Monoclonal antibody treatment drives rapid culture conversion in SARS-CoV-2 infection

Julie Boucau, Kara W Chew, Manish C Choudhary, Rinki Deo, James Regan, James P Flynn, Charles R Crain, Michael D Hughes, Justin Ritz, Carlee Moser, Joan A Dragavon, Arzhang C Javan, Ajay Nirula, Paul Klekotka, Alexander L Greninger, Robert W Coombs, William A Fischer 2nd, Eric S Daar, David A Wohl, Joseph J Eron, Judith S Currier, Davey M Smith, POSITIVES study team, Jonathan Z Li, Amy K Barczak, ACTIV-2/A5401 Study Team, Julie Boucau, Kara W Chew, Manish C Choudhary, Rinki Deo, James Regan, James P Flynn, Charles R Crain, Michael D Hughes, Justin Ritz, Carlee Moser, Joan A Dragavon, Arzhang C Javan, Ajay Nirula, Paul Klekotka, Alexander L Greninger, Robert W Coombs, William A Fischer 2nd, Eric S Daar, David A Wohl, Joseph J Eron, Judith S Currier, Davey M Smith, POSITIVES study team, Jonathan Z Li, Amy K Barczak, ACTIV-2/A5401 Study Team

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies (mAbs) are among the treatments recommended for high-risk ambulatory persons with coronavirus 2019 (COVID-19). Here, we study viral culture dynamics post-treatment in a subset of participants receiving the mAb bamlanivimab in the ACTIV-2 trial (ClinicalTrials.gov: NCT04518410). Viral load by qPCR and viral culture are performed from anterior nasal swabs collected on study days 0 (day of treatment), 1, 2, 3, and 7. Treatment with mAbs results in rapid clearance of culturable virus. One day after treatment, 0 of 28 (0%) participants receiving mAbs and 16 of 39 (41%) receiving placebo still have culturable virus (p < 0.0001). Recrudescence of culturable virus is detected in three participants with emerging mAb resistance and viral RNA rebound. While further studies are necessary to fully define the relationship between shed culturable virus and transmission, these results raise the possibility that mAbs may offer immediate (household) and public-health benefits by reducing onward transmission.

Keywords: COVID; COVID therapies; COVID-19; SARS-CoV-2; mAbs; monoclonal antibodies; resistance; viral culture.

Conflict of interest statement

Declaration of interests J.B., M.C.C., R.D., J. Regan, J.P.F., C.R.C., M.D.H., J. Ritz, C.M., J.A.D., A.C.J., R.W.C., J.S.C., and A.K.B. report no competing interests. K.W.C. reports research grant support to the institution from Merck Sharp & Dohme. A.N. and P.K. are employees and shareholders of Eli Lilly. A.L.G. declares central testing contracts with Abbott and research support from Gilead and Merck outside of the submitted work. W.A.F. reports research funding from Ridgeback Biopharmaceuticals and consultancy fees from Roche and Merck and serves on adjudication committees for Janssen and Syneos. E.S.D. reports consulting fees from Gilead Sciences and Merck and research support to the institution from Gilead Sciences and ViiV. J.J.E. reports serving as an ad hoc consultant to GSK/VIR and as data monitoring committee (DMC) chair for Adagio Phase III studies. D.M.S. reports consulting fees from the following companies: Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Arena Pharmaceuticals, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, Signant Health, and Brio Clinical. J.Z.L. reports consulting for Abbvie and Recovery Therapeutics.

Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Bamlanivimab treatment results in rapid SARS-CoV-2 culture conversion (A) Pre-treatment culture positivity and viral load. Horizontal line indicates median. (B) Pre-treatment TCID50 values versus viral load for individuals with CPE. Spearman correlations: placebo r = 0.7382, p < 0.0001; Bam mAb r = 0.6012, p value = 0.0007. (C) Decay in qPCR-determined viral load over time post-treatment. Horizontal lines connect the medians for each experimental group for each timepoint. (D) Culture positivity and viral load over time post-treatment. . Horizontal line indicates median. Cx, culture; Bam mAb, bamlanivimab monoclonal antibody; ND, not detected. X indicates samples not tested either because of lack of sample availability (one placebo sample day 3) or because VL was at or below the limit of detection.
Figure 2
Figure 2
Emergence of bamlanivimab resistance mutations correlates with recrudescent shedding of culturable virus (A) Viral load and culture positivity at baseline and day 1 post-treatment for four study participants with recrudescent shedding of culturable virus. Cx, culture. (B–E) Viral load and TCID50 for four study participants whose infecting virus developed E484 mutations of the spike protein following bamlanivimab monotherapy.

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