Bamlanivimab as monotherapy in two immunocompromised patients with COVID-19
Authors: Grégory Destras, Souad Assaad, Antonin Bal, Maude Bouscambert-Duchamp, Virginie Avrillon, Bruno Simon, Martine Valette, Jean-Yves Blay, Bruno Lina, Emilie Frobert, Laurence Josset
Journal: The Lancet Microbe (2021)

The monoclonal antibody LY-CoV555 (bamlanivimab) increases viral clearance after a single infusion in high-risk outpatients.1Gottlieb RL Nirula A Chen P et al.Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial.JAMA. 2021; 325: 632-644Crossref PubMed Scopus (630) Google Scholar, 2Chen P Nirula A Heller B et al.SARS-CoV-2 Neutralizing antibody LY-CoV555 in outpatients with COVID-19.N Engl J Med. 2021; 384: 229-237Crossref PubMed Scopus (872) Google Scholar In previous studies, variant escape mutation after bamlanivimab monotherapy occurred in less than 12% of patients within 29 days.1Gottlieb RL Nirula A Chen P et al.Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial.JAMA. 2021; 325: 632-644Crossref PubMed Scopus (630) Google Scholar, 2Chen P Nirula A Heller B et al.SARS-CoV-2 Neutralizing antibody LY-CoV555 in outpatients with COVID-19.N Engl J Med. 2021; 384: 229-237Crossref PubMed Scopus (872) Google Scholar However, immunocompromised patients were not included in these clinical trials. Here, we report virological and clinical follow-up of the first two immunocompromised patients treated with bamlanivimab in our university hospital (Lyon University Hospital, Lyon, France). Patient 1 was a 62-year-old man with angioimmunoblastic T-cell lymphoma and patient 2 was an 87-year-old man with mantle cell lymphoma. A single 700 mg dose of bamlanivimab was administered 3 days after COVID-19 onset and resulted in transient clinical response in both patients (appendix p 1). Patient 1 had two recurrences of fever (from day 4 until day 6 and from day 15 until day 20 after bamlanivimab treatment) and required oxygen supplementation during each episode. Convalescent plasma was infused into patient 1 from day 17 to day 20, leading to clinical improvement and decreased inflammatory syndrome. Patient 2 developed fever (on day 5) and respiratory degradation (from day 8) and died on day 17. Viral isolates from patient 1 and patient 2 belonged to clades 20A.EU2 and 20I/501Y.V1, respectively. At the time of bamlanivimab infusion (day 0), only one non-synonymous intra-host single nucleotide variant (ihSNV) was detected in the Spike in patient 1 (Thr286Ala; frequency 3%), thus no variant was detected at position 484 in the Spike (Glu484) in either patient (appendix p 1). The Glu484Gln and Glu484Lys (patient 1 and patient 2) and Glu484Ala mutations (patient 1), which are known to be involved in neutralising antibody escape and resistance to bamlanivimab,5Starr TN Greaney AJ Addetia A et al.Prospective mapping of viral mutations that escape antibodies used to treat COVID-19.Science. 2021; 371: 850-854Crossref PubMed Scopus (451) Google Scholar appeared for both patients within 7 days. Glu484Lys and Glu484Gln became predominant in patient 1 (90% by day 19) and patient 2 (55% by day 5), respectively. In patient 1, viral loads of SARS-CoV-2 were negatively associated with the proportion of wild-type Glu484. Although the viral load declined in patient 2 at day 5, plasma was positive (4·3 log copies/mL) at day 14, suggesting failure of treatment. Other ihSNVs in the Spike were detected during follow-up (Gln493Arg in patient 1 and Ser494Pro in both patients; appendix p 2). These mutations were also selected for in vitro by bamlanivimab.5Starr TN Greaney AJ Addetia A et al.Prospective mapping of viral mutations that escape antibodies used to treat COVID-19.Science. 2021; 371: 850-854Crossref PubMed Scopus (451) Google Scholar Immunocompromised patients are prone to developing high intra-host diversity.3Choi B Choudhary MC Regan J et al.Persistence and evolution of SARS-CoV-2 in an immunocompromised host.N Engl J Med. 2020; 383: 2291-2293Crossref PubMed Scopus (673) Google Scholar, 4Hoffmann M Arora P Groß R et al.SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies.Cell. 2021; 184: 2384-2393Summary Full Text Full Text PDF PubMed Scopus (594) Google Scholar, 5Starr TN Greaney AJ Addetia A et al.Prospective mapping of viral mutations that escape antibodies used to treat COVID-19.Science. 2021; 371: 850-854Crossref PubMed Scopus (451) Google Scholar Bamlanivimab rapidly selected Spike mutations at position 484 escape variants in two immunocompromised patients. Such variants were not observed within immunocompromised patients admitted to hospital but not treated with bamlanivimab at our hospital in 2021 (n=69, including 23 patients with multiple samples). Although the US Food and Drug Administration revoked emergency use authorisation for bamlanivimab alone, combination treatment with monoclonal antibodies might also select escape variants in immunocompromised patients. This report emphasises the importance of longitudinal SARS-CoV-2 sequencing in this population. We declare no competing interests. BL is a member of the French Scientific Committee for SARS-CoV-2. We thank laboratory technicians and Quentin Semanas for their active participation and help with this study. This study was done as part of the global surveillance of influenza viruses by WHO and by the Centre National de Référence des Virus des Infections Respiratoires, supported by Santé Publique France in France. Patients were included in a temporary authorisation for use cohort for bamlanivimab infusion with unique authorisation (AU-041) for data collection and data sharing and including patient informed consent. Investigations were done in accordance with the General Data Protection Regulation (Regulation [EU] 2016/679 and Directive 95/46/EC) and French data protection law (Law 78–17 on Jan 6, 1978, and Décret 2019–536 on May 29, 2019). Download .pdf (.3 MB) Help with pdf files Supplementary appendix