Munroe Elizabeth S, Grandits Greg A, Hyzy Robert C, Prescott Hallie C, Barrett Thomas W, Dewar Robin L, Engen Nicole, Goodman Anna L, Hatlen Timothy J, Highbarger Helene, Holland Thomas L, Hughes Gareth, Jensen Tomas O, Khan Muhammad A, Kalomenidis Ioannis, Kang Nayon, Laverdure Sylvain, Manian Prasad, Menon Vidya, Patel Ravi, Ramachandruni Srikanth, Rehman Tauseef, Shaw-Saliba Kathryn, Røge Birgit Thorup, Vock David M, Weintrob Amy C, Young Barnaby E, Frosch Anne P
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
Division of Biostatistics and Health Data Science, University of Minnesota, Minneapolis, Minnesota, United States of America.
PLoS One. 2025 Jun 18;20(6):e0325561. doi: 10.1371/journal.pone.0325561. eCollection 2025.
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.
We compared 28 and 90-day anti-SARS-CoV-2 spike protein neutralization activity and anti-SARS-CoV-2 nucleocapsid response for patients hospitalized with COVID-19 infection randomized to receive nMAbs or placebo in the large platform ACTIV-3/TICO trials. We pooled results from four trials of anti-spike nMAbs. For most tested agents, measurements of the spike protein response reflect both the therapeutic and endogenous immune response. Anti-nucleocapsid levels reflect only the endogenous immune response. Data are summarized as mean differences in percent binding inhibition (anti-spike) and signal-to-cutoff (S/C) ratio (anti-nucleocapsid). Linear mixed effects models were fit to compare the longitudinal trajectory between treatment and placebo groups.
Of 2,254 participants in the ACTIV-3/TICO trials modified intention-to-treat population, 2,149 (95.3%) had antibody measures at baseline and at least 1 follow-up day (day 1, 3, or 5) and were included in this analysis. Antibody measures were available for 1,556 (72.4%) participants at day 28 and 1,429 (66.5%) participants at day 90. In participants who received nMAbs, anti-spike neutralization activity was higher at day 28 (mean difference in percent binding inhibition: 7.1% [95%CI: 5.3, 8.9], p < 0.001) and day 90 (mean difference in percent binding inhibition: 7.2% [95% CI: 5.4, 9.0], p < 0.001). Anti-nucleocapsid response was similar at day 28 (mean difference in S/C ratio: 0.02 [95%CI: -0.11, 0.15], p = 0.75) and day 90 (mean difference in S/C ratio: 0.08 [95% CI: -0.05, 0.21], p = 0.22). Similar patterns were observed in all trials.
In patients hospitalized with COVID-19, treatment with nMAbs did not decrease long-term anti-nucleocapsid response compared to placebo, suggesting neutralizing therapies do not suppress the endogenous humoral immune response in this population.
中和性单克隆抗体（nMAbs）已被用于治疗新冠病毒病（COVID-19），并且越来越多地被用于治疗其他感染。然而，人们担心，通过中和严重急性呼吸综合征冠状病毒2（SARS-CoV-2）病毒，nMAbs可能会减少抗原对免疫系统的可及性，从而可能损害内源性多克隆免疫反应并降低长期免疫保护。
在大型平台ACTIV-3/TICO试验中，我们比较了因COVID-19感染住院并随机接受nMAbs或安慰剂治疗的患者在第28天和第90天的抗SARS-CoV-2刺突蛋白中和活性以及抗SARS-CoV-2核衣壳反应。我们汇总了四项抗刺突nMAbs试验的结果。对于大多数受试药物，刺突蛋白反应的测量反映了治疗性和内源性免疫反应。抗核衣壳水平仅反映内源性免疫反应。数据总结为结合抑制百分比（抗刺突）和信号与临界值之比（S/C比）（抗核衣壳）的平均差异。采用线性混合效应模型比较治疗组和安慰剂组之间的纵向轨迹。
在ACTIV-3/TICO试验的改良意向性治疗人群的2254名参与者中，2149名（95.3%）在基线和至少1个随访日（第1、3或5天）有抗体测量值，并被纳入该分析。在第28天，1556名（72.4%）参与者有抗体测量值，在第90天，1429名（66.5%）参与者有抗体测量值。在接受nMAbs治疗的参与者中，第28天的抗刺突中和活性更高（结合抑制百分比的平均差异：7.1%[95%置信区间：5.3，8.9]，p<0.001），第90天也是如此（结合抑制百分比的平均差异：7.2%[95%置信区间：5.4，9.0]，p<0.001）。第28天的抗核衣壳反应相似（S/C比的平均差异：0.02[95%置信区间：-0.11，0.15]，p=0.75），第90天也是如此（S/C比的平均差异：0.08[95%置信区间：-0.05，0.21]，p=0.22）。在所有试验中均观察到类似模式。
在因COVID-19住院的患者中，与安慰剂相比，nMAbs治疗并未降低长期抗核衣壳反应，这表明中和疗法不会抑制该人群的内源性体液免疫反应。
