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.
importantly, in vivo experiments should be designed in a suitable animal model before moving forward to a wide introduction of combination therapy into the clinic. SARS-CoV-2 animal models have been progressively improved [37] and should now be an integral part of the lessons learned from the COVID-19 pandemic [9] .
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/v16020168/s1, Table S1 : IC 50 synergistic potency shift measured in infected VERO E6 cells; Figure S1 : Bi-dimensional (2D) synergy plots of antivirals against the two SARS-CoV-2 strains tested, generated using Synergy Finder 3.0 (https://synergyfinder.fimm.fi/ accessed on 12 October 2023); Figure S2 : Overall combinatorial effects of the three DAA pairs as well as those of the three RDV/mAb groups compared by the Kruskal-Wallis test followed by Mann-Whitney pairwise comparisons between groups.
Author Contributions
Conflicts of Interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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