Affiliation:
1. Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
Abstract
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 (IC50) 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.
Funder
Ministero dell’Università e della Ricerca
EU funding within the NextGenerationEU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases
European Union’s Horizon Europe Research and Innovation Program
Reference37 articles.
1. Characteristics Associated with the Residual Risk of Severe COVID-19 after a Complete Vaccination Schedule: A Cohort Study of 28 Million People in France;Semenzato;Lancet Reg. Health. Eur.,2022
2. Turtle, L., Thorpe, M., Drake, T.M., Swets, M., Palmieri, C., Russell, C.D., Ho, A., Aston, S., Wootton, D.G., and Richter, A. (2023). Outcome of COVID-19 in Hospitalised Immunocompromised Patients: An Analysis of the WHO ISARIC CCP-UK Prospective Cohort Study. PLoS Med., 20.
3. Enhanced Evasion of Neutralizing Antibody Response by Omicron XBB.1.5, CH.1.1, and CA.3.1 Variants;Qu;Cell Rep.,2023
4. Evaluation of Waning of SARS-CoV-2 Vaccine-Induced Immunity: A Systematic Review and Meta-Analysis;Menegale;JAMA Netw. Open,2023
5. COVID-19 Treatments: Then and Now;Mustafa;J. Allergy Clin. Immunol. Pract.,2023