Pharma distributors in talks with U.S. for cut of COVID-19 vaccine shipping deal

 U.S. pharmaceutical distributors are talking to federal officials about increasing the number of companies shipping coronavirus vaccines as part of the Biden administration’s push to speed up inoculations, according to an industry executive and three people familiar with the matter.

President Joe Biden has called the initial phase of the vaccination campaign a “dismal failure” and with vaccinations in the United States at around 1 million per day, the new administration wants to expand and improve the program.

The Trump administration signed an exclusive deal with healthcare distributor McKesson Corp to ship COVID-19 vaccines for the government. That distribution system has broadly worked, but it will face new demands as additional vaccines from Johnson & Johnson and others are added.

Cardinal Health Inc and AmerisourceBergen Corp, which together with McKesson are the biggest healthcare product shippers, have made proposals to take on some distribution. Biden’s team is open to the idea, according to an executive at AmerisourceBergen and two people familiar with the talks. The Biden administration has not yet made a decision, they said.

“We stand ready to support the vaccine rollout and are advocating for the addition of other pharmaceutical distributors to join the effort,” said Heather Zenk, a senior vice president at AmerisourceBergen in an interview with Reuters. Government officials were receptive and are considering the proposal, she said, adding that her company has not “received any formal outreach for contracting at this point.”

The U.S. Department of Health and Human Services declined to comment, saying it is prohibited from sharing information about contract discussions. McKesson did not comment on talks between the U.S. and other companies but said it believes the current approach works best for ensuring safe and fast shipments.

Two vaccines have been authorized for emergency use so far to inoculate adults in the 330 million population of the United States. McKesson has handled shipments from Moderna Inc under the government’s Operation Warp Speed program. Pfizer Inc’s vaccine is not part of the government’s distribution program.

Johnson & Johnson, which is part of Operation Warp Speed, is releasing data on its vaccine candidate next week and it could be authorized in the United States as soon as February.

U.S. officials said in a press conference earlier this week that they will boost vaccine shipments from 8.6 million doses each week to at least 10 million in the coming weeks.

“The current system appears to be faltering at multiple levels so I do think having more distributors involved is prudent,” said Amesh Adalja, a senior scholar at the Johns Hopkins Center for Health Security.

“It will be important however to maintain central coordination,” he added.

Even if the Biden administration does not sign a contract with the distributors in the near term, it may begin working with them to actively prepare for a contingency plan should the United States need additional shipping capacity in the coming weeks or months, one of the sources said.

https://www.reuters.com/article/us-health-coronavirus-vaccines-distribut/exclusive-pharma-distributors-in-talks-with-u-s-for-cut-of-covid-19-vaccine-shipping-deal-sources-idUSKBN29X1KK

American Airlines joins GameStop trading frenzy as calls for probe build

 An almost 60% surge in shares of American Airlines led stellar gains for a series of social-media hyped stocks on Thursday, broadening a battle between small-time traders and major Wall Street institutions that has shaken U.S. and European stock markets.

GameStop, the video game chain whose 1,700% rally has been at the heart of the slugfest in the past week, retreated after initially adding another 37% in early trading.

On Reddit thread WallStreetBets, where calls to buy stocks have helped drive the extraordinary moves, some of its more than 4 million members reported trading platform Robinhood was now preventing investors from buying new shares in GameStop and other of the companies.

Robinhood, one of the biggest of the easy access apps that has spurred the development of a huge online community of amateur traders, did not immediately respond to requests for comment.

Shares in American Airlines soared as much as 60%.

“It does appear that it (American Airlines) may be getting caught up in this day trading frenzy,” said Randy Frederick, vice president of trading and derivatives for Charles Schwab in Austin, Texas.

The dramatic jumps in the stock price of companies including GameStop, BlackBerry Ltd and AMC Corp drew more calls for regulatory scrutiny and action from commentators.

“In terms of short interest being monitored, the U.S. markets are probably the most transparent, but there’s always room for improvement,” former SEC chairman Jay Clayton told CNBC.

In Australia, previously immune to the trend, heavily shorted shares including Webjet and Tassal Group, climbed more than 5% even as Sydney’s benchmark ASX 200 index fell 2%. [.AX]

Trading in European share markets was subdued, with some of this week’s high-flyers including Evotec and Varta nearly flat.

The short squeeze - where traders have to abandon loss-making “short” bets on a stock falling because it has instead risen - fueled a 2% slide in New York’s S&P 500 on Wednesday as investors sold other assets to cover their losses.

Short-sellers are sitting on estimated losses of $71 billion from their positions in U.S. companies so far this year, data from financial data analytics firm Ortex showed.

Futures tracking the main New York index were down another 0.3% on Thursday as Reddit discussion threads again hummed with chatter about a number of stocks. 

In one discussion, thousands of participants responded “We love this stock” to a post that called for more buying of GameStop and cast retail traders as Iron Man against a hedge fund Thanos in a nod to the superhero movie “Avengers: Endgame”.

The war began last week when famed hedge fund short seller Andrew Left of Citron Capital bet against GameStop and was met with a barrage of retail traders betting the other way. He said on Wednesday he had abandoned the bet.

Regarded by market professionals as “dumb money”, the pack of traders, some of them former bankers working for themselves, has become an increasingly powerful force worth 20% of equity orders last year, data from Swiss bank UBS showed.

The only-way-is-up nature of stock markets over the past decade, fueled by a constant flow of newly created money from major central banks, has also made it less risky to bet on shares rising.

The U.S. Federal Reserve kept those taps firmly open at its latest meeting on Wednesday.

This week’s turmoil caught the attention of the White House, with President Joe Biden’s economic team - including Treasury Secretary Janet Yellen on her first full day on the job on Wednesday - “monitoring the situation.”

Massachusetts state regulator William Galvin called on NYSE to suspend trading in GameStop for 30 days to allow a cooling-off period.

“The prospect of intervention here is clearly high, but this will just galvanize the (WallStreetBets) community as it just brings home the feeling of inequality in financial markets,” said Chris Weston, head of research at broker Pepperstone in Melbourne.

“It’s fine to prop up zombie companies through Fed actions but if retail follows a path that greatly distorts asset prices by targeting short sellers, then this gets shut down.”

https://www.reuters.com/article/us-retail-trading/american-airlines-joins-gamestop-trading-frenzy-as-calls-for-probe-build-idUSKBN29X12T

Ortho Clinical Diagnostics prices IPO below the range IPO at $17

 Ortho Clinical Diagnostics, a Carlyle-backed global provider of in vitro diagnostic products, raised $1.3 billion by offering 76 million shares at $17, below the range of $20 to $23. The company increased its offering by 6.0 million shares (9%). At pricing, Ortho Clinical raised 14% less in proceeds than anticipated.

Ortho Clinical Diagnostics plans to list on the Nasdaq under the symbol OCDX. J.P. Morgan, BofA Securities, Goldman Sachs, Barclays, Morgan Stanley, Citi, Credit Suisse, UBS Investment Bank, Evercore ISI and Piper Sandler acted as lead managers on the deal.

Relevant Profile: OCDX

https://www.renaissancecapital.com/IPO-Center/News/75723/Ortho-Clinical-Diagnostics-prices-IPO-below-the-range-IPO-at-$17

Cancer Drug Activity Against SARS-CoV-2, Including B.1.1.7 Variant, in Lab

 Scientists at UC San Francisco’s Quantitative Bioscience Institute (QBI) and the Icahn School of Medicine at Mt. Sinai (ISMMS) in New York have shown that plitidepsin (Aplidin), a drug approved by the Australian Regulatory Agency for the treatment of multiple myeloma, has potent antiviral activity against SARS-CoV-2, the virus that causes COVID-19.

In laboratory experiments reported in Science on Jan. 25, plitidepsin, a compound originally discovered in a Mediterranean sea squirt, was 27.5-fold more potent against SARS-CoV-2 than remdesivir, a drug that received FDA emergency use authorization in 2020 for the treatment of COVID-19. In addition, in two preclinical models of COVID-19, plitidepsin showed a 100-fold reduction in viral replication in the lungs and demonstrated an ability to reduce lung inflammation.

The studies were led by the laboratories of Nevan Krogan, PhD, director of the QBI, part of the UCSF School of Pharmacy, and Adolfo García-Sastre, PhD, professor of microbiology and director of the Global Health and Emerging Pathogens Institute at ISMMS.

In 2020, in response to the COVID-19 pandemic, Krogan, also a senior investigator at Gladstone Institutes, brought many UCSF labs together in the QBI Coronavirus Research Consortium (QCRG), which played a major role in the new research.

In a separate publication posted to the bioRxiv preprint server, the UCSF and ISMMS researchers, in collaboration with Greg Towers, PhD, and Clare Jolly, PhD, of University College London, show that plitidepsin has antiviral activity against the recently identified B.1.1.7 variant of SARS-CoV-2 which is comparable to the drug’s activity against the original SARS-CoV-2 strain. Additionally, they found plitidepsin to be about 100 times more potent than remdesivir in human epithelial cells. 

“From the start, our scientific investigations with the QCRG were to research where and how the SARS-CoV-2 virus was co-opting its human host to thrive, survive and become deadly,” said Krogan. “That research led us to a biologic pathway, the eukaryotic translation machinery, where inhibition of the pathway showed significant antiviral activity in cell culture. One of the promising agents that arose from our screen of drugs that inhibit this pathway was plitidepsin. Our preclinical data showing increased potency compared to remdesivir, and in conjunction with recent early clinical data showing promise in COVID-19 patients, as reported by the drug’s manufacturer, suggest plitidepsin should be further evaluated as a COVID-19 therapy.”

García-Sastre said, “The ongoing COVID-19 pandemic has created an immediate need for antiviral therapeutics that can be moved into the clinic urgently. This led us to screen clinically approved drugs with established safety profiles. Our previous study of the SARS-CoV-2’s interactions with human host cells led us to  a protein  known as eEF1A, which is involved in translating mRNA into proteins, as a potential druggable target to inhibit SARS-CoV-2 replication.” 

The studies were conducted in close collaboration with PharmaMar, a Spanish pharmaceutical  company that first isolated plitidepsin (trade name Aplidin) from a sea organism known as Aplidium albicans.

“Plitidepsin is an extremely potent inhibitor of SARS-CoV-2, but its most important strength is that it targets a host protein rather than a viral protein,” said Kris White, PhD, assistant professor of microbiology at ISMMS, first author of the Science paper. “This means that if plitidepsin is successful in the treatment of COVID-19, the SARS-CoV-2 virus will be unable to gain resistance against it through mutation, which is a major concern with the spread of the new U.K. and South African variants.”
Krogan said the work is further validation of the QCRG’s focus on host proteins as a strategy to fight COVID-19 and other viral diseases.

“It is host mechanisms that permit the SART-CoV-2 virus to wreak havoc,” Krogan said. “By targeting host factors that enable or facilitate disease, we have the potential to have a more far-reaching impact in drug development. In this case, SARS-CoV-2 and its mutant strains, and possibly other viruses that leverage the same pathway, may also be susceptible to the same therapeutic agents that inhibit this virus–host interaction.”

Authorship and funding: This work was funded by grants from the National Institute of Mental Health and the National Institute of Allergy and Infectious Diseases (NIAID), both part of the National Institutes of Health; the Defense Advanced Research Projects Agency; the Center for Research for Influenza Pathogenesis; the Centers of Excellence for Influenza Research and Surveillance of the NIAID; the Centers of Excellence for Integrative Biology of Emerging Infectious Diseases of the Agence Nationale de la Recherche (France); F. Hoffmann-LaRoche AG; Vir Biotechnology, Centre for Integrative Biological Signalling Studies (CIBSS), European Research Council (ERC) and QCRG philanthropic donors. Co-author Kevan Shokat is a Howard Hughes Medical Institute investigator. A complete list of authors and full funding information is available in the Science paper.

https://www.ucsf.edu/news/2021/01/419686/cancer-drug-shows-potent-activity-lab-against-sars-cov-2-including-b117-variant

RNAi-based products: A sustainable alternative to hazardous pesticides

 RNAi-based biocontrol is a great alternative to hazardous pesticides and can contribute towards reversing the alarming decline in farmland birds and beneficial insects (especially pollinating ones).

RNAi is a well-known natural biological process in most organisms (plants, fungi and animals, including humans) that is based on RNA molecules. By creating technology based on this process, it is possible to protect crops and animals from a specific disease or pest.

RNAi-based pest control products can be directly applied using current agricultural practices, such as spray application, trunk injection for tree species, seed soaking, or root drenching through hydroponic systems in greenhouses. For example: you can inject a tree with an RNAi-based product to protect it from a certain disease or pest.

Advantages of RNAi

Compared to hazardous pesticides, RNAi-based products can be designed to be very specific to a pest or pathogen, leaving no negative side effects in the environment or to humankind.

The trend towards the development of RNAi-based products for application against crop pests and pathogens is favored because plants treated with these products are not considered to be genetically modified organisms (GMOs). Unlike GMOs, RNAi-based products delivered externally do not alter the organism's structure, they simply perform their specific task, which is protecting the plant against pests or diseases.

Additionally, because of extensive research over the last few years, RNAi-based technology has a short development time and is affordable in cost, making it a truly interesting alternative to hazardous pesticides.

European Green Deal

The European Commission's Green Deal aims to reduce agrochemical inputs, such as pesticides, fertilizers, and antimicrobials, to achieve greater sustainability and health, and reduce loss of biodiversity while ensuring continued crop protection. RNAi-based technology could be the ideal catalyst to help fulfill the commission's vision.

Technology based on RNA molecules isn't new. It's already been used in the medical world for the COVID-19 vaccine. As a spin-off of the coronavirus vaccine, the existing production capacity for RNA molecules may be ramped up exponentially in the near future to provide the global community with other types of RNA-based vaccines. The same platforms could be converted for use in the production of RNA molecules for agricultural purposes. This would further promote the cost-effective manufacture of sizable volumes of RNAi-based products needed for large-scale pesticide applications.

According to researchers, RNAi-based pest control is still a new concept for the main public and several key tasks will have to be accomplished to enable societal acceptance. The co-creation of new, effective and safe RNAi-based products in collaboration with stakeholders under the responsible research and innovation paradigm promoted by the EU, will help to foster greater knowledge and acceptance of technology. Furthermore, an advancement in understanding consumers' perception will facilitate the successful market introduction of RNAi-based, sustainable products for crop protection.

More information: Clauvis Nji Tizi Taning et al. Does RNAi-Based Technology Fit within EU Sustainability Goals?, Trends in Biotechnology (2020). DOI: 10.1016/j.tibtech.2020.11.008

https://phys.org/news/2021-01-rnai-based-products-sustainable-alternative-hazardous.html

'New coronavirus variants spreading across U.S.'

 New and more infectious coronavirus variants are beginning to appear in the United States, but all have remained vulnerable to the two vaccines now being distributed to Americans, the White House COVID-19 Response Team said Wednesday.

There have been 308 cases of the British variants confirmed in 26 states as of Jan. 26, said Dr. Rochelle Walensky, director of the U.S. Centers for Disease Control and Prevention. The variant has been found in 47 countries to date.

Public health officials this week also identified the first U.S. case of the Brazilian variant, which appeared in Minnesota, Walensky said. That variant has only been spotted in five countries.

A third variant from South Africa, which popped up in 20 countries, has not been detected yet in this country, Walensky added.

"The variants that have been identified recently seem to spread more easily and are more transmissible, which can lead to an increased number of cases and increased stress on our already taxed health care system," Walensky said.

However, these variants do not seem to be able to outmaneuver either the Pfizer or Moderna vaccines, said Dr. Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases, and President Joe Biden's chief medical adviser.

The United Kingdom variant has a "very slight, if at all, impact on vaccine-induced antibodies," Fauci said.

The South African variant, which has yet to reach U.S. soil, is a "bit more problematic" because it appears to respond less well to the vaccines, Fauci said.

"However, and this is an important however, it still is well within the cushion of protection," Fauci said of the South African strain. "You could diminish the vaccine-induced antibody efficacy by a few-fold and still be within the protective range of the vaccine."

Phase 3 clinical trial results are expected within days for a third COVID-19 vaccine produced by Johnson & Johnson, and Fauci said those results could provide more insight into these mutations and their interactions with vaccines.

"It's going to be looking at efficacy not only in the United States but also in South Africa and in Brazil," Fauci said. "We'll have some comparative efficacy which will inform us on where we would go if [the South African] lineage seats itself in the United States."

The CDC is pushing to improve genetic sequencing of new COVID-19 cases across the country, and public health officials are prepared to develop "booster" shots of the existing vaccines that would cover any future mutations that impede vaccine-induced immunity, Fauci said.

"We will be monitoring in real time the effect of antibodies that we induce with the current vaccines and with future vaccines, as to what impact they have on the ability to neutralize these mutants," Fauci said. "As we see them getting further and further toward a more vulnerable part, that's when we trigger…making a version of the same vaccine that in fact would be directed specifically against the relevant mutant."

https://medicalxpress.com/news/2021-01-coronavirus-variants-white-house-experts.html

COVID-19's Achilles heel?

 Researchers at Vanderbilt University Medical Center (VUMC) and the University of Texas Medical Branch (UTMB) at Galveston have discovered what may be the Achilles' heel of the coronavirus, a finding that may help close the door on COVID-19 and possibly head off future pandemics.

The coronavirus is an RNA virus that has, in its enzymatic toolkit, a 'proofreading' exoribonuclease, called nsp14-ExoN, which can correct errors in the RNA sequence that occur during replication, when copies of the virus are generated.

Using cutting-edge technologies and novel bioinformatics approaches, the researchers discovered that this ExoN also regulates the rate of recombination, the ability of the coronavirus to shuffle parts of its genome and even pull in genetic material from other viral strains while it replicates in order to gain evolutionary advantage.

These patterns of recombination, the researchers reported last week in the journal PLOS Pathogens, are conserved across multiple coronaviruses, including SARS-CoV-2, which causes COVID-19, and MERS-CoV, which causes a similar illness, Middle Eastern respiratory syndrome.

"The coronavirus exoribonuclease is therefore a conserved, important target for inhibition and attenuation in the ongoing pandemic of SARS-CoV-2, and in preventing future outbreaks of novel coronaviruses," concluded the paper's first author, Jennifer Gribble, a VUMC graduate student in the laboratory of Mark Denison, MD.

"If you can find a drug that prevents RNA recombination, you really shut down the virus," added Andrew Routh, Ph.D., assistant professor of Biochemistry and Molecular Biology at UTMB and, with Denison, the paper's co-corresponding author. "It's really intriguing in terms of what we understand about virus adaptation and evolution."

Previous studies have shown that coronaviruses are resistant to many nucleoside antiviral drugs, which work by introducing errors in the viral genetic code to block replication. The coronavirus proofreader corrects the errors so replication can proceed.

Only a few drugs are capable of circumventing the proofreader. They include an approved drug, remdesivir, and EIDD-2801 (molnupiravir), an investigational drug now in clinical trials. Both were developed with the help of VUMC scientists.

"Finding that the viral ExoN plays a key role in recombination is exciting," said Denison, director of the Division of Pediatric Infectious Diseases at VUMC who has studied coronaviruses for more than 30 years.

"Knocking out this function (in laboratory studies) leads to decreased recombination and a weaker virus," Denison said. "So we think it may be possible to block this process with drugs as well (and) that it may make other drugs like remdesivir and molnupiravir work even better and last longer."

In 2007 Denison and his colleagues discovered the coronaviruses proofreader. They also found that blocking the enzyme accelerated the rate of uncorrected errors—mutations—and crippled its ability to cause disease in animals.

Several years later they discovered that remdesivir, an investigational antiviral drug, had highly potent activity against a wide range of coronaviruses, both in laboratory and animal tests. In October 2020 remdesivir was approved for emergency use in patients hospitalized with COVID-19.

For the past two years, Gribble and Routh have collaborated in an effort to understand the role of recombination in the replication of RNA viruses, which include influenza, polio, measles, hepatitis C, HIV and Ebola, as well as the coronaviruses.

Using computational software Routh had developed, which can scour virus-sequencing datasets for evidence of "recombination events," Gribble was studying recombination in model experimental viruses, such as coronaviruses that infect mice.

Once the pandemic hit, Routh, Gribble and their colleagues were quickly able to apply this approach to SARS-CoV-2 and other coronaviruses that cause disease in humans. Other VUMC co-authors were Laura Stevens, MS, Maria Agostini, Ph.D., Jordan Anderson-Daniels, Ph.D., James Chappell, MD, Ph.D., Xiaotao Lu, MS, and Andrea Pruijssers, Ph.D.

Recombination does not always result in a "fitter," potentially more virulent virus, Routh noted. If during recombination, for example, some of the genome is deleted, the result is a "defective" viral genome that can mix with, and disable, the more virulent strain.

Coronaviruses frequently produce defective genomes, the researchers found. "That could be useful," Routh said. "You might be able to exploit defective genomes as a way of making new vaccines ... or to perturb replication (of a more virulent strain) ... in the patient."

Much remains to be learned about recombination and the role that plays in the continued spread of evolving variants of SARS-CoV-2 around the world and the ability of anti-viral drugs and vaccines to stop it.

That's why basic science is so important, said Denison, who holds the Edward Claiborne Stahlman Chair in Pediatric Physiology and Cell Metabolism in the Vanderbilt University School of Medicine.

"We need to understand the capacity of all kinds of viruses to move between species and the mechanisms by which they cause disease," he said. "We need to make sure that there are fundamental things that we know about all identified viruses—their genomic sequences, for example, and some basics about their biology."

That takes a lot of creativity, determination—and money. Funding for this study was provided by National Institutes of Health grants AI108197, GM065086 and AI133952, the Dolly Parton COVID-19 Research Fund and the Elizabeth B. Lamb Center for Pediatric Research at Vanderbilt.

More information: Jennifer Gribble et al, The coronavirus proofreading exoribonuclease mediates extensive viral recombination, PLOS Pathogens (2021). DOI: 10.1371/journal.ppat.1009226

https://medicalxpress.com/news/2021-01-door-covid-.html