Virus World

New research in mice finds that molnupiravir stops the replication of the new coronavirus in grafts of human lung tissue.

• A study in mice found that molnupiravir (EIDD-2801) halted the replication of SARS-CoV-2 — the virus that causes COVID-19 — in grafts of human lung tissue.
• The drug also prevented infection when administered 12 hours before exposure to the virus.
• Clinical trials of the drug are ongoing to evaluate its safety in humans and whether it can make patients with COVID-19 less infectious.
• Previous research suggests that the drug could work against a range of coronaviruses that originate in bats, providing protection in future outbreaks.

A drug called molnupiravir, which scientists originally developed to treat influenza, is showing promise as a treatment for COVID-19. A study by researchers at the University of North Carolina (UNC) at Chapel Hill, recently published in Nature, found that the drug dramatically reduced the number of virus particles in a mouse model of the disease. It also protected against infection when given 12 hours before exposure to the virus and every 12 hours thereafter. 

Phase 2 and phase 3 clinical trials of molnupiravir are already under way, with some results expected as soon as March 2021.

In addition to testing the drug’s safety and efficacy, one of the trials is also investigating its effect on “viral shedding,” which is the amount of virus released into the environment by people who have it. Analyzing this helps determine how likely a person is to transmit the virus. Remdesivir, which speeds the recovery of adults hospitalized with the illness and which may reduce mortality rates, is currently the only proven antiviral treatment for COVID-19. One potential advantage of molnupiravir is that patients can take it orally, whereas remdesivir has to be injected. This would make molnupiravir easier to give to lots of people as a preventive, or prophylactic, drug in high risk settings, such as nursing homes and long-term care facilities. Another, more long-term benefit of molnupiravir is that it may be effective against other emerging coronavirus infections that — like SARS-CoV-2 — probably originate in bats.

To test the efficacy of molnupiravir against SARS-CoV-2, the researchers created a completely new model of COVID-19 in mice that may prove useful for testing the efficacy of other antiviral drugs. Human coronaviruses are unable to infect mouse cells unless researchers either adapt the viruses or genetically modify mice to produce receptors that allow them to invade cells. These models also fail to reflect the diversity of cells found in human lungs, where the infection can cause life threatening damage.

To get around these limitations, the researchers implanted human lung tissue into specially bred immunodeficient mice that tolerate foreign tissue

“Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host,” the researchers write in their paper. They demonstrated that the newly emerged human coronaviruses SARS-CoV, MERS-CoV, and SARS-CoV-2 were all able to replicate in the implanted human lung tissue. “Our model allows researchers to directly compare infection between human coronaviruses and the effectiveness of potential preventative and therapeutic approaches,” says co-first author Dr. Lisa Gralinski, assistant professor of epidemiology at UNC. When infected with SARS-CoV-2, the human lung tissue sustained damage similar to that seen in the lungs of COVID-19 patients. The infection also induced an inflammatory response reminiscent of the excess inflammation that characterizes the disease in people.....

Findings published in Nature (Feb. 9, 2021):

https://doi.org/10.1038/s41586-021-03312-w 

Merck has largely stayed out of the COVID-19 battle, but exploded into it with three major deals and collaborations today. First, Merck is buying Austria-based Themis, a vaccines and immune-modulation therapies company focused on infectious diseases and cancer. Merck hasn’t disclosed financial details, except that it is a cash deal to buy all outstanding Themis shares.

Themis has a pipeline of vaccine candidates and immune-modulatory therapies that it has built using its measles virus vector platform. The vector was originally developed by researchers at the Institut Pasteur and licensed exclusively to Themis for specific viral indications. In March, the company joined a consortium with the Institut Pasteur and The Center for Vaccine Research at the University of Pittsburgh, which is supported by monies from the Coalition for Epidemic Preparedness Innovations (CEPI), to develop a vaccine candidate against COVID-19. “Building on the pioneering work of the Institute Pasteur, the Themis team has established specialized expertise that complements Merck’s own capabilities in the discovery, development, manufacturing and global distribution of vaccines,” said Roger M. Perlmutter, president, Merck Research Laboratories. “We are eager to combine our strengths both to develop an effective COVID-19 vaccine in the near term and to build a pandemic preparedness capability directed toward emerging agents that pose a future epidemic threat.”

Secondly, Merck is collaborating with IAVI, a nonprofit scientific research organization focused on global health challenges. They are partnering to develop a vaccine against COVID-19. The vaccine candidate uses the recombinant vesicular stomatitis virus (rVSV) technology that was used for Merck’s Ebola Zaire virus vaccine, ERVEBO. Merck has also entered an agreement with the Biomedical Advanced Research and Development Authority (BARDA), part of the office of the Assistant Secretary for Preparedness and Response within the U.S. Department of Health and Human Services (HSS)....

Scientists often warn about the dangers of pandemic pathogens spreading quickly around the globe. But one virus already sweeps across the world every year, causing tens of millions of infections and hundreds of thousands of deaths: influenza. Now, a new drug that has shown promise in ferrets may help drive down that toll, researchers report today. The drug appears to be more effective than the most commonly used treatment, oseltamivir, and there are hints that it won’t prompt easy resistance in the virus.

Scientists have long been frustrated by the constant shapeshifting of the flu virus, which necessitates an annual reformulation of flu vaccines to reflect commonly circulating strains. When that match is bad, vaccine protection can be low, especially for elderly people who are most at risk. Meanwhile, new influenza drugs have been slow to develop, and those that exist are often inadequate. Oseltamivir, for instance, provides a moderate benefit at best, and only when given early in the infection; whether it prevents hospitalizations and deaths is controversial. What’s more, the flu virus has developed resistance to oseltamivir and to an older drug, amantadine. And there are already reports of flu strains resistant to baloxavir, a drug approved by the U.S. Food and Drug Administration just last year.

To come up with an alternative, scientists at Georgia State University and Emory University, both in Atlanta, investigated a compound named N-hydroxycytidine (NHC), which has been known for years to inhibit a broad range of RNA viruses like the flu. Previously, the researchers had shown that NHC is active against influenza; but in tests on macaques, they found the drug is not taken up well by the body, “a potential deal breaker” for human use, says Georgia State molecular virologist Richard Plemper, one of the researchers leading the new work. The researchers tweaked NHC’s structure to create a new compound named EIDD-2801, which converts back into NHC inside the body. They then tested it in ferrets, the most widely used animal model for influenza. If the ferrets received the compound 12 hours after infection, they did not develop disease at all. Those that received it after 24 hours, when fever had started, produced less virus than control animals that received oseltamivir or no treatment at all. The fever also ended faster in treated animals, the researchers write in Science Translational Medicine. 

“It’s important that they showed a reduction in symptoms in ferrets, because it gets much closer to predicting what happens in people,” says Andrew Pavia, an infectious disease expert at the University of Utah in Salt Lake City. “It’s a major step towards developing a drug for humans.” The scientists also investigated how NHC blocks influenza by sequencing the genomes of flu viruses exposed to the compound. They found that the virus incorporates the drug into its RNA when it replicates, instead of a molecule named cytosine, leading to a cascade of mistakes that virologists call “error catastrophe”—essentially overwhelming the virus with mutations. To test how easily flu becomes resistant to EIDD-2801, the researchers also grew the virus while keeping it exposed to sublethal doses of NHC or slowly increasing the concentration of NHC—methods that typically don’t kill the virus, but give it a chance to evolve resistance. Even though sequencing clearly shows the virus trying to resist the drug, no resistant strains developed. That bodes well, Pavia says, because oseltamivir and other older drugs all eventually fail the test. Still, it doesn’t mean resistance cannot develop, says Albert Osterhaus, a virologist at the University of Veterinary Medicine in Hanover, Germany. Favipiravir, a drug approved in 2014 in Japan for pandemic flu viruses resistant to all other drugs, was thought to have a similarly high barrier to resistance before resistant strains developed....

Published in Science Translational Medicine (October 23, 2019):

https://doi.org/10.1126/scitranslmed.aax5866

The COVID-19 vaccine may spell the end of the pandemic, but while mass vaccination is not available it is vital to stop community transmission. The new antiviral drug MK-4482 / EIDD-2801 or Molnupiravir, has managed to suppress "completely" the transmission of the coronavirus in just 24 hours , according to studies by the Institute of Biomedical Sciences of Georgia State University.  "This is the first demonstration of an orally available drug that quickly blocks the transmission of SARS-CoV-2 , so it could be a game changer," the researchers explained in the work published in the journal Nature Microbiology .  The antiviral drug was developed at Emory University in Atlanta by the drug innovation company Drug Innovation Ventures at Emory (DRIVE), which was licensed by Ridgeback Biotherapeutics, which partnered with Merck & Co. Molnupiravir was originally designed to treat the flu and prevent the virus from making copies of itself, creating errors during viral RNA replication.

The experts detail that tests were carried out on ferrets and it was observed that they presented a reduction in the amount of viral particles. Then those ferrets were put with others that had not been treated. None of the ferrets in the second group became infected with COVID-19.  "We believe that ferrets are a relevant transmission model because they easily spread SARS-CoV-2, but for the most part they do not develop a serious disease, which is very similar to the spread of SARS-CoV-2 in young adults," he said. Dr. Robert Cox, a postdoctoral fellow in the Plemper group and co-lead author of the study.  “We observed early on that MK-4482 / EIDD-2801 has broad spectrum activity against respiratory RNA viruses and that oral treatment of infected animals with the drug reduces the amount of viral particles spread by several orders of magnitude, drastically reducing transmission. These properties made MK-4482 / EIDD / 2801 a powerful candidate for the pharmacological control of Covid-19 ”, the report adds.

If this ferret-based data is translated into humans, Covid-19 patients treated with the drug could become non-infectious within 24 hours of starting treatment. The drug can be taken orally, and treatment can be started early for a triple potential benefit: inhibiting patients' progress to severe disease, shortening the infectious phase to alleviate the emotional and socioeconomic cost of prolonged patient isolation, and containing quickly local outbreaks. Molnupiravir is currently in advanced phase II / III clinical trials. It is being tested in three different doses every 12 hours for five days in patients with SARS-CoV-2.

Findings published in Nat. Microbiology (Dec. 3, 2020):

https://doi.org/10.1038/s41564-020-00835-2

Scientists are hopeful that a new drug -- called EIDD-2801 -- could change the way doctors treat COVID-19. The drug shows promise in reducing lung damage, has finished testing in mice and will soon move to human clinical trials. As of April 3, the novel coronavirus SARS-CoV-2 had infected more than 1 million people with COVID-19 and caused more than 58,000 deaths in a worldwide pandemic. Currently, no antiviral drugs have been approved to treat SARS-CoV-2 or any of the other coronaviruses that cause human disease.

Researchers at the UNC-Chapel Hill Gillings School of Global Public Health are playing a key role in the development and testing of EIDD-2801. Virologists in the lab of William R. Kenan Jr. Distinguished Professor of epidemiology Ralph Baric, are working with colleagues in the lab of Mark Denison, Edward Claiborne Stahlman Professor of pediatrics at Vanderbilt University Medical Center (VUMC), and with George Painter, chief executive officer of the nonprofit DRIVE (Drug Innovation Ventures at Emory) and director of the Emory Institute for Drug Development (EIDD), where EIDD-2801 was discovered.

The results of the team's most recent study were published online April 6 by the journal Science Translational Medicine. The paper includes data from cultured human lung cells infected with SARS-CoV-2, as well as mice infected with the related coronaviruses SARS-CoV and MERS-CoV. The study found that, when used as a prophylactic, EIDD-2801 can prevent severe lung injury in infected mice. EIDD-2801 is an orally available form of the antiviral compound EIDD-1931; it can be taken as a pill and can be properly absorbed to travel to the lungs. When given as a treatment 12 or 24 hours after infection has begun, EIDD-2801 can reduce the degree of lung damage and weight loss in mice. This window of opportunity is expected to be longer in humans, because the period between coronavirus disease onset and death is generally extended in humans compared to mice...

Published in Science Translational Medicine (April 6, 2020):

https://doi.org/10.1126/scitranslmed.abb5883