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Juan Lama
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Small animal models have been a challenge for the study of SARS-CoV-2 transmission, with most investigators using golden hamsters or ferrets. Mice have the advantages of low cost, wide availability, less regulatory and husbandry challenges, and the existence of a versatile reagent and genetic toolbox. However, adult mice do not robustly transmit SARS-CoV-2. Here we establish a model based on neonatal mice that allows for transmission of clinical SARS-CoV-2 isolates. We characterize tropism, respiratory tract replication and transmission of ancestral WA-1 compared to variants Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Omicron BA.1 and Omicron BQ.1.1. We identify inter-variant differences in timing and magnitude of infectious particle shedding from index mice, both of which shape transmission to contact mice. Furthermore, we characterize two recombinant SARS-CoV-2 lacking either the ORF6 or ORF8 host antagonists. The removal of ORF8 shifts viral replication towards the lower respiratory tract, resulting in significantly delayed and reduced transmission in our model. Our results demonstrate the potential of our neonatal mouse model to characterize viral and host determinants of SARS-CoV-2 transmission, while revealing a role for an accessory protein in this context. Here the authors develop a neonatal mouse model for SARS-CoV-2 transmission, characterize differences in viral replication and shedding of variants of concerns, and show that deletion of ORF8 shifts viral replication to the lower respiratory tract and delays transmission. Published in Nature Comm. (May 25, 2023): https://doi.org/10.1038/s41467-023-38783-0
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Juan Lama
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Infected rodents pose no immediate danger to humans, but the research suggests that mutations are helping the coronavirus expand its range of potential hosts. Bats, humans, monkeys, minks, big cats and big apes — the coronavirus can make a home in many different animals. But now the list of potential hosts has expanded to include mice, according to an unnerving new study. Infected rodents pose no immediate risk to people, even in cities like London and New York, where they are ubiquitous and unwelcome occupants of subway stations, basements and backyards. Still, the finding is worrying. Along with previous work, it suggests that new mutations are giving the virus the ability to replicate in a wider array of animal species, experts said. “The virus is changing, and unfortunately it’s changing pretty fast,” said Timothy Sheahan, a virologist at the University of North Carolina at Chapel Hill, who was not involved in the new study. In the study, the researchers introduced the virus into the nasal passages of laboratory mice. The form of the virus first identified in Wuhan, China, cannot infect laboratory mice, nor can B.1.1.7, a variant that has been spreading across much of Europe, the researchers found. But B.1.351 and P1, the variants discovered in South Africa and Brazil, can replicate in rodents, said Dr. Xavier Montagutelli, a veterinarian and mouse geneticist at the Pasteur Institute in Paris, who led the study. The research, posted online earlier this month, has not yet been reviewed for publication in a scientific journal. The results indicate only that infection in mice is possible, Dr. Montagutelli said. Mice caught in the wild have not been found to be infected with the coronavirus, and so far, the virus does not seem to be able to jump from humans to mice, from mice to humans, or from mice to mice. “What our results emphasize is that it is necessary to regularly assess the range of species that the virus can infect, especially with the emergence of new variants,” Dr. Montagutelli said. The coronavirus is thought to have emerged from bats, with perhaps another animal acting as an intermediate host, and scientists worry that the virus may return to what they describe as an animal “reservoir.” Apart from potentially devastating those animal populations, a coronavirus spreading in another species may then acquire dangerous mutations, returning to humans in a form the current vaccines weren’t designed to fend off. Minks are the only animals known to be able to catch the coronavirus from humans and pass it back. In early November, Denmark culled 17 million farmed mink to prevent the virus from evolving into dangerous new variants in the animals. More recently, researchers found that B.1.1.7 infections in domesticated cats and dogs can cause the pets to develop heart problems similar to those seen in people with Covid-19. To establish a successful infection, the coronavirus must bind to a protein on the surface of animal cells, gain entry into the cells, and exploit their machinery to make copies of itself. The virus must also evade the immune system’s early attempts at thwarting the infection. Given all those requirements, it is “quite extraordinary” that the coronavirus can infect so many species, said Vincent Munster, a virologist at the National Institute of Allergy and Infectious Diseases. “Typically, viruses have a more curtailed host range.” Mice are a known reservoir for hantavirus, which causes a rare and deadly disease in people. Even though the coronavirus variants don’t seem to be able to jump from mice to people, there is potential for them to spread among rodents, evolve into new variants, and then infect people again, Dr. Munster said. The variants may also threaten endangered species like black-footed ferrets. “This virus seems to be able to surprise us more than anything else, or any other previous virus,” Dr. Munster said. “We have to err on the side of caution.” Dr. Sheahan said he was more concerned about transmission to people from farm animals and pets than from mice. “You’re not catching wild mice in your house and snuggling — getting all up in their face and sharing the same airspace, like maybe with your cat or your dog,” he said. “I’d be more worried about wild or domestic animals with which we have a more intimate relationship.” But he and other experts said the results emphasized the need to closely monitor the rapid changes in the virus. “It’s like a moving target — it’s crazy,” he added. “There’s nothing we can do about it, other than try and get people vaccinated really fast.” Preprint available in bioRxiv (March 18, 2021):
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Scooped by
Juan Lama
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The U.S. Food and Drug Administration is using a controversial strategy to evaluate the next generation of COVID-19 boosters. The approach is stirring debate as the agency works to make new, hopefully improved, boosters available in September to help prevent severe disease and save lives in the fall and winter. For the first time, the FDA is planning to base its decision about whether to authorize new boosters on studies involving mice instead of humans. "For the FDA to rely on mouse data is just bizarre, in my opinion," says John Moore, an immunologist at Weill Cornell Medicine in New York. "Mouse data are not going to be predictive in any way of what you would see in humans." But others defend the approach, arguing that the country has had enough experience with the vaccines at this point to be confident the shots are safe and that there's not enough time to wait for data from human studies. "We have 500 people a day dying of coronavirus right now. Those numbers sadly might very well rise in the fall and the winter. The question is: 'Can we do something better?'" says Dr. Ofer Levy, a pediatrics and infectious disease researcher at Harvard Medical School who also advises the FDA. "And I think the answer is: 'We can, by implementing this approach.'" The U.K. just approved a new booster The United Kingdom just approved a new booster that targets both the original strain of the virus and the original omicron variant, called BA.1 — a so-called bivalent vaccine. But the FDA rejected BA.1 bivalent boosters last spring. Instead, the FDA told the vaccine companies that make the mRNA vaccines, Moderna and Pfizer and BioNTech, to develop bivalent vaccines that target the dominant omicron subvariants — BA.4 and BA.5 — in the hopes they will offer stronger, longer-lasting protection. That's why the FDA decided to use a new, streamlined strategy for testing the new boosters. The agency is asking the companies to initially submit only the results of tests on mice. Regulators will rely on those results, along with the human neutralizing antibody data from the BA.1 bivalent booster studies, to decide whether to authorize the boosters. The companies will continue to gather more data from human studies; those results probably won't be available until late October or early November. But the big concern is the boosters may not work as well as the mouse data might suggest. Mouse experiments are notoriously unreliable. And with the government telling people not to get the old boosters now and rejecting the first bivalent vaccines, the FDA really needs good evidence that the BA.4/5 boosters are in fact better, critics say. "We need to make sure that we have solid immunogenicity data in people to show that you have a dramatically greater neutralizing antibody response against BA.4, BA.5," says Dr. Paul Offit of the University of Pennsylvania, who also advises the FDA. "I think anything short of that is not acceptable." Some also worry that the approach may further erode the long-faltering efforts to persuade people to get boosted. "I think it would be good to have neutralizing antibody data in a small group of humans," says Dr. Monica Gandhi, an infectious disease researcher at the University of California, San Francisco. "Otherwise, extrapolation may be considered too great." But others agree the time constraints mean the country can't wait for more evidence. The billions of people who have gotten Moderna and Pfizer-BioNTech mRNA vaccines show how safe they are, those experts say. The new booster will be identical to the original vaccines except it will contain genetic coding for two versions of the protein the virus uses to infect cells — the protein from the original vaccine and proteins from the BA.4 and BA.5 omicron subvariants. And some scientists say health officials know enough about how vaccines work to start handling the COVID-19 vaccines like the flu vaccines, which are changed every year to try to match whatever strains are likely to be circulating but aren't routinely tested again every year. "We're going to use all of these data that we've learned through not only from this vaccine but decades of viral immunology to say: 'The way to be nimble is that we're going to do those animal studies," says Deepta Bhattacharya, an immunobiologist at the University of Arizona College of Medicine in Tucson. "We're really not going out too far on a limb here." The companies are expected to submit their data to the FDA by the end of the month and the administration hopes to make millions of doses of the new boosters available starting in September.
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