Posts by Fm1

Vaccination Crisis or False Alarm in Israel? 90% of COVID-19 Patients Fully Vaccinated

Vaccination Crisis or False Alarm in Israel? 90% of COVID-19 Patients Fully Vaccinated

Israel led the pandemic as an organized, prepared, and aligned population that accepted an aggressive, methodical, and overall successful effort leading

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Israel led the pandemic as an organized, prepared, and aligned population that accepted an aggressive, methodical, and overall successful effort leading to one of the most vaccinated populations against SARS-CoV-2, the virus behind COVID-19. But with the delta variant came breakthrough infections. That is, individuals who were fully vaccinated became infected anyway. This raised serious questions concerning some major assumptions around COVID-19 vaccination. Then just last month, the Jerusalem Post reported on 143 COVID-19 patients admitted to the hospital. The popular wisdom to date is that vaccinated people will largely avoid any hospitalization or worse. The idea was that, at least with the delta variant, herd immunity wouldn’t be possible due to transmissibility. At least those who were vaccinated could rest a little easier. Then came this hospitalization report by the Jerusalem Post that revealed 58% of those patients were fully vaccinated, while only 39% were unvaccinated.

This wasn’t supposed to happen. Maayan Jaffe-Hoffman reported that even though there were more vaccinated than unvaccinated in the hospital with breakthrough infections, the actual percentage of those who required invasive treatment was low. Only three fully vaccinated people needed ventilation.

Worsening Crisis

However, now this situation gets a closer look by TrialSite. Recently a top health official here, Dr. Koby Haviv, Director of Jerusalem’s Herzog Hospital, declared the following in a television interview on Channel 13:

“95% of the severe patients are vaccinated. 85%-90% of the hospitalizations are in Fully vaccinated people. We are opening more and more COVID wards. The effectiveness of the vaccine is waning/fading out.”

Moreover, Dr. Haviv continued that “90% of severe COVID-19 hospitalizations are fully vaccinated.” From worsening breakthrough infections to “outbreaks in hospitals” where a single patient can infect a large group, the doctor expressed real concern that won’t be shared in American or British media.

The Interview

For those interested in watching this interview on Israeli television, a Regulatory Affairs Specialist and Computational Biologist, Ran Israeli, posted it via Twitter.

TrialSite had a few reviewers look at the video, and it appears to be real. TrialSite did a review of other media and the right-leaning Epoch Times picked up the story. No major media of any kind appeared to show interest.

Full Throttle Third Vaccine at Herzog Hospital

TrialSite reviewed the Herzog Hospital Facebook page, which listed Dr. Haviv declaring that all patients and staff are getting the third dose of the vaccine. He clarified that this was still the preferred path in Israel, despite the recent interview revealing what appears to be a very different situation than we read about in the United States.

Perhaps this third dose will gain effectiveness. In the meantime, TrialSite will seek to better understand some of these unfolding anomalies.

FLCCC weekly update

Case Report: Administration of Amniotic Fluid-Derived Nanoparticles in Three Severely Ill COVID-19 Patients

Case Report: Administration of Amniotic Fluid-Derived Nanoparticles in Three Severely Ill COVID-19 Patients

Rationale/Objectives: A human coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak worldwide. There is an urgent need to develop…

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Rationale/Objectives: A human coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak worldwide. There is an urgent need to develop new interventions to suppress the excessive immune response, protect alveolar function, and repair lung and systemic organ damage. Zofin (previously known as Organicell Flow) is a novel therapeutic that is derived from the soluble and nanoparticle fraction (extracellular vesicles and exosomes) of human amniotic fluid. Here within, we present the clinical outcomes after Zofin treatment in three critically ill patients suffering from severe, multi-organ complications induced by COVID-19 infection. All patients were diagnosed with COVID-19, developed respiratory failure, and were hospitalized for more than 40 days.

Methods: Zofin was administered to patients concurrently with ongoing medical care who were monitored for 28-days post-therapy. SOFA score assessment, chest X-rays, and inflammatory biomarker testing was performed.

Main Results: There were no adverse events associated with the therapy. The patients showed improvements in ICU clinical status and experienced respiratory improvements. Acute delirium experienced by patients completely resolved and inflammatory biomarkers improved.

Conclusions: Primary outcomes demonstrate the therapy was safe, accessible, and feasible. This is the first demonstration of human amniotic fluid-derived nanoparticles as a safe and potentially efficacious therapeutic treatment for respiratory failure induced by COVID-19 infection.

Delta Troubles? Retrospective Study Led by nference & Mayo Clinic Reveals Pfizer COVID-19 Shot Only 42% Effective During July

Delta Troubles? Retrospective Study Led by nference & Mayo Clinic Reveals Pfizer COVID-19 Shot Only 42% Effective During July

A brand-new study indicates some possibly troubling news concerning COVID-19. Based on a study in preprint, a poor performance from

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A brand-new study indicates some possibly troubling news concerning COVID-19. Based on a study in preprint, a poor performance from Pfizer’s mRNA vaccine has appeared in the July data and could indicate Delta-driven trouble ahead. In sum, the July data produced by this Mayo Clinic and nference retrospective study suggests that Pfizer’s vaccine product known as BNT162b2 was only 42% effective against infection, which has led to some sources for White House officials to sit up and take notice. The study looked at the effectiveness of the Pfizer and Moderna vaccines inside the Mayo Clinic Health System during the January to July period. Moderna’s vaccine was 86% effective against infection for the entire study period, and Pfizer’s was 76%. Yet in July, Moderna was 76% effective, and Pfizer declined to a troubling 42%. These findings were based on Minnesota data, and at least some suggest Delta was dominant at the time. Experts don’t know if this means that the vaccines are less effective over time, less effective against Delta, or perhaps another reason. Venky Soundararajan, a lead author of the study, notes that “Based on the data that we have so far, it is a combination of both factors—The Moderna vaccine is likely — very likely — more effective than the Pfizer vaccine in areas where Delta is the dominant strain, and the Pfizer vaccine appears to have a lower durability of effectiveness.” These study results are not yet peer-reviewed, and experts suggest no takeaways are possible until the study design, methodology, and data analysis are confirmed.

Background of the Players

The study was led by a team out of Mayo Clinic in Minnesota and a firm from Cambridge, Massachusetts, called nference. Founded in 2013, this venture has raised $145 million, according to Crunchbase. It has developed a powerful augmented intelligence software called nferXTM, which is used by Mayo Clinic to synthesize 100+ years of institutional knowledge and in the process generating significant real-world evidence, with insights to advance the discovery and development of diagnostics and therapeutics. Their software apparently has the ability to triangulate insights derived from public and proprietary datasets, working to curate both structured and unstructured data, empowering research units to attack major challenges in drug discovery expeditiously.

Mayo Clinic is one of the most prestigious health systems in the world. For purposes of this retrospective study, the team evaluated individuals who underwent SARS-CoV-2 testing at Mayo Clinic and hospitals affiliated with the umbrella organization—the Mayo Clinic Health System. Hospitals or clinics included facilities in Arizona, Florida, Iowa, Wisconsin, and the home base of Minnesota.

The Study

This retrospective study involved the evaluation of 645,109 persons with at least one SARS-CoV-2 test via PCR. The investigators used the Mayo Clinic electronic health record (EHR) systems operating in different facilities across different states.

Inclusion criteria included those 18 years of age or older, who received at least one dose of either Pfizer-BioNTech BNT162b2 or Moderna’s mRNA-1273 after December 1, 2020, and on or before July 29, 2021. Additionally, participants couldn’t have any previous positive COVID-19 tests before the first vaccine jab. Moreover, the subjects couldn’t have received vaccines from different manufacturers. After applying the inclusion and exclusion criteria, the study team pared back the study count to those that met the protocol—it turned out they had left 119,463 who received BNT162b2 and 60,083 who received mRNA-1273.

Thereafter, the study team utilized an elaborate yet exact matching procedure to “construct cohorts of demographically and clinically similar individuals who were unvaccinated, vaccinated with mRNA-1273 or vaccinated with BNT162b2,” the authors reported in the recent yet to be peer-reviewed paper on the preprint server medRxiv. After that, the team sought out to identify what they refer to as “matched triples,” including 1) one vaccinated; 2) one that received mRNA-1273, and 3) one who received BNT162b2 who match on a set of criteria including sex, race, ethnicity, state of residence, COVID-19 testing history, and date of vaccination.

This approach produced 43,895 matched triples. They uncovered the following;

∙ 43,895 mRNA-1273 vaccinated individuals—35,902 were fully vaccinated

∙ 43,895 BNT162b2 vaccinated individuals—37,573 were fully vaccinated

They then assigned dates and hypothetical vaccination for unvaccinated persons based on the actual dates of associated matched partners. So, for example, they applied a hypothetical initial vaccination date to a subject based on the data halfway between the actual first vaccination dates for the matched mRNA-1273 and BNT162b2 vaccinated subjects.

The team applied a series of other rules and criteria for matching scenarios that can be read in more detail in medRxiv. They followed with the generation of clinical outcomes as well as comparative analyses; defined clinical outcomes of interest; estimated the actual effectiveness of the vaccines against SARS-CoV-2 and severe COVID-19; and assessed longitudinal effectiveness of the two vaccine products. Next, they went on to compare breakthrough infection incidence rates in the matched vaccinated cohorts and breakthrough infection-associated hospitalization, ICU admission, and mortality in the vaccinated matched cohorts.

Finally, the investigators compared potential complications experienced by patients with breakthrough infections and assessed the longitudinal prevalence of SARS-CoV-2 variants.

Pfizer and Moderna Products Have Differences

Again, the study team found that the Moderna vaccine, mRNA-1273, performed superior to Pfizer-BioNTech as the overall results for the study period included 86% for Moderna versus 76% for Pfizer-BioNTech. While for effectiveness as measured against hospitalization, Moderna’s results were 92% versus Pfizer-BioNTech at 85%

Of note, both vaccines demonstrated marked drops in effectiveness during July, which coincides with the spread of the Delta variant, especially in Minnesota, where it hit 70%. While Moderna still had decent effectiveness of 76% against SARS-CoV-2 infection, Pfizer dropped to 42%. Interestingly, the study results revealed comparable results in other states. For example, in Florida, those who were fully vaccinated with mRNA-1273 were 60% safer than those fully vaccinated with BNT162b2.

The above percentages were based on preventing infection. But there is no hard data yet that either vaccine is substantially limited against Delta when it comes to the key measures of hospitalizations and deaths. Some experts expressed caution: “This is the kind of surprising finding that needs confirmation before we should accept its validity,” per Cornell virologist John Moore as reported in Yahoo News.

Some other differences to consider between the Pfizer and Moderna vaccines include the fact that one (Moderna) is dosed higher than the other (Pfizer-BioNTech). And as reported by Caitlin Owens of AXIOS, a Cornell virologist named John Moore shared they use a different shot interval, writing, “There are a few differences between what are known to be similar vaccines …. None of these variables is an obvious smoking gun, although the dosing amount seems the most likely to be a factor.” Moore suggests that no one jumps to any conclusions until this study is further confirmed.

AXIOS’ Ms. Owens was able to elicit a statement from Pfizer in association with the potential to the Delta variant. Interestingly, Pfizer spoke on behalf of Moderna as well, declaring that both “expect to be able to develop and produce a tailor-made vaccine against that variant in approximately 100 days after a decision to do so, subject to regulatory approval.”

Study Limitations

The study team acknowledges several issues or constraints that ultimately limit the findings here. They share that the study cohorts were not completely demographically representative of the entire American population, possibly limiting the generalizability of their findings.

They point out that additional studies need to look at larger, more diverse populations from a range of health systems to have a more robust comparative analysis of mRNA-1273 and BNT162b2. Moreover, of the initial matching done here, the conclusions must be further tested across the country while the authors acknowledge that other unknown risk variables could impact the study results. Of course, this study hasn’t been peer-reviewed as of yet.

nference’s Dr. Soundararajan

Dr. Soundararajan is Co-Founder and Chief Scientific Officer for nference, which did the research together with Mayo Clinic. He is both an entrepreneur and inventor, and his firm was called the “Google of biomedicine” by The Washington Post. Soundararajan has been key in building a “long-term strategic partnership with the Mayo Clinic’s Clinical Data Analytics Platform, enabling the automated de-identification, augmented curation, and commercialization of aggregated biomedical insights from nearly 9.8 million patient’s complete electronic health records.” The doctor has written over 50 articles and papers and has several dozen patents and patent applications under his belt. He got his PhD in Biological Engineering from MIT, “where he developed the first computational models for studying the evolutionary patterns of hyper-mutative viral pathogens at atomic resolution.” Soundararajan has done a fellowship in Genetics at Harvard Medical School and got his B.S. in Electronics and Communication Engineering at the Indian Institute of Technology at Guwahati, India

Antivirals for COVID-19: Merck Secures TGA Provisional Determination for Australian Market

Antivirals for COVID-19: Merck Secures TGA Provisional Determination for Australian Market

TrialSite has written extensively about the need for antiviral-type, early-care treatments targeting COVID-19. Early in the pandemic, this platform

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TrialSite has written extensively about the need for antiviral-type, early-care treatments targeting COVID-19. Early in the pandemic, this platform tracked numerous studies involving repurposed drugs such as ivermectin, favipiravir, hydroxychloroquine, and more. By May of last year, our physician advisors informed us of the grave importance of treating this pathogen early on. If not, the disease can progress to deadly stages. Many nations found this out, with over 4 million deaths worldwide. Over 90% of COVID-19 cases are either asymptomatic or mild-to-moderate, and early treatment could have stopped many more cases from progressing and hence reduced the death count. The U.S. and other prosperous economies have been slow to take on studies investigating ivermectin. Still, slowly and quietly, behind the scenes, Western pharmaceutical companies haven’t ignored the massive potential that the early COVID-19 treatment space represents. In places like Russia, generic producers embraced Favipiravir, which is approved in that country and many others for early-treatment use. TrialSite estimates this market could represent several billion dollars per annum if the market went completely to pharmaceutical producers. Of course, much of the world’s nations cannot afford such pricey medication. Hence the importance of repurposed, generic options. But select pharmaceutical companies have been actively working to reduce the momentum of generic options such as ivermectin to position and prepare for ownership of this lucrative space. Merck makes a version of ivermectin, executing a successful ongoing program that has helped eradicate several tropical parasitic-born diseases. Merck questioned the safety profile of its own drug, despite the incredible success of the Mectizan program. This ivermectin-based program has helped hundreds of millions of people. Ivermectin has been successfully tested in dozens of studies—a total of 62. Even though dozens of positive studies were conducted in numerous countries, Merck went on an aggressive attack against their own product. Of course, the great New Jersey-based pharmaceutical company had an agenda. They received $356 million of U.S. taxpayer money to develop a pharmaceutical treatment targeting COVID-19 and another $1.2 billion in secure contracts offered by the Biden administration, should the drug get accepted by the U.S. Food and Drug Administration (FDA). Now, Merck is wheeling and dealing, most recently in Australia, to start monetizing the pandemic. Australia’s Therapeutic Goods Administration (TGA) opened the door for a provisional approval Down Under.

The Investigational Product

The investigational product was first developed by the Emory Institute for Drug Development Drug Innovation Ventures (DRIVE). Right at the start of the pandemic, Ridgeback Biotherapeutics inked a deal with DRIVE to license the product called EIDD-2801.

Merck didn’t fare well at developing COVID-19 vaccines, so it had to do something to make money off the pandemic. We implored that they develop an ivermectin research program, but there wouldn’t have been much money in that.

Thus, over a year ago, they partnered with Miami-based Ridgeback Biotherapeutics to license Molnupiravir. We reported last year that this was a potentially lucrative market.

Molnupiravir is considered to have broad-spectrum antiviral activity against a spectrum of antiviral viruses and works by inhibiting replication of SARS-CoV-2.

In “Merck’s Incredible Quest for the COVID-19 Blockbuster: A Tainted Path to Early Onset Mild-to-Moderate COVID-19 Therapy,” TrialSite educates all about the background of this investigational product. We also reported on a once-great American pharmaceutical company’s moves to monetize the pandemic.

Since then, Merck has been quietly inking deals around the globe to get Molnupiravir into clinical trials and then through regulatory authorities. TrialSite reported that the New Jersey pharma approached and closed a deal with a handful of generic drug makers in India and the Philippines. Now they appear close to regulatory access in Australia.

While there was concern about the potential for safety issues with the product, that seems to be less of a risk now, given the ongoing studies. In addition, concerns were raised about mutagenic mechanisms. For example, there was controversy when a whistleblower filed a complaint about the drug and the company (Ridgeback). Rick Bright, who was an executive at the U.S. Biomedical Advanced Research and Development Authority (BARDA), declared his concerns that the drug could produce congenital disabilities. Note the early drug developer, George Painter, CEO of DRIVE, the Emory Institute for Drug Development, denied this. He noted that toxicity studies had been carried out and shared with regulators. Otherwise, they wouldn’t have been able to start clinical trials.

Merck Attacks its Own

While TrialSite wasn’t surprised that Merck dismissed ivermectin research, what we didn’t expect was for Merck to attack its own product (a version of ivermectin) and trash the work of numerous dedicated and committed investigators and public health professionals around the world in such a public way.

Unfortunately, the company blatantly put the raw pursuit of money over all else during the pandemic. But in hindsight, and based on what we have observed, it’s entirely expected from most of these companies.

TrialSite refers to this desire early on as “Remdesivir Envy,” as Gilead secured $3 billion in just the first nine months of the pandemic. Other pharmaceutical companies were under enormous pressure to replicate that feat.

A few other companies are racing against Merck to open up this market, including Roche and Pfizer. Merck secured $356 million at the end of 2020 from U.S. taxpayer funds and then a guaranteed purchase of $1.2 billion, should the company make the regulatory finish line in America. The latest $1.2 billion is under the watch of the current POTUS.

Moves in Australia

As it turns out, Australia’s regulator, known as the Therapeutic Goods Administration (TGA), is taking the first steps toward registering Molnupiravir. The TGA has granted provisional determination to Merck (Merck Sharp & Dohme, Australia Pty Ltd or MSD) concerning this drug initially developed by Emory University and then licensed to Ridgeback Pharmaceuticals.

Now TGA is considering the oral antiviral for the treatment of COVID-19 in adults in this country. This is a significant milestone for Merck and establishes a competitive precedent against firms like Roche and Pfizer.

What Does the Provisional Determination Mean?

Now TGA is on the record that it has made a decision that Merck is now available to apply for provisional registration of Molnupiravir as a first step in the process toward use. Undoubtedly, Merck will move expeditiously now to capitalize on this regulatory invitation. The following TGA website explains their different determinations.

Moving Forward

Merck must still complete a global clinical trial with 1800+ patients for this pill taken twice daily upon early diagnosis of COVID-19. In Australia, TrialSite has heard reports from various news sources that thus far, their product looks promising with what is reported as only mild side effects.

The company sponsors a few studies involving the antiviral drug. In one Phase 2/3 study (NCT04575584), the sponsor evaluates the safety, tolerability, and efficacy of Molnupiravir (MK-4482) compared to placebo. The primary study hypothesis here is that the study drug is superior to placebo as assessed by the rate of sustained recovery through Day 29. This study should be wrapping up soon.

In another global Phase 3 study (NCT04575597), the sponsor investigates the drug in a larger study involving 1,850 participants.

And another major Phase 3 study (NCT04939428) runs through April 2022 and involves prophylaxis attributes for household contacts; this is a larger, multicenter, randomized, double-blind, placebo-controlled study seeking to determine the efficacy, safety, and tolerability of Molnupiravir in adults who reside with a person infected with COVID-19. Thus the drug is being used as a prophylaxis for household contacts—another huge potential market.

The endpoint: Molnupiravir will be superior to placebo in preventing laboratory-confirmed COVID-19 infection through Day 14 in participants who do not have confirmed or suspected COVID-19 at the time of screening and randomization.

Molnupiravir is also one of the study drugs in a multi-drug study called AGILE based out of the University of Liverpool.

The drug’s original licensor, Ridgeback Biotherapeutics, reported in March on its Phase 1 study results.

The company reported that the study drug (EIDD-2801/MK-4482) met the Phase 1 study endpoints; this was published in the peer-reviewed journal Antimicrobial Agents and Chemotherapy. They also share that the study drug met primary objectives of the study involving safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of the study drug.

Call to Action: TrialSite will continue to monitor Merck’s activity associated with MK-4482 around the world.

ACTIV-6 Ivermectin Study Finally Gets Going: Kudos to DCRI for Taking it On

ACTIV-6 Ivermectin Study Finally Gets Going: Kudos to DCRI for Taking it On

Duke Clinical Research Institute recently announced the elite research center is participating in the latest National Institute of Health (NIH)

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Duke Clinical Research Institute recently announced the elite research center is participating in the latest National Institute of Health (NIH) Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), which focuses on repurposed, generic therapies targeting COVID-19. Formally titled “The Randomized Trial to Evaluate Efficacy of Repurposed Medications,” this nationwide, double-blind study is expected to enroll up to 15,000 participants across America. Therapies include Ivermectin, Fluvoxamine, and Fluticasone. But other medications are under consideration, according to TrialSite sources. Unfortunately, this kind of study comes quite late in the pandemic process, but it’s better now than never.

TrialSite has been reporting on significant investment in repurposed drugs for well over a year now. While dozens of ivermectin studies have been conducted worldwide, developed economies have been slow to embrace low-cost, effective treatments to help care for the vast segment of the COVID-19 patient market: the 90%+ of patients that are at home, either asymptomatic or with mild-to-moderate symptoms.

At Duke, the ACTIV-6 study is led by Adrian Hernandez, MD, the study’s administrative principal investigator—Dr. Hernandez also serves as executive director of the DCRI. In a recent press release, he went on the record declaring the importance of finding easy-to-administer treatments early on to reduce the risk of COVID-19 hospitalization or death. He said, “Currently, there are no approved prescription medications that can be easily given at home to treat mild-to-moderate symptoms of the virus early in its course to prevent worsening of COVID-19.”

This study leverages PCORnet® infrastructure, called the National Patient-Centered Clinical Research Network, supported by the Patient-Centered Outcomes Research Institute and the Trial Innovation Network. This represents a collaborative initiative within the NCATS Clinical and Translational Science Awards Program that helps address critical roadblocks in clinical trials and accelerate the translation of novel interventions into life-saving therapies.

Delays

TrialSite has been made privy to information of delays in getting this important study off the ground. The study of ivermectin is critical, given the dozens of studies and meta-analyses already completed that demonstrate at least some efficacy and safety. We are not certain the cause of the delays, but given the severity of the ongoing crisis, they are troubling.

Other Repurposed Studies

Another major ivermectin study in America is the COVID-OUT study. The University of Oxford PRINCIPLE study is also looking into ivermectin in the U.K., but TrialSite sources share a real concern with the PRINCIPLE protocol.

Moving Forward

Although TrialSite has been very critical of the NIH and their proclivity to favor vaccines and expensive novel, high-risk pharmaceutical therapeutics during this pandemic, we praise the NIH for finally getting this study going. Susanna Naggie, MD, is the DCRI principal investigator and oversees the coordinating center for the study. She undoubtedly is trying to contribute enough evidence to help society produce more low-cost options to help fight the pandemic. This media platform commends her and the team at DCRI.

In a recent press release, Dr. Naggie declared, “Speeding enrollment in the ACTIV-6 study is of critical importance as the pandemic evolves and highly transmissible variants appear throughout the nation and around the world.” She continued, “The study will yield valuable data on whether repurposed medications can help address the unmet public health need for people experiencing mild-to-moderate COVID-19 symptoms.”

Big Stakes

TrialSite has emphasized the importance of this market for COVID-19, considering the overwhelming number of cases involve either asymptomatic or mild-to-moderate SARS-CoV-2. For well over a year now, what has been desperately needed are both low-cost generic treatments (e.g., ivermectin, et al.) and pharmaceutical developed therapies that potentially will cost more. There are different markets for antiviral-type products with varying price point realities in this age of COVID-19.

The reality is that much of the world cannot afford expensive medication and generic drugs, whether it be ivermectin or something else that needs to be available. That shouldn’t stop pharmaceutical companies from developing other compelling options. Presently, companies such as Merck, Pfizer, and Roche are working on treatments for this market. But on the other hand, there should be absolutely no consortiums actively interfering with access to studies and positive momentum.

The goal now has to be to accelerate access to help transition the world out of this pandemic. This will not happen by vaccination alone, and the NIH knows this—hence why recently, Dr. Anthony Fauci went on the record as to the importance of early treatment orally administered options to combat COVID-19. All along, TrialSite has called out for a combination of vaccines, early treatments, and smart public health policy, factoring in data-driven risks of those most vulnerable to the pathogen.

About DCRI

The DCRI, part of the Duke University School of Medicine, is the largest academic clinical research organization globally. Their mission is to develop, share, and implement the knowledge that improves global health through innovative clinical research. The institute conducts multinational clinical trials, manages major national patient registries, and performs landmark outcomes research. The DCRI is a pioneer in cardiovascular and pediatric clinical research and conducts groundbreaking clinical research across multiple therapeutic areas, including infectious disease, neuroscience, respiratory medicine, and nephrology. The DCRI is also involved with ACTIV studies, serving as the U.S. coordinating center for ACTIV-6, a COVID-19 master protocol study testing immune modulators, and participating in ACTIV-4, which examines optimal oral use anticoagulants to prevent COVID-19-associated blood clots. The DCRI also serves as the coordinating center for major clinical research programs, such as the Environmental Influences On Child Health (ECHO) program, the Antibacterial Resistance Leadership Group (ARLG), the NIH Health Care Systems Research Collaboratory, and the Pediatric Trials Network (PTN).

Lead Research/Investigator for DCRI

Adrian Hernandez, MD, the study’s administrative principal investigator

Susanna Naggie, MD, DCRI principal investigator

Call to Action: Seek to participate in ACTIV-6? Check out the website, and call center, 833-385-1880. To be eligible, participants must be 30 years old or older, have had a positive COVID-19 test within the past 10 days, and have at least two symptoms of the illness for seven days or less. Symptoms include fatigue, difficulty breathing, fever, cough, nausea, vomiting, diarrhea, body aches, chills, headache, sore throat, nasal symptoms, and/or new loss of sense of taste or smell.

Thailand Now Bets its Life on Antivirals as COVID-19 Rages

Thailand Now Bets its Life on Antivirals as COVID-19 Rages

Thailand has seen better days. Now in the midst of the worst surge of the pandemic—driven by the Delta variant—the vaccination program has been

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Thailand has seen better days. Now in the midst of the worst surge of the pandemic—driven by the Delta variant—the vaccination program has been compromised by what appears to be mismanagement and cronyism. As noted in TrialSite’s “Royal Crony Capitalism or a Regal Choice for a Vaccine Production Partner,” we asked whether it’s wise for a nation to lock up all of, or a good portion of, its regional manufacturing capacity to one vendor that has no experience with vaccine production? That certainly doesn’t sound wise, but that’s what happened as the nation awarded the contract to produce the AstraZeneca (Oxford) vaccine to a company called Siam Bioscience, a firm that, according to some critics and some media, never made a vaccine product before. Note that the company is solely owned by King Maha Vajiralongkorn, Thailand’s monarch. And TrialSite cautions one should be careful with their criticism (ourselves included) as insulting the king can lead to a 15-year prison sentence. When TrialSite published this in June, Thailand was already in trouble, in delay with vaccine production with a growing COVID-19 surge. Now the problems compound, and the country must bank on the antiviral early treatment Favipiravir (Avigan) as a Plan B. But they presently have limited production capacity. TrialSite suggests early treatment should be in Plan A along with vaccines and sound public health policy. Thailand hasn’t fared well with any of it.

Current Situation

The Delta-driven SARS-CoV-2 surge is on a tear in Thailand, with daily cases totaling nearly 20,000 and a new daily high death toll of 235, triggering immense fear in this nation of almost 70 million.

Thailand is behind in its COVID-19 vaccination as only about 6.6% of the population has been fully vaccinated, with about 23.5% having received one jab. The botched vaccine rollout as declared in Asia Nikkei occurred during this worst Delta-driven wave of SARS-CoV-2 infections. Now the country is in a mad dash to secure the supply of Favipiravir, a Japanese antiviral under investigation worldwide for COVID-19 use. In fact, many countries, such as Russia and even China, use Favipiravir as one early treatment tool targeting the novel coronavirus. There is some evidence that if used early on, it can help reduce the illness duration, but there are some limitations, including some higher-risk groups that shouldn’t use the product.

But as the crisis grows in Thailand and vaccines remain in short supply, health authorities must secure more Favipiravir supplies to treat the growing numbers of people ill with COVID-19. As it turns out, antivirals of some kind or another are important. Every nation should consider repurposed drugs that show some benefit, from ivermectin and Favipiravir to Fluvoxamine and several others.

The Drug

TrialSite has written extensively about Favipiravir (trade name Avigan). It showed considerable potential as an antiviral targeting COVID-19 early on, but health authorities in the USA had little interest in it. Nor did the media. It was developed by FUJIFILM Toyama Chemical in the late 1990s and authorized by Japanese regulatory authorities in 2014 as a treatment for new or re-emerging flu infections, reports Asia Nikkei.

The drug isn’t approved for the standard treatment of seasonal flu. There have been some concerns about some side effects, including some congenital disabilities in animal testing.

Interestingly, via the Department of Defense (DoD), the U.S government spent over $200 million testing the drug back in 2015. TrialSite reported that the results seemed to go well, but they were never published for national security reasons.

The drug’s used extensively to target COVID-19 in many counties, especially in Russia and influenced countries, Turkey, some of the Middle East, Asia, and some South American countries.

Favipiravir is under investigation in America and in Canada; a partnership involving Appili Therapeutics and Dr. Reddy’s, an Indian generic drug company, submitted a market authorization application to Health Canada at the end of 2020. No word on that regulatory response. The Japanese drug authority pushed back on an application to market the drug for COVID-19—they informed FUJIFILM Toyama Chemical they needed to generate more data.

The Chinese—an Agenda?

TrialSite reported recently that the Chinese military secured a patent in the world’s second-largest economy as measured by GDP as a domestic and potentially export play to sell the product.

The Chinese military (People’s Liberation Army) via an affiliated laboratory sought out and secured a patent for Favipiravir as a drug for early treatment targeting SARS-CoV-2. While the company’s maker, FUJIFILM Toyama Chemical, continues to market and distribute the product, this move by the Chinese military can be considered a commercially and potentially politically hostile move. Undoubtedly, they seek to exploit that patent, cut out the Japanese, and market and sell the product to as many low-and-middle-income countries (LMICs) as possible. Especially given the dysfunctional nature of the global pandemic response, mainly the affluent counties are securing the best vaccines. At the same time, developing countries are stuck with subpar vaccines at best—or no vaccines. Decent antiviral options become a quest literally involving life or death.

Favipiravir (Avigan) in Thailand

Thailand secured the ability to produce a generic version of Favipiravir called “Favir” (200 mg per tablet), registered by the Thailand Food and Drug Administration since last August. Again, the original product called Avigan made by FUJIFILM Toyama Chemical is now generic.

Favipiravir has been an essential medication in the Thailand COVID-19 medical toolkit, with most of the product secured from the Japanese. It is prescribed here and not sold over the counter.

As previously mentioned, India has several companies producing generic versions of Favipiravir, as do Russia and China.

In May, TrialSite reported that the Thailand government rejected a bid by Japan’s FUJIFILM Toyama Chemical to extend a patent for the drug in this country.

Shortages

But the country is now facing shortages. Asia Nikkei reports that the Pharmacy Council of Thailand recently issued a warning letter to the Thai Public Health Ministry that there could be Favipiravir shortages. According to forecasts, the drug’s demand has grown to 30 million pills per month and could reach 50 million if the number of SARS-CoV-2 infections continues to rise.

Capacity Challenges

Apparently, the Thais have figured out how to produce Favipiravir independently; however, they have limited production capacity. Jiraporn Limpananon serves as president of the Government Pharmaceutical Organization (GPO) and recently shared that while they can produce their own generic version of the drug known as Avigan, they only have the capacity and wherewithal to produce 2 million pills per month.

All will be OK?

The Director of the GPO, in the meantime, declared that all would be OK. As reported in Asia Nikkei, Dr. Vitoon Danwiboon sought to reassure the public by declaring that the GPO secured 43.1 million pills or so for August alone, right when they predict could be the apex of SARS-CoV-2 infections. How will they secure these pills? Imports from Japan via the products’ developer, FUJIFILM Toyama Chemical. But that’s a pretty dangerous way to navigate this pandemic.

Dr. Danwiboon suggests that the capacity of GPO will rise, hopefully up to 40 million tablets per month by October. But the public isn’t happy, and counterfeit Favipiravir is sold now online as predatorial business ventures prey on the situation.

Vaccination Challenges

In the meantime, the use of Chinese vaccines in this part is falling far short. As reported recently by the Washington Post, Thailand was among numerous countries in Southeast Asia that bet on Sinovac’s product CoronaVac.

As described in the Washington Post, TrialSite can verify that China used vaccines in some sort of diplomacy scheme. TrialSite observed jingoistic language out of China’s press early on during the start of the pandemic—the country later softened its tone. Of course, the actual origins of SARS-CoV-2 are still up for debate and could trigger more intense discussions depending on what unfolds.

But the vaccine diplomacy of China hasn’t turned out so well here as the vaccine quality is limited, and now countries like Thailand turn to the West, and specifically products from Pfizer-BioNTech and Moderna as potential answers.

As mentioned earlier, Thailand appears to have granted a license to produce the “Oxford” vaccine to the King’s biotech venture, which has struggled to get out of the production gate. The costs of these decisions are now becoming apparent.

Quote from JedRothwell

These people are terminally confused. It is less deadly only because the most vulnerable people have been vaccinated. The low death rate has nothing to do with the variant.

Not anymore than the ones saying it is!

Quote from THHuxleynew

Are CDC spin doctors?

Well - if they are doing their job properly they should be, since they need to encourage everyone to do the right thing. The more effective the spin, the lower the COVID rates and the more the economy can open up.

It amazes me there are actually politicians in the US who are trashing the CDC guidelines and encouraging people to go against them - totally stupid if you are about the economy.

THH

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Politicians of both parties have said very stupid statements along the way but the CDC handed an internal PowerPoint presentation over to the media to maximize the crap presented in the presentation instead of calling there own press conference where it would be presented to the public without the sensational headlines. that is Fearmongering to advance an agenda!

Identification of lectin receptors for conserved SARS-CoV-2 glycosylation sites

https://www.embopress.org/doi/abs/10.15252/embj.2021108375

Abstract

New SARS-CoV-2 variants are continuously emerging with critical implications for therapies or vaccinations. The 22 N-glycan sites of Spike remain highly conserved among SARS-CoV-2 variants, opening an avenue for robust therapeutic intervention. Here we used a comprehensive library of mammalian carbohydrate-binding proteins (lectins) to probe critical sugar residues on the full-length trimeric Spike and the receptor binding domain (RBD) of SARS-CoV-2. Two lectins, Clec4g and CD209c, were identified to strongly bind to Spike. Clec4g and CD209c binding to Spike was dissected and visualized in real time and at single molecule resolution using atomic force microscopy. 3D modelling showed that both lectins can bind to a glycan within the RBD-ACE2 interface and thus interferes with Spike binding to cell surfaces. Importantly, Clec4g and CD209c significantly reduced SARS-CoV-2 infections. These data report the first extensive map and 3D structural modelling of lectin-Spike interactions and uncovers candidate receptors involved in Spike binding and SARS-CoV-2 infections. The capacity of CLEC4G and mCD209c lectins to block SARS-CoV-2 viral entry holds promise for pan-variant therapeutic interventions.

Quote from THHuxleynew

This is typical anti-CDC propaganda.

We do not know precisely how infectious is delta. It is really difficult to get exact figures, and they depend on variables like level of social mixing.

the link above claims CDC is lying saying delta is the same as Chicken Pox when delta has R=6-7 and Chicken pox has R = 9-10

But both of these figures are inexact, and R=6-7 is at the low end of the CDC estimated range 5 - 9.5. Chicken Pox is at the higher end.

You can accuse CDC of being too definite - it would be more precise to say that it could be as transmissable as Chicken Pox. But not of lying. If medics had to be certain in what they say every single statement would be prefixed by a qualifier.

https://www.nationalgeographic…ew-research-holds-answers

A vastly more transmissible virus

To track how easily an infectious disease such as COVID-19 spreads, epidemiologists use a metric called the basic reproductive number or R0 (pronounced “R naught”). R0 is the average number of susceptible people that each infected person is expected to infect. It is difficult to be certain about the R0 for ancient pandemics, but for the 1918 influenza pandemic, the average infected person is thought to have passed the disease to between two and three people, giving it an R0 of between 2.0 and 3.0. The first SARS coronavirus epidemic of 2002, has an R0 of three; for the second coronavirus epidemic—Middle East Respiratory Syndrome (MERS) first identified in 2012—R0 was between 0.69 to 1.3.

Now the CDC estimates that people infected with Delta pass the virus to between five and 9.5 people. This is higher than the original virus identified in Wuhan, China, which had an R0 between 2.3 and 2.7, and the Alpha variant which had an R0 between four and five. Delta can be as infectious as chicken pox, which has an R0 between 9 and 10.

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Promote Fearmongering to advance their vaccine agenda. Spin doctors!

Mike Rowe is right about the unvaccinated

Mike Rowe is right about the unvaccinated

Over the weekend, television host Mike Rowe responded to a user on Facebook who had asked him why he didn’t do more to encourage his viewers to get the coronavirus vaccines. Rowe’s response was one of the better I’ve seen: He said he had gotten vaccinated as soon as he was able, that he believed the vaccines work, but he understands the reasons why so many people are still hesitant.

The Bulwark’s Jonathan V. Last took Rowe’s reasonable reply and distorted it to accuse the Dirty Jobs star of peddling anti-vaccine rhetoric. I won’t bother responding to every one of Last’s points because Rowe has already done a great job of that himself here:

But I will just say this: Last managed to write more than 1,000 words trying to debunk Rowe’s point without actually addressing Rowe’s point at all, which is that one of the reasons so many people remain wary of the government’s vaccination efforts is because of the many mistakes that public officials such as Dr. Anthony Fauci and Vice President Kamala Harris made.

If Last wants to defend Fauci, Harris, and every single other irresponsible official who messed up during the pandemic, that’s fine. But the fact still remains that their mistakes cost our institutions much-needed credibility, and that lack of credibility has fostered distrust not only in the system but in the solution that the system provided.

Rowe put it this way:

The point I was trying to make, is that half the country has lost faith in our most important institutions. We have a massive credibility problem, exacerbated by powerful people who not only moved the goalposts time and time again, but championed the same restrictions they chose to ignore. In my view, this steady drip of hypocrisy helped foster a deep level of mistrust among millions of unvaccinated Americans.

Last tries to work his away around this argument by dismissing the vaccine-hesitant as a bunch of Trump supporters who are too stupid to understand what’s best for them medically and too selfish to think about anyone but themselves. The only thing this claim reveals is that Last is so consumed by his own partisanship that he can’t help but make everything a matter of Bad MAGA-types vs. Everyone Else, when in reality vaccine hesitancy is much more complicated than politics allows. As Rowe points out, minorities still tend to be more vaccine-hesitant than white people. There are many reasons for this, and none of them have to do with Trump.

But let’s focus on the Republican vaccine skeptics because that’s what Last wants to do. I happen to know many of these types, and I’ve found that the best way to broach the topic of vaccination is to meet them where they're at, which is exactly what Rowe tried to do in his original comment. Yes, the original coronavirus projections were completely wrong. Yes, the government’s lockdown efforts did a lot more harm than good, and the continued imposition of restrictions has gotten out of control. And yes, many of our officials were dishonest and hypocritical. All of these complaints are true and justified. But consider this: The vast majority of people who are in the hospital right now with the coronavirus are unvaccinated. The people most likely to end up with long-term symptoms are the unvaccinated. You don’t need to pay attention to Fauci anymore because those numbers speak for themselves.

We’ll never be able to convince everybody, and that’s OK. But Rowe has a much better chance than Last, who doesn’t really seem interested in persuading anyone at all.

CDC at it again, spreading fear through lies

The CDC Said The Delta Variant Is As Contagious As Chickenpox. That's Not Accurate

NPR Cookie Consent and Choices

In a leaked report, the Centers for Disease Control and Prevention made a surprising claim about the delta variant of the coronavirus: It "is as transmissible as: - Chicken Pox," the agency wrote in a slideshow presentation leaked to the Washington Post on July 26.

Chickenpox is one of the most contagious viruses known. Each individual can spread the virus to as many as "90% of the people close to that person," the CDC reports.

Is the delta variant that contagious as well?

The short answer is, "No," says evolutionary biologist and biostatician Tom Wenseleers at the University of Leuven

"Yeah, I didn't find the CDC's statement entirely accurate," says Wenseleers, who was one of the first scientists to formally calculate the transmission advantage of the alpha and delta variants over the original versions of SARS-CoV2.

Nonetheless, delta is still highly transmissible, he adds. "It's probably the most contagious respiratory virus that we know, for the moment."

Here's why.

When scientists measure a virus's transmissibility, they often use what's known as R0, or "R nought. " It's the number of people a sick person will infect when the entire population is vulnerable to the virus.

"So it's the virus's potential of spreading, given ideal conditions for the virus, when no one has any immunity," says computational biologist Karthik Gangavarapu at the Scripps Research Institute.

For example, the flu has an R0 of about two. Each person infected with flu passes the virus onto two people on average. Some people will infect more than two people and some will infect fewer. But over the time, the average will be about two.

Chickenpox, on the other hand, is way more contagious, Gangavarapu says. Chicken pox has an R0 of about 9 or 10. So each person with chickenpox infects about 10 other people on average. Outbreaks are explosive.

For SARS-CoV-2, the R0 has actually risen over the course of the pandemic as the virus evolved. When the coronavirus first emerged in 2019, SARS-CoV2 was slightly more contagious than flu, Gangavarapu says. "The initial COVID-19 strain had an R0 between two and three."

Then about a year later, the virus began to mutate quickly. The alpha variant emerged, likely in the U.K., and was more transmissible than the original strain. A few months later, the delta variant emerged, most likely in India. It was even more transmissible than alpha.

"For the delta variant, the R0 is now calculated at between six and seven," Wenseleers says. So it's two- to three-times as contagious as the original version of SARS-CoV-2 (R0 = 2 to 3) but less contagious than the chickenpox (R0 = 9 to 10).

So why did the CDC say the delta variant was "just as transmissible as" the chickenpox.

For one, the leaked document underestimated the R0 for chickenpox and overestimated the R0 for the delta variant. "The R0 values for delta were preliminary and calculated from data taken from a rather small sample size," a federal official told NPR. The value for the chickenpox (and other R0s in the slideshow) came from a graphic from the New York Times, which wasn't completely accurate.

"At the end of the day, this delta variant is much more transmissible than the alpha variant," the official added. "That's the message people need to take from this." The official requested anonymity because they were not authorized to speak to the media on this topic.

The difference between an R0 of three and six is massive. For example, with the original strain of SARS-CoV-2, one person would infect about three people, and each of those people would infect three more. So after only two rounds of transmission, cases would rise by nine (3 x 3 = 9). After three rounds, cases would rise by 27 (3 x 3 x 3 = 27). But with the delta variant, the first person would infect six others, who would each then infect six more people. So after two rounds of transmission, cases would already rise by 36 (6 x 6 = 36). After three rounds, cases would surge by 216 (6 x 6 x 6 = 216).

With an R0 of six, delta will be extremely difficult to slow down unless populations reach high levels of vaccination, Wenseleers says. And even then surges in cases will still occur, as is now happening in Iceland and parts of the U.S. The vaccine is less than 90% percent effective at stopping infections with delta, and vaccinated people can still spread the virus. In addition, people who aren't vaccinated have a very high risk of infection, Wenseleers says. "Anyone that chooses not to get vaccinated will in all likelihood get infected by the delta variant over the coming months."

For example, in San Francisco, daily case levels are rapidly rising toward those seen last winter despite the fact that more than 70% of the population is vaccinated per San Francisco Department of Public Health reports.

Although cases of delta are inevitable, hospitalizations aren't, Wenseleers points out. "As long as people would get vaccinated, then we will not get huge wave of hospitalizations." For example, the city of San Francisco has had 3,041 people hospitalized with COVID-19 since March 18, 2020. Only 16 of them were fully vaccinated.

Delta Variant Far Less Deadly than Previous Variants, According to TrialSite Analysis

Delta Variant Far Less Deadly than Previous Variants, According to TrialSite Analysis

TrialSite can confirm that the Delta variant is far less deadly than previous versions of SARS-CoV-2 based on an original analysis of the data from The

trialsitenews.com

TrialSite can confirm that the Delta variant is far less deadly than previous versions of SARS-CoV-2 based on an original analysis of the data from The New York Times and Our World in Data. TrialSite assumes that most cases now occurring during this latest pandemic surge are due to the Delta variant.

It would appear that the transmissibility of the Delta variant is severe, and hospitalization is worsening in mostly southern states. We argue that the situation is still unfolding, so our assumptions and perspective may change if we see new data trends that contradict today’s evaluation. While breakthrough infections appear on the rise, the CDC doesn’t track such infections if they do not involve hospitalization. This is a mistake as many vaccinated people are at home quite ill.

Herein, we exhibit that the previous SARS-CoV-2 surges were far more deadly because the media doesn’t seem to touch on this subject. To demonstrate this, we go back to the previous pandemic surges: first from April 1, 2020, to August 1, 2020, and a bigger surge that occurred starting December 1, 2020, to early March 2021.

We list the number of daily new cases based on a 7-day average and the reported number of daily deaths based on the same 7-day average. The first major wave of the pandemic occurred from April 1, 2020, to August 15, 2020. During this surge, while the number of new daily cases was lower than in subsequent surges, the death rates were far higher with the wild-type SARS-CoV-2. What follows is a breakdown of the numbers for the TrialSite reader.

First Pandemic Surge

Date New Cases (7-day avg) Deaths Mortality Ratio %

April 1, 2020 20,974 610 2.91%

April 15, 2020 29,993 2,196 7.32%

May 1, 2020 28,553 1,935 6.78%

May 15, 2020 22,779 1,446 6.35%

June 1, 2020 21,518 989 4.60%

June 15, 2020 22,133 725 3.28%

July 1, 2020 43,767 881 2.01%

July 15, 2020 63,165 727 1.15%

Aug 1, 2020 62,594 1,229 1.96%

During the first pandemic’s surge, the mortality ratio (as defined by new daily cases and daily deaths ratio based on 7-day averages) clearly shows what many already know—because the novel coronavirus was new, there were no treatments and the risk profiles were not well understood yet—by far, the deadliest variant was that original wild-type variant from Wuhan, China.

What became clear during the first surge is that although there were far fewer cases, the mortality ratio was extremely high, spiking up to 7.32% by April 15. The mean mortality rate for this particular surge was a significantly high 4.04%.

Again, there are several elements behind this. SARS-CoV-2 was brand new, and health systems and hospitals didn’t know how to treat it. Moreover, some of the breakthroughs that came later on, such as the dexamethasone findings from the RECOVERY trial, helped reduce subsequent death rates. Although medical authorities in the United States and Europe don’t accept select repurposed and generic early-stage COVID-19 treatments, substantial real-world data indicates drugs like ivermectin may have helped to mitigate the pandemic’s severity in places like India and Mexico. These treatments are also in use off-label in the United States. But suffice to say, SARS-CoV-2 was significantly more deadly during this first pandemic surge.

The Second Pandemic Surge

Date New Cases (7-day avg) Deaths Mortality Ratio %

Oct 1, 2020 43,444 712 1.64%

Oct 15, 2020 54,715 701 1.28%

Nov 1, 2020 82,835 825 1.00%

Nov 15, 2020 150,349 1,148 0.76%

Dec 1, 2020 161,263 1,542 0.96%

Dec 15, 2020 217,320 2,481 1.14%

Jan 1, 2021 195,173 2,513 1.29%

Jan 15, 2021 232,172 3,307 1.42%

Feb 1, 2021 146,664 3,160 2.15%

Feb 15, 2021 85,762 3,030 3.53%

March 1, 2021 67,512 2,043 3.03%

March 15, 2021 55,051 1,397 2.54%

April 1, 2021 65,402 893 1.37%

The number of cases in the second surge far exceeded the first surge, ranging from October 1, 2020, to April 1, 2021. Moreover, the total volume of death was far higher. But was the mortality ratio higher? We could expect it to be lower as several breakthroughs occurred throughout the world, improving techniques in keeping people alive. These include various clinical trial findings, the authorization of remdesivir, and the considerable use of the off-label treatments ivermectin and hydroxychloroquine as well as others. Moreover, a couple of companies had their monoclonal antibody treatments authorized on an emergency use basis, contributing to better urgent COVID-19 care. The mean mortality ratio for this second surge was 1.70%, far lower than what was experienced during the first surge at 4.04%. Vaccines rolled out at the end of 2020 and would have started to have some impact by the end of quarter 1 2021.

Now fast forward to the most recent stretch of the pandemic, driven by the Delta variant of interest.

Delta Variant Surge

Wave of Pandemic New Cases (7-day avg) Deaths Mortality Ratio %

July 1, 2021 19,722 256 1.30%

July 15, 2021 28,488 280 0.98%

Aug 1, 2021 79,763 362 0.45%

Aug 9, 2021 124,470 553 0.44%

The Delta-driven surge grew after the 4th of July, which was predictable given the huge crowds congregating during that holiday. And while the mainstream media and the government’s official line is that this surge is a pandemic of the unvaccinated, substantial numbers of vaccinated individuals experienced breakthrough infections (the CDC doesn’t count these cases in hospitals). TrialSite has demonstrated how some of the world’s most vaccinated places are having major Delta-driven surges—clearly, this isn’t just a pandemic of the unvaccinated.

Notably, more treatments are now in place, and about 50% of the country has been fully vaccinated. Consequently, the average mortality ratio during the Delta surge is 0.79%, which is far lower than the previous averages. Below we break down the mortality rates for each surge of the pandemic.

Mortality Ratios During Pandemic

Date Median Mortality Ratio

April – Aug 2020 4.04%

Oct 1, 2020 – April 1, 2020 1.70%

July 1, 2021 – Aug 9, 2021 0.79%

What is clear is that the mortality ratio of the first surge was over five times as high as the most recent Delta-driven surge of the pandemic. Moreover, the first deadliest period was nearly 2.2 times as fatal as the second surge, with the largest number of deaths, at least according to this metric.

Of course, a confluence of factors and forces affect this ratio, including vaccination and various treatment approaches. And while the Delta variant appears more transmissible, according to this ratio, it is far less deadly than past variants, including the wild-type variant from Wuhan, China.

Now, this isn’t to trivialize the current situation. Some states, particularly Texas and Florida, face dangerous pressure now on ICU capacity. This analysis is meant to put the entire evolving situation in perspective. The mainstream media isn’t reporting on these numbers nor is the current POTUS administration

Note the source for this analysis was the New York Times and Our World in Data.

Pfizer Foreign COVID-19 Vaccine Contracts Drive a Hard Bargain

Pfizer Foreign COVID-19 Vaccine Contracts Drive a Hard Bargain

A July 28 piece from America’s Frontline Doctors raises ethical concerns about Pfizer’s COVID-19 contracts. While this media group is considered biased by

trialsitenews.com

A July 28 piece from America’s Frontline Doctors raises ethical concerns about Pfizer’s COVID-19 contracts. While this media group is considered biased by many—that is tagged as a right win group—the article provides images of the contracts in question, so we will focus on the hard evidence and try to take any obvious opinionating by the Frontline Doctors with a grain of salt. The first document to emerge is an agreement between Pfizer and the nation of Albania. Information security expert Ehden Biber was also able to locate contracts with Brazil (Portuguese), the European Commission, and the Dominical Republic. Frontline’s Chief Science Officer Dr. Michael Yeadeon reviewed the Albania contract and offered that it, “looks genuine—I know the basic anatomy of these agreements and nothing is missing that I’d expect to be present, and I’ve seen no clues that suggest it’s fake.” A slightly-jarring clause in the Albania deal, notes, “if there are any laws or regulations in your country under which Pfizer could be prosecuted, you agree to change the law or regulation to close that off.” Biber offered that the deals, which are mostly similar, cover vaccines for COVID-19 or mutations, it also covers, “any device, technology, or product used in the administration of or to enhance the use or effect of, such vaccine.”

No Returns

The deals also say that in the event of a cure emerging, the nations still have to buy the same volume of vaccine, and Biber thinks this could be related to the possible suppression of ivermectin. More, the contracts note, “Pfizer shall have no liability for any failure to deliver doses in accordance with any estimated delivery dates… nor shall any such failure give Purchaser any right to cancel orders for any quantities of Product.” Next, the deals give Pfizer the right to, “decide on necessary adjustments to the number of Contracted Doses and Delivery Schedule due to the Purchaser…based on principles to be determined by Pfizer…Purchaser shall be deemed to agree to any revision.” Unlike our local Target, nations cannot return vaccines, no matter the circumstances: “Pfizer will not, in any circumstances, accept any returns of Product (or any dose)…no Product returns may take place under any circumstances.”

Secrecy Built into Contract

Next is what Biber calls the “big secret”: the fact that the revealed deals show a price of $12.00 per dose as little as 250,000 units, while Pfizer charged Uncle Sam $19.50 per dose. Other clauses include, “This agreement is above any local law of the state—Purchaser hereby agrees to indemnify, defend and hold harmless Pfizer, BioNTech (and) their Affiliates…from and against any and all suits, claims, actions, demands, losses, damages, liabilities, settlements, penalties, fines, costs, and expenses….” Key, the agreement calls for secrecy, “Each Recipient shall safeguard the confidential and proprietary nature of the Disclosing Party’s Confidential Information with at least the same degree of care as it holds its own confidential or proprietary information of like kind.” So, absent the leaking of these documents in this case, the nature of these contracts might never be known.

Will FDA mRNA Vaccine Approval Ignore the “Elephant (not) in the Room”: Ultra-Low Absolute Risk Reductions?

Will FDA mRNA Vaccine Approval Ignore the “Elephant (not) in the Room”: Ultra-Low Absolute Risk Reductions?

Note that views expressed in this opinion article are the writer’s personal views and not necessarily those of TrialSite. Dr. Ron Brown – Opinion

trialsitenews.com

Note that views expressed in this opinion article are the writer’s personal views and not necessarily those of TrialSite.

Dr. Ron Brown – Opinion Editorial

August 10, 2021

When the FDA authorized the COVID-19 mRNA vaccines for emergency use, the FDA did not notify the public of both the vaccines’ relative risk reduction measures (vaccine efficacy of approximately 95%) and absolute risk reduction measures (approximately 1%). Medicina | Free Full-Text | Outcome Reporting Bias in COVID-19 mRNA Vaccine Clinical Trials (mdpi.com). The FDA’s failure to report the vaccines’ absolute risk reductions violates the FDA’s own guidelines for communicating evidence-based risks and benefits to the public. Communicating Risks and Benefits: An Evidence-Based User’s Guide | FDA. The FDA advises authorities to “Provide absolute risks, not just relative risks. Patients are unduly influenced when risk information is presented using a relative risk approach; this can result in suboptimal decisions. Thus, an absolute risk format should be used.”

Acknowledged by the Lancet Microbe, failure to address this issue of unreported absolute risk reduction measures is the “elephant (not) in the room” in the FDA’s emergency use authorization (EUA) of the COVID-19 mRNA vaccines. COVID-19 vaccine efficacy and effectiveness—the elephant (not) in the room – The Lancet Microbe.

For a full explanation of the relative and absolute risk reductions in the COVID-19 mRNA vaccines, see my video: Dr. Ron Brown Discusses Outcome Reporting Bias in COVID-19 mRNA Clinical Trials | Interview – YouTube

Currently, EUA rules do not allow authorized vaccines to be mandated. Employers can’t require Covid-19 vaccination under an EUA – STAT (statnews.com). Now the pressure is on for the COVID-19 vaccines to be licensed and approved by the FDA. Much of the motivation behind this rush forward is driven by demand for vaccine mandates by businesses, governments, schools, universities, and the military, with Dr. Fauci leading the cries from the Peanut Gallery. Fauci expects ‘flood’ of vaccine mandates once FDA gives jabs full approval | The Independent

“This is a dystopian world we’re living in,” cried Dr Fauci. Yes, Dr. Fauci, and you helped create it when you mixed up case fatality rates and infection fatality rates and misled U.S. Congress in March 2020 by claiming the coronavirus is 10 times more deadly than seasonal influenza. Public Health Lessons Learned From Biases in Coronavirus Mortality Overestimation (cambridge.org).

And the FDA will no doubt continue to ignore the elephant (not) in the room as it continues to mislead the public about the COVID-19 mRNA vaccines’ almost non-existent clinical efficacy.

Delta+

We should not dismiss the possibility of eradicating COVID-19: comparisons with smallpox and polio

Summary box

With the success of public health and social measures (PHSMs) at eliminating COVID-19 in several jurisdictions, combined with the arrival of safe and highly effective vaccines, the question is raised: is global eradication of COVID-19 feasible?

Our scoring for eradicability suggests that COVID-19 eradication might be slightly more feasible than for polio (although only two of three serotypes eradicated to date), but much less so than smallpox.

The main challenges are probably around achieving high vaccination coverage and the potential need to update vaccine designs. Yet an advantage for COVID-19 eradication, over that for smallpox and polio, is that PHSMs can complement vaccination. There is also very high global interest in COVID-19 control due to the massive scale of the health, social and economic burden.

There is a need for a more formal expert review of the feasibility and desirability of attempting COVID-19 eradication by the WHO or coalitions of national health agencies.

Introduction

Elimination and eradication of disease are among the ultimate goals of public health1 (for definitions see box 1). Vaccination has globally eradicated smallpox, rinderpest (a cattle disease that caused famines2) and two of the three serotypes of poliovirus.3 Three other vaccine-preventable diseases are eradicable globally with current technology,4 with measles the leading contender and with MMR vaccination potentially eradicating mumps and rubella at the same time. Some other diseases are close to being eradicated but without use of vaccines such as with the Guinea Worm Eradication Programme.5 Similarly, China has recently eliminated malaria with a range of non-vaccination tools, to become the 40th country to be certified malaria-free.6

Box 1 Definitions of key disease control terms from the Dahlem Workshop19

Control: The reduction of disease incidence, prevalence, morbidity or mortality to a locally acceptable level as a result of deliberate efforts; continued intervention measures are required to maintain the reduction. Example: diarrhoeal diseases.

Elimination of disease: Reduction to zero of the incidence of a specified disease in a defined geographical area as a result of deliberate efforts; continued intervention measures are required. Example: neonatal tetanus.

Elimination of infections: Reduction to zero of the incidence of infection caused by a specific agent in a defined geographical area as a result of deliberate efforts; continued measures to prevent re-establishment of transmission are required. Example: measles, poliomyelitis.

Eradication: Permanent reduction to zero of the worldwide incidence of infection caused by a specific agent as a result of deliberate efforts; intervention measures are no longer needed. Example: smallpox.

Extinction: The specific infectious agent no longer exists in nature or in the laboratory. Example: none.

Is COVID-19 also potentially eradicable? Or is it inevitably endemic having established itself across the world? Commentators have focused on the challenges of reaching population (herd) immunity,7 yet population immunity is not essential and was not achieved for smallpox, which was eradicated through ring vaccination.

As proof of concept for COVID-19 eradication, several countries and jurisdictions have achieved elimination without vaccination, using new and established public health and social measures (PHSMs) (eg, border control, physical distancing, mask wearing, testing and contact tracing supported by genome sequencing).8 Successful jurisdictions have included those with vast land borders such as China, high population densities such as Hong Kong,9 but also island nations such as Iceland and New Zealand, although with occasional outbreaks from border control failures that have been brought under control.10

Comparisons with smallpox and polio for eradicability

To make comparisons between smallpox, polio, and COVID-19, we consider established technical factors that favour the eradicability of vaccine-preventable diseases, published in 19994 (table 1). To this list we added additional technical, socio-political, and economic factors that are likely to favour achieving eradication. On our scoring for eradicability using a three-point relative scale across 17 variables, the mean (total) scores were smallpox at 2.7 (43/48), then COVID-19 at 1.6 (28/51), and finally polio at 1.5 (26/51) (table 1). While our analysis is a preliminary effort with various subjective components, it does seem to put COVID-19 eradicability into the realms of being possible, especially in terms of technical feasibility.

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Table 1

Factors favouring the eradicability of vaccine-preventable diseases with comparisons between smallpox, polio and COVID-19 (graded for the relative strength of favourability in supporting eradication*)

The technical challenges of COVID-19 eradicability (relative to smallpox and polio) include poor vaccine acceptance, and the emergence of more variants that may be more transmissible or have greater immuno-evasion, potentially allowing vaccine escape so they can outrun global vaccination programmes.11 Nevertheless, there are of course limits to viral evolution, so we can expect the virus to eventually reach peak fitness12 and new vaccines can be formulated.

Other challenges would be the high upfront costs (for vaccination and upgrading health systems), and achieving the necessary international cooperation in the face of ‘vaccine nationalism’ and government-mediated ‘antiscience aggression’.13

Another concern is the risk of the persistence of the pandemic virus in non-human animal reservoirs. However, wild animal infections with SARS-CoV-2 appear to be fairly rare to date,14 and when companion animals become infected they do not appear to re-infect humans.15 Infections among farmed animals could potentially be controlled by quarantining and culling. Furthermore, COVID-19 vaccines for domestic animals are being developed (as they were for the eradication of rinderpest2) and oral vaccine in bait has effected successful regional elimination of rabies in wild foxes.16 Furthermore, the problem of Guinea worm infection in domestic dogs has not stopped the global eradication efforts for that disease,5 since various non-vaccination control measures can be successfully used in dogs.

On the other hand, the massive scale of the health, social and economic burden from COVID-19 in most of the world means that there is unprecedented global interest in disease control and massive investment in vaccination against the pandemic. There is also the advantage for COVID-19 eradication over these other diseases in that PHSMs can be highly effective and can complement vaccination. The upgrading of health systems to facilitate COVID-19 eradication could also have large co-benefits for controlling other diseases (and indeed eradicating measles as well). Collectively these factors might mean that an ‘expected value’ analysis could ultimately estimate that the benefits outweigh the costs, even if eradication takes many years and has a significant risk of failure.

Potential next steps

The preliminary assessment we have performed indicates the value of further work on the potential for the eradication of COVID-19. This work would ideally be done by the WHO, but failing that it could be done by coalitions of national-level agencies working collaboratively. Any expert review needs to consider two main questions: (1) Could sustained COVID-19 eradication be technically feasible with currently available technologies? (2) Should eradication be attempted based on its desirability in terms of benefits versus costs (which provides the context of opportunity cost) and the risk of failure? It should also take a more sophisticated approach than we have by giving the different categories weights and also by making comparisons with measles, where elimination has been achieved at times for large regions (eg, the Americas17) and which is potentially eradicable.5 Modelling work that integrates both the health and economic aspects of COVID-19 control (as per recent work in Australia18) should also inform the decision-making processes.

Conclusions

In this very preliminary analysis, COVID-19 eradication seems slightly more feasible than for polio, but much less so than for smallpox. There is a need for a more formal expert review of the feasibility and desirability of attempting COVID-19 eradication by the WHO or other agencies.

I can't cope with multiple inputs': Qualitative study of the lived experiences of 'brain fog' after Covid-19

Abstract

Objective To explore the lived experience of brain fog i.e the wide variety of neurocognitive symptoms that can follow Covid-19. Design and setting UK wide longitudinal qualitative study comprising online interviews and focus groups with email follow-up. Method 50 participants were recruited from a previous qualitative study of the lived experience of long Covid (n = 23) and online support groups for people with persistent neurological problems following Covid-19 (n = 27). In remotely held focus groups, participants were invited to describe their cognitive symptoms and comment on others accounts. Individuals were followed up by email 4-6 months later. Data were audiotaped, transcribed, anonymised and coded in NVIVO. They were analysed by an interdisciplinary team with expertise in general practice, clinical neuroscience, the sociology of chronic illness and service delivery, and checked by three people with lived experience of brain fog. Results 84% of participants were female and 60% were White British ethnicity. Most had never been hospitalised for Covid-19. Qualitative analysis revealed the following themes: mixed views on the appropriateness of the term brain fog; rich descriptions of the experience of neurocognitive impairments (especially executive function, attention, memory and language), accounts of how the illness fluctuated, and in some but not all cases, resolved, over time; the profound psychosocial impact of the condition on relationships, personal and professional identity; self-perceptions of guilt, shame and stigma; strategies used for self-management; challenges accessing and navigating the healthcare system; and participants search for physical mechanisms to explain their symptoms. Conclusion These qualitative findings complement research into the epidemiology and underlying pathophysiological mechanisms for neurological symptoms after Covid-19. Services for such patients should include: an ongoing therapeutic relationship with a clinician who engages with the illness in its personal, social and occupational context as well as specialist services that are accessible, easily navigable, comprehensive, and interdisciplinary.

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SARS-CoV-2 variants of concern have acquired mutations associated with an increased spike cleavage

SARS-CoV-2 variants of concern have acquired mutations associated with an increased spike cleavage

For efficient cell entry and membrane fusion, SARS-CoV-2 spike (S) protein needs to be cleaved at two different sites, S1/S2 and S2’ by different cellular…

www.biorxiv.org

Abstract

For efficient cell entry and membrane fusion, SARS-CoV-2 spike (S) protein needs to be cleaved at two different sites, S1/S2 and S2’ by different cellular proteases such as furin and TMPRSS2. Polymorphisms in the S protein can affect cleavage, viral transmission, and pathogenesis. Here, we investigated the role of arising S polymorphisms in vitro and in vivo to understand the emergence of SARS-CoV-2 variants. First, we showed that the S:655Y is selected after in vivo replication in the mink model. This mutation is present in the Gamma Variant Of Concern (VOC) but it also occurred sporadically in early SARS-CoV-2 human isolates. To better understand the impact of this polymorphism, we analyzed the in vitro properties of a panel of SARS-CoV-2 isolates containing S:655Y in different lineage backgrounds. Results demonstrated that this mutation enhances viral replication and spike protein cleavage. Viral competition experiments using hamsters infected with WA1 and WA1-655Y isolates showed that the variant with 655Y became dominant in both direct infected and direct contact animals. Finally, we investigated the cleavage efficiency and fusogenic properties of the spike protein of selected VOCs containing different mutations in their spike proteins. Results showed that all VOCs have evolved to acquire an increased spike cleavage and fusogenic capacity despite having different sets of mutations in the S protein. Our study demonstrates that the S:655Y is an important adaptative mutation that increases viral cell entry, transmission, and host susceptibility. Moreover, SARS-COV-2 VOCs showed a convergent evolution that promotes the S protein processing.

Discussion

Emerging SARS-CoV-2 VOCs contain novel spike polymorphisms with unclear functional consequences on epidemiology, viral fitness, and antigenicity. In this study, we evaluated the impact of different spike mutations on viral infection, pathogenicity, and in vivo transmission. We found that in the mink animal model the 655Y spike substitution is selected after infection with the WA1 isolate. Phylogenetic analysis of genome sequences collected worldwide showed an early sporadic appearance of S:655Y during the first pandemic wave in New York in March 2020, and the presence of this mutation in several posterior lineages, including SARS-CoV-2 Gamma variant, pointing to a potential role in adaptation and evolution. To better understand the impact of this polymorphism, we isolated and in vitro characterized a panel of SARS-CoV-2 viruses bearing the 655Y spike mutation. Our results demonstrated that S:655Y enhances the viral growth and the spike protein processing required for optimal cell entry and viral-host membrane fusion. In addition, we performed viral competition and transmission experiments in the hamster animal model and showed that S:655Y became predominant in both direct infected and direct contact animals. Finally, we showed that VOCs converge to gain spike cleavage efficiency and fusogenic potential.

Here, we demonstrate that viruses containing the H655Y polymorphism confer a growth advantage in both VeroE6 and human-like Vero-TMPRSS2 cells. Interestingly, the early human isolate NY7 harboring the 655Y mutation also showed higher replication in human Caco-2 cells. However, it is known that other mutations outside of the S gene could be impacting viral replication and infection (37, 38). Therefore, we confirmed the S:655Y mutation alone was responsible for the enhanced growth and spike cleavage phenotype when comparing WA1 wild type and WA1-655Y isolates. These variants have the same viral protein amino acid sequence except for the amino acid present at position 655 of the spike. Since most of the isolates used in this study contain a constellation of mutations across the genome that could increase viral fitness, comparison of both viruses in parallel allowed to detect differences in growth and spike cleavage that can be attributed only to 655Y polymorphism. S:655Y is present in the S1 spike domain outside of the RBD and has been associated with a decrease of the neutralizing activity when targeted by some monoclonal antibodies(26). However, H655Y has been also naturally selected in cats and mice suggesting a beneficial impact of this substitution in widen viral host range and susceptibility (27, 28). Our data further supports this argument because we also found that S:655Y is selected after replication in minks, a natural host for SARS-CoV-2. Besides, when we assessed the viral transmission efficiency of 655Y versus the ancestor 655H in competition experiments in the hamster model, we also found that 655Y becomes more prevalent, as the bulk of infectious viruses recovered from the infected animals harbored this mutation, except for one hamster. This indicates that S:655Y can overcome S:655H in vivo.

Intense worldwide surveillance has established that SARS-CoV-2 variants are constantly emerging. In particular, the spike protein has shown high plasticity (6). Most of the spike mutations associated with a decrease in neutralization by antibodies against earlier viruses are located in the RBD or N-terminal domain (NTD), which are critical for binding and interacting with the ACE2 cellular receptor. While mutations at these domains may impact SARS-CoV-2 vaccine efficacy, it is also vital to characterize other mutations that might explain the gain in transmissibility observed for the VOCs. Since the Gamma variant that emerged in November 2020 also harbors the 655Y polymorphism (Figure 5A), we decided to investigate its phenotype in vitro. Similar to the earlier S:655Y isolates, this variant also exhibited an increase in spike processing efficiency. More importantly, this phenotype was also confirmed in all emerging VOCs analyzed when infections were performed in the Vero-TMPRSS2 cells indicating that additional mutations within S confer this advantage. Most likely, the spike mutations P681H in Alpha variant-first identified in United Kingdom-and P681R harbored by Kappa and Delta variants-first emerged in India-allowed this enhanced S cleavage. Interestingly, for these variants, optimal cleavage appeared to be dependent on TMPRSS2 protease activity (Figure 5D).

To confirm the cleavage at the putative furin cleavage site, we determined the relative abundance of the furin cleaved peptide produced after the 685-terminal arginine. We observed higher amount of cleavage at this position as compared to the previous circulating viruses, although lower amounts were detected in Alpha, Kappa and Delta variants as compared to the viruses harboring the 655Y mutation. This suggests that a change in residue 681 may introduce an additional cleavage site, perhaps recognized by TMPRSS2 protease that enhances spike cleavage of these variants and produces an additional cleavage peptide different in size and amino acid sequences. Further research is needed to confirm the existence of a recognition site for additional proteases different than furin in the amino acid motif SH/RRRAR when the P681S/H mutation is present. In any case, all the VOCs analyzed proved to be strong syncytia inducers which could potentially indicate a role in pathogenesis and lung damage mediated by TMPRSS2 activity after infection in humans (39). On the other hand, the Beta variant, which was first identified in South Africa in October 2020, does not contain a change in the furin cleavage site or in the spike position 655, but instead a change in the residue found at position 701. Although this residue is found around 20 amino acids away from the furin cleavage motif, we found similar results when the extent of the spike processing was investigated (Figure 4A-E; 5D-G). It is important to note that the VOCs investigated in here independently acquired S mutations around the furin cleavage site that became epidemiologically more prevalent in humans. When we investigated the spatial distribution by superimposition of the crystal structure of the S protein, we found that these highly prevalent polymorphisms were all located in close proximity to the furin site loop (Figure 4A). Any substitution in this protein domain is likely to have an effect on the structural integrity and dynamics, potentially impacting the accessibility of the polybasic site to the relevant protease and likely facilitating the recognition by furin.

In summary, our study demonstrates that the 655Y spike polymorphism, present in the Gamma VOC, is a key determinant of SARS-CoV-2 infection and transmission. The selection and increasing frequency of S:655Y in the human population and following SARS-CoV-2 infection of different animal models such as cats, mice and minks suggests this mutation is associated with an improvement of viral fitness and adaptation to diverse hosts through an increased cleavage of the spike protein. Additionally, we provide evidence of adaptative mutations that SARS-CoV-2 VOCs have been acquired and are associated with an increased spike protein processing. This has significant implications in the understanding of the viral determinants that can impact viral transmissibility, viral evolution, and possibly SARS-CoV-2 antigenicity and pathogenicity.