Brain-dead or what? This photograph of a meeting of the cabinet taken just a few hours before the PM urged people to wear masks in crowded indoor spaces...
Early COVID Care Experts Launches Online Hub for Early Treatment
Early COVID Care Experts Launches Online Hub for Early Treatment
TrialSite shares some important news with the community—the recent launch of https://earlycovidcare.org/, an online hub for early treatment advocacy by the Early COVID Care Experts (ECCE). This site offers guidance for clinicians, scientific evidence supporting early treatment, and resources to help patients find doctors who are willing to prescribe.
Perhaps 90% or more of SARS-CoV-2 infections are mild-to-moderate in severity and for the duration of the pandemic passionate, dedicated physicians evangelized the importance of treating COVID-19 early on. Unfortunately to this day, the established protocol involves no care other than over-the-counter drugs and rest. Consequently, patients diagnosed with COVID-19 are sent home and instructed to come back to the hospital if conditions materially worsen. But how many of this type of scenario could be avoided with early care?
At earlycovidcare.org, those interested can learn about the history, safety, and current usage of effective drug treatments for COVID-19, and find COVID-expert doctors who are available either in person or by telemedicine to provide expert outpatient, early treatment for COVID patients.
Early COVID Care Experts include prominent physicians dedicated to safe and effective early treatment options including Dr. Peter McCullough, Dr. Harvey Risch, Dr. George Fareed, and Dr. Ramin Oskoui.
Call to Action: We invite you to visit their new site to review the evidence in support of COVID treatments, find guidance for clinicians, or see the latest from the Early COVID Care Experts. You may also email them at [email protected] for more information.
The tangled history of mRNA vaccines
Hundreds of scientists had worked on mRNA vaccines for decades before the coronavirus pandemic brought a breakthrough.
In late 1987, Robert Malone performed a landmark experiment. He mixed strands of messenger RNA with droplets of fat, to create a kind of molecular stew. Human cells bathed in this genetic gumbo absorbed the mRNA, and began producing proteins from it1.
Realizing that this discovery might have far-reaching potential in medicine, Malone, a graduate student at the Salk Institute for Biological Studies in La Jolla, California, later jotted down some notes, which he signed and dated. If cells could create proteins from mRNA delivered into them, he wrote on 11 January 1988, it might be possible to “treat RNA as a drug”. Another member of the Salk lab signed the notes, too, for posterity. Later that year, Malone’s experiments showed that frog embryos absorbed such mRNA2. It was the first time anyone had used fatty droplets to ease mRNA’s passage into a living organism.
Those experiments were a stepping stone towards two of the most important and profitable vaccines in history: the mRNA-based COVID-19 vaccines given to hundreds of millions of people around the world. Global sales of these are expected to top US$50 billion in 2021 alone.
But the path to success was not direct. For many years after Malone’s experiments, which themselves had drawn on the work of other researchers, mRNA was seen as too unstable and expensive to be used as a drug or a vaccine. Dozens of academic labs and companies worked on the idea, struggling with finding the right formula of fats and nucleic acids — the building blocks of mRNA vaccines.
Today’s mRNA jabs have innovations that were invented years after Malone’s time in the lab, including chemically modified RNA and different types of fat bubble to ferry them into cells (see ‘Inside an mRNA COVID vaccine’). Still, Malone, who calls himself the “inventor of mRNA vaccines”, thinks his work hasn’t been given enough credit. “I’ve been written out of history,” he told Nature.
Inside an mRNA COVID vaccine: infographic that shows the innovations used in the mRNA and nanoparticle of the vaccine.
Nik Spencer/Nature; Adapted from M. D. Buschmann et al. Vaccines 9, 65 (2021)
The debate over who deserves credit for pioneering the technology is heating up as awards start rolling out — and the speculation is getting more intense in advance of the Nobel prize announcements next month. But formal prizes restricted to only a few scientists will fail to recognize the many contributors to mRNA’s medical development. In reality, the path to mRNA vaccines drew on the work of hundreds of researchers over more than 30 years.
The story illuminates the way that many scientific discoveries become life-changing innovations: with decades of dead ends, rejections and battles over potential profits, but also generosity, curiosity and dogged persistence against scepticism and doubt. “It’s a long series of steps,” says Paul Krieg, a developmental biologist at the University of Arizona in Tucson, who made his own contribution in the mid-1980s, “and you never know what’s going to be useful”.
The beginnings of mRNA
Malone’s experiments didn’t come out of the blue. As far back as 1978, scientists had used fatty membrane structures called liposomes to transport mRNA into mouse3 and human4 cells to induce protein expression. The liposomes packaged and protected the mRNA and then fused with cell membranes to deliver the genetic material into cells. These experiments themselves built on years of work with liposomes and with mRNA; both were discovered in the 1960s (see ‘The history of mRNA vaccines’).
The history of mRNA vaccines: A timeline that shows the key scientific innovations in the development of mRNA vaccines.
Nik Spencer/Nature; Adapted from U. Şahin et al. Nature Rev. Drug Discov. 13, 759–780 (2014) and X. Hou et al. Nature Rev. Mater. https://doi.org/gmjsn5 (2021).
Back then, however, few researchers were thinking about mRNA as a medical product — not least because there was not yet a way to manufacture the genetic material in a laboratory. Instead, they hoped to use it to interrogate basic molecular processes. Most scientists repurposed mRNA from rabbit blood, cultured mouse cells or some other animal source.
That changed in 1984, when Krieg and other members of a team led by developmental biologist Douglas Melton and molecular biologists Tom Maniatis and Michael Green at Harvard University in Cambridge, Massachusetts, used an RNA-synthesis enzyme (taken from a virus) and other tools to produce biologically active mRNA in the lab5 — a method that, at its core, remains in use today. Krieg then injected the lab-made mRNA into frog eggs, and showed that it worked just like the real thing6.
Both Melton and Krieg say they saw synthetic mRNA mainly as a research tool for studying gene function and activity. In 1987, after Melton found that the mRNA could be used both to activate and to prevent protein production, he helped to form a company called Oligogen (later renamed Gilead Sciences in Foster City, California) to explore ways to use synthetic RNA to block the expression of target genes — with an eye to treating disease. Vaccines weren’t on the mind of anyone in his lab, or their collaborators.
RNA in general had a reputation for unbelievable instability,” says Krieg. “Everything around RNA was cloaked in caution.” That might explain why Harvard’s technology-development office elected not to patent the group’s RNA-synthesis approach. Instead, the Harvard researchers simply gave their reagents to Promega Corporation, a lab-supplies company in Madison, Wisconsin, which made the RNA-synthesis tools available to researchers. They received modest royalties and a case of Veuve Clicquot Champagne in return.
Patent disputes
Years later, Malone followed the Harvard team’s tactics to synthesize mRNA for his experiments. But he added a new kind of liposome, one that carried a positive charge, which enhanced the material’s ability to engage with the negatively charged backbone of mRNA. These liposomes were developed by Philip Felgner, a biochemist who now leads the Vaccine Research and Development Center at the University of California, Irvine.
Despite his success using the liposomes to deliver mRNA into human cells and frog embryos, Malone never earned a PhD. He fell out with his supervisor, Salk gene-therapy researcher Inder Verma and, in 1989, left graduate studies early to work for Felgner at Vical, a recently formed start-up in San Diego, California. There, they and collaborators at the University of Wisconsin–Madison showed that the lipid–mRNA complexes could spur protein production in mice7.
Then things got messy. Both Vical (with the University of Wisconsin) and the Salk began filing for patents in March 1989. But the Salk soon abandoned its patent claim, and in 1990, Verma joined Vical’s advisory board.
Malone contends that Verma and Vical struck a back-room deal so that the relevant intellectual property went to Vical. Malone was listed as one inventor among several, but he no longer stood to profit personally from subsequent licensing deals, as he would have from any Salk-issued patents. Malone’s conclusion: “They got rich on the products of my mind.”
Verma and Felgner categorically deny Malone’s charges. “It’s complete nonsense,” Verma told Nature. The decision to drop the patent application rested with the Salk’s technology-transfer office, he says. (Verma resigned from the Salk in 2018, following allegations of sexual harassment, which he continues to deny.)
Malone left Vical in August 1989, citing disagreements with Felgner over “scientific judgment” and “credit for my intellectual contributions”. He completed medical school and did a year of clinical training before working in academia, where he tried to continue research on mRNA vaccines but struggled to secure funding. (In 1996, for example, he unsuccessfully applied to a California state research agency for money to develop a mRNA vaccine to combat seasonal coronavirus infections.) Malone focused on DNA vaccines and delivery technologies instead.
In 2001, he moved into commercial work and consulting. And in the past few months, he has started publicly attacking the safety of the mRNA vaccines that his research helped to enable. Malone says, for instance, that proteins produced by vaccines can damage the body’s cells and that the risks of vaccination outweigh the benefits for children and young adults — claims that other scientists and health officials have repeatedly refuted.
Manufacturing challenges
In 1991, Vical entered into a multimillion-dollar research collaboration and licensing pact with US firm Merck, one of the world’s largest vaccine developers. Merck scientists evaluated the mRNA technology in mice with the aim of creating an influenza vaccine, but then abandoned that approach. “The cost and feasibility of manufacturing just gave us pause,” says Jeffrey Ulmer, a former Merck scientist who now consults with companies on vaccine-research issues.
Researchers at a small biotech firm in Strasbourg, France, called Transgène, felt the same way. There, in 1993, a team led by Pierre Meulien, working with industrial and academic partners, was the first to show that an mRNA in a liposome could elicit a specific antiviral immune response in mice8. (Another exciting advance had come in 1992, when scientists at the Scripps Research Institute in La Jolla used mRNA to replace a deficient protein in rats, to treat a metabolic disorder9. But it would take almost two decades before independent labs reported similar success.)
The Transgène researchers patented their invention, and continued to work on mRNA vaccines. But Meulien, who is now head of the Innovative Medicines Initiative, a public–private enterprise based in Brussels, estimated that he needed at least €100 million (US$119 million) to optimize the platform — and he wasn’t about to ask his bosses for that much for such a “tricky, high-risk” venture, he says. The patent lapsed after Transgène’s parent firm decided to stop paying the fees needed to keep it active.
Meulien’s group, like the Merck team, moved to focus instead on DNA vaccines and other vector-based delivery systems. The DNA platform ultimately yielded a few licensed vaccines for veterinary applications — helping, for example, to prevent infections in fish farms. And just last month, regulators in India granted emergency approval to the world’s first DNA vaccine for human use, to help ward off COVID-19. But for reasons that are not completely understood, DNA vaccines have been slow to find success in people.
Still, the industry’s concerted push around DNA technology has had benefits for RNA vaccines, too, argues Ulmer. From manufacturing considerations and regulatory experience to sequence designs and molecular insights, “many of the things that we learned from DNA could be directly applied to RNA”, he says. “It provided the foundation for the success of RNA.”
Continuous struggle
In the 1990s and for most of the 2000s, nearly every vaccine company that considered working on mRNA opted to invest its resources elsewhere. The conventional wisdom held that mRNA was too prone to degradation, and its production too expensive. “It was a continuous struggle,” says Peter Liljeström, a virologist at the Karolinska Institute in Stockholm, who 30 years ago pioneered a type of ‘self-amplifying’ RNA vaccine.
“RNA was so hard to work with,” says Matt Winkler, who founded one of the first RNA-focused lab supplies companies, Ambion, in Austin, Texas, in 1989. “If you had asked me back [then] if you could inject RNA into somebody for a vaccine, I would have laughed in your face.”
The mRNA vaccine idea had a more favourable reception in oncology circles, albeit as a therapeutic agent, rather than to prevent disease. Beginning with the work of gene therapist David Curiel, several academic scientists and start-up companies explored whether mRNA could be used to combat cancer. If mRNA encoded proteins expressed by cancer cells, the thinking went, then injecting it into the body might train the immune system to attack those cells.
Curiel, now at the Washington University School of Medicine in St Louis, Missouri, had some success in mice10. But when he approached Ambion about commercialization opportunities, he says, the firm told him: “We don’t see any economic potential in this technology.”
Another cancer immunologist had more success, which led to the founding of the first mRNA therapeutics company, in 1997. Eli Gilboa proposed taking immune cells from the blood, and coaxing them to take up synthetic mRNA that encoded tumour proteins. The cells would then be injected back into the body where they could marshal the immune system to attack lurking tumours.
Gilboa and his colleagues at Duke University Medical Center in Durham, North Carolina, demonstrated this in mice11. By the late 1990s, academic collaborators had launched human trials, and Gilboa’s commercial spin-off, Merix Bioscience (later renamed to Argos Therapeutics and now called CoImmune), soon followed with clinical studies of its own. The approach was looking promising until a few years ago, when a late-stage candidate vaccine failed in a large trial; it has now largely fallen out of fashion.
But Gilboa’s work had an important consequence. It inspired the founders of the German firms CureVac and BioNTech — two of the largest mRNA companies in existence today — to begin work on mRNA. Both Ingmar Hoerr, at CureVac, and Uğur Şahin, at BioNTech, told Nature that, after learning of what Gilboa had done, they wanted to do the same, but by administering mRNA into the body directly.
There was a snowball effect,” says Gilboa, now at the University of Miami Miller School of Medicine in Florida.
Start-up accelerator
Hoerr was the first to achieve success. While at the University of Tübingen in Germany, he reported in 2000 that direct injections could elicit an immune response in mice12. He created CureVac (also based in Tübingen) that year. But few scientists or investors seemed interested. At one conference where Hoerr presented early mouse data, he says, “there was a Nobel prizewinner standing up in the first row saying, ‘This is completely shit what you’re telling us here — completely shit’.” (Hoerr declined to name the Nobel laureate.)
Eventually, money trickled in. And within a few years, human testing began. The company’s chief scientific officer at the time, Steve Pascolo, was the first study subject: he injected himself13 with mRNA and still has match-head-sized white scars on his leg from where a dermatologist took punch biopsies for analysis. A more formal trial, involving tumour-specific mRNA for people with skin cancer, kicked off soon after.
Şahin and his immunologist wife, Özlem Türeci, also began studying mRNA in the late 1990s, but waited longer than Hoerr to start a company. They plugged away at the technology for many years, working at Johannes Gutenberg University Mainz in Germany, earning patents, papers and research grants, before pitching a commercial plan to billionaire investors in 2007. “If it works, it will be ground-breaking,” Şahin said. He got €150 million in seed money.
The same year, a fledgling mRNA start-up called RNARx received a more modest sum: $97,396 in small-business grant funding from the US government. The company’s founders, biochemist Katalin Karikó and immunologist Drew Weissman, both then at the University of Pennsylvania (UPenn) in Philadelphia, had made what some now say is a key finding: that altering part of the mRNA code helps synthetic mRNA to slip past the cell’s innate immune defences.
Fundamental insights
Karikó had toiled in the lab throughout the 1990s with the goal of transforming mRNA into a drug platform, although grant agencies kept turning down her funding applications. In 1995, after repeated rejections, she was given the choice of leaving UPenn or accepting a demotion and pay cut. She opted to stay and continue her dogged pursuit, making improvements to Malone’s protocols14, and managing to induce cells to produce a large and complex protein of therapeutic relevance15.
In 1997, she began working with Weissman, who had just started a lab at UPenn. Together, they planned to develop an mRNA-based vaccine for HIV/AIDS. But Karikó’s mRNAs set off massive inflammatory reactions when they were injected into mice.
She and Weissman soon worked out why: the synthetic mRNA was arousing16 a series of immune sensors known as Toll-like receptors, which act as first responders to danger signals from pathogens. In 2005, the pair reported that rearranging the chemical bonds on one of mRNA’s nucleotides, uridine, to create an analogue called pseudouridine, seemed to stop the body identifying the mRNA as a foe17.
Few scientists at the time recognized the therapeutic value of these modified nucleotides. But the scientific world soon awoke to their potential. In September 2010, a team led by Derrick Rossi, a stem-cell biologist then at Boston Children’s Hospital in Massachusetts, described how modified mRNAs could be used to transform skin cells, first into embryonic-like stem cells and then into contracting muscle tissue18. The finding made a splash. Rossi was featured in Time magazine as one of 2010’s ‘people who mattered’. He co-founded a start-up, Moderna in Cambridge.
Moderna tried to license the patents for modified mRNA that UPenn had filed in 2006 for Karikó’s and Weissman’s invention. But it was too late. After failing to come to a licensing agreement with RNARx, UPenn had opted for a quick payout. In February 2010, it granted exclusive patent rights to a small lab-reagents supplier in Madison. Now called Cellscript, the company paid $300,000 in the deal. It would go on to pull in hundreds of millions of dollars in sublicensing fees from Moderna and BioNTech, the originators of the first mRNA vaccines for COVID-19. Both products contain modified mRNA.
RNARx, meanwhile, used up another $800,000 in small-business grant funding and ceased operations in 2013, around the time that Karikó joined BioNTech (retaining an adjunct appointment at UPenn).
The pseudouridine debate
Researchers still argue over whether Karikó and Weissman’s discovery is essential for successful mRNA vaccines. Moderna has always used modified mRNA — its name is a portmanteau of those two words. But some others in the industry have not.
Researchers at the human-genetic-therapies division of the pharmaceutical firm Shire in Lexington, Massachusetts, reasoned that unmodified mRNA could yield a product that was just as effective if the right ‘cap’ structures were added and all impurities were removed. “It came down to the quality of the RNA,” says Michael Heartlein, who led Shire’s research effort and continued to advance the technology at Translate Bio in Cambridge, to which Shire later sold its mRNA portfolio. (Shire is now part of the Japanese firm Takeda.)
Although Translate has some human data to suggest its mRNA does not provoke a concerning immune response, its platform remains to be proved clinically: its COVID-19 vaccine candidate is still in early human trials. But French drug giant Sanofi has been convinced of the technology’s promise: in August 2021, it announced plans to acquire Translate for $3.2 billion. (Heartlein left last year to found another firm in Waltham, Massachusetts, called Maritime Therapeutics.)
CureVac, meanwhile, has its own immune-mitigation strategy, which involves altering the genetic sequence of the mRNA to minimize the amount of uridine in its vaccines. Twenty years of working on that approach seemed to be bearing fruit, with early trials of the company’s experimental vaccines for rabies19 and COVID-1920 both proving a success. But in June, data from a later-stage trial showed that CureVac’s coronavirus vaccine candidate was much less protective than Moderna’s or BioNTech’s.
In light of those results, some mRNA experts now consider pseudouridine an essential component of the technology — and so, they say, Karikó’s and Weissman’s discovery was one of the key enabling contributions that merits recognition and prizes. “The real winner here is modified RNA,” says Jake Becraft, co-founder and chief executive of Strand Therapeutics, a Cambridge-based synthetic-biology company working on mRNA-based therapeutics.
Not everyone is so certain. “There are multiple factors that may affect the safety and efficacy of an mRNA vaccine, chemical modification of mRNA is only one of them,” says Bo Ying, chief executive of Suzhou Abogen Biosciences, a Chinese company with an mRNA vaccine for COVID-19 now in late-stage clinical testing. (Known as ARCoV, the product uses unmodified mRNA.)
Fat breakthrough
As for linchpin technologies, many experts highlight another innovation that was crucial for mRNA vaccines — one that has nothing to do with the mRNA. It is the tiny fat bubbles known as lipid nanoparticles, or LNPs, that protect the mRNA and shuttle it into cells.
This technology comes from the laboratory of Pieter Cullis, a biochemist at the University of British Columbia in Vancouver, Canada, and several companies that he founded or led. Beginning in the late 1990s, they pioneered LNPs for delivering strands of nucleic acids that silence gene activity. One such treatment, patisiran, is now approved for a rare inherited disease.
After that gene-silencing therapy began to show promise in clinical trials, in 2012, two of Cullis’s companies pivoted to explore opportunities for the LNP delivery system in mRNA-based medicines. Acuitas Therapeutics in Vancouver, for example, led by chief executive Thomas Madden, forged partnerships with Weissman’s group at UPenn and with several mRNA companies to test different mRNA–LNP formulations. One of these can now be found in the COVID-19 vaccines from BioNTech and CureVac. Moderna’s LNP concoction is not much different.
The nanoparticles have a mixture of four fatty molecules: three contribute to structure and stability; the fourth, called an ionizable lipid, is key to the LNP’s success. This substance is positively charged under laboratory conditions, which offers similar advantages to the liposomes that Felgner developed and Malone tested in the late 1980s. But the ionizable lipids advanced by Cullis and his commercial partners convert to a neutral charge under physiological conditions such as those in the bloodstream, which limits the toxic effects on the body.
What’s more, the four-lipid cocktail allows the product to be stored for longer on the pharmacy shelf and to maintain its stability inside the body, says Ian MacLachlan, a former executive at several Cullis-linked ventures. “It’s the whole kit and caboodle that leads to the pharmacology we have now,” he says.
By the mid-2000s, a new way to mix and manufacture these nanoparticles had been devised. It involved using a ‘T-connector’ apparatus, which combines fats (dissolved in alcohol) with nucleic acids (dissolved in an acidic buffer). When streams of the two solutions merged, the components spontaneously formed densely packed LNPs21. It proved to be a more reliable technique than other ways of making mRNA-based medicines.
Once all the pieces came together, “it was like, holy smoke, finally we’ve got a process we can scale”, says Andrew Geall, now chief development officer at Replicate Bioscience in San Diego. Geall led the first team to combine LNPs with an RNA vaccine22, at Novartis’s US hub in Cambridge in 2012. Every mRNA company now uses some variation of this LNP delivery platform and manufacturing system — although who owns the relevant patents remains the subject of legal dispute. Moderna, for example, is locked in a battle with one Cullis-affiliated business — Arbutus Biopharma in Vancouver — over who holds the rights to the LNP technology found in Moderna’s COVID-19 jab.
An industry is born
By the late 2000s, several big pharmaceutical companies were entering the mRNA field. In 2008, for example, both Novartis and Shire established mRNA research units — the former (led by Geall) focused on vaccines, the latter (led by Heartlein) on therapeutics. BioNTech launched that year, and other start-ups soon entered the fray, bolstered by a 2012 decision by the US Defense Advanced Research Projects Agency to start funding industry researchers to study RNA vaccines and drugs. Moderna was one of the companies that built on this work and, by 2015, it had raised more than $1 billion on the promise of harnessing mRNA to induce cells in the body to make their own medicines — thereby fixing diseases caused by missing or defective proteins. When that plan faltered, Moderna, led by chief executive Stéphane Bancel, chose to prioritize a less ambitious target: making vaccines.
That initially disappointed many investors and onlookers, because a vaccine platform seemed to be less transformative and lucrative. By the beginning of 2020, Moderna had advanced nine mRNA vaccine candidates for infectious diseases into people for testing. None was a slam-dunk success. Just one had progressed to a larger-phase trial.
But when COVID-19 struck, Moderna was quick off the mark, creating a prototype vaccine within days of the virus’s genome sequence becoming available online. The company then collaborated with the US National Institute of Allergy and Infectious Diseases (NIAID) to conduct mouse studies and launch human trials, all within less than ten weeks.
BioNTech, too, took an all-hands-on-deck approach. In March 2020, it partnered with New York-based drug company Pfizer, and clinical trials then moved at a record pace, going from first-in-human testing to emergency approval in less than eight months.
Both authorized vaccines use modified mRNA formulated in LNPs. Both also contain sequences that encode a form of the SARS-CoV-2 spike protein that adopts a shape more amenable to inducing protective immunity. Many experts say that the protein tweak, devised by NIAID vaccinologist Barney Graham and structural biologists Jason McLellan at the University of Texas at Austin and Andrew Ward at Scripps, is also a prize-worthy contribution, albeit one that is specific to coronavirus vaccines, not mRNA vaccination as a general platform
Some of the furore in discussions of credit for mRNA discoveries relates to who holds lucrative patents. But much of the foundational intellectual property dates back to claims made in 1989 by Felgner, Malone and their colleagues at Vical (and in 1990 by Liljeström). These had only a 17-year term from the date of issue and so are now in the public domain.
Even the Karikó–Weissman patents, licensed to Cellscript and filed in 2006, will expire in the next five years. Industry insiders say this means that it will soon become very hard to patent broad claims about delivering mRNAs in lipid nanoparticles, although companies can reasonably patent particular sequences of mRNA — a form of the spike protein, say — or proprietary lipid formulations.
Firms are trying. Moderna, the dominant player in the mRNA vaccine field, which has experimental shots in clinical testing for influenza, cytomegalovirus and a range of other infectious diseases, got two patents last year covering the broad use of mRNA to produce secreted proteins. But multiple industry insiders told Nature they think these could be challengeable.
We don’t feel there’s a lot that is patentable, and certainly not enforceable,” says Eric Marcusson, chief scientific officer of Providence Therapeutics, an mRNA vaccines company in Calgary, Canada.
Nobel debate
As for who deserves a Nobel, the names that come up most often in conversation are Karikó and Weissman. The two have already won several prizes, including one of the Breakthrough Prizes (at $3 million, the most lucrative award in science) and Spain’s prestigious Princess of Asturias Award for Technical and Scientific Research. Also recognized in the Asturias prize were Felgner, Şahin, Türeci and Rossi, along with Sarah Gilbert, the vaccinologist behind the COVID-19 vaccine developed by the University of Oxford, UK, and the drug firm AstraZeneca, which uses a viral vector instead of mRNA. (Cullis’s only recent accolade was a $5,000 founder’s award from the Controlled Release Society, a professional organization of scientists who study time-release drugs.)
Some also argue that Karikó should be acknowledged as much for her contributions to the mRNA research community at large as for her discoveries in the lab. “She’s not only an incredible scientist, she’s just a force in the field,” says Anna Blakney, an RNA bioengineer at the University of British Columbia. Blakney gives Karikó credit for offering her a speaking slot at a major conference two years ago, when she was still in a junior postdoc position (and before Blakney co-founded VaxEquity, a vaccine company in Cambridge, UK, focusing on self-amplifying-RNA technology). Karikó “is actively trying to lift other people up in a time when she’s been so under-recognized her whole career”.
Although some involved in mRNA’s development, including Malone, think they deserve more recognition, others are more willing to share the limelight. “You really can’t claim credit,” says Cullis. When it comes to his lipid delivery system, for instance, “we’re talking hundreds, probably thousands of people who have been working together to make these LNP systems so that they’re actually ready for prime time.”
“Everyone just incrementally added something — including me,” says Karikó.
Looking back, many say they’re just delighted that mRNA vaccines are making a difference to humanity, and that they might have made a valuable contribution along the road. “It’s thrilling for me to see this,” says Felgner. “All of the things that we were thinking would happen back then — it’s happening now.”
Nature 597, 318-324 (2021)
So meany working together now its interesting, maybe they will solve the bigger puzzle's
Israeli scientists say their antiviral drug could stop COVID-19
A team of Israeli scientists say that a drug previously used in an uncontrolled fashion to treat HIV has a direct antiviral effect against coronavirus, sending patients home virus-free within only a few days.
Code Pharma, which is headquartered in the Netherlands but has its research and development office in Israel and an Israeli CEO, recently completed a Phase I trial of its drug Codivir for use against coronavirus. On Monday, the Israeli research team that will support the Phase II trial applied for permission from the Helsinki Committee to move forward at the Barzilai Medical Center.
The Phase II study, which will involve around 150 patients and is expected to launch in the next month, will also take place in Spain, Brazil and South Africa. According to Code Pharma CEO Zyon Ayni, the goal is to complete the trial within about three to six months and then already apply for emergency use authorization of the drug.
In the first and second wave of the COVID-19 pandemic, many of the drugs with putative or proven antiviral mechanisms of action have not proven themselves to significantly prolong life expectancy,” said Prof. Shlomo Maayan, director of the Infectious Disease division at Barzilai. He is advising Code Pharma as it moves forward with Codivir but receives no financial or other compensation.
“Codivir has a very good safety profile and a very impressive antiviral effect, both in laboratory conditions and in a phase I clinical trial in humans,” he said. “We eagerly await the results of the double-blind studies using Codivir. It may be a breakthrough in the field of antiviral therapy for early COVID-19 patients.”
The Phase I trial was recently completed in Brazil at Casa de Saúde – Vera Cruz Hospital in São Paulo, Brazil, under the approval of the National Research Ethics Commission (CONEP). Twelve patients between the ages of 18 and 60 with mild to moderate coronavirus participated in the study.
Seven of the volunteers were tested sequentially using a standard PCR swab test every two days from the time they began receiving the treatment, which like insulin is given subcutaneously – injection under the skin.
Patients received two injections per day for 10 days.
Maayan said that five of the patients showed a very profound decline in the viral load during the treatment. Codivir significantly suppressed viral replication in all patients with an antiviral effect noted as early as three days after the beginning of treatment.
Moreover, the safety profile of the drug was very good. There were no significant side effects from the treatment itself, Ayni said, nor did those who received the drug show any signs of side effects that are very often associated with COVID-19 infections.
Manuscripts describing these results have been submitted to a peer-reviewed journal.
CODIVIR IS based on a short 16 amino-acid peptide derived from the HIV-1 integrase. It was first discovered by researchers at the Hebrew University, who are still involved with the company.
“The initial idea was to eradicate HIV-infected cells,” the CEO explained, noting that the drug seemed to induce HIV cell death in pre-clinical trials. Around the time that the coronavirus pandemic was beginning, Code Pharma was testing the drug unofficially in HIV patients in the Congo.
“One hospital there started administering it to COVID-19 patients, too, and they got completely better – some in hours and some in days,” Ayni said.
The hospital then requested additional doses, which it administered in an unofficial clinical trial, where doctors divided and tracked patients who received Codivir and patients who did not. All of the patients were between the ages of 35 and 78 and were being treated in the intensive care unit – though he said the ICU in the Congo does not look like a Western ICU, meaning the patients were only receiving oxygen.
“The doctor gave them the medication and saw that in only nine days, two patients completely recovered and the rest got much better and almost had no trace of the virus. Of the 15 people who did not receive the medication, 14 died.
“It was very clear we were onto something, but we did not know what,” Ayni said.
So, the company decided to conduct in-vitro studies at the well-respected Virology Research Services in London, with what Maayan described as “excellent results.”
“We saw complete elimination of the virus in 90% to 100% of cells in less than 24 hours,” Ayni said, noting that the results play out slightly differently in people. However, one thing was clear to Code Pharma: The laboratory studies demonstrated a potent antiviral activity.
The lab results are what led to the Brazil trial.
The Phase II multinational trial will be double-blind and also evaluate Codivir in the treatment of mild to moderate cases.
“The idea is that if the data we generated from Phase I with no controls repeats itself, this will be a significant achievement,” Maayan said. “If the results do not repeat themselves, then it is a no-go.
“But with both the laboratory results and the Phase I trial so encouraging, it looks promising,” he said.
Due to the high levels of COVID infection continuing around the world, the company is already preparing to submit emergency approval requests to several countries once the Phase II trial is complete, Ayni said. It is also preparing for mass production of Codivir at different sites worldwide.
“The world is in need of an antiviral medication against COVID.”
A thermostable oral SARS-CoV-2 vaccine induces mucosal and protective immunity
Abstract
An ideal protective vaccine against SARS-CoV-2 should not only be effective in preventing disease, but also in preventing virus transmission. It should also be well accepted by the population and have a simple logistic chain. To fulfill these criteria, we developed a thermostable, orally administered vaccine that can induce a robust mucosal neutralizing immune response. We used our platform based on retrovirus-derived enveloped virus-like particles (e-VLPs) harnessed with variable surface proteins (VSPs) from the intestinal parasite Giardia lamblia, affording them resistance to degradation and the triggering of robust mucosal cellular and antibody immune responses after oral administration. We made e-VLPs expressing various forms of the SARS-CoV-2 Spike protein (S), with or without membrane protein (M) expression. We found that prime-boost administration of VSP-decorated e-VLPs expressing a pre-fusion stabilized form of S and M triggers robust mucosal responses against SARS-CoV-2 in mice and hamsters, which translate into complete protection from a viral challenge. Moreover, they dramatically boosted the IgA mucosal response of intramuscularly injected vaccines. We conclude that our thermostable orally administered e-VLP vaccine could be a valuable addition to the current arsenal against SARS-CoV-2, in a stand-alone prime-boost vaccination strategy or as a boost for existing vaccines.
Discussion
The differences observed between the same formulations administered either orally or intramuscularly in these animals suggest that although the oral route is expected to show a higher degree of variation among animals, this was not the case. This could be explained by the type of generated Igs. Notably, considering the i.m. administration was done in the absence of any added adjuvant, the high immunogenicity of VSP-e-VLPs can be explained by the adjuvant properties of the VSPs, which have been demonstrated to activate TLR-419. The immunogenicity of the e-VLPs lacking VSPs may mainly rely on the particulate nature of VLPs and the repetitive exposure of the antigen on their surface, even TLR-signaling as been described43.
Our results first show that it is possible to co-express SARS-CoV-2 envelope proteins together with Giardia VSPs on e-VLPs to generate mucosal Igs and NAbs against SARS-CoV-2 after oral administration. While plain e-VLPs did not generate any Ab responses, VSP-decorated e-VLPs (VSP-e-VLPs) generated Ab responses in the range of, if not higher than, the response to i.m. administration. This is remarkable as it indicates that the SARS-CoV-2 Env proteins are well protected from degradation by VSPs as they preserve their proper conformation, which is needed for NAb production. Thus, this extends our previous results with e-VLP expressing HA of influenza19, demonstrating the versatility of the VSP-e-VLP platform. Actually, the dual properties of VSPs were confirmed: they not only afford protection from degradation, but also have a potent adjuvant effect. Indeed, when vaccines are administered i.m., VSP-e-VLP always led to higher titers of antibodies than their plain e-VLPs. Of note, a SARS-CoV-2 VLP based on our platform technology15 was independently reported to generate a good NAb response after i.m. administration, but with no reports of IgA at mucosal sites.
Besides its ease, oral administration is known for also having the advantage of triggering better mucosal immunity. This is indeed the case here, with high levels of plasma but also bronchoalveolar lavage IgA detectable only after oral administration. This is an obvious advantage for a vaccine against SARS-CoV-2, as it should reduce viral transmission. In this line, SARS-CoV-2 was still detected in BAL of i.m. vaccinated macaques that otherwise appeared protected from infection. Whether a better mucosal response, as afforded by VSP-e-VLPs, will completely sterilize challenged macaques requires further investigation.
We have not tested the specific T cell response in this study. However, it is known that e-VLPs do induce robust cellular responses; indeed, using VSP-HA-VLPs, a strong cytotoxic T lymphocyte response was generated that was able to kill HA-expressing tumor cells25. Moreover, the IgG and IgA responses here are notoriously T cell-dependent and the good antibody response thus attests to a good T cell response44. In this line, we previously showed that the fusion of a viral peptide to Gag, the retroviral protein precursor that drives the formation and release of the viral particle/VLPs, produces additional strong T cell responses against this peptide12. The fusion to Gag of large fragments or the SARS-CoV-2 N structural protein, or a stretch of immunodominant and/or conserved peptides, would be a mean to further enhance the immunogenicity of VSP-e-VLPs and enhance protection against variants.
SARS-CoV-2 e-VLPs and VSP-e-VLPs could be used as a stand-alone vaccine, likely with a prime-boost scheme of administration. VSP-e-VLPs are thermostable 19, retaining their properties at room temperature and tolerating several freeze-thaw cycles, and could thus be particularly advantageous for vaccination in countries where refrigeration of vaccine supplies is problematic. VSP-e-VLPs could also be used as a boost for other vaccine designs. In this regard, it is still unknown how long the protection afforded by the currently used vaccines will last. The follow-up of infected patients indicates that, at least for some patients, the persistence of NAbs and the duration of protection might last a few months45. These findings, plus the advent of viral variants, make it likely that the global population will need to boost the immune response of vaccinees regularly. For some vaccine designs, and particularly those based on adenoviral vectors, the re-administration of the same vector might not be very efficient due to the immune response generated against the vector. For these, a boost with VSP-e-VLPs might be particularly interesting. For other vaccine designs, and especially if repeated administrations are needed over the years, an orally administered vaccine might be more acceptable.
The SARS-CoV-2 pandemic calls for vaccination of very large groups of people. This requires a suitable production of vaccine with an excellent safety profile. Noteworthy, we contributed to the design of an anti-CMV e-VLP vaccine based on our e-VLP platform that has already been used in patients, demonstrating scalable GMP production and an excellent safety profile15,17,46.
Altogether, given the specific issues of each vaccine design (thermostability, side effects, lack of mucosal immunity induction, immunogenicity against the vector, among other benefits), the availability of multiple vaccines against SARS-CoV-2 improves our chances of controlling the pandemic. In this regard, a thermostable orally administered e-VLP vaccine will be a valuable addition to the current arsenal against this virus.
Just how bad is this delta Variant?
The COVID-19 Hospitalization Metric in the Pre- and Post-vaccination Eras as a Measure of Pandemic Severity: A Retrospective, Nationwide Cohort Study
Abstract
Importance: Since the early days of the pandemic, COVID-19 hospitalizations have been used as a measure of pandemic severity. However, case definitions do not include assessments of disease severity, which may be impacted by prior vaccination.
Objective: To measure how the severity of respiratory disease changed among inpatients with documented SARS-CoV-2 infection and to measure the impact of vaccination status on these trends, in order to evaluate the accuracy of the metric of “hospitalization plus a positive SARS-CoV-2 test” for tracking pandemic severity.
Design: Retrospective cohort of inpatients with laboratory-confirmed SARS-CoV-2. All data were obtained from electronic health records.
Setting: Multi-center, nationwide study conducted in the healthcare system of the US Department of Veterans Affairs (VA) from March 1, 2020, through June 30, 2021.
Participants: All VA patients admitted to a VA hospital with a laboratory-confirmed SARS-CoV-2 infection within the 14-days prior to admission or during the hospital admission.
Main Outcome: Moderate-to-severe COVID-19 disease, defined by use of any supplemental oxygen or documented SpO2 <94%, during an inpatient hospitalization between one day before and two weeks after a positive SARS-CoV-2 test.
Exposure: SARS-CoV-2 vaccination status at the time of hospitalization. Patients were regarded as fully vaccinated starting 14 days after receiving the second of a 2-dose regimen or 14 days after receipt of a single-dose vaccine.
Results: Among 47,742 admissions in 38,508 unique patients with laboratory-confirmed SARS-CoV-2, N=28,731 met the criteria for moderate-to-severe COVID-19. The proportion with moderate-to-severe disease prior to widespread vaccine availability was 64.0% (95% CI, 63.1-64.9%) versus 52.0% in the later period (95% CI, 50.9-53.2%), p-value for non-constant effect, <0.001. Disease severity in the vaccine era among hospitalized patients was lower among both unvaccinated (55.0%, 95% CI, 53.7-56.4%) and vaccinated patients (42.6%, 95% CI, 40.6-44.8%).
Conclusions and Relevance: The proportion of hospitalizations that are due to severe COVID-19 has changed with vaccine availability, thus, increasing proportions of mild and asymptomatic cases are included in hospitalization reporting metrics. The addition of simple measures of disease severity to the case definition of a SARS-CoV-2 hospitalization is a straightforward and objective change that should improve the value of the metric for tracking SARS-CoV-2 disease burden.
US approaching Delta wave peak but Covid-19 virus expected to become endemic
WASHINGTON (AFP) - The latest coronavirus wave in the United States driven by the Delta variant could soon peak, but experts warn against complacency and expect the virus will be part of everyday life for years to come.
The seven-day-average of daily cases as of Monday (Sept 13) was 172,000, its highest level of this surge even as the growth rate is slowing and cases are headed down in most states, according to data compiled by the Covid Act Now tracker.
But more than 1,800 people are still dying a day, and over 100,000 remain hospitalised with severe Covid-19 - a grim reminder of the challenges authorities have faced in getting enough Americans vaccinated in the face of misinformation and a polarised political climate.
Bhakti Hansoti, an associate professor in emergency medicine at John Hopkins University and expert in Covid-19 critical care told AFP she saw the US following a similar trajectory to India.
Countries in western Europe have also seen similar downturns in their Delta surges.
But while Hansoti breathed a sigh of relief when the spring wave ended, "I'm a little hesitant this time around," she admitted.
The possible emergence of newer variants of concern and the advent of colder weather leading to more socialization indoors could lead to a rebound, "unless we learn from the lessons of the fourth wave."
Angela Rasmussen, a virologist at University of Saskatchewan in Canada, added she was not certain the fourth wave was over.
"If you look at the fall-winter wave, there were periods in which there was a steep exponential increase, and then it looked like it was falling - and then there would be another increase." To ensure gains are sustained, rapidly increasing the number of people vaccinated is vital. Currently 63.1 percent of the eligible population over-12 are fully vaccinated, or 54 per cent of the total population.
This places the United States well behind global leaders like Portugal and the UAE (81 and 79 percent fully vaccinated), despite its abundance of shots.
The administration of President Joe Biden last week announced a number of new measures to ramp up the immunization campaign, including new vaccine requirements on companies of over 100 employees, but the impact is yet to be clearly seen.
Two Americas
Beyond vaccinations, experts want to see other interventions continue.
Thomas Tsai, a surgeon and health policy researcher at Harvard, said hotspots need to follow through on masking, adding that the US should also look to other countries that have adopted widespread rapid testing for schools and businesses.
Such tests are available either for free or at a very nominal cost in Germany, Britain and Canada but remain around US$25 (S$33.60) for a two-pack in the US, despite the Biden administration's efforts to drive costs down through a deal with retailers.
Of course, the impact of all measures depends on their uptake, and in this regard, a clear and consistent pattern has emerged of two Americas: liberal-leaning regions are far more compliant than conservative.
Prior to the Delta wave, some experts declared that, between the percent of people vaccinated and those who had gained immunity through natural infection, the country was approaching the point of herd immunity.
Rasmussen said those predictions had proven incorrect and it remained too early to say when this threshold would be reached.
"There are still parts of the country where the adult vaccination rate is less than 50 percent," she noted.
Going endemic
Though Delta has out-competed all previous variants and is currently dominant, SARS-CoV-2 continues to evolve rapidly and virologists fear that more dangerous variants might emerge.
"I don't want to be a doomsayer, but I also want to have some humility, because I don't think we know a lot about the basic function of many of these mutations," said Rasmussen.
Still, experts are hopeful that vaccines will continue to blunt the worst outcomes for most people and look forward to their authorisation in children under-12 in the months to come.
It's expected that certain populations like the elderly and those with weakened immune systems may need boosters as well as high community vaccination rates to protect them.
Rather than eradication, the goal has shifted toward taming the virus for vaccinated people such that in rare cases of breakthrough infections, the disease is more flu-like.
However, uncertainties remain: for instance, people with breakthrough Covid infections might still get long Covid.
Greg Poland, an infectious diseases expert at Mayo Clinic, predicted humanity would be dealing with Covid "well past the lifespan of the next many generations." "We are still immunising against aspects of the 1918 influenza virus," he said.
Israeli scientists say their antiviral drug could stop COVID-19
https://m.jpost.com/health-and…-stop-covid-19-679437/amp
A team of Israeli scientists say that a drug previously used in an uncontrolled fashion to treat HIV has a direct antiviral effect against coronavirus, sending patients home virus-free within only a few days....
Sounds quite familar....but the question is: why not use the other well-known and working drug and run through a double-blinded multinational study to get an approval in use against Sars-Cov2? Why now a drug intended for use in treating HIV?
at least 48x
Reading disability?? Written was 40.
Reading disability?? Written was 40.
Does that change your claim substantially? 
Seven of the volunteers were tested sequentially using a standard PCR swab test every two days from the time they began receiving the treatment, which like insulin is given subcutaneously – injection under the skin.
Patients received two injections per day for 10 days.
Maayan said that five of the patients showed a very profound decline in the viral load during the treatment. Codivir significantly suppressed viral replication in all patients with an antiviral effect noted as early as three days after the beginning of treatment.
Moreover, the safety profile of the drug was very good.
Only works for 5 out of 7 patients starts on day 3 and needs two injections/day. What a joy for big pharma and doctors...
Ivermectin works after ours needs no doctors and works in all patients ...and cost almost nothing....
Conclusions and Relevance: The proportion of hospitalizations that are due to severe COVID-19 has changed with vaccine availability, thus, increasing proportions of mild and asymptomatic cases are included in hospitalization reporting metrics.
Key: Disease severity in the vaccine area among hospitalized patients was lower among both unvaccinated (55.0%, 95% CI, 53.7-56.4%) and vaccinated patients (42.6%, 95% CI, 40.6-44.8%).
This means Delta is in fact more harmless than Alpha or Gamma.
Does that change your claim substantially?
We eagerly await your Münster research result!
.but the question is: why not use the other well-known and working drug and run through a double-blinded multinational study to get an approval in use against Sars-Cov2?
Which drug? They are running double blind tests on a wide range of drugs. (I saw a list somewhere, but I cannot find it. Does anyone else know where it is?)
I should have named it, it seems...;-) I thought that most here were aware of ivermectin, which is a strong antiviral drug, but limited to its approved use only...
I thought that most here were aware of ivermectin, which is a strong antiviral drug
Ivermectin is not an antiviral drug. It is an anti-parasite drug. It has some antiviral effects in in vitro studies, but only in concentrations hundreds of times too high for the human body. Many other substances have antiviral effects, but they are not safe for human consumption at levels high enough to kill viruses. There is no substantive clinical evidence that ivermectin has any efficacy against COVID.
Israel: Boosters still show no overall effect. Yesterday cases 9624: (daily figures on https://datadashboard.health.gov.il/COVID-19/general) Worldometer 12'940! (different deadlines. First one Israel local time)
US free masons killing target yesterday reached 1888 (NYT)! Still options ahead to reach 9/11 level again....
India: Kerala is a bit improving only 60% of India's cases and deaths a bit below 50% of India. 1 death in UP. The overall picture is constant with a moderate declining rate and still one failing state.
Despite its anti-parasit intended use it seems to show at least the same if not more powerful antiviral performance....people don't seem to die or show severe side effects with the used medication in UP.... ?
Ivermectin is not an antiviral drug. It is an anti-parasite drug. It has some antiviral effects in in vitro studies, but only in concentrations hundreds of times too high for the human body.
Why do you repeat this nonsense again and again. Its a sign of stupidity or propaganda. Ivermectin has been use to end the Zikka epidemic! This has been done clandestine to not reveal how powerful Ivermectin is.
The concentration FUD is a free masons propaganda trick based on a fringe statement by FM sponsored researchers...
Ivermectin works perfectly in preventing CoV-19 by using the standard human doses of 20mg/100kg.
So Ivermectin is by far the most potent antiviral we have, what big pharma does not much enjoy...
Infections are falling rapidly in Japan, but deaths are still at their peak. This shows how long the lag is. Japan now has a larger percent of the population vaccinated than the U.S., after a slow start.
