What data is available regarding bamlanivimab/etesevimab against the COVID-19 Delta variant?

Comment by InpharmD Researcher

Limited in vitro data shows that combination bamlanivimab and etesevimab may not be effective against the Delta strain of COVID-19, although a case report of a vaccinated father with the Delta variant observed resolution of symptoms after treatment. Bamlanivimab seems to be resistant by certain mutations of COVID-19 and the production of bamlanivimab/etesevimab has been halted since June 25 due to these observations.

Background

A 2021 observational study assessed the sensitivity of the SARS-CoV-2 Delta variant (B1.617.2) to monoclonal antibodies that target the receptor-binding domain (RBD) including bamlanivimab (LY-CoV555) and etesevimab (LY-CoV016). A strain of the Delta variant was isolated from a patient with COVID-19 who had traveled to India and returned to France. The neutralization of the Delta variant by bamlanivimab and etesevimab was presented in graphs. Bamlanivimab had low antiviral activity versus the Delta variant at concentrations between 0.001 µg/mL and 0.1 µg/mL, which may be caused by an RBD mutation, L452R, acting as an escape mutation for this antibody. The activity of bamlanivimab increased between concentrations of 0.1 µg/mL and 10 µg/mL, but was still relatively low. Etesevimab had higher activity against the Delta variant compared to bamlanivimab between concentrations of 0.001 µg/mL and 10 µg/mL. Increasing activity of etesevimab against the Delta variant occurred between 0.001 µg/mL and 0.01 µg/mL. Little change in activity occurred after 0.01 µg/mL for etesevimab. Additionally, the binding of bamlanivimab to Vero cells infected with the Delta variant was evaluated using flow cytometry. Bamlanivimab did not bind to the Delta variant in this experiment, which may explain the escape of the Delta variant from neutralization by certain antibodies. [1]

A 2021 observational study evaluated whether various neutralizing antibodies are able to inhibit host cell entry driven by the S protein of the SARS-CoV-2 Delta variant (B.1.617). Bamlanivimab did not block entry driven by the S protein, which is due to bamlanivimab resistance mutations found in the epitope recognized by the antibody. However, etesevimab resulted in blocked entry driven by the S protein. Combination of bamlanivimab and etesevimab did not result in effective inhibition of the S protein-driven cell entry. These results show bamlanivimab monotherapy may not be effective for treatment of patients with the Delta variant. [2]

The production of bamlanivimab/etesevimab has been halted by the manufacturer until further notice. Furthermore, the combination product is not recommended for use. This is due to in vitro assays indicating that bamlanivimab and etesevimab together are not active against P.1/Gamma and B.1.315/Beta variants of COVID-19 which are trending upwards in the United States (exceeding 11% at the time of this publication). [3]

References:

[1] Planas D, Veyer D, Baidaliuk A, et al. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Nature. 2021;596(7871):276-280. doi:10.1038/s41586-021-03777-9
[2] Rodrigues FF, Morais MI, Melo ISF, et al. Clindamycin inhibits nociceptive response by reducing tumor necrosis factor-α and CXCL-1 production and activating opioidergic mechanisms. Inflammopharmacology. 2020;28(2):551-561. doi:10.1007/s10787-019-00670-w
[3] U.S. Department of Health & Human Services. Pause in the Distribution of bamlanivimab/etesevimab. https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Bamlanivimab-etesevimab/Pages/bamlanivimab-etesevimab-distribution-pause.aspx. Published June 25, 2021. Accessed September 8, 2021.
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What data is available regarding bamlanivimab/etesevimab against the Delta variant?

Please see Table 1 for your response.

Monoclonal Antibody Therapy in a Vaccine Breakthrough SARS-CoV-2 Hospitalized Delta (B.1.617.2) Variant Case
Design Case series
Results

A 63-year-old man (Patient A) and his 25-year-old son (Patient B) both tested positive for SARS-CoV-2 by reverse transcription-polymerase chain reaction (RT-PCR) on June 3, 2021, after seeing each other the previous weekend. Both patients experienced upper respiratory symptoms and headaches during their course and had previously received two doses of the BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine 22 days apart in March and April of 2021. Patient A's symptoms became more severe after his diagnosis, and he presented to a hospital in New York where a SARS-CoV-2 IgG semi-quantitative anti-spike protein antibody suggested a strong immune response to the vaccine at 178 AU/mL (negative < 5 AU/mL). Patient A was discharged after receiving an infusion of bamlanivimab/etesevimab. The patient reported the resolution of his symptoms the following morning and had a negative repeat SARS-CoV-2 PCR.

The nasopharyngeal swabs containing positive SARS-CoV-2 specimens were assessed for genetic variants by next-generation sequencing (NGS). Patient A's specimen contained the Delta variant lineage with 35 mutations, including 9 in the spike protein.
Study Author Conclusions

The patient had typical signs of the Delta variant at hospitalization including no fever, no loss of smell or taste, and no shortness of breath. There was a strong, positive SARS-CoV-2 IgG seen. However, monoclonal antibody (mAb) therapy with bamlanivimab/etesevimab may have been effective in treating the patient since he experienced clinical improvement within 12 hours of receiving therapy and was free of all symptoms within 24 hours.

Despite the Emergency Use Authorization by the U.S. Food and Drug Administration issued for bamlanivimab and etesevimab for the treatment of patients with mild and moderate COVID-19 who are at high risk of progressing to severe COVID-19 and/or hospitalization, there are currently no data regarding the use of mAb therapy for patients with high anti-spike IgG serum levels. While there are no reports of reduced susceptibility of mAb therapy to the Delta variant, there have been reports of reduced susceptibility of variants including E484K to mAb therapy. With only slight differences in vaccine effectiveness versus the Delta variant compared to other variants after 2 doses of BNT162b2, it is difficult to determine whether the patient's improvement in clinical course was due to vaccine effectiveness or mAb therapy with bamlanivimab/etesevimab.
References:

Connor BA, Couto-Rodriguez M, Barrows JE, et al. Monoclonal Antibody Therapy in a Vaccine Breakthrough SARS-CoV-2 Hospitalized Delta (B.1.617.2) Variant Case [published online ahead of print, 2021 Jul 13]. Int J Infect Dis. 2021;110:232-234. doi:10.1016/j.ijid.2021.07.029