In addition to vaccines, antiviral drugs should also help prevent severe courses of Covid-19. A research team has now investigated how well these active ingredients also help against the omicron variant of Sars-CoV-2 in infection tests on cell cultures. It was found that all eight active ingredients tested, including remdesivir, molnupiravir and paxlovid, are just as effective against omicron as against the delta variant. In addition, the experiments provided evidence that Omicron is less able to block the cellular defense mechanism using interferon than earlier forms of coronavirus. This could explain why the course is usually milder.
Since emerging in southern Africa late last year, the severely mutated omicron variant of Sars-CoV-2 has spread globally. It is now the dominant form of the coronavirus in most regions. It differs from the original type of Covid-19 pathogen by around 50 mutations, including several that make it more infectious. Tests also show that the antibodies against the omicron variant formed by vaccination or previous infections are only partially effective. This makes vaccination breakthroughs more likely, even if the T cell response that continues ensures a mild course. Overall, the mutated form of the corona virus seems to cause less severe courses than its predecessor Delta. However, it is not yet clear why this is the case.
Less effective in inhibiting the interferon response
A German-British research team led by Denisa Bojkova from the Goethe University in Frankfurt has now examined in more detail how
Cells respond to omicron variant infection and how well antiviral agents can control infection. For their study, they exposed cultures of hamster cells and two human cell lines to infection with two isolates of the omicron variant and one of the delta variant. They observed that omicron was less able to spread in cultures in which the cells had an intact and strong interferon defense reaction. During this cellular defense reaction, the cells produce the messenger substance interferon, which has an antiviral effect and at the same time acts as an alarm messenger for the immune system. The delta variant, on the other hand, was able to replicate equally well in all cultures, regardless of interferon status.
According to the research team, this suggests that the omicron variant is less able to suppress the cellular interferon response than Delta. In line with this, the mutated virus form carries several mutations in protein regions that contribute to blocking the interferon response in earlier variants. As the scientists explain, the less efficient interferon inhibition could be a reason why Omicron shows less severe Covid 19 courses. “Our cell culture experiments provide an initial explanation as to why omicron infections often result in mild clinical courses: Apparently, unlike delta, omicron cannot prevent the infected cells from producing and releasing interferon,” explains co-author Martin Michaelis from the university of Kent.
Antiviral drugs continue to work
In a second experiment, the research team tested how well eight antiviral drugs that are currently being tested in clinical studies or have already been approved work against the omicron variant. Remdesivir, the molnupiravir derivative EIDD-1931, ribavirin, favipravir, the Paxlovid component PF-07321332 and the protease inhibitors nafamostat, camostat and aprotinin were tested. The result here: All eight substances showed comparable effectiveness in the cell culture tests against the omicron and delta variants. “This shows that the mutations in the omicron variant have not caused any substantial changes in the drug sensitivity profile of the virus,” the scientists explain. This confirms that the viral enzymes and replication processes required for virus replication have hardly changed at Omikron.
“Although our cell culture experiments cannot of course be directly transferred to the much more complex situation in patients, they give hope that the enormous efforts to develop Covid-19 drugs were not in vain,” says Bojkova’s colleague Jindrich Cinatl. “So we can be confident that a wide range of active ingredients with different mechanisms of action will soon be available against the new omicron virus variant.”
Source: Denisa Bojkova (Goethe-University Frankfurt am Main) et al., Cell Research, doi: 10.1038/s41422-022-00619-9