Clinical, Virologic, and Immunologic Evaluation of Symptomatic Coronavirus Disease 2019 Rebound Following Nirmatrelvir/Ritonavir Treatment
Brian P Epling, Joseph M Rocco, Kristin L Boswell, Elizabeth Laidlaw, Frances Galindo, Anela Kellogg, Sanchita Das, Allison Roder, Elodie Ghedin, Allie Kreitman, Robin L Dewar, Sophie E M Kelly, Heather Kalish, Tauseef Rehman, Jeroen Highbarger, Adam Rupert, Gregory Kocher, Michael R Holbrook, Andrea Lisco, Maura Manion, Richard A Koup, Irini Sereti, Brian P Epling, Joseph M Rocco, Kristin L Boswell, Elizabeth Laidlaw, Frances Galindo, Anela Kellogg, Sanchita Das, Allison Roder, Elodie Ghedin, Allie Kreitman, Robin L Dewar, Sophie E M Kelly, Heather Kalish, Tauseef Rehman, Jeroen Highbarger, Adam Rupert, Gregory Kocher, Michael R Holbrook, Andrea Lisco, Maura Manion, Richard A Koup, Irini Sereti
Abstract
Background: Nirmatrelvir/ritonavir, the first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease inhibitor, reduces the risk of hospitalization and death by coronavirus disease 2019 (COVID-19) but has been associated with symptomatic rebound after therapy completion.
Methods: Six individuals with relapse of COVID-19 symptoms after treatment with nirmatrelvir/ritonavir, 2 individuals with rebound symptoms without prior antiviral therapy and 7 patients with acute Omicron infection (controls) were studied. Soluble biomarkers and serum SARS-CoV-2 nucleocapsid protein were measured. Nasal swabs positive for SARS-CoV-2 underwent viral isolation and targeted viral sequencing. SARS-CoV-2 anti-spike, anti-receptor-binding domain, and anti-nucleocapsid antibodies were measured. Surrogate viral neutralization tests against wild-type and Omicron spike protein, as well as T-cell stimulation assays, were performed.
Results: High levels of SARS-CoV-2 anti-spike immunoglobulin G (IgG) antibodies were found in all participants. Anti-nucleocapsid IgG and Omicron-specific neutralizing antibodies increased in patients with rebound. Robust SARS-CoV-2-specific T-cell responses were observed, higher in rebound compared with early acute COVID-19 patients. Inflammatory markers mostly decreased during rebound. Two patients sampled longitudinally demonstrated an increase in activated cytokine-producing CD4+ T cells against viral proteins. No characteristic resistance mutations were identified. SARS-CoV-2 was isolated by culture from 1 of 8 rebound patients; Polybrene addition increased this to 5 of 8.
Conclusions: Nirmatrelvir/ritonavir treatment does not impede adaptive immune responses to SARS-CoV-2. Clinical rebound corresponds to development of a robust antibody and T-cell immune response, arguing against a high risk of disease progression. The presence of infectious virus supports the need for isolation and assessment of longer treatment courses.
Clinical trials registration: NCT04401436.
Keywords: COVID-19; COVID-19 rebound; COVID-19 transmission; antiviral therapy; nirmatrelvir/ritonavir.
Conflict of interest statement
Potential conflicts of interest. E. G. reports grants or contracts from the National Science Foundation and NIH and a leadership or fiduciary role in other board, society, committee, or advocacy group for American Society for Microbiology (ASM, unpaid). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.
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References
- Center for Drug Evaluation and Research (CDER) . Emergency Use Authorization (EUA) for Paxlovid (nirmatrelvir tablets co-packaged with ritonavir tablets) Center for Drug Evaluation and Research (CDER) Review. Silver Spring, MD: Food and Drug Administration, 2021. Available at: . Accessed 27 August 2022.
- Hammond J, Leister-Tebbe H, Gardner A, et al. . Oral nirmatrelvir for high-risk, nonhospitalized adults with COVID-19. N Engl J Med 2022; 386:1397–408.
- Charness M, Gupta K, Stack G, et al. . Rapid relapse of symptomatic Omicron SARS-CoV-2 infection following early suppression with nirmatrelvir/ritonavir. Research Square [Preprint]. May 23, 2022. [cited 2022 Aug 9]. Available from: 10.21203/-1588371/v3.
- Gupta K, Strymish J, Stack G, et al. . Rapid relapse of symptomatic SARS-CoV-2 infection following early suppression with nirmatrelvir/ritonavir. Research Square [Preprint, Version 1]. April 26, 2022. [cited 2022 Aug 9]. Available from: 10.21203/-1588371/v1..
- Nussenblatt V, Roder AE, Das S, et al. . Yearlong COVID-19 infection reveals within-host evolution of SARS-CoV-2 in a patient with B-cell depletion. J Infect Dis 2022; 225:1118–23.
- Bennett RS, Postnikova EN, Liang J, et al. . Scalable, micro-neutralization assay for assessment of SARS-CoV-2 (COVID-19) virus-neutralizing antibodies in human clinical samples. Viruses 2021; 13:893.
- ACTIV-3/TICO Bamlanivimab Study Group, Lundgren JD, Grund B, et al. . Responses to a neutralizing monoclonal antibody for hospitalized patients with COVID-19 according to baseline antibody and antigen levels: a randomized controlled trial. Ann Intern Med 2022; 175:234–43.
- Klumpp-Thomas C, Kalish H, Drew M, et al. . Standardization of ELISA protocols for serosurveys of the SARS-CoV-2 pandemic using clinical and at-home blood sampling. Nat Commun 2021; 12:113.
- Tan CW, Chia WN, Qin X, et al. . A SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2-spike protein-protein interaction. Nat Biotechnol 2020; 38:1073–8.
- Boucau J, Uddin R, Marino C, et al. . Characterization of virologic rebound following nirmatrelvir-ritonavir treatment for COVID-19. Clin Infect Dis 2022. doi:10.1093/cid/ciac512.
- Davis HE, Morgan JR, Yarmush ML. Polybrene increases retrovirus gene transfer efficiency by enhancing receptor-independent virus adsorption on target cell membranes. Biophys Chem 2002; 97:159–72.
- Keeton R, Tincho MB, Ngomti A, et al. . T cell responses to SARS-CoV-2 spike cross-recognize Omicron. Nature 2022; 603:488–92.
- Lucas C, Wong P, Klein J, et al. . Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature 2020; 584:463–9.
- Ranganath N, O'Horo JC, Challener DW, et al. . Rebound phenomenon after nirmatrelvir/ritonavir treatment of coronavirus disease-2019 in high-risk persons. Clin Infect Dis 2022. doi:10.1093/cid/ciac481.
- Long QX, Liu BZ, Deng HJ, et al. . Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat Med 2020; 26:845–8.
- Carlin AF, Clark AE, Chaillon A, et al. . Virologic and immunologic characterization of COVID-19 recrudescence after nirmatrelvir/ritonavir treatment. Clin Infect Dis 2022. doi:10.1093/cid/ciac496.
- Sefik E, Qu R, Junqueira C, et al. . Inflammasome activation in infected macrophages drives COVID-19 pathology. Nature 2022; 606:585–93.
- Lage SL, Amaral EP, Hilligan KL, et al. . Persistent oxidative stress and inflammasome activation in CD14(high)CD16(-) monocytes from COVID-19 patients. Front Immunol 2022; 12:799558.
- Lage SL, Rocco JM, Laidlaw E, et al. . Activation of complement components on circulating blood monocytes from COVID-19 patients. Front Immunol 2022; 13:815833.
- Wang C, Li Y, Kaplonek P, et al. . The kinetics of SARS-CoV-2 antibody development is associated with clearance of RNAemia. mBio 2022; e0157722. doi:10.1128/mbio.01577-22.
Source: PubMed