Feeds:
Posts
Comments

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


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

Reporter: Aviva Lev-Ari, PhD, RN

 

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

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

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

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

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

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

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

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

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

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

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

SOURCE

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

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

WATCH VIDEO

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

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

Read Full Post »


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.

SIGN UP FOR OUR DAILY NEWSLETTER
Get more great content like this delivered right to you!

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

Read Full Post »


The complication of Pfizer’s Vaccine Distribution’s Plan

Reporter : Irina Robu, PhD

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

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

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

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

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

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

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

SOURCE

Read Full Post »


Detecting SARS-COV-2 antibodies in serum and plasma samples

Reporter: Irina Robu, PhD

Convalescent plasma therapy is a possible treatment under investigation where antibodies from recovered patients are transfused to current COVID-19 patients with the intent to help them fight the infection and buy time until their immune system can produce antibodies. Yet, not all recovered patients have the same quantity of antibody titers suitable for such transfusions. In some patients it will minimize the severity of the disease length.

The U.S. Food and Drug Administration authorized convalescent plasma therapy for patients with coronavirus disease 2019 and it permitted to be used during the pandemic because there is no approved treatment for COVID-19. The donated blood is processed to remove cells, leaving behind liquid and antibody.   

Companies like Forte Bío are developing instruments such as Octet HTX Instrument, Octet RED384 Octet RED96e Instrument and Octet K2 Instrument to detect SARS-COV-2 antibodies in serum and plasma samples. The Octet technology allows quantification with high resolution comparable to an HPLC . The instrument utilizes BLI enabling label-free detection for protein quantitation and kinetic characterization at unmatched speed and throughput. The instrument can  measure up to 96 samples simultaneously allowing both unlimited characterization capacity for various applications and custom assay tailoring to maximize analytical throughput or sensitivity and preventing bottlenecks. 

 How are antibodies tested ?

  1. Immobilize a virus protein such as the receptor binding domain (RBD) of the SARS CoV-2 spike protein.
  2. Dip the coronavirus biosensor into diluted patient plasma or serum samples.
  3. Block the biosensor with non-relevant serum or blocking buffer if needed to prevent non-specific binding.

Even the researchers believe that the risk to donors is low, there are additional risks such as allergic reactions, lung damage, difficulty breathing or infections such as HIV, hepatitis B and Donated blood must be tested for safety prior to administering to patients.

What to expect ? It is up to the doctor treating the patient, if convalescent plasma therapy is an option.  Even though data from clinical trials suggest that convalescent plasma may diminish the severity or duration of the COVID19, more research is needed to determine if convalescent plasma therapy is an effective treatment.

SOURCE

https://www.fortebio.com/covid19research19research

https://www.medrxiv.org/content/10.1101/2020.07.17.20156281v1

 

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

https://pharmaceuticalintelligence.com/2020/05/18/race-to-develop-antibody-drugs-for-covid-19

https://pharmaceuticalintelligence.com/2020/05/18/race-to-develop-antibody-drugs-for-covid-19

 

 

Read Full Post »


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

Read Full Post »


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

Reporter : Irina Robu, PhD

A research team at University of Pittsburg School of Medicine identified an antibody component that is 10 times smaller than a full-sized antibody. Their research published in Cell, indicates that the drug, Ab8 based on it is effective in mice and hamsters. The research was started by screening a library of about 100 billion antibody fragments to identify candidates that bound tightly to the spike protein on SARS-CoV-2’s surface, which the virus uses to enter and infect human cells.

A typical antibody consists of two heavy chains and two light chains. The chosen molecule is the variable domain of the heavy chain of an immunoglobulin, which is a type of antibody. The heavy chain variable domain is essential for binding with an antigen. Ab8 was created by fusing the variable, heavy chain domain with part of the immunoglobulin tail region, giving it immune functions but doing so with a molecule that’s about half the size of a full immunoglobulin.

The smaller size of the antibody can improve the therapeutic efficacy for infectious diseases and can be delivered through inhalation. Their research showed that Ab8 completely neutralized SARS-CoV-2 in lab dishes. The drug developed showed that inhibited the virus in lung tissue in animal body even at the lowest dose 2 mg/kg as compared to untreated controls.

The research team is looking to determine the drug effect in hamsters, which were reported to have better clinical signatures of COVID-19. And the hamsters that got the drug display less severe pneumonia that did the control animals. Drugs with alternative administration routers could provide additions to the first wave of COVID-19 therapies and vaccines.

What is more important, Ab8 does not appear to bind to human cells which is a good sign that it won’t have negative side effects.

SOURCE

https://www.fiercebiotech.com/research/small-sized-biologic-against-covid-19-shows-promise-animal-models

 

 

Read Full Post »


FDA Authorizes Convalescent Plasma for COVID-19 Patients

Reporter: Irina Robu, PhD

The U.S. Food and Drug Administration authorized convalescent plasma therapy in August 2020 for people with coronavirus disease 2019. The convalescent plasma shows promising efficacy in hospitalized patients with COVID-19 and the benefits outweighs the risk  and FDA gave emergency use authorization. The approval is not  for any particular convalescent plasma product, but for preparation collected by FDA registered blood establishments from individuals whose plasma contains anti-SARS-CoV-2 antibodies, and who meet all donor eligibility requirements.

What exactly is convalescent plasma ? It is blood donated from patients who have recovered from COVID-19 has antibodies to the virus that causes it. The donated blood is processed by removing blood cells, leaving behind plasma and antibodies, which can be given to people with COVID-19 to boost their ability to fight the virus. According to FDA, COVID-19 covalescent plasma with high antibody titer can be effective in reducing mortality in hospitalized patients, but low antibody titer can be used based on health care provider discretion.  FDA also indicated that COVID-19 convalescent plasma may be effective in lessening the severity or shortening the length of COVID-19 illness in some hospitalized patients.

To confirm the results, the FDA recommended randomized trialsas COVID-19 convalescent plasma does not yet describe a new standard of care based on the current available evidence.

SOURCE

https://www.medpagetoday.com/infectiousdisease/covid19/88225?xid=NL_breakingnewsalert_2020-08-23

Read Full Post »


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

 

Read Full Post »


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

Read Full Post »


COVID concern in Cardiology: Asymptomatic patients who have been previously infected demonstrating evidence on MRI of scarring or myocarditis

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

 

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

Indeed, many viruses can cause inflammation and weakening of the heart.

So far there is no established action to take for prevention, and management is based on clinical manifestations of heart failure: shortness of breath, particularly if worse laying flat or worse with exertion, leg swelling (edema), blood tests showing elevated brain natriuretic peptide (BNP or proBNP, a marker of heart muscle strain), and a basic metabolic panel that may show “pre-renal azotemia” (elevation of BUN and Creatinine, typically in a ratio >20:1) and/or hyponatremia (sodium concentration below 135 mEq/dL). If any of the above are suspected, it is reasonable to get transthoracic echocardiography for systolic and diastolic function. If either systolic or diastolic function by ultrasound show significant impairment not improved by usual therapy (diuretic, ACEI/ARB/ARNI, blocker, aldosterone inhibitor e.g. spironolactone) then an MRI scar map may be considered (MRI scar maps show retention of gadolinium contrast agent by injured heart muscle, first demonstrated by Dr. Justin Pearlman during angiogenesis research MRI studies).

There is no controversy in the above, the controversy is a rush to expanded referral for cardiac MRI without clear clinical evidence of heart impairment, at a stage when there is no established therapy for possible detection of myocarditis (cardiac inflammation). General unproven measures for inflammation may include taking ginger and tumeric supplements if well tolerated by the stomach, drinking 2 cups/day of Rooibos Tea if well tolerated by the liver.

Canakinumab was recommended by one research group to treat inflammation and risk to the heart if the blood test hsCRP is elevated (in addition to potential weakening of muscle, inflammation activates complement, makes atherosclerosis lesions unstable, and thus may elevate risk of heart attack, stroke, renal failure or limb loss from blocked blood delivery). The canakinumab studies were published in NEJM and LANCET with claims of significant improvement in outcomes, but that was not approved by FDA or confirmed by other groups, even though it has biologic plausibility. https://www.thelancet.com/journals/lancet/article/PIIS0140-67361732247-X/fulltext

 

Some Heart Societies Agree on Cautions for COVID-Myocarditis Screening

— Official response has been modest, though

Such evidence of myocardial injury and inflammation on CMR turned up in a German study among people who recovered from largely mild or moderate cases of COVID-19 compared with healthy controls and risk factor-matched controls.

Then an Ohio State University study showed CMR findings suggestive of myocarditis in 15% of collegiate athletes after asymptomatic or mild SARS-CoV-2 infection.

But an open letter from some 50 medical professionals across disciplines emphasized that “prevalence, clinical significance and long-term implications” of such findings aren’t known. The letter called on the 18 professional societies to which it was sent on Tuesday to release clear guidance against CMR screening in the general population to look for post-COVID heart damage in the absence of symptoms.

The Society for Cardiac Magnetic Resonance quickly responded with a brief statement from its chief executive officer, Chiara Bucciarelli-Ducci, MD, PhD, agreeing that routine CMR in asymptomatic patients after COVID-19 “is currently not justified… and it should not be encouraged.”

She referred clinicians to the multisociety guidelines on clinical indications of CMR when deciding whether to scan COVID-19 patients. “While CMR is an excellent imaging tool for diagnosing myocarditis in patients with suspected disease, we do not recommend its use in patients without symptoms,” she added.

The American Heart Association didn’t put out any written statement but offered spokesperson Manesh Patel, MD, chair of its Diagnostic and Interventional Cath Committee.

“The American Heart Association’s position on this is that in general we agree that routine cardiac MRI should not be conducted unless in the course of a study” for COVID-19 patients, he said. “There’s a lot of evolving information around people with COVID, and certainly asymptomatic status, whether it’s recent or prior, it’s not clearly known what the MRI findings will mean or what the long-term implications are without both a control group and an understanding around population.”

The ACC opted against taking a stand. It provided MedPage Today with the following statement from ACC President Athena Poppas, MD:

“We appreciate the authors’ concerns about the potential mischaracterization of the long-term impact of myocarditis after a COVID-19 diagnosis and the need for well-designed clinical trials and careful, long term follow-up. The pandemic is requiring everyone make real-time decisions on how to best care for heart disease patients who may be impacted by COVID-19. The ACC is committed to helping synthesize and provide the most up-to-date, high quality information possible to the cardiovascular care team. We will continue to review and assess the scientific data surrounding cardiac health and COVID-19 and issue guidance to help our care team.”

While the open letter noted that some post-COVID patients have been asking for CMR, Walsh noted that primary care would likely see the brunt of any such influx. She personally has not had any patients ask to be screened.

SOURCE

https://www.medpagetoday.com/infectiousdisease/covid19/88704?xid=nl_covidupdate_2020-09-21

Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial

Summary

Background

Inflammation in the tumour microenvironment mediated by interleukin 1β is hypothesised to have a major role in cancer invasiveness, progression, and metastases. We did an additional analysis in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), a randomised trial of the role of interleukin-1β inhibition in atherosclerosis, with the aim of establishing whether inhibition of a major product of the Nod-like receptor protein 3 (NLRP3) inflammasome with canakinumab might alter cancer incidence.

Methods

We did a randomised, double-blind, placebo-controlled trial of canakinumab in 10 061 patients with atherosclerosis who had had a myocardial infarction, were free of previously diagnosed cancer, and had concentrations of high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater. To assess dose–response effects, patients were randomly assigned by computer-generated codes to three canakinumab doses (50 mg, 150 mg, and 300 mg, subcutaneously every 3 months) or placebo. Participants were followed up for incident cancer diagnoses, which were adjudicated by an oncology endpoint committee masked to drug or dose allocation. Analysis was by intention to treat. The trial is registered with ClinicalTrials.govNCT01327846. The trial is closed (the last patient visit was in June, 2017).

Findings

Baseline concentrations of hsCRP (median 6·0 mg/L vs 4·2 mg/L; p<0·0001) and interleukin 6 (3·2 vs 2·6 ng/L; p<0·0001) were significantly higher among participants subsequently diagnosed with lung cancer than among those not diagnosed with cancer. During median follow-up of 3·7 years, compared with placebo, canakinumab was associated with dose-dependent reductions in concentrations of hsCRP of 26–41% and of interleukin 6 of 25–43% (p<0·0001 for all comparisons). Total cancer mortality (n=196) was significantly lower in the pooled canakinumab group than in the placebo group (p=0·0007 for trend across groups), but was significantly lower than placebo only in the 300 mg group individually (hazard ratio [HR] 0·49 [95% CI 0·31–0·75]; p=0·0009). Incident lung cancer (n=129) was significantly less frequent in the 150 mg (HR 0·61 [95% CI 0·39–0·97]; p=0·034) and 300 mg groups (HR 0·33 [95% CI 0·18–0·59]; p<0·0001; p<0·0001 for trend across groups). Lung cancer mortality was significantly less common in the canakinumab 300 mg group than in the placebo group (HR 0·23 [95% CI 0·10–0·54]; p=0·0002) and in the pooled canakinumab population than in the placebo group (p=0·0002 for trend across groups). Fatal infections or sepsis were significantly more common in the canakinumab groups than in the placebo group. All-cause mortality did not differ significantly between the canakinumab and placebo groups (HR 0·94 [95% CI 0·83–1·06]; p=0·31).

Interpretation

Our hypothesis-generating data suggest the possibility that anti-inflammatory therapy with canakinumab targeting the interleukin-1β innate immunity pathway could significantly reduce incident lung cancer and lung cancer mortality. Replication of these data in formal settings of cancer screening and treatment is required.

Funding

Novartis Pharmaceuticals.

Read Full Post »

Older Posts »