Paul Marc-Kendy, Choudhary Manish C, Heaps Amy L, Deo Rinki, Moisi Daniela, Gordon Kelley C, Mellors John W, Moser Carlee, Klekotka Paul, Landay Alan, Currier Judith S, Eron Joseph J, Chew Kara W, Smith Davey M, Sieg Scott F, Parikh Urvi M, Li Jonathan Z
Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA.
University of Pittsburgh School of Medicine, Pittsburgh, PA.
Pathog Immun. 2024 Aug 21;9(2):79-93. doi: 10.20411/pai.v9i2.718. eCollection 2024.
Anti-SARS-CoV-2 monoclonal antibodies (mAbs) have played a key role as an anti-viral against SARS-CoV-2, but there is a potential for resistance to develop. The interplay between host antibody responses and the development of monoclonal antibody (mAb) resistance is a critical area of investigation. In this study, we assessed host neutralizing antibody (nAb) responses against both ancestral virus and those with treatment-emergent E484K bamlanivimab resistance mutations.
Study participants were enrolled in the ACTIV-2/Advancing Clinical Therapeutics Globally (ACTG) A5401 phase 2 randomized, placebo-controlled trial of bamlanivimab 700 mg mAb therapy (NCT04518410). Anterior nasal and nasopharyngeal swabs were collected for SARS-CoV-2 RNA testing and S gene next-generation sequencing to identify the E484K bamlanivimab resistance mutation. Serum nAb titers were assessed by pseudovirus neutralization assays.
Higher baseline (pre-treatment) nAb titers against either ancestral or E484K virus was associated with lower baseline viral load. Participants with emerging resistance had low levels of nAb titers against either ancestral or E484K nAb at the time of study entry. Participants with emergent E484K resistance developed significantly higher levels of E484K-specific nAb titers compared to mAb-treated individuals who did not develop resistance. All participants who developed the E484K mAb resistance mutation were eventually able to clear the virus.
Emerging drug resistance after SARS-CoV-2-specific mAb therapy led to a heightened host neutralizing antibody response to the mAb-resistant variant that was associated with eventual viral clearance. This demonstrates the interplay between the antiviral treatment-directed viral evolution and subsequent host immune response in viral clearance.
抗SARS-CoV-2单克隆抗体（mAb）作为抗SARS-CoV-2病毒药物发挥了关键作用，但存在产生耐药性的可能性。宿主抗体反应与单克隆抗体（mAb）耐药性发展之间的相互作用是一个关键研究领域。在本研究中，我们评估了宿主针对原始病毒以及具有治疗后出现的E484K巴瑞替尼耐药突变的病毒的中和抗体（nAb）反应。
研究参与者参加了ACTIV-2/全球推进临床治疗（ACTG）A5401期2项随机、安慰剂对照的700mg巴瑞替尼mAb治疗试验（NCT04518410）。收集前鼻和鼻咽拭子进行SARS-CoV-2 RNA检测和S基因下一代测序，以鉴定E484K巴瑞替尼耐药突变。通过假病毒中和试验评估血清nAb滴度。
针对原始病毒或E484K病毒的较高基线（治疗前）nAb滴度与较低的基线病毒载量相关。出现耐药性的参与者在研究入组时针对原始病毒或E484K nAb的nAb滴度水平较低。与未产生耐药性的mAb治疗个体相比，出现E484K耐药性的参与者产生的E484K特异性nAb滴度水平显著更高。所有产生E484K mAb耐药突变的参与者最终都能够清除病毒。
SARS-CoV-2特异性mAb治疗后出现的耐药性导致宿主对mAb耐药变体的中和抗体反应增强，这与最终的病毒清除相关。这证明了抗病毒治疗导向的病毒进化与随后宿主免疫反应在病毒清除中的相互作用。
