Archive for the ‘COVID-19’ Category

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

Posted in coronavirus, Coronavirus Gene Expression, COVID-19, COVID-19, Drug Development Process, Genetics & Innovations in Treatment, Genetics & Pharmaceutical, Genome Biology, Image Processing/Computing, Infectious Disease Immunodiagnostics, Mechanisms of infection by SARS-CoV-2, Medical Imaging Technology, Mutagenesis, Population Health Management, Proteins, SARS-CoV-2, SARS-CoV-2 circulating variants , SARS-CoV-2 Viral Variants, Uncategorized, Vaccinology, Variation in human protein-coding regions, virology, Virology - Vector-borne DIsease, Virtual Drug Molecule Screening targeting SAR-CoV-2 proteins, tagged ACE2 receptor, Antibody, Boston Children's Hospital, cryo-electron microscopy, D614G mutation, genetic code, SARS-CoV-2 Entry Factors, spike protein, vaccine development on April 10, 2021| Leave a Comment »

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

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

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

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

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

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

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

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

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

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

The work

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

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

IMAGE SOURCE: Zhang J, et al., Science

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

Forthcoming directions by Bing Chen and Team

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

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

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

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

Main Source:

Abstract

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

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

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

COVID-19-vaccine rollout risks and challenges

Reporter : Irina Robu, PhD

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

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

Reporter: Aviva Lev-Ari, PhD, RN

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

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

Reporter: Aviva Lev-Ari, PhD, RN

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

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

Reporter: Aviva Lev-Ari, PhD, RN

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

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

Reporter : Irina Robu, PhD

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

Miniproteins against the COVID-19 Spike protein may be therapeutic

Reporter: Stephen J. Williams, PhD

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

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

Posted in COVID-19, COVID-19 effects on Human Heart, Economic Impact of Coronavirus Pandemic, Evolution of Biology Through Culture, Population Health Management, Population Health Management, Genetics & Pharmaceutical, Seasonality & Environmental Factors in Resurgence, T-cell response to SARS-CoV-2 infection, Treatment Protocols for COVID-19, Vaccinology, Virus Infective Acute Respiratory Syndrome: SARS-CoV on March 30, 2021| Leave a Comment »

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

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 4/13/2021

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

FREE

Andrea M. Lerner, MD

Daphne A. Robinson, PhD

Linda Yang, PhD

, … View all authors

Author, Article and Disclosure Information

https://doi.org/10.7326/M21-1043

Abstract

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

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

Reported symptoms are wide-ranging and may involve nearly all organ systems, with fatigue, dyspnea, cognitive dysfunction, anxiety, and depression often described (2–5). Although abnormalities in imaging studies and functional testing have been reported, the long-term clinical significance of some of these findings is not yet clear (3, 6, 7). Postacute manifestations of COVID-19 have been seen in persons of all demographic groups and include reports of multisystem inflammatory syndrome in children (8, 9). Although the epidemiology of the diverse manifestations of postacute COVID-19 is not yet known, the expansive global burden of SARS-CoV-2 infection suggests that the potential public health effects of postacute COVID-19 are significant if even a small proportion of persons with SARS-CoV-2 infection have prolonged recovery or do not return to their baseline health.

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

SOURCE

https://www.acpjournals.org/doi/10.7326/M21-1043

UPDATED on 4/7/2021

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

Sarah Edmonds

April 07, 2021

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

START QUOTE

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

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

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

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

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

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

High Rate of Neurologic, Psychiatric Disorders

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

SOURCE

https://www.medscape.com/viewarticle/948882?src=mkm_covid_update_210407_MSCPEDIT&uac=93761AJ&impID=3298205&faf=1

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

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

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

Neural basis of Emotion

Desire for Social Interaction

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

START QUOTE

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

START QUOTE

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

SOURCE

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

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

https://www.wired.com/story/weird-science-of-loneliness-brains/?bxid=5be9cb353f92a40469de971e&cndid=22119822&esrc=bounceX&source=EDT_WIR_NEWSLETTER_0_DAILY_ZZ&utm_brand=wired&utm_campaign=aud-dev&utm_mailing=WIR_Daily_033021&utm_medium=email&utm_source=nl&utm_term=list1_p1

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T cells recognize recent SARS-CoV-2 variants

Posted in Coronavirus Gene Expression, COVID-19, Immune-Mediation (independent immunopathology: lung and reticuloendothelial system), Mechanisms of infection by SARS-CoV-2, Population Health Management, Genetics & Pharmaceutical, SARS-CoV-2, SARS-CoV-2 circulating variants , T-cell response to SARS-CoV-2 infection, Virtual Drug Molecule Screening targeting SAR-CoV-2 proteins, Virus Infective Acute Respiratory Syndrome: SARS-CoV, tagged CD8+ T cell, epitopes, mutation, t-lymphocytes on March 30, 2021| Leave a Comment »

T cells recognize recent SARS-CoV-2 variants

Reporter: Aviva Lev-Ari, PhD, RN

CD8+ T cell responses in COVID-19 convalescent individuals target conserved epitopes from multiple prominent SARS-CoV-2 circulating variants

Andrew D Redd, Alessandra Nardin, Hassen Kared, Evan M Bloch, Andrew Pekosz, Oliver Laeyendecker, Brian Abel, Michael Fehlings, Thomas C Quinn, Aaron A R TobianOpen Forum Infectious Diseases, ofab143, https://doi.org/10.1093/ofid/ofab143Published: 30 March 2021 Article history

Abstract

This study examined whether CD8+ T-cell responses from COVID-19 convalescent individuals (n=30) potentially maintain recognition of the major SARS-CoV-2 variants (n=45 mutations assessed). Only one mutation found in B.1.351-Spike overlapped with a previously identified epitope (1/52), suggesting that virtually all anti-SARS-CoV-2 CD8+ T-cell responses should recognize these newly described variants.

Key words:

CD8+ T cell, SARS-CoV-2, COVID-19, Convalescent patients

Topic:

SOURCE

https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab143/6189113

Original paper:

Andrew D Redd, Alessandra Nardin, Hassen Kared, Evan M Bloch, Andrew Pekosz, Oliver Laeyendecker, Brian Abel, Michael Fehlings, Thomas C Quinn, Aaron A R Tobian, CD8+ T cell responses in COVID-19 convalescent individuals target conserved epitopes from multiple prominent SARS-CoV-2 circulating variants, Open Forum Infectious Diseases, 2021;, ofab143, https://doi.org/10.1093/ofid/ofab143

Tuesday, March 30, 2021

T cells recognize recent SARS-CoV-2 variants

Healthy Human T Cell Scanning electron micrograph of a human T lymphocyte (also called a T cell) from the immune system of a healthy donor. NIAID

What

When variants of SARS-CoV-2 (the virus that causes COVID-19) emerged in late 2020, concern arose that they might elude protective immune responses generated by prior infection or vaccination, potentially making re-infection more likely or vaccination less effective. To investigate this possibility, researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and colleagues analyzed blood cell samples from 30 people who had contracted and recovered from COVID-19 prior to the emergence of virus variants. They found that one key player in the immune response to SARS-CoV-2—the CD8+ T cell—remained active against the virus.

The research team was led by NIAID’s Andrew Redd, Ph.D., and included scientists from Johns Hopkins University School of Medicine, Johns Hopkins Bloomberg School of Public Health and the Immunomics-focused company, ImmunoScape.

The investigators asked whether CD8+ T cells in the blood of recovered COVID-19 patients, infected with the initial virus, could still recognize three SARS-CoV-2 variants: B.1.1.7, which was first detected in the United Kingdom; B.1.351, originally found in the Republic of South Africa; and B.1.1.248, first seen in Brazil. Each variant has mutations throughout the virus, and, in particular, in the region of the virus’ spike protein that it uses to attach to and enter cells. Mutations in this spike protein region could make it less recognizable to T cells and neutralizing antibodies, which are made by the immune system’s B cells following infection or vaccination.

Although details about the exact levels and composition of antibody and T-cell responses needed to achieve immunity to SARS-CoV-2 are still unknown, scientists assume that strong and broad responses from both antibodies and T cells are required to mount an effective immune response. CD8+ T cells limit infection by recognizing parts of the virus protein presented on the surface of infected cells and killing those cells.

In their study of recovered COVID-19 patients, the researchers determined that SARS-CoV-2-specific CD8+ T-cell responses remained largely intact and could recognize virtually all mutations in the variants studied. While larger studies are needed, the researchers note that their findings suggest that the T cell response in convalescent individuals, and most likely in vaccinees, are largely not affected by the mutations found in these three variants, and should offer protection against emerging variants.

Optimal immunity to SARS-Cov-2 likely requires strong multivalent T-cell responses in addition to neutralizing antibodies and other responses to protect against current SARS-CoV-2 strains and emerging variants, the authors indicate. They stress the importance of monitoring the breadth, magnitude and durability of the anti-SARS-CoV-2 T-cell responses in recovered and vaccinated individuals as part of any assessment to determine if booster vaccinations are needed.

SOURCE

https://www.nih.gov/news-events/news-releases/t-cells-recognize-recent-sars-cov-2-variants

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COVID-related financial losses at Mass General Brigham

Posted in Accountable Care Organizations, COVID-19, Economic Impact of Coronavirus Pandemic, Health Care System by Country, Health Economics and Outcomes Research, Health Law & Patient Safety, Healthcare costs and reimbursement, HealthCare IT, Healthcare Reform, Hospital-based Medical Innovations, Population Health Management, Population Health Management, Genetics & Pharmaceutical, SARS-CoV-2, Seasonality & Environmental Factors in Resurgence, Serology tests for coronavirus antibodies, Technology Capital Expenses, Treatment Protocols for COVID-19, Uninsured and Underinsured, United States, Virus Infective Acute Respiratory Syndrome: SARS-CoV on March 28, 2021| Leave a Comment »

COVID-related financial losses at Mass General Brigham

Reporter: Aviva Lev-Ari, PhD, RN

Based on

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

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

START QUOTE

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

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

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

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

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

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

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

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

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

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

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

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

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

END QUOTE

SOURCE

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

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

Reporter: Aviva Lev-Ari, PhD, RN

BASED on

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

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

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

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

START QUOTE

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Posted in COVID-19, Mechanisms of infection by SARS-CoV-2, Population Health Management, Population Health Management, Genetics & Pharmaceutical, SARS-CoV-2, Virtual Drug Molecule Screening targeting SAR-CoV-2 proteins, Virus Infective Acute Respiratory Syndrome: SARS-CoV on March 27, 2021| Leave a Comment »

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

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 4/1/2021

Coronavirus: More work needed to rule out China lab leak theory says WHO

START QUOTE

The head of the World Health Organization (WHO) has said further investigation is needed to conclusively rule out that Covid-19 emerged from a laboratory in China.

Tedros Adhanom Ghebreyesus said that although a lab leak was the least likely cause, more research was needed.

The US and other countries have criticised China for failing to provide the WHO with sufficient data.

Beijing has always dismissed the allegations of a virus leak.

A report by WHO and Chinese experts released on Tuesday, said the lab leak explanation was highly unlikely and the virus had probably jumped from bats to humans via another intermediary animal.

China has yet to respond to the WHO’s latest statement.

‘All hypothesis on the table’

However the theory that the virus might have come from a leak in a laboratory “requires further investigation, potential with additional missions involving specialist experts,” Dr Tedros said on Tuesday.

“Let me say clearly that as far as WHO is concerned, all hypothesis remain on the table,” he added.

Five days that shaped the Wuhan outbreak

UK scientist defends WHO Wuhan fact-finding mission

The virus was first detected in Wuhan, in China’s Hubei province in late 2019. An international team of experts travelled to to the city in January to probe the origins of the virus.

The team investigated all possibilities, including one theory that the virus had originated at the Wuhan Institute of Virology. The institute is the world’s leading authority on the collection, storage and study of bat coronaviruses.

International criticism

In response to the WHO report, the US and 13 allies including South Korea, Australia and the UK voiced concern over the findings and urged China to provide “full access” to experts.

The statement said the mission to Wuhan was “significantly delayed and lacked access to complete, original data and samples”.

“Scientific missions like these should be able to do their work under conditions that produce independent and objective recommendations and findings.”

The group pledged to work together with the WHO.

Former US President Donald Trump was among those who supported the theory that the virus might have escaped from a lab.

WHO investigation team leader, Peter Ben Embarek said on Tuesday his team had felt under political pressure, including from outside China but said he was never pressed to remove anything from the team’s final report.

He also confirmed his team had found no evidence that any laboratories in Wuhan were involved in the outbreak.

MORE …

SOURCE

https://www.bbc.com/news/world-asia-china-56581246

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Ex-CDC Director Robert Redfield believes COVID-19 came from Wuhan lab

By Lia Eustachewich

March 26, 2021 | 10:03am | Updated

START QUOTE

The former director of the Centers for Disease Control and Prevention believes the virus that causes COVID-19 escaped from a lab in Wuhan, China, according to a new interview.

Robert Redfield told CNN on Friday that it was his “opinion” that SARS-CoV-2 — the new coronavirus responsible for killing 2.7 million people globally — did not evolve naturally.

“I’m of the point of view that I still think the most likely etiology of this pathology in Wuhan was from a laboratory — escaped,” said Redfield, who led the CDC during the height of the pandemic. “Other people don’t believe that. That’s fine. Science will eventually figure it out.”

Researchers believe the deadly and highly transmissible strain of coronavirus behind the global pandemic mutated from a virus that infects animals — namely, bats — to one that sickens humans.

But some believe the virus was somehow released from the Wuhan Institute of Virology — which is the only lab in China authorized to study the most dangerous known pathogens, according to Axios.

“It’s not unusual for respiratory pathogens that are being worked on in a laboratory to infect the laboratory worker. … That’s not implying any intentionality,” Redfield said. “It’s my opinion, right? But I am a virologist. I have spent my life in virology.

“I do not believe this somehow came from a bat to a human and at that moment in time, that the virus came to the human, became one of the most infectious viruses that we know in humanity for human-to-human transmission.”

Redfield said usually when a virus jumps from animals to humans, “it takes a while for it to figure out how to become more and more efficient in human-to-human transmission.”

SOURCE

https://nypost.com/2021/03/26/ex-cdc-director-believes-covid-19-came-from-wuhan-lab/?utm_campaign=SocialFlow&utm_source=NYPTwitter&utm_medium=SocialFlow

START QUOTE

What they’re saying: “I’m of the point of view that I still think the most likely etiology of this pathology in Wuhan was from a laboratory. Escaped. Other people don’t believe that. That’s fine. Science will eventually figure it out,” Redfield told CNN’s Sanjay Gupta.

“It’s not unusual for respiratory pathogens that are being worked on in a laboratory to infect the laboratory worker. … That’s not implying any intentionality. It’s my opinion, right? But I am a virologist. I have spent my life in virology,” he continued.
“I do not believe this somehow came from a bat to a human and at that moment in time that the virus came to the human, became one of the most infectious viruses that we know in humanity for human-to-human transmission.”

Between the lines: Lab accidents in the U.S. are not especially rare, as USA Today’s Alison Young noted in a recent opinion piece arguing why the Wuhan lab theory cannot be ruled out. The CDC itself experienced a possible contamination in a lab where it was making COVID-19 test kits early in the pandemic.

What to watch: The WHO team is expected to soon publish a 300-page final report on its investigation, after scrapping plans for an interim report amid mounting tensions between the U.S. and China.

SOURCE

https://www.axios.com/wuhan-lab-coronavirus-cdc-director-c599cf7b-9e30-4314-909b-a9bdac28ead6.html?utm_source=twitter&utm_medium=social&utm_campaign=editorial&utm_content=health-covid

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FDA emergency use authorization would bring the public a third vaccine for the novel coronavirus – J&J single vaccine – Authorized on 2/28/2021

Posted in COVID-19, Population Health Management, Genetics & Pharmaceutical, SARS-CoV-2, Vaccinology, Virus Infective Acute Respiratory Syndrome: SARS-CoV on March 1, 2021| Leave a Comment »

FDA emergency use authorization would bring the public a third vaccine for the novel coronavirus – J&J single vaccine – Authorized on 2/28/2021

Reporter: Aviva Lev-Ari, PhD, RN

J&J’s Covid-19 vaccine gets vote of confidence from FDA advisory panel

The committee voted 22-0 on the question of whether the benefits of Johnson & Johnson’s Covid-19 vaccine outweigh its risks. FDA emergency use authorization would bring the public a third vaccine for the novel coronavirus.

By FRANK VINLUAN

Post a comment / Feb 26, 2021 at 7:35 PM

The U.S. is one step closer to making available another Covid-19 vaccine after a panel of experts voted unanimously Friday to recommend emergency use authorization for a shot developed by Johnson & Johnson.

The independent panel, comprised of mostly physicians, voted 22-0 to support the vaccine with no one abstaining. These votes aren’t binding on the FDA, but the agency often follows the recommendations of its panels. A decision could come as early as this weekend. The two Covid vaccines currently cleared for emergency use received their authorizations the day after their respective advisory panel meetings.

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The Johnson & Johnson vaccine would offer an alternative to the ones currently available from the Pfizer and BioNtech alliance, and Moderna. Those messenger RNA vaccines must be distributed and stored at ultra-cold temperatures, then thawed before use. Those shots are given as two doses, weeks apart. The J&J vaccine can be kept at refrigerator temperatures. Another key difference is that the J&J jab requires a single shot. Together, those features will make the J&J vaccine easier to distribute to more people in more places through distribution channels that are already in place.

Panel members expressed support for the J&J vaccine, saying that the safety and efficacy data supported its authorization. But panelists also cautioned the public against picking vaccine favorites.

“It’s important that people do not think one vaccine is better than another,” said Cody Meissner, an infectious disease expert and professor of pediatrics at the Tufts University School of Medicine. “There is no preference for one vaccine over another and all vaccines work with what appears to be equal safety and equal efficacy as of this time.”

GUIDANCE DOCUMENT

Emergency Use Authorization for Vaccines to Prevent COVID-19 Guidance for Industry FEBRUARY 2021

Download the Final Guidance Document

Final

Docket Number:

FDA-2020-D-1137

Issued by:

Center for Biologics Evaluation and Research

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

FDA is issuing this guidance to provide sponsors of requests for Emergency Use Authorization (EUA) for COVID-19 vaccines with recommendations regarding the data and information needed to support the issuance of an EUA under section 564 of the FD&C Act (21 U.S.C. 360bbb-3) for an investigational vaccine to prevent COVID-19 for the duration of the COVID-19 public health emergency.

SOURCE

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/emergency-use-authorization-vaccines-prevent-covid-19

FDA Statement on Vaccines and Related Biological Products Advisory Committee Meeting

The following is attributed to Acting Commissioner Janet Woodcock, M.D. and Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research

NEWS PROVIDED BY

U.S. Food and Drug Administration

Feb 26, 2021, 18:50 ET

SILVER SPRING, Md., Feb. 26, 2021 /PRNewswire/ — Following today’s positive advisory committee meeting outcome regarding the Janssen Biotech Inc. COVID-19 Vaccine, the U.S. Food and Drug Administration has informed the sponsor that it will rapidly work toward finalization and issuance of an emergency use authorization. The agency has also notified our federal partners involved in vaccine allocation and distribution so they can execute their plans for timely vaccine distribution.

Additional Resources:

Media Contact: FDA Office of Media Affairs, 301-796-4540
Consumer Inquiries: Email or 888-INFO-FDA

SOURCE

https://www.prnewswire.com/news-releases/fda-statement-on-vaccines-and-related-biological-products-advisory-committee-meeting-301236757.html

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COVID-19-vaccine rollout risks and challenges

Posted in COVID-19, COVID-19, Population Health Management, Genetics & Pharmaceutical, tagged Coronavirus Vaccines, COVID-19, logistics, Quality Control, Raw materials on February 17, 2021| Leave a Comment »

COVID-19-vaccine rollout risks and challenges

Reporter : Irina Robu, PhD

BioNTech and Pfizer and Moderna COVID-19 vaccines received Emergency Use Authorization in January 2021 in Canada, European Union, United Kingdom and United States. However, in certain places COVID-19 has hit a few hindrances such as stockpiles have accumulated, deployment to vulnerable countries and at-risk groups has been slower than expected. Yet, experts can see the light at the end of the tunnel of the pandemic. In United States, hundred of organization take a vital role in vaccine deployment, adapting their operations to meet the demands for volume, speed and better technology. Tens of thousands of transporters, vaccine handlers, medical and pharmacy staff, and frontline workers have mandatory training on the specific characteristics of each manufacturer’s distinct vaccines.

The common operating model provides the details of end-to-end vaccine deployment. Possible areas of risk to the rapid delivery of COVID-19 vaccines in the United States include:

Raw-materials constraints in production scaling

Scaling access to material and boosting production levels can cause logistical, contractual and even diplomatic challenges, requiring new forms of collaboration. The top two US manufacturers, for example, can produce 280 million vials per year, capable of holding up to 2.8 billion doses.

Quality-assurance challenges in manufacturing

Generating yields to produce a new class of vaccines—such as those based on mRNA or viral vectors—at an unprecedented scale (1.8 billion to 2.3 billion doses by mid-2021), manufacturers have required massive volumes of inputs, a larger technical workforce.

Cold-chain logistics and storage-management challenges

Manufacturers and distributors are preparing to maintain cold-chain requirements for distribution and long-term storage of mRNA-based vaccines. Large amounts of dry ice may be needed at various locations before administration.

Increased labor requirements

Complex protocols for handling and preparing COVID-19 vaccines have the potential to strain labor capacities or divert workers from other critical roles.

Wastage at points of care

Errors in storing, preparing, or scheduling administration of doses at points of care will have significant consequences and proper on-site storage conditions are also of critical importance.

IT challenges

IT systems, including vaccine-tracking systems and immunization information systems will be vital for allocating, distributing, recording, and monitoring the deployment of vaccines.

There are several possible approaches to help mitigate each of the six risks discussed, each with practical steps for organization to take across the common operating model.

Building resilient raw-materials supplies

Resilience planning.Producers can partner with global suppliers of raw materials and ancillary-product manufacturers to create redundancies.
Collaboration between industry and government.Ongoing industry engagement with government is essential for ramping-up production and maintaining high levels of production.

Scaling manufacturing within quality guidelines

Scale manufacturing in new and existing facilities. Various digital and analytics tools can help expand capacity and scale more quickly.
Assure quality and yield in current facilities. By continuing to coordinate with regulators, manufacturers and authorities can certify that procedures and dosage quality meet both long-established and newly issued guidelines.
Establish predictable supplier plans. Each manufacturing stakeholder can follow a clearly defined plan and they can also conduct regular cross-functional risk reviews to ensure that quality.

Optimizing the cold chain

Build redundancy into distribution.Manufacturers, distributers should quickly identify points of failure and creating redundancies at each stage.
Leverage feedback loops.Reporting systems could be set up to capture supply-chain disruption events as soon as they happen, with data used to refine best practices and procedures and avoid further losses.
Use point-of-care stock management.Vaccine inventories can be redistributed to locations with greater demand. Strategies to avoid over stockpiling must confirm maintenance of the cold chain to prevent risks to the receiving administration site.

Addressing labor shortages

Use several types of point-of-care facilities.Rely on hospitals and primary-care locations for vaccine administration, in addition to retail pharmacies.
Streamline administration across sites.Deploying vaccines at larger, streamlined vaccination sites can be more efficient and improve patient safety, labor utilization, and speed of vaccination.

Reducing spoilage at points of care

Track and monitor spoilage at points of care.Manufacturers and distributors can collaborate to establish the means to identify and trace instances of spoilage. They can learn from experience and refine guidance, training, certification, and allocation to optimize utilization of doses.
Pace first-dose allocation.Allocation of first doses to populations and locations where the need is greatest and the confidence in the availability of second doses is high (such as healthcare professionals and vulnerable populations in nursing homes).
Prioritize second doses.Authorities can help ensure that the recommended two-dose course schedule for such vaccines as the Pfizer-BioNTech, Moderna, and AstraZeneca vaccines are duly completed.
Establish recipient commitment.Vaccine recipients could be asked to commit to second-dose appointments at their point of care before first-dose administration.
Manage certification.National and local government institutions can collaborate to ensure that vaccination certifications are withheld until recipients receive their second dose.

Meeting IT challenges

Balance IT upgrades and resilience.Stakeholders should identify IT systems that can be relied upon in the deployment of COVID-19 vaccines and assess their ability to perform at scale.
Share cyberthreat intelligence.COVID-19-vaccine stakeholders should agree upon common requirements and processes for generating and sharing threat intelligence.
Establish means of demonstrating immunity.Manufacturers and distributers can commission systems to track and verify that vaccine recipients have demonstrated immunity. if it will release them from travel limits and other pandemic-related restrictions.

Although not one organization is involved for managing vaccine deployment, but the risks can be fully address if organizations align on lead organization to build scenarios to test responses to emerging crises. The groups could align on lead organizations to manage issues while building scenarios to test responses to emerging crises. The benefits in managing each of these risks could be demonstrated with compelling metrics and communications. As COVID-19-vaccine rollouts commence, the steps mentioned above can be undertaken by manufactures, distributors and governments.

SOURCE

https://www.mckinsey.com/business-functions/risk/our-insights/the-risks-and-challenges-of-the-global-covid-19-vaccine-rollout?cid=other-eml-nsl-mip-mck&hlkid=19a51f848bee4d00806d2da81315f70d&hctky=2071733&hdpid=062f1841-f911-48f3-ab14-a9f92e30721f#

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Glycosylation and its Role in SARS-CoV-2 Viral Pathogenesis

Posted in Biomarkers: Inflammation, COVID-19, Glycosylation and its Role in SARS-CoV-2 Viral Pathogenesis, Mechanisms of infection by SARS-CoV-2, Population Health Management, Genetics & Pharmaceutical, SARS-CoV-2, SARS-CoV-2 Viral Variants on February 15, 2021| Leave a Comment »

Glycosylation and its Role in SARS-CoV-2 Viral Pathogenesis

Author: Meg Baker, PhD

N-Glycosylation and COVID19

Glycobiology

N-linked glycosylation (NLG) is a complex biosynthetic process that regulates proper folding of proteins through and intracellular transport of proteins to the secretory pathway. This co- and post-translational modification occurs by a series of enzymatic reactions, which results in the transfer of a core glycan from the lipid carrier to a protein substrate and the possibility for further remodeling of the glycan. The enzymes are located in the cytosolic and the luminal side of the ER membrane. The study of NLG and related effects of glycans is called glycobiology.

NLG takes place at sites specified in the protein sequence itself. N-linked oligosaccharides are attached via a GlcNAc linked to the side chain nitrogen of Asn found in the consensus sequence NXT/S (X ≠ P) known as the ‘glycosylation sequon’. Formation of a precursor branched carbohydrate chain, the lipid-linked oligosaccharide (LLO) structure, takes place in the endoplasmic reticulum. The LLO consists of a Glc3Man9GlcNAc2 molecule (three glucose, nine mannose, and two N-acetylglucosamine sugars) linked to a dolichol pyrophosphate. The enzyme oligosaccharyltransferase then moves it to an Asn in the polypeptide.

The removal of the three glucose sugars from the new N-linked glycan signals that the structure is ready for transport to the Golgi where mannose is removed yielding a carbohydrate chain containing five–nine mannose sugars. Further removal of mannose residues can lead to the core structure containing three mannose and two N-acetylglucosamine residues, which may then be elongated with a variety of different monosaccharides including galactose, N-acetylglucosamine (aka NAG or GlcNac), N-acetylgalactosamine, fucose, and sialic acid, many of which can also exist in sulfated form.

The enzymes involved in this essential process are evolutionarily conserved. However, the genes and their specific functions, have evolved uniquely for each selected organism. Therefore, each organism and each individual cell, depending on genetic background and influenced by nutritional and such things as disease status, will decorate secreted proteins in a unique manner.

The advent of biologic medicines (protein based therapeutics) presents the challenge of making sure that the primary protein sequence is specified but also that the manufacture of the protein – typically in a eukaryotic cell host capable of glycosylation – will take place with some degree of reproducibility. The large number of monoclonal antibody therapeutics absolutely require glycosylation for proper structural integrity but are generally made in rodent or other nonhuman cells. Thus, the term “biosimilar” rather than generic is the term being used to connote the variation which will necessarily result due to different manufacturing process even of the same genetic sequence.

Viral Glycoproteins

It should be obvious that the viral genome is not large enough to encompass the collection of enzymes required for glycosylation of any type and viral glycoproteins are formed by the host cell in which the virus is replicating. The study of the impact of glycan content and composition on viral infectivity and, more importantly, vaccine development is a subject which has been late to be addressed largely due to the technical difficulty and lack of methods for analyzing protein glycan composition. However, progress is being made. Raska et al. (J Biol Chem 2010 Jul 2; 285(27): 20860–20869. Glycosylation Patterns of HIV-1 gp120 Depend on the Type of Expressing Cells and Affect Antibody Recognition) was able to perform such an analysis on the HIV-1 virus albeit almost 30 years after its emergence in human populations. The findings of this study may explain, in part, the difficulty in developing a vaccine against HIV.

SARS-CoV-2 spike protein (P0DTC2 uniprot.org) – as so popularly depicted – is a trimer poking out of the lipid coat that protects it’s genome. The spike protein, like gp120 in HIV, is the point of contact with the human cell ACE2 receptor it uses to gain entry. The spike protein contains two functional external subunits, designated S1 and S2. S1 separated by a furin cleavage site from S2, forms the apex of the trimeric spike structure, is responsible for attachment to the ACE2 receptor. S2 is responsible for fusion to the cell membrane. (PDB: 6VSB shows a 3D image of the protein structure, including glycan positions). There are 22 glycans per polypeptide or 66 per spike trimer protein (Watanabe et al. 2021 Site-specific glycan analysis of the SARS-CoV-2 spike. Science 17 Jul 2020:Vol. 369, Issue 6501, pp. 330-333 ).

Although shielding of receptor binding sites by glycans is a common feature of viral glycoproteins, Watanabe (ibid) note the low mutation rate of SARS-CoV-2 and that as yet, there have been no observed mutations to N-linked glycosylation sites.

The development of a vaccine or individual antibodies or antibody cocktails with neutralizing (viral entry blocking or virocidal activity) is also influenced by the presence or absence of glycans and how well they target the natural conformation of the spike protein. Papageorgiou et al. The SARS-CoV-2 Spike Glycoprotein as a Drug and Vaccine Target: Structural Insights into Its Complexes with ACE2 and Antibodies. Cells 2020 Oct 22;9(11):2343. doi: 10.3390/cells9112343. SARS-CoV-2 Spike – Stanford Coronavirus Antiviral Research Database It should be noted that the mRNA vaccines (or other nucleic acid formats) may obviate these analysis because the immune response is to a spike protein made and glycosylated in the human host’s own body and therefore will be customized to each individual in some sense.

Glycans may themselves represent drug targets. Casolino et al. suggest an essential structural role of N-glycans at sites N165 and N234 in modulating the conformational dynamics of the spike’s receptor binding domain (RBD), which is responsible for ACE2 recognition (Casolino et al. 2020. Beyond Shielding: The Roles of Glycans in the SARS-CoV-2 Spike Protein ACS Cent Sci. 2020 Oct 28; 6(10): 1722–1734),

COVID19 Variants

SARS-CoV-2 lineage B.1.1.7 likely arose in the United Kingdom in September 2019 and is characterized by 17 mutations, including 8 in the spike protein (Rambaut et al., 2020). Other lineages, including B.1.351, initially detected in South Africa (Tegally et al., 2020), and most recently lineage P.1, first documented in the Amazonia region of Brazil (Faria et al., 2020), carry additional mutations. All three lineages are characterised by a N501Y (Asn to Tyr) mutation in the spike protein, while both B.1.351 and P.1 also carry the spike mutation E484K. In addition, both B.1.1.7 and B.1.351, but not P.1, have acquired short sequence deletions in the spike protein. N501Y is in the receptor-binding domain (RBD) but is not a glycosylation site.

Reference

See the CDC Emerging SARS-CoV-2 Variants | CDC

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

Posted in Coronavirus Gene Expression, COVID-19, Population Health Management, Genetics & Pharmaceutical, SARS-CoV-2, SARS-CoV-2 Viral Variants on February 12, 2021| Leave a Comment »

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

Reporter: Aviva Lev-Ari, PhD, RN

NIH experts discuss SARS-CoV-2 viral variants

Editorial emphasizes need for global response.

The rise of several significant variants of SARS-CoV-2, the virus that causes COVID-19, has attracted the attention of health and science experts worldwide. In an editorial published today in JAMA: The Journal of the American Medical Association, experts from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, outline how these variants have arisen, concerns about whether vaccines currently authorized for use will continue to protect against new variants, and the need for a global approach to fighting SARS-CoV-2 as it spreads and acquires additional mutations.

The article was written by NIAID Director Anthony S. Fauci, M.D.; John R. Mascola, M.D., director of NIAID’s Vaccine Research Center (VRC); and Barney S. Graham, M.D., Ph.D., deputy director of NIAID’s VRC.

The authors note that the overlapping discovery of several SARS-CoV-2 variants has led to confusing terms used to name them. The appearance of SARS-CoV-2 variants is so recent that the World Health Organization and other groups are still developing appropriate nomenclature for the different variants.

Numerous SARS-CoV-2 variants have emerged over the last several months. The authors note that the variants known as B.1.1.7 (first identified in the United Kingdom) and B.1.351 (first identified in South Africa) concern scientists because of emerging data suggesting their increased transmissibility.

Variants can carry several different mutations, but changes in the spike protein of the virus, used to enter cells and infect them, are especially concerning. Changes to this protein may cause a vaccine to be less effective against a particular variant. The authors note that the B.1.351 variant may be partially or fully resistant to certain SARS-CoV-2 monoclonal antibodies currently authorized for use as therapeutics in the United States.

The recognition of all new variants, including a novel emergent strain (20C/S:452R) in California, requires systematic evaluation, according to the authors. The rise of these variants is a reminder that as long as SARS-CoV-2 continues to spread, it has the potential to evolve into new variants, the authors stress. Therefore, the fight against SARS-CoV-2 and COVID-19 will require robust surveillance, tracking, and vaccine deployment worldwide.

The authors also note the need for a pan-coronavirus vaccine. Once researchers know more about how the virus changes as it spreads, it may be possible to develop a vaccine that protects against most or all variants. While similar research programs are already in place for other diseases, such as influenza, the changing nature of SARS-CoV-2 indicates that they will be necessary for this virus.

SOURCE

https://www.nih.gov/news-events/news-releases/nih-experts-discuss-sars-cov-2-viral-variants

Editorial

February 11, 2021

SARS-CoV-2 Viral Variants—Tackling a Moving Target

John R. Mascola, MD¹; Barney S. Graham, MD, PhD¹; Anthony S. Fauci, MD²

Author Affiliations Article Information

JAMA. Published online February 11, 2021. doi:10.1001/jama.2021.2088

In this issue of JAMA, Zhang and colleagues¹ report the emergence of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant in Southern California that accounted for 44% (37 of 85) of samples collected and studied in January 2021. The terminology of viral variation can be confusing because the media and even scientific communications often use the terms variant, strain, and lineage interchangeably. The terminology reflects the basic replication biology of RNA viruses that results in the introduction of mutations throughout the viral genome. When specific mutations, or sets of mutations, are selected through numerous rounds of viral replication, a new variant can emerge. If the sequence variation produces a virus with distinctly different phenotypic characteristics, the variant is co-termed a strain. When through genetic sequencing and phylogenetic analysis a new variant is detected as a distinct branch on a phylogenetic tree, a new lineage is born.

New variants become predominant through a process of evolutionary selection that is not well understood. Once identified, several questions arise regarding the potential clinical consequences of a new variant: Is it more readily transmitted; is it more virulent or pathogenic; and can it evade immunity induced by vaccination or prior infection? For these reasons, new viral variants are studied, leading to the terms variant under investigation or variant of concern.

To communicate effectively about new SARS-CoV-2 variants, a common nomenclature is needed, which like the virus, is evolving. Fortunately, the World Health Organization (WHO) is working on a systematic nomenclature that does not require a geographic reference, since viral variants can spread rapidly and globally. Currently, the terminology is overlapping, as reflected in the report by Zhang et al.¹ This new variant (CAL.20C) is termed lineage 20C/S:452R in Nextstrain nomenclature,² referring to the parent clade 20C and spike alteration 452R. Similarly, using a distinct PANGO nomenclature,³ this variant derives from lineage B (B.1.429 and B.1.427). While alterations in any viral genes can have implications for pathogenesis, those arising in the spike protein that mediates viral entry into host cells and is a key target of vaccines and monoclonal antibodies are of particular interest. The new variant, identified in California and termed 20C/S:452R, has 3 amino acid changes in the spike protein, represented using the single-letter amino acid nomenclature: S13I, W152C, and L452R. To interpret this new set of alterations, it is useful to review what is known about recent variants that have become predominant in other regions of the world.

During the early phase of the SARS-CoV-2 pandemic, there were only modest levels of genetic evolution; however, more recent information indicates that even a single amino acid substitution can have biological implications. Starting in April 2020, the original SARS-CoV-2 strain was replaced in many regions of the world by a variant called D614G, which was subsequently shown to increase the efficiency of viral replication in humans and was more transmissible in animal models.⁴^–6 The D614G strain appears to position its receptor binding domain to interact more efficiently with the ACE2 receptor, and it is associated with higher nasopharyngeal viral RNA loads, which may explain its rise to dominance.

In October 2020, sequencing analysis in the UK detected an emerging variant, later termed B.1.1.7 or 20I/501Y.V1, which is now present and rapidly spreading in many countries.⁷ B.1.1.7 contains 8 mutations in the spike protein and maintains the D614G mutation. One of these, N501Y, appears to further increase the spike protein interaction with the ACE2 receptor. Epidemiological studies indicate that the B.1.1.7/20I/501Y.V1 strain is 30% to 80% more effectively transmitted and results in higher nasopharyngeal viral loads than the wild-type strain of SARS-CoV. Also of concern are retrospective observational studies suggesting an approximately 30% increased risk of death associated with this variant.⁸

Another notable variant, 20H/501Y.V2 or B.1.351, was first identified is South Africa, where it has rapidly become the predominant strain.⁹ Cases attributed to this strain have been detected in multiple countries outside of South Africa, including recent cases in the US. B.1.351 shares the D614G and N501Y mutations with B.1.1.1.7; thus, it is thought to also have a high potential for transmission. There are no data yet to suggest an increased risk of death due to this variant. Importantly, this constellation of mutations—9 total in the spike protein—add yet another dimension of concern. B.1.351 strains are less effectively neutralized by convalescent plasma from patients with coronavirus disease 2019 (COVID-19) and by sera from those vaccinated with several vaccines in development.¹⁰^–12 The decrement in neutralization can be more than 10-fold with convalescent plasma and averages 5- to 6-fold less with sera from vaccinated individuals. Fortunately, neutralization titers induced by vaccination are high, and even with a 6-fold decrease, serum can still effectively neutralize the virus.

Nonetheless, these data are concerning because they indicate that viral variation can result in antigenic changes that alter antibody-mediated immunity. This is highlighted by in vitro studies showing the B.1.351 strain to be partially or fully resistant to neutralization by certain monoclonal antibodies, including some authorized for therapeutic use in the US.¹² The prevalent strains in the US appear to remain sensitive to therapeutic monoclonal antibodies; however, recent evolutionary history raises the concern that the virus could be only a few mutations away from more substantive resistance.

COVID-19 vaccine development has been an extraordinary success; however, it is unclear how effective these vaccines will be against the new variants. The interim data from 2 randomized placebo-controlled vaccine studies, the rAd26 from Janssen and a recombinant protein from Novavax, offer some insight. The Janssen study included sites in the US, Brazil, and South Africa with efficacy against COVID-19 at 72%, 66%, and 57%, respectively.¹³ Novavax reported efficacy from studies in the UK and South Africa with overall efficacy of 89% and 60%, respectively.¹⁴ Viral sequence data from infected patients showed that the B.1.351 strain was responsible for the majority of infections in South Africa. Lower vaccine efficacy in the South Africa cohort could be related to antigenic variation or to geographic or population differences. Despite the reduced efficacy, the rAd26 vaccine was 85% effective overall in preventing severe COVID-19, and protection was similar in all regions.

These data suggest that current vaccines could retain the ability to prevent hospitalizations and deaths, even in the face of decreased overall efficacy due to antigenic variation. It is unclear whether changes in vaccine composition will be needed to effectively control the COVID-19 pandemic; however, it is prudent to be prepared. Some companies have indicated plans to manufacture and test vaccines based on emerging variants, and such studies will provide important information on the potential to broaden the immune response.

The recognition of a novel emergent variant, 20C/S:452R, in the most populous US state necessitates further investigation for implications of enhanced transmission. In particular, the L452R mutation in the spike protein could affect the binding of certain therapeutic monoclonal antibodies. The emergence of this and other new variants is likely to be a common occurrence until the spread of this virus is reduced. This emphasizes the importance of a global approach to surveillance, tracking, and vaccine deployment. The approach should be systematic and include in vitro assessment of sensitivity to neutralization by monoclonal antibodies and vaccinee sera, vaccine protection of animals against challenge with new strains, and field data defining viral sequences from breakthrough infections in vaccinees. The infrastructure and process used for tracking and updating influenza vaccines could be used to inform that process. Finally, SARS-CoV-2 will be with the global population for some time and has clearly shown its tendency toward rapid antigenic variation, providing a “wake-up call” that a sustained effort to develop a pan-SARS-CoV-2 vaccine is warranted.

SOURCE

https://jamanetwork.com/journals/jama/fullarticle/2776542

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

Posted in Biomarkers: Inflammation, Coronavirus Gene Expression, COVID-19, Immune-Mediation (independent immunopathology: lung and reticuloendothelial system), Mechanisms of infection by SARS-CoV-2, Population Health Management, Genetics & Pharmaceutical, SARS-CoV-2, Serology tests for coronavirus antibodies, T-cell response to SARS-CoV-2 infection, Treatment Protocols for COVID-19, Vaccinology on February 8, 2021| Leave a Comment »

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

Reporter: Aviva Lev-Ari, PhD, RN

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

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

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

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

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

Pfizer/BioNTech and Pfizer/BioNTech – 28 days apart

Pfizer/BioNTech and Pfizer/BioNTech – 12 weeks apart – (control group)

Oxford/AstraZeneca and Oxford/AstraZeneca – 28 days apart

Oxford/AstraZeneca and Oxford/AstraZeneca – 12 weeks apart – (control group)

Oxford/AstraZeneca and Pfizer/BioNTech – 28 days apart

Oxford/AstraZeneca and Pfizer/BioNTech – 12 weeks apart

Pfizer/BioNTech and Oxford/AstraZeneca – 28 days apart

Pfizer/BioNTech and Oxford/AstraZeneca – 12 weeks apart

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

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

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

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

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