Researchers unlock omicron secrets to better understand COVID-19 – Washington University School of Medicine in St. Louis

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Studies show that omicron is resistant to antibodies; causes milder disease in mice, hamsters

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When South African scientists announced in November that they had identified a new variant of the virus that causes COVID-19, they also reported two disturbing details: first, the genome of this new variant was strikingly different from that of any previous variant, containing dozens of mutations compared to the original virus that appeared in 2019; and two, that the new variant – dubbed omicron – was spreading like wildfire.

The world needed to know quickly how much immunity to COVID-19 – whether due to vaccination or previous infection – and therapies would withstand this new variant.

Researchers from Washington University School of Medicine in St. Louis, led by Michael S. Diamond, MD, Ph.D., Professor of Medicine Herbert S. Gasser, immediately began investigating the new variant of SARS-CoV-2, the virus that causes COVID-19. Within weeks, they had data showing that omicron was a mixed bag: it could resist most antibody therapies, but it was less able to cause severe lung disease, at least in mice and animals. hamsters.

“What omicron demonstrates is that the intrinsic pathogenicity of a virus — its ability to cause disease — is only one factor to consider in the context of a pandemic,” Diamond said, also Professor of Molecular Microbiology and Pathology and Immunology. “The omicron variant is less pathogenic, but it is not not pathogenic. It can still cause serious illness and kill people. When large numbers of people are infected in a short time, even if only a small fraction become seriously ill, it can still be enough to overwhelm the health care system. Add to that the fact that many of our antibody therapies have lost their effectiveness, and you have the crisis we had this winter. »

Diamond worked with Jacques Boon, PhDAssociate Professor of Medicine, Molecular Microbiology and Pathology and Immunology, and his colleagues from SARS-CoV-2 Viral Evolution Assessment (SAVE) Program to study the ability of omicron to cause serious diseases. The SAVE program was created by the National Institute of Allergy and Infectious Diseases to rapidly characterize emerging variants and monitor their potential impact on COVID-19 vaccines, treatments and diagnostics.

The omicron wave first peaked in South Africa. Early reports from the country said the huge wave of infections was followed by a surprisingly low wave of hospitalizations and deaths. This encouraging news suggested that omicron might cause milder disease than previous variants. But the South African and American populations are very different. South Africa is much younger and has a lower vaccination rate but a higher rate of previous infection and a different pattern of high-risk health conditions. It was unclear whether the United States would follow the same path as South Africa.

To separate the role of the virus itself from demographic factors such as average age and pre-existing immunity, Boon, Diamond and colleagues studied animals infected with the variant. The group tested omicron variants from three people in four strains of mice and two strains of hamsters. For comparison, they infected separate groups of animals with the original strain of SARS-CoV-2 or the beta variant, which emerged in South Africa in the fall of 2020. The beta caused a large wave of infections in South Africa in 2020 before spreading globally. People infected with beta were more likely to become seriously ill and require hospitalization than those infected with other variants.

Compared to animals infected with the original strain or the beta variant, animals infected with omicron lost less weight, had less virus in the nose and lungs, had lower levels of inflammation and lost less respiratory function.

“Omicron virus is milder in all rodent models of COVID-19 disease that we have tested,” Boon said. “This suggests it may also be less capable of causing serious disease in humans, although we can’t say that for sure because people, obviously, are very different from mice and hamsters. But that’s not true. “Because it’s milder doesn’t mean it’s harmless. People are still being hospitalized and dying every day, so it’s important to continue to take precautions against infection.”

The disease severity study was published in Nature, with co-corresponding authors Boon, Diamond and Yoshihiro Kawaoka, DVM, PhD, professor of virology at the University of Wisconsin-Madison.

During this time, Diamond also began studying omicron’s ability to resist antibody therapies. The virus that causes COVID-19 uses its spike protein to get inside cells. Due to the spike’s critical importance to the virus, all COVID-19 vaccines and antibody therapies used in the United States target the protein. Omicron has 30 mutations in its spike gene, enough for scientists to worry that some anti-spike antibodies may fail against omicron’s very different spike protein.

Diamond, along with scientist and first author Laura VanBlargan, PhD, and her colleagues tested all antibodies then cleared by the Food and Drug Administration to treat or prevent COVID-19 — including antibodies made by AstraZeneca, Celltrion, Eli Lilly, Regeneron and Vir Biotechnology — for their ability to prevent the omicron variant from infecting cells. The antibodies were tested individually and in the combinations for which they were authorized to be used.

Most of the antibodies were much weaker against omicron than against the original virus. Many have completely failed. Only Vir’s antibody, known as sotrovimab, retained the power to neutralize the omicron variant. These data, published in Nature Medicine in January, contributed to a growing pile of evidence that many antibody-based COVID-19 therapies fail to help people with omicron. As omicron became the dominant variant in January, accounting for nearly all COVID-19 cases in the United States, the FDA withdrew approval of all antibody-based COVID-19 therapies except for sotrovimab .

Halfmann PJ, Iida S, Iwatsuki-Horimoto K, et al. The SARS-CoV-2 Omicron virus causes attenuated disease in mice and hamsters. Nature. January 21, 2022. DOI: 10.1038/s41586-022-04441-6

The disease severity study was supported by National Institutes of Health (NIH) grant and contract numbers R01AI157155, 75N93021810, 75N93021C00014, Center for Research in Influenza Pathogenesis and Transmission, HHSN272201700008C, HHSN272201700041I, 75N93020F00001 / A38, P51OD011132, R56AI147623, HHSN272201400004C, 75N93021C00017, P01AI060699, R01AI129269, R01DK130425, 5T32AI007647-22, 75N93019C00051 75N93021C00016 and the St. Jude Research and Response Influenza is Center of Excellence; the Defense Advanced Research Projects Agency, grant number HR0011-19-2-319 0020; Japan Agency for Medical Research and Development (AMED) Emerging and Re-emerging Infectious Disease Research Program, grant numbers JP20fk0108412, JP21fk0108615, JP20fk0108472, and JP21fk0108104; AMED’s Project Fostering Support for Drug Discovery, Grant Number JP20nk0101632; AMED’s Japan Program for Infectious Disease Research and Infrastructure, grant number JP21wm0125002; the 2020 Woodruff Health Sciences Center COVID-19 CURE Award; Emory School of Medicine; and the National Institute of Allergy and Infectious Diseases Intramural Program.

VanBlargan LA, Errico JM, Halfmann PJ, Zost SJ, Crowe Jr. JE, Purcell LA, Kawaoka Y, Corti D, Fremont DH, Diamond MS. An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes neutralization by therapeutic monoclonal antibodies. Natural medicine. January 19, 2022. DOI: 10.1038/s41591-021-01678-y

The antibody study was supported by the National Institutes of Health (NIH), grant and contract numbers R01AI157155, U01AI151810, 75N93021C00014, HHSN272201700060C, 75N93019C00062, and 75N93019C00051; the Defense Advanced Research Project Agency, grant number HR0011-18-2-0001; Japanese Infectious Disease Research and Infrastructure Program of the Japan Agency for Medical Research and Development, grant number JP21wm0125002; and the Dolly Parton COVID-19 Research Fund at Vanderbilt University Medical Center.

The 1,700 doctors at the University of Washington Medical School are also part of the medical staff of Barnes-Jew and St. Louis Children’s hospitals. The School of Medicine is a leader in medical research, teaching, and patient care, and is currently #4 in National Institutes of Health (NIH) research funding. Through its affiliations with Barnes-Jewish and St. Louis Children’s Hospitals, the School of Medicine is linked to BJC Healthcare.

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