Long-term Anti-SARS-CoV-2 Antibody Trajectories After Neutralizing Monoclonal Antibody Treatment
Elizabeth S. Munroe, Greg A. Grandits, Robert C. Hyzy, Hallie C. Prescott, Thomas W. Barrett, Robin L. Dewar, Nicole Engen, Anna L. Goodman, Timothy J. Hatlen, Helene Highbarger, Thomas L. Holland, Gareth Hughes, Tomas O. Jensen, Muhammad A. Khan, Ioannis Kalomenidis, Nayon Kang, Sylvain Laverdure, Prasad Manian, Vidya Menon, Ravi Patel, Srikanth Ramachandruni, Tauseef Rehman, Kathryn Shaw-Saliba, Birgit Thorup Røge, David M. Vock, Amy C. Weintrob, Barnaby E. Young, Anne P. Frosch
Abstract
Neutralizing monoclonal antibodies (nMAbs) have been used to treat COVID-19 and are increasingly being used to treat other infections. However, there is concern that by neutralizing the SARS-CoV-2 virus, nMAbs may decrease the availability of antigens to the immune system, potentially impairing the endogenous polyclonal immune response and decreasing long-term immune protection.
Introduction
Passive immunization with neutralizing monoclonal antibodies (nMAbs) has been successful in managing several viral infections, including preventing RSV in infants and treating Ebola. NMAbs also played an important role in COVID-19 primary prevention and post-exposure prophylaxis. Additionally, several large, multi-center randomized controlled trials found that administering nMAbs against the SARS-CoV-2 spike protein reduced COVID-19-related hospitalization and death in outpatients with mild-to-moderate COVID-19 infection and risk factors for disease progression.
Methods:
This was a pre-specified secondary analysis of trials conducted through the ACTIV-3/TICO platform (NCT04501978), a phase III multicenter, adaptive, randomized, blinded platform trial of therapeutics for hospitalized patients with COVID-19 [25]. In this study, we compared long-term (28-day and 90-day) antibody responses among patients treated with nMAb vs placebo across four trials of novel SARS-CoV-2 nMAbs. We also compared long-term antibody responses among patients treated with two other molecules with activity against SARS-CoV-2 vs placebo.
Discussion
In this prespecified secondary analysis of over 2,000 patients enrolled in ACTIV-3/TICO randomized trials, participants hospitalized for severe COVID-19 who were treated with SARS-CoV-2 anti-spike nMAbs had similar 28-day and 90-day anti-nucleocapsid responses as participants who received placebo. These results suggest that treatment with nMAbs during hospitalization for severe COVID-19 does not impair host humoral immune response to the target antigen or other viral antigens. Similar findings were demonstrated for the neutralizing anti-spike DARPin studied on this platform.
Acknowledgments
The authors would like to thank the participants in the ACTIV-3/TICO trials and the study teams. See Supplement Acknowledgement file for a full list of STRIVE Network and Therapeutics for Inpatients with COVID-19 (TICO) study team members. This material is the result of work supported with resources and use of facilities at the Ann Arbor VA Medical Center. This manuscript reflects views of the authors and does not represent the views of the Department of Veterans Affairs or the US government. Data are posted to https://public-data.ccbr.umn.edu/.
Citation: Munroe ES, Grandits GA, Hyzy RC, Prescott HC, Barrett TW, Dewar RL, et al. (2025) Long-term anti-SARS-CoV-2 antibody trajectories after neutralizing monoclonal antibody treatment. PLoS One 20(6): e0325561. https://doi.org/10.1371/journal.pone.0325561
Editor: Elisabetta Pilotti, University of Verona, ITALY
Received: December 11, 2024; Accepted: May 15, 2025; Published: June 18, 2025.
Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Data Availability: Data for the ACTIV-3/TICO trials are publicly available at https://public-data.ccbr.umn.edu/.
Funding: This research was, in part, funded by the National Institutes of Health (NIH) Agreement 1OT2HL156812-01. The trial was sponsored and primarily funded by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, in part with federal funds from the NIAID and the National Cancer Institute, NIH, under contract 75N91019D00024, task order numbers 75N91020F00014 and 75N91020F00039. The work was funded under Subcontract 18X107C under Leidos Biomeds's Prime Contract HHSN261200800001E, NIH. NIH Grant U01-AI136780. The following authors received relevant funding support: • Author ESM was supported by Grant Number F32 HL 172463 from the National Institutes of Health, National Heart, Lung, and Blood institute. • Author BEY was supported by Singapore National Medical Research Council (NMRC, grant number COVID19RF-0005). • Author ALG receives funding to support salary from the Medical Research Council (MC_UU_00004/05).
Competing interests: Author BEY has received honoraria/speaker fees from Astra-Zeneca, Gilead, Sanofi, Pfizer, Moderna (paid to their institution and outside of the submitted work). All other authors report no competing interests.
