Resistance mutations to nirsevimab are rare in respiratory syncytial virus (RSV)

Nirsevimab is an antibody targeting the respiratory syncytial virus (RSV). Available in France since September 2023, it is indicated in neonates and infants for the prevention of bronchiolitis caused by RSV. However, its widespread use raises the question of the emergence of resistance mutations. The POLYRES study, the largest prospective surveillance study of nirsevimab breakthrough infections to date, has just delivered its conclusions. This work, coordinated by Prof. Slim Fourati and Prof. Marie-Anne Rameix-Welti¹, was funded by the ANRS MIE with the support from the French Ministry of Higher Education and Research as part of the EMERGEN Consortium². Scientists from AP-HP (including Henri Mondor University Hospitals), Inserm, Institut Pasteur and the Universities of Paris-Est-Créteil and Versailles-Saint-Quentin-en-Yvelines, members of the ANRS MIE virology network teams, have shown that nirsevimab resistance mutations in RSV are very rare. The results of this study have just been published in the Lancet Infectious Diseases on October 15^th, 2024.

Respiratory syncytial virus (RSV) is the main cause of bronchiolitis, a lower respiratory tract infection in infants. Two groups of RSV (RSV-A and RSV-B) circulate alternately or together. Every year, RSV is responsible for more than 33 million cases of bronchiolitis worldwide, leading to the deaths of 100,000 children, mainly in low-income countries. In France, the disease is responsible for around 480,000 cases a year. It is by far the most common cause of hospitalisation in children, leading to more than 26,000 paediatric hospitalisations every year. Nirsevimab, a new neutralising antibody³ against the virus, became available in France in September 2023. This monoclonal antibody⁴ targets a specific antigenic site (the epitope⁵ Ø) of the RSV surface F protein, which is involved in viral multiplication, and blocks the virus. Due to the genetically variable forms of RSV, there is a theoretical risk of the emergence of variants carrying mutations resistant to neutralisation by nirsevimab, even in the absence of selection pressure. This risk could increase with the widespread preventive use of nirsevimab. During the phase IIb/III clinical trials, only 48 RSVs infecting children treated with nirsevimab could be studied, and escape mutations⁶ were found in two of them.  The aim of the POLYRES study was to assess the risk of viral escape from nirsevimab in a large cohort using a large, multicentre, real-life observational study conducted during the 2023-2024 winter season.

The study included 695 RSV infected infants, 349 of whom had received nirsevimab prophylaxis. RSV-A was the most dominant circulating virus this season and was found in 86.6% of infected children. The teams analysed the characteristics of RSV-A and RSV-B in nasopharyngeal swabs collected as part of the children's routine care. Full-length sequencing of the viral genome was conducted to identify potential mutations in the Ø site, the nirsevimab binding site (genotypic analysis⁷ ). The ability of nirsevimab to inhibit viral multiplication in cell culture was also investigated (phenotypic analysis⁸ ). Analysis of 472 RSV-A viruses (half from treated children) revealed no nirsevimab resistance mutation in the Ø site of the F protein. Of the 73 children infected with RSV-B, 24 had received nirsevimab prophylaxis. In these 24 children, two isolates of RSV-B had resistance mutations to the antibody. One mutation has been described before and the other is described here for the first time.

"This study is the largest surveillance study of nirsevimab virological failures to date. It was made possible thanks to collaborative synergy with the consortium of virologists at the ANRS MIE. It is a nationwide project that will help identify the resistance phenomenon associated with the widespread use of the drug. This type of study is essential for analysing the evolutionary dynamics of viruses, in the light of existing medical solutions" explains Prof Marie-Anne Rameix-Welti, head of the National Reference Centre for Respiratory Infection Viruses at the Institut Pasteur, and head of the M3P unit (Institut Pasteur, Inserm U1173).

"The low prevalence of nirsevimab resistance mutations in treated patients is reassuring. However, escape mutations have been observed in a few RSV-Bs from treated patients, prompting caution and highlighting the importance of active molecular surveillance in the context of future wider global use of nirsevimab. These results are essential in the fight against this disease and in anticipating any form of resistance", adds Prof Slim Fourati, Head of the Virology Unit-Respiratory Viruses, CHU Henri Mondor, Inserm U955.

In conclusion, the results of the POLYRES study support the continued use of nirsevimab for RSV prophylaxis in all newborns worldwide.

3 Neutralising antibodies are specific antibodies that prevent infection by blocking the virus from entering the target cells. They do this by forming an antigen-antibody complex which inhibits the biological activity of the antigen (a substance foreign to the body capable of triggering an immune response aimed at eliminating it)

4 Monoclonal antibodies consist of a single type of antibody (polyclonal antibodies have several types). They are used in medicine.

5 Monoclonal antibodies consist of a single type of antibody (polyclonal antibodies have several types). They are used in medicine.

6 Escape mutations enable the virus to thwart the action of antibodies in the human immune system.

7 Genotypic tests are based on the identification of mutations that confer resistance to the virus.

8 Phenotyping, carried out using phenotypic tests, makes it possible to define the sensitive or resistant nature of the virus. This is done by culturing the virus in the presence of the antiviral being studied.