Covid-19 News

  • Murine monoclonal antibodies against RBD of SARS-CoV-2 neutralize authentic wild type SARS-CoV-2 as well as B.1.1.7 and B.1.351 viruses and protect in vivo in a mouse model in a neutralization dependent manner


    https://www.biorxiv.org/conten…/2021.04.05.438547v1.full


    Abstract

    After first emerging in December 2019 in China, severe acute respiratory syndrome 2 (SARS-CoV-2) has since caused a pandemic leading to millions of infections and deaths worldwide. Vaccines have been developed and authorized but supply of these vaccines is currently limited. With new variants of the virus now emerging and spreading globally, it is essential to develop therapeutics that are broadly protective and bind conserved epitopes in the receptor binding domain (RBD) or the whole spike of SARS-CoV-2. In this study, we have generated mouse monoclonal antibodies (mAbs) against different epitopes on the RBD and assessed binding and neutralization against authentic SARS-CoV-2. We have demonstrated that antibodies with neutralizing activity, but not non-neutralizing antibodies, lower viral titers in the lungs when administered in a prophylactic setting in vivo in a mouse challenge model. In addition, most of the mAbs cross-neutralize the B.1.351 as well as the B.1.1.7 variants in vitro.


    Importance Crossneutralization of SARS-CoV-2 variants by RBD-targeting antibodies is still not well understood and very little is known about the potential protective effect of non-neutralizing antibodies in vivo. Using a panel of mouse monoclonal antibodies, we investigate both of these aspects.


    Discussion

    The RBD of the spike protein of SARS-CoV-2 is relatively plastic and can tolerate extensive mutations, at least in vitro. The plasticity of the RBD is alarming because extensive changes in the RBD could reduce the efficacy of current vaccines and additional booster vaccinations with updated vaccines may be needed for protection in the future (15, 16). We tested all 14 isolated mAbs for binding to a whole panel of mutant RBDs. While some mAbs lost binding for many mutant RBDs, other mAbs maintained binding well across the board. However, binding was not in all cases directly linked to neutralization. All of the neutralizing mAbs maintained binding and neutralizing activity to B.1.1.7 (N501Y) relatively well. However, two mAbs lost neutralizing activity against B.1.351 and one of these mAbs only showed a relatively low reduction in binding to E484K and B.1.351 RBDs. The second one showed a stronger reduction in binding which agrees better with loss of neutralizing activity. Other hotspots for loss of binding for neutralizing antibodies included amino acid positions 487 and 490.


    For four of the neutralizing mAbs low resolution structures were solved using single particle EM. They included KL-S-1D2 which lost neutralizing activity to B.1.351. Our low resolution structural analysis precludes interpretation of molecular interactions but the reduction or loss of neutralization of B1.1.7 and B.1.351 by KL-S-1D2 suggests that N501 and E484 form critical interactions.


    Protection in vivo by neutralizing mAbs could be a function of Fc-Fc receptor interaction. This has been shown for other mAbs developed against SARS-CoV-2 which showed less protection in vivo when the Fc was mutated (25). While the role of Fc-FcR interactions based effector functions for SARS-CoV-2 targeting antibodies is not fully understood yet, it is likely that these effector functions contribute to protection (26). This has also been demonstrated for influenza viruses as well as ebolaviruses (27, 28). We tested all isolated mAbs for their protective effect in a mouse model and found that the only correlation with protection was neutralizing activity while non-neutralizing antibodies had no effect. However, there is an important caveat that needs to be discussed for this experiment. All non-neutralizing antibodies that we isolated were of the IgG1 subtype, which in mice, is known to have low affinity for activating FcRs. This is in contrast to murine IgG2a and IgG2b which have high affinity for these FcRs. Therefore, we can only conclude that non-Fc-FcR based interactions do not contribute to protection by non-neutralizing antibodies. In fact, the two antibodies that provided the best protection, especially on day 3, KL-S-1D2 and KL-S-2C3, are both of the IgG2a subtype. While KL-S-1D2 showed the best in vitro neutralization of all isolated mAbs, which could cause this phenotype, KL-S-2C3’s in vitro activity was lower but still showed stronger activity in vivo than other mAbs. This could be seen as evidence that Fc-FcR interactions, especially engagement with activating FcRs, which is an important component of protection. Of note, the vast majority of antibodies induced in humans to SARS-CoV-2 spike by natural infection or vaccination are IgG1 and in humans – unlike in mice - IgG1 has strong affinity for activating FcRs (29).


    In summary, we describe several antibodies to the SARS-CoV-2 RBD that maintain strong neutralizing activity against the B.1.1.7 as well as B.1.351 variant. These mAbs, if humanized, may be further developed into ‘variant resistant’ therapeutics.

  • What's the mechanism here?

    One nasty side effect of CoV-19 is the triggered autoimmune response, that leads to an increase in ACE-2 receptors expression.



    This helps explain an Autoimmune response.


    Physiological effects of modulating the interleukin-6 axis


    https://academic.oup.com/rheum…e/57/suppl_2/ii43/4898142


    Abstract

    IL-6 is a pleiotropic cytokine involved in many biological functions that affect tissues beyond the immune system and the vasculature. This multifunctional cytokine exerts its actions via the classic signalling pathway when it binds to the transmembrane IL-6 receptor (IL-6R) or via the trans-signalling pathway upon binding to the soluble form of IL-6R (sIL-6R). In general, classic IL-6 signalling is responsible for the anti-inflammatory properties of IL-6, whereas trans-signalling is responsible for the pro-inflammatory actions of IL-6. As a result, dysregulation of the IL-6 axis can lead to the onset or development of several disease states, particularly autoimmune and inflammatory disorders, including RA and GCA. This pathological role of IL-6 means that pharmacologic modulation of the IL-6 axis is a rational therapeutic approach; however, multiple predictable, but often underappreciated, effects on tissues and organs beyond the blood vessels may also occur.

  • Look at Sweden: https://www.worldometers.info/coronavirus/country/sweden/


    Near peek number of cases. All time low in death 4/day last week.


    What is wrong there??

    75% of the deaths are from elderly care and most of them are vaccinated now. That translates to around 25deaths a day from the peak number and currently we are around 20deaths per day.

    Our hospitalization is very high atm and icu cases are younger and close to the autumn peak. So the nurses and doctors here are working overtime. I'm hiding at home waiting for my vaccination.

    We are vaccinating mostly 70years and above. Here 16% has gotten their first vaccine shot.

  • I'm hiding at home waiting for my vaccination.

    Just buy some cheap Ivermectin. There is no reason to hide. Worldometer only shows 4 deaths/day in average for Sweden.


    Only rule people need to follow: Use an FP98 mask for trains/shops. Medical masks have absolute no value for 1.1.7.1.


    Basically all people with severe infections get in from long stays indoors. Most of the time from the partner.

  • Sunlight Linked With Lower COVID-19 Deaths – And NOT Because of Vitamin D


    https://scitechdaily.com/sunli…because-of-vitamin-d/amp/


    Increased exposure to the sun’s rays — specifically UVA — could act as a simple public health intervention if further research establishes it causes a reduction in mortality rates, experts say.


    Researchers from the University of Edinburgh compared all recorded deaths from Covid-19 in the continental US from January to April 2020 with UV levels for 2,474 US counties for the same time period.


    The study found that people living in areas with the highest level of exposure to UVA rays — which makes up 95 percent of the sun’s UV light — had a lower risk of dying from Covid-19 compared with those with lower levels. The analysis was repeated in England and Italy with the same results.


    The researchers took into account factors known to be associated with increased exposure to the virus and risk of death such as age, ethnicity, socioeconomic status, population density, air pollution, temperature, and levels of infection in local areas.


    The observed reduction in risk of death from Covid-19 could not be explained by higher levels of vitamin D, the experts said. Only areas, with insufficient levels of UVB to produce significant vitamin D in the body, were included in the study.


    One explanation for the lower number of deaths, which the researchers are following up, is that sunlight exposure causes the skin to release nitric oxide. This may reduce the ability of SARS Coronavirus2 — the cause of Covid-19 — to replicate, as has been found in some lab studies.


    Previous research from the same group has shown that increased sunlight exposure is linked to improved cardiovascular health, with lower blood pressure and fewer heart attacks. As heart disease is a known risk factor in dying from Covid-19, this could also explain the latest findings.


    The team says that due to the observational nature of the study, it is not possible to establish cause and effect. However, it may lead to interventions that could be tested as potential treatments.


    The paper has been published in the British Journal of Dermatology, an official publication of the British Association of Dermatologists.

  • AstraZeneca woes grow as Australia, Philippines, African Union curb COVID-19 shots


    https://mobile.reuters.com/article/amp/idUSKBN2BV2BA


    Australia and the Philippines limited use of AstraZeneca's COVID-19 vaccine on Thursday, while the African Union dropped plans to buy the shot amid global shortages, dealing further blows to the company's hopes to deliver a vaccine for the world.


    The vaccine - developed with Oxford University and considered a frontrunner in the global vaccine race - has been plagued by safety concerns and supply problems since Phase III trial results were published in December, with Indonesia the latest country forced to seek doses from other drugmakers.


    The Philippines suspended the use of AstraZeneca shots for people under age 60 after Europe's regulator said on Wednesday it found rare cases of blood clots among some adult recipients, although it still believes that the vaccine’s benefits outweighed its risks.

    Australia recommended people under 50 should get Pfizer's COVID-19 vaccine in preference to AstraZeneca's, a policy shift it warned would hold up its inoculation campaign.


    AstraZeneca's shot is sold at cost, for a few dollars a dose. It is by far the cheapest and most high-volume launched so far, and has none of the extreme refrigeration requirements of some other COVID-19 vaccines, making it likely to be the mainstay of many inoculation programmes in the developing world.


    But more than a dozen countries have at one time suspended or partially suspended use of the shot, first on concerns about efficacy in older people, and now on worries about rare dangerous side effects in younger people.


    That, coupled with production setbacks, will delay the rollout of vaccines across the globe as governments scramble to find alternatives to tame the pandemic that has killed more than 3 million.

  • I got my j&j yesterday, no side effects my wifes temp raised for about 8 hours but normal today, then I read this.........


    U.S. Bet Big on Covid Vaccine Manufacturer Even as Problems Mounted

    The Baltimore plant that recently had to scrap up to 15 million ruined doses had flouted rules and downplayed errors, according to internal audits, ex-employees and clients. Other doses had to be scrapped last year.


    https://www.nytimes.com/2021/0…mergent-biosolutions.html


    WASHINGTON — More than eight years ago, the federal government invested in an insurance policy against vaccine shortages during a pandemic. It paid Emergent BioSolutions, a Maryland biotech firm known for producing anthrax vaccines, to have a factory in Baltimore always at the ready.


    When the coronavirus pandemic arrived, the factory became the main U.S. location for manufacturing Covid-19 vaccines developed by Johnson & Johnson and AstraZeneca, churning out about 150 million doses as of last week.


    But so far not a single dose has been usable because regulators have not yet certified the factory to allow the vaccines to be distributed to the public. Last week, Emergent said it would destroy up to 15 million doses’ worth of the Johnson & Johnson vaccine after contamination with the AstraZeneca vaccine was discovered.


    Emergent and government health officials have long touted their partnership as a success, but an examination by The New York Times of manufacturing practices at the Baltimore facility found serious problems, including a corporate culture that often ignored or deflected missteps and a government sponsor, the Biomedical Advanced Research and Development Authority, that acted more as a partner than a policeman.Previously undisclosed internal documents and interviews with current and former federal officials and former company employees depict a factory operation that was ill-equipped to take on such a mammoth manufacturing task, despite Emergent’s having received a $163 million federal contract to improve the facility and prepare it for high-volume production.


    The loss of the Johnson & Johnson doses was not the first time the company threw out coronavirus vaccine for fear of contamination. Between early October and January, Emergent discarded five lots of AstraZeneca vaccine — each the equivalent of two million to three million doses — because of contamination or suspected contamination, according to internal logs, a government official and a former company supervisor.


    Audits and investigations — including ones conducted in 2020 by Johnson & Johnson, AstraZeneca, two federal agencies and Emergent’s own quality evaluators — found that Emergent had not followed some basic industry standards at the Baltimore plant, and identified repeated shortcomings in efforts to disinfect and prevent contamination.


    While audits always find problems, federal officials and outside experts said that the pattern of lapses suggested deeper quality issues.

  • Scientists work toward an elusive dream: a simple pill to treat Covid-19


    https://www.statnews.com/2021/…e-pill-to-treat-covid-19/


    The world has vaccines that can prevent most cases of Covid-19. It even has drugs that can help with the most serious symptoms of the disease. Now what it needs is a Tamiflu for SARS-CoV-2.


    It would be a pill, exquisitely calibrated to target SARS-CoV-2, with tolerable side effects and a low price tag. And it would work just as well as those antibody treatments that require an hourlong intravenous infusion, but it would come in a handy packet patients could take home.


    “We’re looking for something I could give everyone in an urgent care setting who comes in with exposure or a positive test,” said Nathaniel Erdmann, an infectious disease specialist at the University of Alabama at Birmingham Hospital who treats Covid-19. “An easy, oral, safe drug.”

    As simple as that sounds, the process of actually developing new antiviral treatments is overwhelmingly complicated, even outside of a pandemic. Things can go disastrously wrong at countless steps along the way, whether drugs are too weak to stop the viral spread or too sloppy to be safe. And SARS-CoV-2 is consistently evolving, meaning scientists have to outfox natural selection itself to stay ahead of the game.


    The common cold is often caused by a coronavirus, after all. And, as scientists ruefully joke, after billions of dollars spent on research and development, there’s still no cure for that.

    But in the case of Covid-19, it’s not for lack of trying. While the breathless search for a Covid-19 vaccine got most of the attention, the National Institutes of Health was running a sweeping parallel effort to find treatments for the disease itself.


    Some drugs ended up being dead ends, like the malaria drug hydroxychloroquine, and some were unexpected successes, like the lifesaving steroid dexamethasone. Among the bright spots was Gilead Sciences’ remdesivir, an intravenous antiviral that proved to modestly reduce the length of hospitalization for patients with Covid-19. Likewise the antibody treatments from Eli Lilly and Regeneron, which helped keep high-risk patients out of the hospital.


    Still missing, however, is what NIH Director Francis Collins called his “dream”: a highly effective pill that can be given immediately after diagnosis.


    “It’s just a damn long pathway,” Collins said in an interview. First scientists have to find molecular vulnerability in a virus, and then comes the process of screening hundreds of thousands of would-be drugs to find the few that latch onto that target. Then medicinal chemists get to work on honing a Goldilocks molecule that balances power, specificity, and safety, and if everything goes well in the Petri dish, there’s still months of animal testing to do before a single human being can take a pill in a clinical trial.


    “But I will tell you that this is an extremely high priority for Tony Fauci and Francis Collins and the Biden administration, to work with these companies to try to make sure that we speed this up,” Collins said. “Because this pandemic is going to be with us — even with great vaccines — and people are going to get sick.”


    There is hope, even in the short term. Any day now, Merck is expected to present pivotal data on an oral treatment akin to remdesivir. Behind that is a treatment from Atea Pharmaceuticals, first developed for hepatitis C virus, which could have pivotal results in the coming months. Neither is purpose-built for the virus that causes Covid-19, but experts said the treatments could still tick many of the boxes of a hoped-for antiviral.


    Perhaps most promising is a novel antiviral from Pfizer, a drug engineered specifically for the virus SARS-CoV-2 that entered its first clinical trial last month.


    Scientists are crossing their fingers that each one demonstrates at least a marginal benefit, as the history of virology suggests the best bet for beating back Covid-19 will be a cocktail of treatments with complementary effects. But beyond the immediate crisis, experts hope society learns two key lessons: Antiviral development is really hard, and it’s even harder if you wait for a pandemic to start investing in it.

    We need to start thinking about biomedical research as essential infrastructure,” said Angela Rasmussen, a virologist at Georgetown University’s Center for Global Health Science and Security. “It reinforces that preparedness is not just about how prepared we are to innovate our way out of a crisis. It really does mean investing in drugs that may not have an obvious application when we’re developing them up front.”


    How to make an antiviral

    The fundamental problem, for drug hunters, is that viruses don’t fight fair.


    As soon as SARS-CoV-2 takes hold, it begins using the body’s natural machinery to replicate itself. That gives the virus an edge. Scientists might spot scores of vulnerabilities in a virus, but the majority of them are sure to be shared by the host, making them unsafe targets to attack with a drug.


    “If you look at the number of antivirals that exist compared to the number of antibiotics, there are so many fewer antivirals,” said Brianne Barker, a biology professor at Drew University who specializes in the body’s response to viral infection. “The reason for that is that viruses use our cells to reproduce, so you’re looking for a drug that hits some part of the viral reproduction without hurting our cells. And that’s not easy.”


    Step one in the antiviral-development process is clearing that hurdle again and again, in the lab, in animals, and in healthy human volunteers.


    The next challenge relates to timing. The precise moment of viral infection starts a countdown clock as the virus gradually awakens the immune system, creating a narrow window of time after which an antiviral is likely useless.


    “For most viral diseases, the acute ones, the disease is really caused by the host’s response to it,” Rasmussen said. “If that virus gets a foothold and sets off all of these abnormal host processes, the horse is already out of the barn, so to speak.”


    For SARS-CoV-2, it can take anywhere from a few days to two weeks for those abnormal immune processes to kick in. That means any clinical trial for an antiviral requires a delicate design. Patients must have confirmed infections, but if they’re already experiencing serious symptoms of Covid-19, they might be too far along to benefit.


    Once a would-be antiviral developer has solved the timing problem, then there’s the conundrum of choosing a dose. In normal circumstances, dosing is a precise science, studied in tiered, escalating studies designed to isolate the perfect amount of drug that can achieve a benefit at minimal risk.


    In the immediacy of the pandemic, drug developers have understandably sped past some of that methodical work, making educated guesses in the spirit of emergency. That makes each antiviral trial a high-wire scientific act, said Craig Rayner, an executive at the drug development consultancy Certara who worked on Tamiflu. Choosing the right dose can determine not only whether a trial will succeed, but also the manufacturing, rollout, and final cost of the drug in question.


    “For every milligram above what is considered optimal, you’re wasting it,” Rayner said. “And for every milligram below, you’re putting everything at risk, because the virus has a chance to be clever and evolve around it.”


    That leads to the next hurdle in developing antivirals: Even if you succeed, one drug is never enough. Unless a given antiviral can block 100% of viral replication, in time, evolution is going to kick in.


    “In any other aspect of pharma, you’d never need to have 100% efficacy,” Barker said. “But with antivirals, if you allow any replication at all, the virus is going to mutate around the drug.”


    In the long-term, the best bet for controlling SARS-CoV-2 is widespread vaccination backed up by a combination antiviral treatment, experts said — a drug cocktail that targets multiple facets of the virus to minimize the risk of mutation.


    But first, they need that Tamiflu.


    The leading contenders

    The first drug poised to check all the boxes of an ideal antiviral is molnupiravir, invented at the Emory Institute for Drug Development and developed by Merck and Ridgeback Biotherapeutics. The drug is what’s known as a nucleoside analog, designed to throw a wrench in the process of viral replication by tricking SARS-CoV-2 into corrupting its own genetic material.


    Merck has enrolled about 3,000 patients, both hospitalized and recently diagnosed, in a pivotal trial that will determine whether molnupiravir can help clear SARS-CoV-2 from the body faster than placebo and keep patients out of the hospital. Data are expected in the coming weeks, and experts are particularly focused on whether Merck’s drug can prevent patients with mild symptoms from developing severe Covid-19.


    Behind Merck’s drug is a treatment from Atea Pharmaceuticals that builds on prior antiviral success. Atea’s drug, AT-527, targets an enzyme key to viral replication, a similar approach to Gilead Sciences’ curative treatments for hepatitis C. Later this year, Atea expects to have Phase 2 data on AT-527’s benefits for patients in and out of the hospital. The company is also planning a larger, Phase 3 study on outpatients.


    Experts are hopeful that both drugs can make a difference. They’ve selected targets that are likely to minimize the risk of side effects, and they’ve designed studies that should determine whether they work in that key post-diagnosis window. However, some expressed concern that because neither treatment was specifically engineered for SARS-CoV-2, there remains a substantial risk that each will come up short. When it comes to repurposed antivirals, “theoretically they should work great,” Rasmussen said, “but in reality a lot of times they don’t.”


    An antiviral from Pfizer, now in the earliest stages of human testing, could address that problem. Catchily named PF-07321332, Pfizer’s drug targets SARS-CoV-2’s backbone enzyme, the linchpin of the virus’s replication process. That enzyme, called 3CL, is one of two that are specific to all coronaviruses. That means if Pfizer can find the right dose, and run the right trials, it might have a treatment not just for SARS-CoV-2 but future pandemic viruses.


    “What we might end up doing here is curing the common cold,” Collins said. “Then I wouldn’t have to listen to those jokes anymore.”

  • Scientists work toward an elusive dream: a simple pill to treat Covid-19


    https://www.statnews.com/2021/…e-pill-to-treat-covid-19/

    A typical pharma advertisement. Firstly, it mentions Tamiflu three times, speaking as if it were a great thing to have against the flu! (Yeah as if only we had something like Tamiflu against the coronavirus!)


    Secondly it talks about a potential take-home pill for Covid-19 that would eliminate 100 percent of the virus, at a cheap cost, but that is oh so difficult to find. (more funding please).


    Thirdly, it decidedly fails to mention ivermectin, and writes off hydroxychloroquine.


    Some truth however, in the midst of the pharmadrivel :

    “For most viral diseases, the acute ones, the disease is really caused by the host’s response to it,” Rasmussen said.

  • Anyways, Canada is now entering into our third wave, with Toronto as the epicentre. Toronto has just entered into its third stay at home order, schools now closed and only essential businesses open to the public. I hear that Toronto has been the most locked down city in North America over the course of the pandemic. (What have our lockdowns and mask mandates gotten us?) Most cases in Toronto now are the new "variants of concern" which apparently infect younger people more readily. This may also be why our mortality rate is down : more young people are getting infected.

    Cooking with Ontario Premier

    Doug Ford.

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    Controversial Alberta Church.


    https://www.rebelnews.com/high…_raid_on_gracelife_church



    https://www.citynews1130.com/2…d-19-alberta-church-shut/