instead, myocardial tissue samples more typically show vascular or perivascular inflammation (endothelialitis) without leukocytic infiltration or myocyte damage.

There remain important unknowns regarding the intermediate and long-term sequelae of COVID-19 infection among hospital survivors. In an autopsy series of patients who died from confirmed COVID-19 without clinical or histological evidence of fulminant myocarditis,7 viral RNA was identified in myocardial tissue in 24 of 39 cases, with viral load of more than 1000 copies/μg of RNA in 16 cases. A cytokine response panel demonstrated upregulation of 6 proinflammatory genes (tumor necrosis factor, interferon γ, CCL4, and interleukin 6, 8, and 18) in the 16 myocardial samples with the high viral RNA levels.

Whether a subclinical viral load and associated cytokine response such as this in survivors of COVID-19 could translate into subsequent myocardial dysfunction and clinical heart failure require further investigation. However, the results of a recent biomarker and cardiac magnetic resonance (CMR) imaging study provide evidence to support this concern.6 Among 100 patients who were studied by CMR after recovery from confirmed COVID-19 infection, of whom 67 did not require hospitalization during the acute phase, left ventricular volume was greater and ejection fraction was lower than that of a control group. Furthermore, 78 patients had abnormal myocardial tissue characterization by CMR, with elevated T1 and T2 signals and myocardial hyperenhancement consistent with myocardial edema and inflammation, and 71 patients had elevated levels of high-sensitivity troponin T. Three patients with the most severe CMR abnormalities underwent myocardial biopsy, with evidence of active lymphocytic infiltration.6 It is noteworthy that all 100 patients in this series had negative COVID-19 test results at the time of CMR study (median, 71 days; interquartile range [IQR], 64-92 days after acute infection). The results of these relatively small series should be interpreted cautiously until confirmed by larger series with longer follow-up and with confirmed clinical outcomes. But the findings do underscore the uncertainty regarding the long-term cardiovascular consequences of COVID-19 in patients who have ostensibly recovered. Of note, a randomized clinical trial of anticoagulation to reduce the risk of thrombotic complications in the posthospital phase of COVID-19 infection is under development through the National Institutes of Health’s set of ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines) initiatives.

In addition, the indirect effects of COVID-19 have become a major concern. Multiple observations during the COVID-19 pandemic confirm a sudden and inexplicable decline in rates of hospital admissions for ST–segment elevation myocardial infarction and other acute coronary syndromes beginning in March and April 2020. This has been a universal experience, with similar findings reported from multiple countries around the world in single-center observations, multicenter registries, and national databases. A concerning increase in out-of-hospital cardiac arrests has also been reported.8 These data suggest that COVID-19 has influenced health care–seeking behavior resulting in fewer presentations of acute coronary syndromes in emergency departments and more out-of-hospital events. Failure to seek appropriate emergency cardiac care could contribute to the observations of increased number of deaths and cardiac arrests, more than the anticipated average during this period8,9 with worse outcomes among those who ultimately do seek care.10 Recent data suggest that admission rates for myocardial infarction may be returning to baseline,10 but outcomes will improve only if patients seek care promptly and hospital systems are not overwhelmed by COVID-19 surges.

Given the ongoing activity of COVID-19, very clear messaging to the public and patients should include the following: heed the warning signs of heart attack, act promptly to initiate emergency medical services, and seek immediate care in hospitals, which have taken every step needed to be safe places. And especially, the messaging should continuously underscore the most important considerations that have been extant since this crisis began—wear a mask and practice physical distancing. In the meantime, the generation of rigorous evidence to inform best practices for diagnosis and management of COVID-19–related cardiovascular disease is a global imperative.

Corresponding Author: Robert O. Bonow, MD, MS, Division of Cardiology, Northwestern University Feinberg School of Medicine, 676 N St Clair St, Ste 600, Chicago, IL 60611 (r-bonow@northwestern.edu)

SOURCE

https://jamanetwork.com/journals/jama/fullarticle/2770858

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