Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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
ORCID logo ,
Chiara Paletti
,
Federica Giammarino
,
Francesco Saladini
ORCID logo ,
Maurizio Zazzi
ORCID logo ,
Ilaria Vicenti
* ORCID logo
Version 1 : Received: 29 December 2023 / Approved: 3 January 2024 / Online: 3 January 2024 (19:28:07 CET)

A peer-reviewed article of this Preprint also exists.

Fiaschi, L.; Biba, C.; Varasi, I.; Bartolini, N.; Paletti, C.; Giammarino, F.; Saladini, F.; Zazzi, M.; Vicenti, I. 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. Viruses 2024, 16, 168. Fiaschi, L.; Biba, C.; Varasi, I.; Bartolini, N.; Paletti, C.; Giammarino, F.; Saladini, F.; Zazzi, M.; Vicenti, I. 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. Viruses 2024, 16, 168.

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 linear shift of a drug effective concentration (IC50) at increasing concentrations of the companion drug, although the effect was prominent with DAA/DAA combinations but minimal or null with RDV/mAb combinations. These results support a cooperative effects of dual drug combinations in vitro, which should be further investigated in animal models before introduction into the clinic.

Keywords

SARS-CoV-2; mAbs; DAA; Combination antiviral therapy; In vitro synergism; Omicron variant

Subject

Biology and Life Sciences, Virology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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