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To mitigate the loss of lives during the COVID-19 pandemic, emergency use authorization was given to several anti-SARS-CoV-2 monoclonal antibody (mAb) therapies for the treatment of mild-to-moderate COVID-19 in patients with a high risk of progressing to severe disease. Monoclonal antibodies used to treat SARS-CoV-2 target the spike protein of the virus and block its ability to enter and infect target cells. Monoclonal antibody therapy can thus accelerate the decline in viral load and lower hospitalization rates among high-risk patients with variants susceptible to mAb therapy. However, viral resistance has been observed, in some cases leading to a transient viral rebound that can be as large as 3-4 orders of magnitude. As mAbs represent a proven treatment choice for SARS-CoV-2 and other viral infections, evaluation of treatment-emergent mAb resistance can help uncover underlying pathobiology of SARS-CoV-2 infection and may also help in the development of the next generation of mAb therapies. Although resistance can be expected, the large rebounds observed are much more difficult to explain. We hypothesize replenishment of target cells is necessary to generate the high transient viral rebound. Thus, we formulated two models with different mechanisms for target cell replenishment (homeostatic proliferation and return from an innate immune response antiviral state) and fit them to data from persons with SARS-CoV-2 treated with a mAb. We showed that both models can explain the emergence of resistant virus associated with high transient viral rebounds. We found that variations in the target cell supply rate and adaptive immunity parameters have a strong impact on the magnitude or observability of the viral rebound associated with the emergence of resistant virus. Both variations in target cell supply rate and adaptive immunity parameters may explain why only some individuals develop observable transient resistant viral rebound. Our study highlights the conditions that can lead to resistance and subsequent viral rebound in mAb treatments during acute infection., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: K.W.C. has received research funding to her institution from Merck Sharp & Dohme and consulted for Pardes Biosciences. D.M.S. has consulted for the following companies Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Lucira, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, and Evidera. E.S.D. has consulted for Gilead, Merck, ViiV and Theratechnologies and received research funding to his institution from Gilead and ViiV. D.A.W. has consulted for Gilead Sciences, ViiV Healthcare, Janssen Pharmaceuticals, and Theratechnologies, and has university grant funding from Gilead Sciences, ViiV Healthcare, and Merck and Co. J. J. E. is on the DMC for Adagio/Invyvid and has consulted for Gilead Sciences and Merck & Co. J. S. C. has consulted for Merck & Co., J.Z.L. has consulted for Abbvie. The other authors have declared that no competing interests exist., (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.)

Background: In the USA, nirmatrelvir/ritonavir is authorized for the treatment of mild-to-moderate COVID-19 in patients at least 12 years of age, at high risk for progression to severe COVID-19., Objectives: To estimate the impact of outpatient nirmatrelvir/ritonavir on COVID-19 hospitalization risk in a US healthcare system., Methods: We conducted a cohort study using electronic health records among outpatients with a positive SARS-CoV-2 PCR test between January and August 2022. We evaluated the association of nirmatrelvir/ritonavir therapy with time to hospitalization by estimating adjusted HRs and assessed the impact of nirmatrelvir/ritonavir on predicted COVID-19 hospitalizations using machine-learning methods., Results: Among 44 671 patients, 4948 (11%) received nirmatrelvir/ritonavir, and 201 (0.4%) were hospitalized within 28 days of COVID-19 diagnosis. Nirmatrelvir/ritonavir recipients were more likely to be older, white, vaccinated, have comorbidities and reside in areas with higher average socioeconomic status. The 28 day cumulative incidence of hospitalization was 0.06% (95% CI: 0.02%-0.17%) among nirmatrelvir/ritonavir recipients and 0.52% (95% CI: 0.46%-0.60%) among non-recipients. For nirmatrelvir/ritonavir versus no therapy, the age-adjusted HR was 0.08 (95% CI: 0.03-0.26); the fully adjusted HR was 0.16 (95% CI: 0.05-0.50). In the machine-learning model, the primary features reducing predicted hospitalization risk were nirmatrelvir/ritonavir, younger age, vaccination, female gender and residence in a higher socioeconomic status area., Conclusions: COVID-19 hospitalization risk was reduced by 84% among nirmatrelvir/ritonavir recipients in a large, diverse healthcare system during the Omicron wave. These results suggest that nirmatrelvir/ritonavir remained highly effective in a setting substantially different than the original clinical trials., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Camostat inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vitro. We studied the safety and efficacy of camostat in ACTIV-2/A5401, a phase 2/3 platform trial of therapeutics for COVID-19 in nonhospitalized adults., Methods: We conducted a phase 2 study in adults with mild-to-moderate COVID-19 randomized to oral camostat for 7 days or a pooled placebo arm. Primary outcomes were time to improvement in COVID-19 symptoms through day 28, proportion of participants with SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) from nasopharyngeal swabs through day 14, and grade ≥3 treatment-emergent adverse events (TEAEs) through day 28., Results: Of 216 participants (109 randomized to camostat, 107 to placebo) who initiated study intervention, 45% reported ≤5 days of symptoms at study entry and 26% met the protocol definition of higher risk of progression to severe COVID-19. Median age was 37 years. Median time to symptom improvement was 9 days in both arms (P = .99). There were no significant differences in the proportion of participants with SARS-CoV-2 RNA

Background: Prospective evaluations of long COVID in outpatients with coronavirus disease 2019 (COVID-19) are lacking. We aimed to determine the frequency and predictors of long COVID after treatment with the monoclonal antibody bamlanivimab in ACTIV-2/A5401., Methods: Data were analyzed from participants who received bamlanivimab 700 mg in ACTIV-2 from October 2020 to February 2021. Long COVID was defined as the presence of self-assessed COVID symptoms at week 24. Self-assessed return to pre-COVID health was also examined. Associations were assessed by regression models., Results: Among 506 participants, median age was 51 years. Half were female, 5% Black/African American, and 36% Hispanic/Latino. At 24 weeks, 18% reported long COVID and 15% had not returned to pre-COVID health. Smoking (adjusted risk ratio [aRR], 2.41 [95% confidence interval {CI}, 1.34- 4.32]), female sex (aRR, 1.91 [95% CI, 1.28-2.85]), non-Hispanic ethnicity (aRR, 1.92 [95% CI, 1.19-3.13]), and presence of symptoms 22-28 days posttreatment (aRR, 2.70 [95% CI, 1.63-4.46]) were associated with long COVID, but nasal severe acute respiratory syndrome coronavirus 2 RNA was not., Conclusions: Long COVID occurred despite early, effective monoclonal antibody therapy and was associated with smoking, female sex, and non-Hispanic ethnicity, but not viral burden. The strong association between symptoms 22-28 days after treatment and long COVID suggests that processes of long COVID start early and may need early intervention., Clinical Trials Registration: NCT04518410., Competing Interests: Potential conflicts of interest. T. H. E. serves as a consultant for Tonix Pharmaceuticals. N. J. received salary support to the institution from Sagent Pharmaceuticals. D. A. W. has received funding to his institution to support research and honoraria for advisory boards and consulting from Gilead Sciences. E. S. D. receives consulting fees from Gilead Sciences, Merck, and GSK/ViiV and research support through his institution from Gilead Sciences and GSK/ViiV. J. Z. L. has received research funding from Merck. P. K. is an employee and shareholder of Eli Lilly. J.J.E. is an ad hoc consultant to GSK/VIR, data monitoring committee chair for Adagio Phase 3 studies. J. S. C. has consulted for Merck and Company. D. M. S. has consulted for Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Arena Pharmaceuticals, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, Signant Health, and Brio Clinical. K. W. C. received research funding to institution from Merck Sharp & Dohme and is a consultant for Pardes Biosciences. 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Time to symptom resolution measures were used in outpatient coronavirus disease 2019 (COVID-19) treatment trials without prior validation., Methods: ACTIV-2/A5401 trial participants completed a COVID-19 diary assessing 13 targeted symptoms and global experience (overall COVID-19 symptoms, return to pre-COVID-19 health) daily for 29 days. We evaluated concordance of time to sustained (2 days) resolution of all targeted symptoms (TSR) with resolution of overall symptoms and return to health in participants receiving placebo., Results: The analysis included 77 high-risk and 81 standard-risk participants with overall median 6 days of symptoms at entry and median age 47 years, 50% female, 82% white, and 31% Hispanic/Latino. Correlation between TSR and resolution of overall symptoms was 0.80 and 0.68, and TSR and return to health, 0.66 and 0.57 for high- and standard-risk groups, respectively. Of the high- and standard-risk participants, 61% and 79%, respectively, achieved targeted symptom resolution, of which 47% and 43%, respectively, reported symptom recurrence. Requiring >2 days to define sustained resolution reduced the frequency of recurrences., Conclusions: There was good internal consistency between TSR and COVID-19-specific global outcomes, supporting TSR as a trial end point. Requiring >2 days of symptom resolution better addresses natural symptom fluctuations but must be balanced against the potential influence of non-COVID-19 symptoms., Clinical Trials Registration: NCT04518410., Competing Interests: Potential conflicts of interest . K. W. C. reports research funding to the institution from Merck Sharp & Dohme; and is a consultant for Pardes Biosciences. D. A. W. has received funding to the institution to support research; and honoraria for advisory boards and consulting from Gilead Sciences. E. S. D. receives consulting fees from Gilead Sciences, Merck, and GSK/ViiV; and research support through the institution from Gilead Sciences and GSK/ViiV. J. J. E. is an ad hoc consultant to GSK/VIR; and data monitoring committee chair for Adagio phase 3 studies. J. S. C. has consulted for Merck and Company. D. M. S. has consulted for Evidera, Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Arena Pharmaceuticals, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, Signant Health, and Brio Clinical. 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: There is little information regarding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA as a predictor for clinical outcomes in outpatients with mild-to-moderate coronavirus disease 2019 (COVID-19)., Methods: Anterior nasal (AN) and plasma SARS-CoV-2 RNA data from 2115 nonhospitalized adults who received monoclonal antibodies (mAbs) or placebo in the ACTIV-2/A5401 trial were analyzed for associations with hospitalization or death., Results: One hundred two participants were hospitalized or died through 28 days of follow-up. Higher day 0 (pretreatment) AN RNA was associated with increasing risk of hospitalization/death (risk ratio [RR], 1.24 per log10 copies/mL [95% confidence interval {CI}, 1.04-1.49]) among placebo recipients, ranging from 3% to 16% for <2 to ≥6 log10 copies/mL. Although only 1% had quantifiable levels, there was a similar trend across day 0 plasma RNA categories. Higher day 3 AN RNA was associated with subsequent hospitalization/death among placebo recipients (RR, 1.42 per log10 copies/mL [95% CI, 1.00-2.03]), but not mAb recipients (RR, 1.02 per log10 copies/mL [95% CI, 0.68-1.56]). The proportion of treatment effect (reduction in hospitalizations/deaths after day 3 for mAb vs placebo) explained by day 3 AN RNA was 8%., Conclusions: SARS-CoV-2 RNA levels are predictive of hospitalization/death in the natural history setting, but AN RNA levels may not be a reliable surrogate marker of mAb treatment effect in COVID-19 trials. Clinical Trials Registration. NCT04518410., Competing Interests: Potential conflicts of interest. K. W. C. has received research funding (paid to institution) from Merck Sharp & Dohme and is a consultant for Pardes Biosciences. J. J. E. is an ad hoc consultant to GSK/VIR and the data monitoring committee chair for Adagio phase 3 studies. J. Z. L. has consulted for AbbVie. W. A. F. has received research funding (paid to institution) from Ridgeback Biopharmaceuticals; served on adjudication committees for Janssen and Syneos; and consulted for Roche and Merck. P. K. is an employee and shareholder of Eli Lilly. D. M. is an employee of Brii Biosciences. D. A. W. has received funding (paid to institution) to support research and honoraria for advisory boards and consulting from Gilead Sciences. E. S. D. has received consulting fees from Gilead Sciences, Merck, and GSK/ViiV and research support (paid to institution) from GSK and ViiV. J. S. C. has consulted for Merck and Co. D. M. S. has consulted for Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Arena Pharmaceuticals, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, Signant Health, and Brio Clinical. 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Immunocompromised individuals are disproportionately affected by severe coronavirus disease 2019, but immune compromise is heterogenous, and viral dynamics may vary by the degree of immunosuppression. In this study, we categorized ACTIV-2/A5401 participants based on the extent of immunocompromise into none, mild, moderate, and severe immunocompromise. Moderate/severe immunocompromise was associated with higher nasal viral load at enrollment (adjusted difference in means: 0.47 95% confidence interval, .12-.83 log10 copies/mL) and showed a trend toward higher cumulative nasal RNA levels and plasma viremia compared to nonimmunocompromised individuals. Immunosuppression leads to greater viral shedding and altered severe acute respiratory syndrome coronavirus 2 viral decay kinetics. Clinical Trials Registration. NCT04518410., Competing Interests: Potential conflicts of interest. K. W. C. receives research funding from Merck, Sharp & Dohme (paid to institution) and Amgen (research contract with institution); consultancy for Pardes Biosciences; honoraria to the author for continuing medical education presentations (not-for-profit organization) from the International Antiviral Society–USA (IAS-USA); and participation on a data and safety monitoring board (DSMB) or advisory board for the University of California, San Francisco (UCSF) (served as Chair of a safety monitoring committee for an investigator-initiated study where the sponsor is UCSF). E. S. D. receives consulting fees from Gilead Sciences, Merck, and GSK/ViiV; research support through the institution from Gilead Sciences and GSK/ViiV; participation on a DSMB or advisory board for Gilead and ViiV; and reports support from NIH. D. A. W. has received funding to institution to support research and honoraria for advisory boards and consulting from Gilead Sciences and grant or contracts from Lilly. J. Z. L. has consulted for AbbVie and received a research grant from Merck. J. J. E. is an ad hoc consultant to GSK/Vir Biotechnology and is data monitoring committee chair for Adagio phase 3 studies. J. S. C. has consulted for Merck and Co and reports a leadership or fiduciary role in other board, society, committee, or advocacy groups as a volunteer for the Board of Directors of the IAS-USA and the Foundation Board, Conference on Retroviruses and Opportunistic Infections. D. M. S. has consulted for Bayer Healthcare, Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, and Pharma Holdings; has grants or contracts from NIH (DK131532, AI169609, DA047039, AI036214, AI131385, AI100665, AI126620, funding provided to institution), the James B. Pendleton Charitable Trust John, and the Mary Tu Foundation, including payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events for Medscape (COVID treatment), American Institute continuing medical education (COVID treatment), and Kiadis; stock or stock options for Model Medicine, Linear Therapies, and Cv Biosciences; and receipt of equipment, materials, drugs, medical writings, gifts, or other services from the James B. Pendleton Charitable Trust. C. M. reports participation on a DSMB for BONE STAR. 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Adaptive platform trials were implemented during the coronavirus disease 2019 (COVID-19) pandemic to rapidly evaluate therapeutics, including the placebo-controlled phase 2/3 ACTIV-2 trial, which studied 7 investigational agents with diverse routes of administration. For each agent, safety and efficacy outcomes were compared to a pooled placebo control group, which included participants who received a placebo for that agent or for other agents in concurrent evaluation. A 2-step randomization framework was implemented to facilitate this. Over the study duration, the pooled placebo design achieved a reduction in sample size of 6% versus a trial involving distinct placebo control groups for evaluating each agent. However, a 26% reduction was achieved during the period when multiple agents were in parallel phase 2 evaluation. We discuss some of the complexities implementing the pooled placebo design versus a design involving nonoverlapping control groups, with the aim of informing the design of future platform trials. Clinical Trials Registration. NCT04518410., Competing Interests: Potential conflicts of interest. C. B. M. participated on a data safety monitoring board for the BONE STAR study. K. W. C. has received research funding to the institution from Merck Sharp & Dohme; and is a consultant for Pardes Biosciences. E. S. D. receives consulting fees from Gilead Sciences, Merck, and GSK/ViiV; and research support through the institution from Gilead Sciences and GSK/ViiV. D. A. W. has received funding to the institution to support research and honoraria for advisory boards and consulting from Gilead Sciences. J. S. C. has consulted for Merck and Company. J. J. E. is an ad hoc consultant to GSK/VIR; and data monitoring committee chair for Adagio phase 3 studies. D. M. S. has consulted for Evidera, Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Arena Pharmaceuticals, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, Signant Health, and Brio Clinical. 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Clinical Trials Registration ClinicalTrials.gov Identifier: NCT04518410., Competing Interests: Potential conflicts of interest. JSC has consulted for Merck and Company. KWC reports research funding to the institution from Merck Sharp & Dohme and is a consultant for Pardes Biosciences. CM participated on a Data Safety Monitoring Board for the BONE STAR study. JJE is an ad hoc consultant to GSK/VIR and data monitoring committee chair for Adagio Phase III studies. DMS has consulted for Evidera, Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Arena Pharmaceuticals, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, Signant Health, and Brio Clinical. DAW has received funding to the institution to support research and honoraria for advisory boards and consulting from Gilead Sciences. ESD receives consulting fees from Gilead Sciences, Merck, and GSK/ViiV and research support through the institution from Gilead Sciences and GSK/ViiV. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Most clinical trials evaluating coronavirus disease 2019 (COVID-19) therapeutics include assessments of antiviral activity. In recently completed outpatient trials, changes in nasal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA levels from baseline were commonly assessed using analysis of covariance (ANCOVA) or mixed models for repeated measures (MMRM) with single imputation for results below assay lower limits of quantification (LLoQ). Analyzing changes in viral RNA levels with singly imputed values can lead to biased estimates of treatment effects. In this article, using an illustrative example from the ACTIV-2 trial, we highlight potential pitfalls of imputation when using ANCOVA or MMRM methods, and illustrate how these methods can be used when considering values

Understanding variant-specific differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral kinetics may explain differences in transmission efficiency and provide insights on pathogenesis and prevention. We evaluated SARS-CoV-2 kinetics from nasal swabs across multiple variants (Alpha, Delta, Epsilon, Gamma) in placebo recipients of the ACTIV-2/A5401 trial. Delta variant infection led to the highest maximum viral load and shortest time from symptom onset to viral load peak. There were no significant differences in time to viral clearance across the variants. Viral decline was biphasic with first- and second-phase decays having half-lives of 11 hours and 2.5 days, respectively, with differences among variants, especially in the second phase. These results suggest that while variant-specific differences in viral kinetics exist, post-peak viral load all variants appeared to be efficiently cleared by the host. Clinical Trials Registration. NCT04518410., Competing Interests: Potential conflicts of interest. K. W. C. received research funding to institution from Merck Sharp & Dohme, and was a consultant for Pardes Biosciences. J. Z. L. was a consultant for AbbVie and received research support from Merck. 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: SAB-185, a novel fully human IgG polyclonal immunoglobulin product, underwent phase 2 evaluation for nonhospitalized adults with mild-moderate coronavirus disease 2019 (COVID-19)., Methods: Participants received intravenous SAB-185 3840 units/kg (low-dose) or placebo, or 10 240 units/kg (high-dose) or placebo. Primary outcome measures were nasopharyngeal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA < lower limit of quantification (LLOQ) at study days 3, 7, and 14, time to symptomatic improvement, and safety through day 28., Results: Two-hundred thirteen participants received low-dose SAB-185/placebo (n = 107/106) and 215 high-dose SAB-185/placebo (n = 110/105). The proportions with SARS-CoV-2 RNA < LLOQ were higher for SAB-185 versus placebo at days 3 and 7 and similar at day 14, and significantly higher at day 7 for high-dose SAB-185 versus placebo only, relative risk 1.23 (95% confidence interval, 1.01-1.49). At day 3, SARS-CoV-2 RNA levels were lower with low-dose and high-dose SAB-185 versus placebo: differences in medians of -0.78 log10 copies/mL (P = .08) and -0.71 log10 copies/mL (P = .10), respectively. No difference was observed in time to symptom improvement: median 11/10 days (P = .24) for low-dose SAB-185/placebo and 8/10 days (P = .50) for high-dose SAB-185/placebo. Grade ≥3 adverse events occurred in 5%/13% of low-dose SAB-185/placebo and 9%/12% of high-dose SAB-185/placebo., Conclusions: SAB-185 was safe and generally well tolerated and demonstrated modest antiviral activity in predominantly low-risk nonhospitalized adults with COVID-19. Clinical Trials Registration. NCT04518410., Competing Interests: Potential conflicts of interest. B. T. has received honoraria for advisory boards and consulting from Gilead Sciences. K. W. C. has received research funding to the institution from Merck Sharp & Dohme and consulted for Pardes Biosciences. E. S. D. receives consulting fees from Gilead Sciences, Merck, and GSK/ViiV; and research support through the institution from Gilead Sciences and GSK/ViiV. D. A. W. has received funding to the institution to support research and honoraria for advisory boards and consulting from Gilead Sciences. J. Z. L. has consulted for Abbvie. A. L. G. reports contract testing from Abbott, Cepheid, Novavax, Pfizer, Janssen, and Hologic; and research support from Gilead and Merck, outside of the described work. J. J. E. is an ad hoc consultant to GSK/VIR; and data monitoring committee chair for Adagio phase 3 studies. J. S. C. has consulted for Merck and Company. D. M. S. has consulted for Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Arena Pharmaceuticals, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, Signant Health, and Brio Clinical. C. B. and T. L. are employees of SAB Biotherapeutics. 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Development of safe and effective SARS-CoV-2 therapeutics is a high priority. Amubarvimab and romlusevimab are noncompeting anti-SARS-CoV-2 monoclonal antibodies with an extended half-life., Objective: To assess the safety and efficacy of amubarvimab plus romlusevimab., Design: Randomized, placebo-controlled, phase 2 and 3 platform trial. (ClinicalTrials.gov: NCT04518410)., Setting: Nonhospitalized patients with COVID-19 in the United States, Brazil, South Africa, Mexico, Argentina, and the Philippines., Patients: Adults within 10 days onset of symptomatic SARS-CoV-2 infection who are at high risk for clinical progression., Intervention: Combination of monoclonal antibodies amubarvimab plus romlusevimab or placebo., Measurements: Nasopharyngeal and anterior nasal swabs for SARS-CoV-2, COVID-19 symptoms, safety, and progression to hospitalization or death., Results: Eight-hundred and seven participants who initiated the study intervention were included in the phase 3 analysis. Median age was 49 years (quartiles, 39 to 58); 51% were female, 18% were Black, and 50% were Hispanic or Latino. Median time from symptom onset at study entry was 6 days (quartiles, 4 to 7). Hospitalizations and/or death occurred in 9 (2.3%) participants in the amubarvimab plus romlusevimab group compared with 44 (10.7%) in the placebo group, with an estimated 79% reduction in events ( P  < 0.001). This reduction was similar between participants with 5 or less and more than 5 days of symptoms at study entry. Grade 3 or higher treatment-emergent adverse events through day 28 were seen less frequently among participants randomly assigned to amubarvimab plus romlusevimab (7.3%) than placebo (16.1%) ( P  < 0.001), with no severe infusion reactions or drug-related serious adverse events., Limitation: The study population was mostly unvaccinated against COVID-19 and enrolled before the spread of Omicron variants and subvariants., Conclusion: Amubarvimab plus romlusevimab was safe and significantly reduced the risk for hospitalization and/or death among nonhospitalized adults with mild to moderate SARS-CoV-2 infection at high risk for progression to severe disease., Primary Funding Source: National Institute of Allergy and Infectious Diseases of the National Institutes of Health., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-3428.

Importance: Development of effective, scalable therapeutics for SARS-CoV-2 is a priority., Objective: To test the efficacy of combined tixagevimab and cilgavimab monoclonal antibodies for early COVID-19 treatment., Design, Setting, and Participants: Two phase 2 randomized blinded placebo-controlled clinical trials within the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-2/A5401 platform were performed at US ambulatory sites. Nonhospitalized adults 18 years or older within 10 days of positive SARS-CoV-2 test and symptom onset were eligible and were enrolled from February 1 to May 31, 2021., Interventions: Tixagevimab-cilgavimab, 300 mg (150 mg of each component) given intravenously (IV) or 600 mg (300 mg of each component) given intramuscularly (IM) in the lateral thigh, or pooled placebo., Main Outcomes and Measures: Coprimary outcomes were time to symptom improvement through 28 days; nasopharyngeal SARS-CoV-2 RNA below the lower limit of quantification (LLOQ) on days 3, 7, or 14; and treatment-emergent grade 3 or higher adverse events through 28 days., Results: A total of 229 participants were randomized for the IM study and 119 were randomized for the IV study. The primary modified intention-to-treat population included 223 participants who initiated IM tixagevimab-cilgavimab (n = 106) or placebo treatment (n = 117) (median age, 39 [IQR, 30-48] years; 113 [50.7%] were men) and 114 who initiated IV tixagevimab-cilgavimab (n = 58) or placebo treatment (n = 56) (median age, 44 [IQR, 35-54] years; 67 [58.8%] were women). Enrollment in the IV study was stopped early based on a decision to focus on IM product development. Participants were enrolled at a median of 6 (IQR, 4-7) days from COVID-19 symptom onset. Significant differences in time to symptom improvement were not observed for IM tixagevimab-cilgavimab vs placebo or IV tixagevimab-cilgavimab vs placebo. A greater proportion in the IM tixagevimab-cilgavimab arm (69 of 86 [80.2%]) than placebo (62 of 96 [64.6%]) had nasopharyngeal SARS-CoV-2 RNA below LLOQ at day 7 (adjusted risk ratio, 1.33 [95% CI, 1.12-1.57]) but not days 3 and 14; the joint test across time points favored treatment (P = .003). Differences in the proportion below LLOQ were not observed for IV tixagevimab-cilgavimab vs placebo at any of the specified time points. There were no safety signals with either administration route., Conclusions: In these 2 phase 2 randomized clinical trials, IM or IV tixagevimab-cilgavimab was safe but did not change time to symptom improvement. Antiviral activity was more evident in the larger IM trial., Trial Registration: ClinicalTrials.gov Identifier: NCT04518410.

Background: Although symptom and viral rebound have been reported after nirmatrelvir-ritonavir treatment, the trajectories of symptoms and viral load during the natural course of COVID-19 have not been well described., Objective: To characterize symptom and viral rebound in untreated outpatients with mild to moderate COVID-19., Design: Retrospective analysis of participants in a randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04518410)., Setting: Multicenter trial., Patients: 563 participants receiving placebo in the ACTIV-2/A5401 (Adaptive Platform Treatment Trial for Outpatients With COVID-19) platform trial., Measurements: Participants recorded the severity of 13 symptoms daily between days 0 and 28. Nasal swabs were collected for SARS-CoV-2 RNA testing on days 0 to 14, 21, and 28. Symptom rebound was defined as a 4-point increase in total symptom score after improvement any time after study entry. Viral rebound was defined as an increase of at least 0.5 log 10 RNA copies/mL from the immediately preceding time point to a viral load of 3.0 log 10 copies/mL or higher. High-level viral rebound was defined as an increase of at least 0.5 log 10 RNA copies/mL to a viral load of 5.0 log 10 copies/mL or higher., Results: Symptom rebound was identified in 26% of participants at a median of 11 days after initial symptom onset. Viral rebound was detected in 31% and high-level viral rebound in 13% of participants. Most symptom and viral rebound events were transient, because 89% of symptom rebound and 95% of viral rebound events occurred at only a single time point before improving. The combination of symptom and high-level viral rebound was observed in 3% of participants., Limitation: A largely unvaccinated population infected with pre-Omicron variants was evaluated., Conclusion: Symptom or viral relapse in the absence of antiviral treatment is common, but the combination of symptom and viral rebound is rare., Primary Funding Source: National Institute of Allergy and Infectious Diseases.

Acute Coronavirus Disease 2019 symptoms limit daily activities, but little is known about its association with severe acute respiratory syndrome coronavirus 2 viral burden. In this exploratory analysis of placebo recipients in the ACTIV-2/A5401 platform trial, we showed that high anterior nasal RNA levels and detectable plasma RNA were associated with delayed symptom improvement. Clinical Trials Registration. https://clinicaltrials.gov/ct2/show/NCT04518410., Competing Interests: Potential conflicts of interest. L. J. H.: reports grants or contracts from NIH/NIAID 3 UM1 AI068636-16S1 and NIH/NIAID T32 AI007358 (paid to institution). K. W. C.: research funding to the institution from Merck, Sharp & Dohme (paid to institution) and Amgen (research contract with institution), consultant for Pardes Biosciences, honoraria to the author for CME presentations (not-for-profit organization) from International Antiviral Society–USA, participation on a Data Safety Monitoring Board or Advisory Board for University of California, San Francisco (UCSF) (served as Chair of a Safety Monitoring Committee for an investigator-initiated study where the sponsor is UCSF). E. S. D.: receives consulting fees from Gilead Sciences, Merck, and GSK/ViiV and research support through the institution from Gilead Sciences and GSK/ViiV and reports support from NIH, including participation on a Data Safety Monitoring Board or Advisory Board for Gilead and ViiV. D. A. W. has received funding to the institution to support research and honoraria for advisory boards and consulting from Gilead Sciences and grant or contracts from Lilly. J. Z. L. has consulted for AbbVie and received a research grant from Merck. J. J. E. is an ad hoc consultant to GSK/Vir Biotechnology and is data monitoring committee (DMC) chair for Adagio phase III studies. J. S. C. has consulted for Merck and Company and reports a leadership or fiduciary role in other board, society, committee, or advocacy groups as a volunteer for the Board of Directors International Antiviral Society–USA and the Foundation Board, Conference on Retroviruses and Opportunistic Infections. D. M. S. has consulted for Bayer Healthcare, Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, and Pharma Holdings; has grants or contracts from NIH (DK131532, AI169609, DA047039, AI036214, AI131385, AI100665, AI126620: funding provided to institution), The James B. Pendleton Charitable Trust, and The James B. Pendleton Charitable Trust John and Mary Tu Foundation, including payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events for Medscape (COVID treatment), American Institute Continuing Medical Education (COVID treatment), and Kiadis; stock or stock options for Model Medicine, Linear Therapies, and Cv Biosciences; and receipt of equipment, materials, drugs, medical writings, gifts, or other services from The James B. Pendleton Charitable Trust. T. H. E. receives consulting fees from Tonix Pharmaceuticals. C. M. reports participation on a Data Safety Monitoring Board for BONE START. 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., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Despite the widespread use of SARS-CoV-2-specific monoclonal antibody (mAb) therapy for the treatment of acute COVID-19, the impact of this therapy on the development of SARS-CoV-2-specific T cell responses has been unknown, resulting in uncertainty as to whether anti-SARS-CoV-2 mAb administration may result in failure to generate immune memory. Alternatively, it has been suggested that SARS-CoV-2-specific mAb may enhance adaptive immunity to SARS-CoV-2 via a "vaccinal effect." Bamlanivimab (Eli Lilly and Company) is a recombinant human IgG1 that was granted FDA emergency use authorization for the treatment of mild to moderate COVID-19 in those at high risk for progression to severe disease. Here, we compared SARS-CoV-2-specific CD4+ and CD8+ T cell responses of 95 individuals from the ACTIV-2/A5401 clinical trial 28 days after treatment with bamlanivimab versus placebo. SARS-CoV-2-specific T cell responses were evaluated using activation-induced marker assays in conjunction with intracellular cytokine staining. We demonstrate that most individuals with acute COVID-19 developed SARS-CoV-2-specific T cell responses. Overall, our findings suggest that the quantity and quality of SARS-CoV-2-specific T cell memory were not diminished in individuals who received bamlanivimab for acute COVID-19. Receipt of bamlanivimab during acute COVID-19 neither diminished nor enhanced SARS-CoV-2-specific cellular immunity.

Amidst the therapeutic void at the onset of the COVID-19 pandemic, a critical mass of scientific and clinical interest coalesced around COVID-19 convalescent plasma (CCP). To date, the CCP literature has focused largely on safety and efficacy outcomes, but little on implementation outcomes or experience. Expert opinion suggests that if CCP has a role in COVID-19 treatment, it is early in the disease course, and it must deliver a sufficiently high titer of neutralizing antibodies (nAb). Missing in the literature are comprehensive evaluations of how local CCP programs were implemented as part of pandemic preparedness and response, including considerations of the core components and personnel required to meet demand with adequately qualified CCP in a timely and sustained manner. To address this gap, we conducted an evaluation of a local CCP program at a large U.S. academic medical center, the University of North Carolina Medical Center (UNCMC), and patterned our evaluation around the dimensions of the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to systematically describe key implementation-relevant metrics. We aligned our evaluation with program goals of reaching the target population with severe or critical COVID-19, integrating into the structure of the hospital-wide pandemic response, adapting to shifting landscapes, and sustaining the program over time during a compassionate use expanded access program (EAP) era and a randomized controlled trial (RCT) era. During the EAP era, the UNCMC CCP program was associated with faster CCP infusion after admission compared with contemporaneous affiliate hospitals without a local program: median 29.6 hours (interquartile range, IQR: 21.2-48.1) for the UNCMC CCP program versus 47.6 hours (IQR 32.6-71.6) for affiliate hospitals; (P<0.0001). Sixty-eight of 87 CCP recipients in the EAP (78.2%) received CCP containing the FDA recommended minimum nAb titer of ≥1:160. CCP delivery to hospitalized patients operated with equal efficiency regardless of receiving treatment via a RCT or a compassionate-use mechanism. It was found that in a highly resourced academic medical center, rapid implementation of a local CCP collection, treatment, and clinical trial program could be achieved through re-deployment of highly trained laboratory and clinical personnel. These data provide important pragmatic considerations critical for health systems considering the use of CCP as part of an integrated pandemic response., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Actavis, Tetraphase, Sanofi-Pasteur, MedImmune, Astellas, Merck, Allergan, T2Biosystems, Roche, Achaogen, Neumedicine, Shionogi, Pfizer, Entasis, QPex, Wellspring, Karius, Utility, Johnson&Johnson, Novartis, Cidara, BSAC, Ridgeback Biopharmaceuticals, Janssen, Syneos. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2022 Root et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

To evaluate the co-circulation of respiratory viruses during the SARS-CoV-2 Alpha surge, we performed a molecular respiratory panel on 1,783 nasopharyngeal swabs collected between January 15 and April 15, 2021, from symptomatic outpatients that tested negative for SARS-CoV-2 in North Carolina. Of these, 373 (20.9%) were positive for at least 1 virus tested on the panel. Among positive tests, over 90% were positive for rhinovirus and/or enterovirus, either as a single infection or coinfection, illustrating persistent co-circulation of some respiratory viruses despite active infection control measures., (Copyright © 2022 Association for Professionals in Infection Control and Epidemiology, Inc. All rights reserved.)

Background: Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectious virus isolation in outpatients with coronavirus disease 2019 (COVID-19) has been associated with viral RNA levels and symptom duration, little is known about the host, disease, and viral determinants of infectious virus detection., Methods: COVID-19 adult outpatients were enrolled within 7 days of symptom onset. Clinical symptoms were recorded via patient diary. Nasopharyngeal swabs were collected to quantitate SARS-CoV-2 RNA by reverse transcriptase polymerase chain reaction and for infectious virus isolation in Vero E6-cells. SARS-CoV-2 antibodies were measured in serum using a validated ELISA assay., Results: Among 204 participants with mild-to-moderate symptomatic COVID-19, the median nasopharyngeal viral RNA was 6.5 (interquartile range [IQR] 4.7-7.6 log10 copies/mL), and 26% had detectable SARS-CoV-2 antibodies (immunoglobulin (Ig)A, IgM, IgG, and/or total Ig) at baseline. Infectious virus was recovered in 7% of participants with SARS-CoV-2 antibodies compared to 58% of participants without antibodies (prevalence ratio [PR] = 0.12, 95% confidence interval [CI]: .04, .36; P = .00016). Infectious virus isolation was also associated with higher levels of viral RNA (mean RNA difference +2.6 log10, 95% CI: 2.2, 3.0; P < .0001) and fewer days since symptom onset (PR = 0.79, 95% CI: .71, .88 per day; P < .0001)., Conclusions: The presence of SARS-CoV-2 antibodies is strongly associated with clearance of infectious virus. Seropositivity and viral RNA levels are likely more reliable markers of infectious virus clearance than subjective measure of COVID-19 symptom duration. Virus-targeted treatment and prevention strategies should be administered as early as possible and ideally before seroconversion., Clinical Trials Registration: NCT04405570., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

There is an urgent need for an effective, oral, direct-acting therapeutic to block transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and prevent progression to severe coronavirus disease 2019 (COVID-19). In a phase 2a double-blind, placebo-controlled, randomized, multicenter clinical trial, we evaluated the safety, tolerability, and antiviral efficacy of the nucleoside analog molnupiravir in 202 unvaccinated participants with confirmed SARS-CoV-2 infection and symptom duration <7 days. Participants were randomized 1:1 to receive molnupiravir (200 mg) or placebo and then 3:1 to receive molnupiravir (400 or 800 mg) or placebo, orally twice daily for 5 days. Antiviral activity was assessed by reverse transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2 RNA in nasopharyngeal swabs. Infectious virus was assessed by inoculation of cultured Vero cells with samples from nasopharyngeal swabs and was detected by RT-PCR. Time to viral RNA clearance (primary endpoint) was decreased in the 800-mg molnupiravir group (median 14 days) compared to the placebo group (median 15 days) (log rank P value = 0.013). Of participants receiving 800 mg of molnupiravir, 92.5% achieved viral RNA clearance compared with 80.3% of placebo recipients by study end (4 weeks). Infectious virus (secondary endpoint) was detected in swabs from 1.9% of the 800-mg molnupiravir group compared with 16.7% of the placebo group at day 3 of treatment ( P = 0.016). At day 5 of treatment, infectious virus was not isolated from any participants receiving 400 or 800 mg of molnupiravir compared with 11.1% of placebo recipients ( P = 0.034 and 0.027, respectively). Molnupiravir was well tolerated across all doses.

Introduction: Symptoms associated with SARS-CoV-2 infection remain incompletely understood, especially among ambulatory, non-hospitalized individuals. With host factors, symptoms predictive of SARS-CoV-2 could be used to guide testing and intervention strategies., Methods: Between March 16 and September 3, 2020, we examined the characteristics and symptoms reported by individuals presenting to a large outpatient testing program in the Southeastern US for nasopharyngeal SARS-CoV-2 RNA RT-PCR testing. Using self-reported symptoms, demographic characteristics, and exposure and travel histories, we identified the variables associated with testing positive using modified Poisson regression., Results: Among 20,177 tested individuals, the proportion positive was 9.4% (95% CI, 9.0-9.8) and was higher for men, younger individuals, and racial/ethnic minorities (all P<0.05); the positivity proportion was higher for Hispanics (26.9%; 95% CI. 24.9-29.0) compared to Blacks (8.6%; 95% CI, 7.6-9.7) or Whites (5.8%; 95% CI, 5.4-6.3). Individuals reporting contact with a COVID-19 case had the highest positivity proportion (22.8%; 95% CI, 21.5-24.1). Among the subset of 8,522 symptomatic adults who presented for testing after May 1, when complete symptom assessments were performed, SARS-CoV-2 RNA PCR was detected in 1,116 (13.1%). Of the reported symptoms, loss of taste or smell was most strongly associated with SARS-CoV-2 RNA detection with an adjusted risk ratio of 3.88 (95% CI, 3.46-4.35). The presence of chills, fever, cough, aches, headache, fatigue and nasal congestion also significantly increased the risk of detecting SARS-CoV-2 RNA, while diarrhea or nausea/vomiting, although not uncommon, were significantly more common in those with a negative test result. Symptom combinations were frequent with 67.9% experiencing ≥4 symptoms, including 19.8% with ≥8 symptoms; report of greater than three symptoms increased the risk of SARS-CoV-2 RNA detection., Conclusions: In a large outpatient population in the Southeastern US, several symptoms, most notably loss of taste or smell, and greater symptom burden were associated with detection of SARS-CoV-2 RNA. Persons of color and those with who were a contact of a COVID-19 case were also more likely to test positive. These findings suggest that, given limited SARS-CoV-2 testing capacity, symptom presentation and host characteristics can be used to guide testing and intervention prioritization., Competing Interests: The authors have declared that no competing interests exist.