Clinical Trial

. 2022 Jul 19;3(7):100678.

doi: 10.1016/j.xcrm.2022.100678. Epub 2022 Jun 20.

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

Julie Boucau¹, Kara W Chew², Manish C Choudhary³, Rinki Deo³, James Regan³, James P Flynn³, Charles R Crain³, Michael D Hughes⁴, Justin Ritz⁴, Carlee Moser⁴, Joan A Dragavon⁵, Arzhang C Javan⁶, Ajay Nirula⁷, Paul Klekotka⁷, Alexander L Greninger⁵, Robert W Coombs⁵, William A Fischer 2nd⁸, Eric S Daar⁹, David A Wohl⁸, Joseph J Eron⁸, Judith S Currier², Davey M Smith¹⁰; POSITIVES study team¹¹; Jonathan Z Li¹², Amy K Barczak¹³; ACTIV-2/A5401 Study Team

Affiliations

¹ The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
² Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁴ Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
⁶ National Institutes of Health, Bethesda, MD, USA.
⁷ Lilly Research Laboratories, Eli Lilly and Company, San Diego, CA, USA.
⁸ Department of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
⁹ Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁰ Department of Medicine, University of California San Diego, La Jolla, CA, USA.
¹¹ Massachusetts General Hospital, Boston, MA, USA.
¹² Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: jli@bwh.harvard.edu.
¹³ The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: abarczak@mgh.harvard.edu.

PMID: 35793677
PMCID: PMC9213028
DOI: 10.1016/j.xcrm.2022.100678

Clinical Trial

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

Julie Boucau et al. Cell Rep Med. 2022.

. 2022 Jul 19;3(7):100678.

doi: 10.1016/j.xcrm.2022.100678. Epub 2022 Jun 20.

Authors

Affiliations

¹ The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
² Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁴ Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
⁶ National Institutes of Health, Bethesda, MD, USA.
⁷ Lilly Research Laboratories, Eli Lilly and Company, San Diego, CA, USA.
⁸ Department of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
⁹ Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁰ Department of Medicine, University of California San Diego, La Jolla, CA, USA.
¹¹ Massachusetts General Hospital, Boston, MA, USA.
¹² Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: jli@bwh.harvard.edu.
¹³ The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: abarczak@mgh.harvard.edu.

PMID: 35793677
PMCID: PMC9213028
DOI: 10.1016/j.xcrm.2022.100678

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.

PubMed Disclaimer

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.

Figures

**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**
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.

See this image and copyright information in PMC

Update of

Monoclonal antibody treatment drives rapid culture conversion in SARS-CoV-2 infection.
Boucau J, Chew KW, Choudhary M, Deo R, Regan J, Flynn JP, Crain CR, Hughes MD, Ritz J, Moser C, Dragavon JA, Javan AC, Nirula A, Klekotka P, Greninger AL, Coombs RW, Fischer WA 2nd, Daar ES, Wohl DA, Eron JJ, Currier JS, Smith DM, Li JZ, Barczak AK; ACTIV-2/A5401 Study Team. Boucau J, et al. medRxiv [Preprint]. 2021 Dec 30:2021.12.25.21268211. doi: 10.1101/2021.12.25.21268211. medRxiv. 2021. Update in: Cell Rep Med. 2022 Jul 19;3(7):100678. doi: 10.1016/j.xcrm.2022.100678. PMID: 35018382 Free PMC article. Updated. Preprint.

References

1. Planas D., Saunders N., Maes P., Guivel-Benhassine F., Planchais C., Buchrieser J., Bolland W.-H., Porrot F., Staropoli I., Lemoine F., et al. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization. Nature. 2022;602:671–675. doi: 10.1038/s41586-021-04389-z. - DOI - PubMed
1. Planas D., Veyer D., Baidaliuk A., Staropoli I., Guivel-Benhassine F., Rajah M.M., Planchais C., Porrot F., Robillard N., Puech J., et al. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Nature. 2021;596:276–280. doi: 10.1038/s41586-021-03777-9. - DOI - PubMed
1. Dougan M., Azizad M., Chen P., Feldman B., Frieman M., Igbinadolor A., Kumar P., Morris J., Potts J., Baracco L., et al. Bebtelovimab, alone or together with bamlanivimab and etesevimab, as a broadly neutralizing monoclonal antibody treatment for mild to moderate, ambulatory COVID-19. medRxiv. 2022 doi: 10.1101/2022.03.10.22272100. Preprint at. - DOI
1. Westendorf K., Zentelis S., Wang L., Foster D., Vaillancourt P., Wiggin M., Lovett E., van der Lee R., Hendle J., Pustilnik A., et al. LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants. Cell Rep. 2022;39:110812. doi: 10.1016/j.celrep.2022.110812. - DOI - PMC - PubMed
1. Takashita E., Kinoshita N., Yamayoshi S., Sakai-Tagawa Y., Fujisaki S., Ito M., Iwatsuki-Horimoto K., Halfmann P., Watanabe S., Maeda K., et al. Efficacy of antiviral agents against the SARS-CoV-2 omicron subvariant BA.2. N. Engl. J. Med. 2022;386:1475–1477. doi: 10.1056/NEJMc2201933. - DOI - PMC - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Update of

References

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous