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In Vitro Combinatorial Activity of Direct Acting Antivirals and Monoclonal Antibodies against the Ancestral B.1 and BQ.1.1 SARS-CoV-2 Viral Variants

Fiaschi et al., Viruses, doi:10.3390/v16020168
Jan 2024  
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In vitro study showing additive or synergistic antiviral effects with combinations of COVID-19 therapeutics nirmatrelvir, molnupiravir, remdesivir, and monoclonal antibodies sotrovimab, bebtelovimab, cilgavimab and tixagevimab against ancestral B.1 and Omicron BQ.1.1 SARS-CoV-2 variants in Vero E6 cells. Authors found specific concentrations of antiviral pairs with higher than expected cooperative effects, including marked synergistic shifts in IC50 values, although overall weighted synergy scores indicated additivity. Combinations were similarly effective against both viruses. Confirmation experiments supported synergistic interactions, especially for dual antiviral combinations, while cooperative effects between remdesivir and monoclonal antibodies were less pronounced.
Fiaschi et al., 23 Jan 2024, peer-reviewed, 9 authors. Contact: (corresponding author),,,,,,,,
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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In Vitro Combinatorial Activity of Direct Acting Antivirals and Monoclonal Antibodies against the Ancestral B.1 and BQ.1.1 SARS-CoV-2 Viral Variants
Lia Fiaschi, Camilla Biba, Ilenia Varasi, Niccolò Bartolini, Chiara Paletti, Federica Giammarino, Francesco Saladini, Maurizio Zazzi, Ilaria Vicenti
Viruses, doi:10.3390/v16020168
Combination antiviral therapy may be helpful in the treatment of SARS-CoV-2 infection; however, no clinical trial data are available, and combined use of direct-acting antivirals (DAA) and monoclonal antibodies (mAb) has been reported only anecdotally. To assess the cooperative effects of dual drug combinations in vitro, we used a VERO E6 cell-based in vitro system with the ancestral B.1 or the highly divergent BQ.1.1 virus to test pairwise combinations of the licensed DAA, including nirmatrelvir (NRM), remdesivir (RDV) and the active metabolite of molnupiravir (EIDD-1931) as well the combination of RDV with four licensed mAbs (sotrovimab, bebtelovimab, cilgavimab, tixagevimab; tested only with the susceptible B.1 virus). According to SynergyFinder 3.0 summary and weighted scores, all the combinations had an additive effect. Within DAA/DAA combinations, paired scores with the B.1 and BQ.1.1 variants were comparable. In the post hoc analysis weighting synergy by concentrations, several cases of highly synergistic scores were detected at specific drug concentrations, both for DAA/DAA and for RDV/mAb combinations. This was supported by in vitro confirmation experiments showing a more than a linear shift of a drug-effective concentration (IC 50 ) at increasing concentrations of the companion drug, although the effect was prominent with DAA/DAA combinations and minimal or null with RDV/mAb combinations. These results support the cooperative effects of dual drug combinations in vitro, which should be further investigated in animal models before introduction into the clinic.
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