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Molecular rationale for SARS-CoV-2 spike circulating mutations able to escape bamlanivimab and etesevimab monoclonal antibodies.

ABSTRACT: The purpose of this work is to provide an in silico molecular rationale of the role eventually played by currently circulating mutations in the receptor binding domain of the SARS-CoV-2 spike protein (S-RBD_CoV‑2) in evading the immune surveillance effects elicited by the two Eli Lilly LY-CoV555/bamlanivimab and LY-CoV016/etesevimab monoclonal antibodies. The main findings from this study show that, compared to the wild-type SARS-CoV-2 spike protein, mutations E484A/G/K/Q/R/V, Q493K/L/R, S494A/P/R, L452R and F490S are predicted to be markedly resistant to neutralization by LY-CoV555, while mutations K417E/N/T, D420A/G/N, N460I/K/S/T, T415P, and Y489C/S are predicted to confer LY-CoV016 escaping advantage to the viral protein. A challenge of our global in silico results against relevant experimental data resulted in an overall 90% agreement. Thus, the results presented provide a molecular-based rationale for all relative experimental findings, constitute a fast and reliable tool for identifying and prioritizing all present and newly reported circulating spike SARS-CoV-2 variants with respect to antibody neutralization, and yield substantial structural information for the development of next-generation vaccines and monoclonal antibodies more resilient to viral evolution.

SUBMITTER: Laurini E

PROVIDER: S-EPMC8511038 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The severity of coronavirus disease 2019 (COVID-19) ranges from mild to death, with high morbidity and mortality rates reported amongst a vulnerable subset of patients termed high risk. While vaccines remain the primary option for COVID-19 prevention, neutralizing monoclonal antibodies (mAbs), such as bamlanivimab and etesevimab, have been shown to benefit certain subpopulations after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Unlike vaccine-derived immunity that develops over time, administration of neutralizing mAbs is an immediate and passive immunotherapy, with the potential to reduce disease progression, emergency room visits, hospitalizations, and death. Bamlanivimab alone and together with etesevimab hold emergency use authorizations in several countries globally, with countries increasingly transitioning to the use of bamlanivimab and etesevimab together and other authorized mAbs on the basis of their evolving variant landscape, regulatory authorizations, and access to drugs. The current guidelines for the administration of bamlanivimab alone or together with etesevimab are informed by an iterative process of testing and development. Herein the rationale for these guidelines is provided by sharing the learnings that have been gathered throughout the development process of these mAbs. In addition, this review addresses the most common clinical questions received from health care professionals (HCPs) and patients regarding indicated population, dose, use with other medications and vaccines, duration of protection, and variants in clinical practice. As prevalence of SARS-CoV-2 variants can differ by country and state, prescribing HCPs should consider the prevalence of bamlanivimab and etesevimab resistant variants in their area, where data are available, regarding potential efficacy impact when considering treatment options.Trial Registration: ClinicalTrials.gov identifier: NCT04427501; NCT04411628; NCT04497987; NCT04634409.

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Molecular rationale for SARS-CoV-2 spike circulating mutations able to escape bamlanivimab and etesevimab monoclonal antibodies.

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